Nom-059-ssa1-2015 Bpf Medicamentos_inglës.docx

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MINISTRY OF HEALTH Mexican Official NORM, NOM-059-SSA1-2015, Good manufacturing practices for drug products On the margin a seal with the National Badge, that says: United States of Mexico.- Ministry of Health. MIKEL ANDONI ARRIOLA PEÑALOSA, Federal Commissioner for the Protection against Sanitary Risks and President of the National Consulting Committee on Regulations and Sanitary Fostering, based on the provision of articles: 39 of the Organic Law of Federal Civil Service; 4 of the Federal Law of Administrative Procedures; 3rd, fractions XXII and XXIV, 13 Paragraph A fraction I, 17 bis fraction III, 194, 194 bis, 195, first paragraph, 197, 198, fraction I, 201, 210, 212, 213, 214, 221, 222, 225, 226, 227, 257, 258, 259, 260, 261 and 282 Bis of the General Law of Health; 38 fraction II, 39 fraction V, 40 fractions I, V, XI and XII; 41, 43, 47 fraction IV of the Federal Law on Metrology and Standardization; 9, 10, 11, 15, 100, 102, 109 and 111 of the Regulations on Health Supplies; 28, of the Regulations of the Federal Law on Metrology and Standardization; and 3 fraction I verbatim b) and II, and 10 fractions IV and VIII, of the Regulations of the Federal Commission for the Protection against Sanitary Risks, and CONSIDERING That on June 30th, 2015, in compliance with the foreseen on article 46 fraction I of the Federal Law on Metrology and Standardization, the blueprint of the current Mexican Official Norm was approved by the National Consulting Committee on Regulations and Sanitary Fostering. That on September 9, 2015, in compliance with the resolution of the National Consulting Committee on Regulations and Sanitary Fostering Committee and the foreseen on article 47 fraction I of the Federal Law on Metrology and Standardization, the project of the current Mexican Official Norm was published in the Federation’s Official Bulletin, in order that in the following sixty natural days after said publication, the interested parties may submit their remarks to the aforementioned Committee. That on a previous date the answers to said remarks received by the aforementioned Committee were published in the Federation’s Official Bulletin, in terms of article 47 fraction III of the Federal Law on Metrology and Standardization, and That in regard to the previous considerations and having the approval of the National Consulting Committee on Regulations and Sanitary Fostering, the following is issued: MEXICAN OFFICIAL NORM NOM-059-SSA1-2015, GOOD MANUFACTURING PRACTICES OF DRUG PRODUCTS FOREWORD In the elaboration of the current Mexican Official Norm the following institutions and organisms took part: MINISTRY OF HEALTH. Federal Commission for the Protection Against Sanitary Risks. Permanent Commission of the Mexican United States. GENERAL HEALTHFULNESS COUNCIL. Supplies of the Health Sector Basic Chart Interinstitutional Commission. MEXICAN SOCIAL SECURITY INSTITUTE. Supplies of the Health Sector Basic Chart Interinstitutional Division STATE EMPLOYEES’ SECURITY AND SOCIAL SERVICES INSTITUTE. NATIONAL AUTONOMOUS UNIVERSITY OF MEXICO. School of Chemistry NATIONAL POLYTECHNIC INSTITUTE National School of Biological Sciences NATIONAL CHAMBER OF THE PHARMACEUTICAL INDUSTRY. NATIONAL CHAMBER OF THE TRANSFORMATION INDUSTRY. Medical Sector NATIONAL ACADEMY OF PHARMACEUTICAL SCIENCES, A.C.

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MEXICAN PHARMACEUTICAL ASSOCIATION, A.C. NATIONAL COLLEGE OF CHEMICAL PHARMACEUTICAL BIOLOGISTS MEXICO, A.C. CHEMICAL PHARMACEUTICAL PRODUCTION, A.C. MEXICAN ASSOCIATION OF PHARMACEUTICAL LABORATORIES, A.C. MEXICAN ASSOCIATION OF PHARMACEUTICAL INVESTIGATION INDUSTRIES, A.C. NATIONAL ASSOCIATION OF MEDICINES MANUFACTURERS, A.C. NATIONAL ASSOCIATION OF THE HOMEOPATHIC PHARMACEUTICAL INDUSTRY, A.C. INDEX 1. Objective and Field of Application 2. References 3. Definitions 4. Symbols and Abbreviations 5. Quality Management System 6. Quality risk management 7. Personnel 8. Facilities and equipment 9. Qualification and Validation 10. Manufacturing System 11. Quality Control Laboratory 12. Finished product release 13. Product Recall 14. Manufacturing by Contract 15. Final disposal of residues 16. Good storage and distribution practices 17. Concordance with International and Mexican Norms 18. Bibliography 19. Observance 20. Validity 21. Appendixes 21.1 Regulatory Appendix A. Manufacturing areas classification 21.2 Regulatory Appendix B. Annual Review 1.0 Objective and field of application This Mexican Official Norm establishes the minimum necessary requirements needed for the manufacturing process of medications for human use, commercialized in the country and/or with investigational purposes. This Mexican Official Norm is mandatory for all the establishments committed to the manufacturing and/or importing of drug products commercialized in the country, as well as for the conditioning warehouses, deposits and distribution of drug products as well as raw materials for their manufacturing. 2. References For the correct application of the current Mexican Official Norm, it is necessary to consult the following Official Norms or the ones superseded: 2.1 NOM-002/1-SCT/2009. Listing of hazardous substances and materials most frequently transported, instructions and use of containers and packages, intermediate recipients for bulk material (RIG S), large containers and packages, portable tanks, containers for gas of multiple elements and containers for bulk materials for transport of hazardous materials and residues. 2.2 NOM-002-SEMARNAT-1996. Which establishes the maximum permissible limits of contaminants in wastewater discharges to sewer systems urban or municipal. 2.3 NOM-005-STPS-1998. Concerning health and safety conditions in the workplace for handling, transport and storage of hazardous chemicals.

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2.4 NOM-020-STPS-2011. Pressure vessels, cryogenic vessels and steam generators or boilers Operation - Safety Conditions. 2.5 NOM-026-STPS-2008. Colors and signs of safety and health, and identification of risks from fluids conducted by pipes. 2.6 NOM-052-SEMARNAT-2005. Which establishes the characteristics, the process of identification, classification and listing of hazardous waste. 2.7 NOM-062-ZOO-1999. Technical specifications for production, care and use of laboratory animals. 2.8 NOM-072-SSA1-2012. Labeling of drug products and herbal remedies. 2.9 NOM-073-SSA1-2005. Drug products and drug substances stability. 2.10 NOM-087-SEMARNAT-SSA1-2002. Environmental protection-Environmental Infectious Hazardous Waste- Classification and management specifications.

health,

Biological

2.11 NOM-164-SSA1-2013. Good manufacturing practices for drug substances. 2.12 NOM-220-SSA1-2012. Installation and operation of pharmacological surveillance. 2.13 NOM-241-SSA1-2012. Good manufacturing practices for establishments dedicated to the manufacture of medical devices. 2.14 NOM-253-SSA1-2012. For the disposition of human blood and derivatives for therapeutic purposes. 2.15 NOM-257-SSA1-2014. In the field of biotech products.

3. Definitions For the purpose of this Mexican Official Norm, it is understood by: 3.1 Sanitary finish, to the finish given to the inner surfaces of areas with the purpose of avoiding accumulation of viable and non-viable particles and making easier their cleaning. 3.2 Corrective Action, to the activities that are planned and executed, in order to correct a deviation or a noncompliance. 3.3 Preventive Action, to the activities that are planned and executed, in order to eliminate the cause of a deviation or noncompliance or any other potentially undesirable situation and avoid its repetition. 3.4 Technical agreement, it is a document formalized and detailed where conditions to perform activities or services among the parties are described, as well as the obligations and responsibilities of each part, especially those concerned with quality and GMP. 3.5 Adventitious agents, contaminant microorganisms from a cell culture and/or from the starting materials and which are of animal origin (mycoplasmas-spiroplasmas, rickettsias, virus, priones or other molecular forms) and that entered adventitiously into the manufacturing process having the potential to contaminate the prokaryotic cells or eukaryotic cells used in the production. 3.6 Storage, to the conservation of supplies, bulk products and finished products in areas with established conditions. 3.7 Conditioning, to the needed operations for which a bulk product must go through to get to its final presentation as finished product. It is considered primary when is in direct contact with the drug product and secondary when the drug product is into the primary packaging. 3.8 Area, to the room or group of rooms and spaces designed and built under defined specifications. 3.9 Aseptic area, to the area designed, built and maintained with the purpose of having within preestablished limits the number of viable and non-viable particles on surfaces and environment. 3.10 Self-contained area, to the complete and separate area regarding to operation, including personnel and equipment flow. This includes physical barriers as well as independent air systems, even though it does not necessarily imply two different separate buildings. 3.11 Quality Assurance, to the collection of planned and systematic activities that a company accomplishes, with the purpose of offering confidence that a product or service complies with the specified quality.

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3.12 Audit, to the systematic process, independent and documented, to get evidence and evaluate it in an objective manner, with the purpose of determining the level of compliance with the established criteria. 3.13 Self-contention, the set of physical and operational conditions in order to avoid the release of high risk particles to the outside, including physical barriers, collectors and air systems independent and dedicated, as well as the treatment of effluents of air, water and materials before their final disposition. 3.14 Working Cell Bank, prepared with aliquots from a homogeneous suspension of cells obtained by culturing the Master Cell Bank under defined culture conditions. 3.15 Master Cell Bank, is the aliquot from a cell collection that in his growth has been prepared from cloned cells under defined conditions, contained into multiple vessels and stored under specific conditions. 3.16 Bar, it is the unit of measure of pressure, which is equivalent to 100 kPa or a million bars, approximately one atmosphere. 3.17 Bioload, the level and type of microorganisms that may be present in any of the elements for manufacture (supplies, installations, personnel, among others). 3.18 Biosafety, set of measures and actions intended for the protection of the personnel, community and environment for handling of agents which represents a health risk. It is classifies as follows: 3.18.1 Biosafety Level 1. It is characterized by a basic level of containment without special primary and secondary barriers, in which well-characterized agents not representing a potential risk to personnel and the environment are handled. 3.18.2 Biosafety Level 2. It is a level where agents representing a moderate risk for personnel and environment are handled; access should be avoided when work is being performed and it must be done in biosafety cabinets or other equipment for physical contention. 3.18.3 Biosafety Level 3. It is applied for handling of lethal pathogen agents which can cause serious diseases or potentially fatal. All operations should be performed inside the biosafety cabinets or other closed system. The area must have special design characteristics which allow a controlled access, the previous decontamination of materials and avoid the release of aerosols to the outside. 3.18.4 Biosafety Level 4. This level is used whenever there is handling of dangerous and exotic agents which present a high risk and may be potentially fatal, without vaccines or available treatments; represent a serious risk for personnel, community and environment. All operations should be performed within a biosafety cabinet Class III, or in a biosafety cabinet Class II combined with the use of a pressurized suit; the building must be independent or in an isolate zone; the air supply must be dedicated for each area and the air must be decontaminated before exit; all materials used must be decontaminated before exit and personnel should change the clothes and take a shower before exit. 3.19 Bigotry, to the set of facilities, furniture and buildings intended to housing and maintenance of laboratory animals during one or several phases of their life cycle, i.e., birth, development, reproduction and death. 3.20 Good manufacturing practices for storage and distribution, these are part of quality assurance, which ensures the maintenance of quality of medicines through all steps of the supply chain from the site of manufacture to the pharmacy. 3.21 Good manufacturing practices, to the collection of guidelines and activities related among them, destined to ensure that pharmaceutical products manufactured have and keep the identity, purity, safety, efficacy and quality required for their use. 3.22 Good laboratory practices, the set of rules, operating procedures and practices established to ensure the quality and integrity of the activities performed in the lab and of the analytical data obtained from assays and tests. 3.23 Manifold, equipment or apparatus designed to allow venting, vacuum or filling synchronized from one or more gas containers. 3.24 Calibration, the demonstration that the results obtained from a particular instrument or device are within the specified limits, compared with those produced by a reference or traceable standard over a range of measures established. 3.25 Quality, the compliance of established specifications to guarantee the suitability of use.

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3.26 Qualification, the specific tests conducted based on scientific knowledge, to demonstrate that equipment, critical systems, facilities, personnel and suppliers are in compliance with the previously established requirements, which must be concluded before process validation. 3.27 Performance qualification, the documented evidence that facilities, systems, and equipment are performed in compliance with acceptance criteria previously established. 3.28 Design qualification, the documented evidence showing that the proposed design of facilities, systems and equipment is convenient for the purpose intended. 3.29 Installation qualification, the documented evidence that the facilities, systems and equipment have been correctly installed according to the design specifications previously established. 3.30 Operation qualification, the documented evidence that proves that equipment, facilities and systems operate consistently, in compliance with the design specifications established 3.31 Manufacturing campaign, the manufacture of a set of lots of the same product within a defined period of time followed by cleaning activities and, if necessary, sanitization, before the change to another product. Different products are not produced at the same time, but using the same equipment. 3.32 Training, those activities headed to generate or develop abilities in personnel. 3.33 Certificate of Analysis, it is the summary of results obtained from the determinations performed in samples of product, raw materials, materials or any other supply, including the references of the analytical methods or test methods used and the determination of the compliance with previously established specifications, assessed by an authorized person. 3.34 Certificate of Good Manufacturing Practices, it is a document issued by the Health Authority of a country, after a visit of sanitary check-up performed to an establishment, to confirm the compliance status of the GMPs according to dispositions applicable. 3.35 Dynamic conditions, those where the facility is functioning in the defined operating mode with the specified number of personnel. 3.36 Static conditions, those where the air system is functioning under the defined operating mode with the complete and installed production equipment, without personnel present. 3.37 Connection for cylinder coupling, it is the screw connection of the cylinder valve which couples and connects a tube or flexible hose or a pressure regulator to the cylinder, avoiding mistakes when there is an interchange in the use of gases. 3.38 Contamination, the presence of undesirable physical, chemical or biological entities. 3.39 Cross contamination, presence of undesirable physical, chemical or biological entities, coming from a different process or product. 3.40 Contaminant, the undesirable impurities, chemical or microbiological in nature, or foreign matter present in a supply, intermediate, and/or finished product. 3.41 Container of medicinal gas, the vessel designed to contain gas under pressure as compressed gas, liquefied to cryogenic liquid, and is classified in four groups: cylinder, thermal (dewar), storage tank and cistern. 3.42 Change control, assessment and documentation of any change which could have an impact on product quality. 3.43 In process control, the verifications performed during the manufacture for follow up and, if necessary, process adjustment. 3.44 Acceptance criteria, to the specifications, standards or pre-defined intervals that must be complied with under pre-established test conditions. 3.45 Quarantine, it is the status of inputs and products which prevent the disposition for a subsequent stage and/or release and it can be evidenced by the physical separation or other means. 3.46 Deviation or non-conformance, the non-compliance of a requirement previously established. 3.47 Master Document, the authorized document that contains the information to realize and control the operation of the processes and activities related with the manufacturing of a product. 3.48 Efficacy, the degree to which an intervention or treatment leads to an expected result in certain conditions, measured in the context of a Clinical Trial or Preclinical Controlled.

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3.49 Packaging, the sequence of operations by which a pharmaceutical formula is placed in its primary packaging. 3.50 Specification, to the description of a material, substance or product including its quality parameters, its acceptance limits and reference methods used for their determination. 3.51 Blind Study, the ignorance of patients and/or investigators if subjects are receiving or not the investigational product or the control ones (or standard) in a clinical trial. 3.52 Batch manufacturing record, set of documents proven that a batch of product has been manufactured and controlled according the master document. 3.53 Manufacture, all operations involved in the manufacture or production of a drug product from the reception of inputs, release, storage and distribution as finished product. 3.54 Expiry date, is the date which indicates the end of the useful life cycle of the medicinal product. 3.55 Reanalysis date, the limit date to use a drug substance or additive; their use may continue after a new sampling and analysis in order to confirm that is still complying the quality specifications established. 3.56 Fiber, any contaminant particle with a length at least three times bigger than its thickness. 3.57 Electronic signature, it is the compilation of computational data or any symbol or several symbols, executed, adopted or authorized by an individual, to be legally attached and which is equivalent to the autograph signature of the individual. 3.58 Compressed gas, when packaged under pressure it is entirely gaseous at -50 ° C. 3.59 Cryogenic gas, is the gas liquefied at 1.013 bar and temperature below -150°C. 3.60 Liquefied gas, when packaged under pressure, is partially liquid (gas in a liquid) at -50°C. 3.61 Quality risk management, is the systemic process for assessment, control, communication and review of risks for quality of drug products through its life cycle. 3.62 Viral inactivation, removal of viral activity, by a chemical or physical method. 3.63 Facility, the areas, equipment and services intended to perform an operation or specific process. 3.64 Working instructions, is the detailed, sequential and specific description of a task. 3.65 Inputs, are all those raw materials, primary packaging materials, conditioning materials and products received in a facility. 3.66 Concurrent release, it is the release of a batch of the drug product, for the distribution, manufactured according a protocol of process qualification, which complies the criteria for its release, established before the protocol has been completed. 3.67 Batch release, a judgement indicating the product disposition from a systemic review to ensure quality from all aspects, particularly those of the Good Manufacturing Practices. 3.68 Parametric release, it is a release system which is applied to sterile products manufactured by a terminal sterilization process, based on the compliance of critical parameters for sterilization, obtained during manufacturing process and the compliance with specific requirements of GMP, without performing the sterility test. 3.69 Cleaning, it is a process performed to decrease the presence of non-viable particles to established levels. 3.70 Cell line, it is a type of cell population with defined characteristics developed by serial subcultures from a parent cell population. 3.71 Media fill, is the simulated filling operation that uses culture media instead the product, reproducing the operation conditions, such that the culture media comes in contact with the equipment surfaces, closure systems, environment and process operations. 3.72 Working seed lot, it is a culture of microorganisms derived from one master seed lot or from an intermediate seed lot. It is intended for use in production. 3.73 Master seed lot, it is the culture of a microorganism derived from the pre-master seed lot, distributed into containers in a single operation in order to ensure its homogeneity and stability and to prevent any contamination.

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3.74 Quality manual, is the document that describes the Quality Management System according with policies and objectives of quality, established in the same manual. 3.75 Contract manufacturing, is the process or a process stage involved with the manufacture of a medicinal product, performed by a third party in a facility different from that of the owner of the Sanitary Registry; the contractor may be national, international, temporary or permanent. 3.76 Printed material, any label, insert or packaging material present in final product. 3.77 Investigational drug products, is the dosage form of a drug product or a biological product, from which there are not any previous experience in the country, not registered by the Ministry and therefore, are not distributed commercially, and also as drug products registered and approved for sale, when they are investigated for modalities, indications, dosage and routes of administration different from those authorized, including the use as combination products. 3.78 Retention samples, sampling of raw materials and finished product in a sufficient amount to perform two complete analysis, except for sterility and pyrogens test. 3.79 Sample, the amount of material which represents the lot to be examined. 3.80 Lot number, numeric or alfa-numeric combination to identify specifically one lot. 3.81 Packaging order, it is a copy of the master order for packaging to which a lot number is assigned and is used for dispensing and record of materials for packaging of drug product. 3.82 Manufacturing order, it is a copy of the master order or formula for manufacturing to which a lot number is assigned and is used for dispensing and record of inputs for the production of a lot of the medicinal product. 3.83 Viable particles, any particle that under the appropriate environmental conditions may reproduce. 3.84 Passage, successive transference of microorganisms and cell cultures through the various culture media. Every transfer represents a passage number. 3.85 Worst case, it is the condition or set of conditions which cover limits and circumstances higher and/or lower of the process, within the standard operating procedures, which have the greatest failure opportunity in the process when is compared to ideal conditions. Such conditions not necessarily produce failures in the product or process. 3.86 Reanalysis period, time during which a drug or additive which is kept under the conditions specified by the manufacturer, remains within the quality specifications for use. 3.87 Placebo, it is an inert substance, without pharmacological activity, used supposedly as a medication. 3.88 Validation master plan, it is the document which specifies the information with regard to activities of validation to be performed by the facility, where details and deadlines are defined for each activity of validation. Responsibilities related with such plan must be established. 3.89 Potency, therapeutic activity of the drug product just as it is indicated by the proper tests of the laboratory or by clinical data controlled and developed in an adequate form. 3.90 Standard Operating Procedure, document which contains the necessary instructions to perform an operation in a reproducible way. 3.91 Production, the operations involved in processing of health supplies in order to transform them in a bulk product. 3.92 Bulk product, the product in any stage of production process before primary package process. 3.93 Returned product, is the distributed product which returns to the establishment. 3.94 Intermediate product, material obtained during the production stages before becoming in a bulk product. 3.95 Semifinished product, the product within the primary package that will be subjected to subsequent steps to become a finished product. 3.96 Finished product, it is the drug product on its final presentation. 3.97 Environmental monitoring program, chronological sequence of activities to assess compliance with the established parameters of viable and non-viable particles in a controlled environment. 3.98 Protocol, written working plan to establish objectives, procedures, methods and acceptance criteria, to perform a study.

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3.99 Purge or venting, the process to release gas or fluids contained in a vessel or a filling system 3.100 Complaint, any observation from a customer, related to product quality. 3.101 Recovery, subject a part of a batch to the same stage of the conditioning process due to failures in the predetermined specifications. 3.102 Cold chain, set of logistic systems designed, comprising personnel, infrastructure, equipment and procedures, to keep the products in specific conditions of uninterrupted temperature, during storage, transport and distribution. 3.103 Electronic registry, set of information, including electronic data (text, numbers, and graphs) which is created, modified, kept, filed, restored or transmitted through a computerized system. 3.104 Registry, the document which presents evidence of performed actions to demonstrate the compliance of activities or instructions. 3.105 Final yield, the amount of product obtained at the end of the process with respect to planned amount. 3.106 Theoretical yield, amount of product expected through a process, according to calculations. 3.107 Report, document containing the operations performed, projects or specific investigations, including results, conclusions or recommendations. 3.108 Reprocess, to subject one lot, total or partial, to one or more stages defined of the validated operation process due to noncompliance of specifications. 3.109 Requirement, is the circumstance or necessary condition for the compliance of an obligation. 3.110 Rework, to subject one lot, total or partial, to one or more stages not defined of the validated operation process due to noncompliance of specifications. 3.111 Annual review of product or review of the product quality, historical analysis of the quality of a product, taking as a reference all current regulatory documents in the chemical pharmaceutical national environment, the international criteria usually recognized, as well as the internal guidelines of each company. 3.112 Robustness, the capacity of a process to be non-sensitive to factors which could affect it under established conditions. 3.113 Sanitization, the action to remove or decrease the levels of viable particles by means of physical and chemical agents, performed after cleaning. 3.114 Secretariat, Health Ministry. 3.115 Safety, assessment of the benefit produced by a medicinal product in front of the possible risks in certain moment. 3.116 Computerized system, any equipment, process or operation having coupled one or more computers and a software associated or a group of hardware components designed and assembled to perform a specific group of functions. 3.117 Container-closure system, the set of packaging materials which contain and protect the pharmaceutical form. Includes both, primary and secondary package, being the last an additional protection for the product. 3.118 Quality Management System, the way of how the organization leads and controls the activities associated with quality. 3.119 Vector-host system, is the genetic element able to introduce deoxyribonucleic acid and cause a replication and expression into a host cell. 3.120 Critical systems, are those that have a direct impact in processes and products. 3.121 Technology transfer, it is a systemic process followed to deliver the knowledge and experience during development and/or marketing to another unit responsible and authorized. This process includes the transfer of documentation and the proven capacity of the receiver unit about the effective performance of the critical elements of the transferred technology until satisfaction of all parties and the compliance of the current norms. 3.122 Traceability, the capacity of rebuild the history, location of an element or activity, by means of identification registries. 3.123 Validation, documented evidence generated through the collection and scientific assessment of the data obtained in qualification and of the specific tests throughout the life cycle of a product, in order to

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demonstrate the functionality, consistency and robustness of a given process with regard to the capacity to deliver a quality product. 3.124 Cleaning validation, documented evidence that the cleaning process for areas and equipment used in the manufacture of medicinal products reduces to a pre-established level the residues of the cleaning agent and processed product. 3.125 Prospective validation, is the one concluded previously to the marketing of drug products. 3.126 Check valve, is a valve that normally allows fluid to flow through it in only one direction. 3.127 Check valve of minimum pressure, provided with an anti-return system maintaining a defined pressure (between 300 and 500 kPa over the atmospheric pressure) to prevent contamination during use.

4.

Symbols and abbreviations

4.1 Symbols When in this Norm a reference is made to the following symbols, it will be understood as follows: 4.2 Abbreviations When in this Norm a reference is made to the following abbreviations, it will be understood as follows English

Spanish

4.2.1

BCG

BCG

Vaccine Chalmette Guerin Bacillus

4.2.2

GAD

BAD

Good Storage and Distribution Practices

4.2.3

GDP

BPD

Good Documentation Practices

4.2.4

GULP

BPL

Good Laboratory Practices

4.2.5

GMP

BUFF

Good Manufacturing Practices

4.2.6

BSE

BSE

Bovine spongiform encephalopathies

4.2.7

CAPA

ACAP

Corrective actions preventive actions

4.2.8

CNTS

Centro Nacional de la Transfusión Sanguínea

4.2.9

COFEPRIS

Federal Commission for the Protection against Sanitary Risks

DCI

International Common Denomination

4.2.11

EMSF

Master file of the manufacturing site

4.2.12

FEUM

Pharmacopeia of United States of Mexico

4.2.13

FHOEUM

Homeopathic Pharmacopeia of the United States of Mexico

4.2.10

INN

4.2.14

HEPA

HEPA

High Efficiency Particulate Air

4.2.15

RH

HR

Relative Humidity

4.2.16

HVAC

HVAC

Heating, Ventilation and Air Conditioning

4.2.17

IPP

Information for Prescribing

4.2.18

n.a.

Not applicable

4.2.19

NAE

Sterility Assurance Level

PAT

Process Analytical Technology

PIC/S

Pharmaceutical Inspection Co-operation Scheme

4.2.20

PAT

4.2.21 4.2.22

VMP

PMV

Validation Master Plan

4.2.23

SOP

PNO

Standard operating procedure

RAP

Product annual review

4.2.24

Friday, February 5th, 2016 4.2.25 4.2.26 5.

CFU

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TSE

Transmissible Spongiform Encephalopathies

UFC

Colony forming units

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Quality Management System

5.1 General 5.1.1 The Quality Management System represents the set of adopted measures planned and systematized, in order to ensure that medicinal products having the required quality for the intended use. Quality Management incorporates, therefore, the norms of BPF, BPD, BPAD, BPL and the principles of Risk Management, including the use of the proper tools. 5.1.2 Quality by Design is applied throughout the life cycle of product, from manufacturing of the drug product in investigational phase, the technology transfer, the manufacture at commercial scale, until the discontinuation of the product. Quality Management should be extended to the period of pharmaceutical development, must favor innovation and continuous improvement, and to strengthen the union between pharmaceutical development and the manufacturing activities. 5.1.3 It is the responsibility of the Directorate-General or Direction to implement and maintain the Quality Management System, determining and providing appropriate resources (human, financial, facilities and adequate equipment) to improve continuously the effectivity. 5.1.4 Quality Management must ensure that: 5.1.4.1 The manufacture of drug products is performed following a Quality Management System supported by a quality policy and by a documentation system which has been designed, planned, implemented, maintained and subjected to continuous improvement, which allows that products can only be commercialized or supplied once that they have been released by the Quality Unit with the proper quality attributes. 5.1.4.2 Product and process knowledge are managed through the entire life cycle of the product. 5.1.4.3 Drug products are designed and developed having in mind the requirements of the GMPs. 5.1.4.4 The operations of production and quality control are clearly described and adopt BPF and BPL. 5.1.4.5 The responsibilities of the personnel in the Quality Management System must be clearly defined. 5.1.4.6 Appropriate measures are taken, so the manufacture, supply, use of raw materials, packaging materials and their selection and follow-up of suppliers be the correct ones, and verifying that each delivery comes from the approved supply-chain. 5.1.4.7 There are technical procedures or agreements of quality to ensure the management of the activities outsourced. 5.1.4.8 A state of control is established and maintained for the process execution and the quality of the product by monitoring and the results of this measures are taken into account for the release of the batch, for the investigation of deviations, and to conduct preventive actions to eliminate the recurrence. 5.1.4.9 All necessary controls are applied on intermediate products, as well as in-process controls and validations. 5.1.4.10 Continuous improvement is provided. 5.1.4.11 There are measures in place for prospective assessment of planned changes as well as their previous approval for implementation, considering the notification and approval of regulatory authorities, if applies. 5.1.4.12 After implementing any planned change, an evaluation is carried on to confirm that all quality objectives have been achieved. 5.1.4.13 During the investigation of deviations, suspicion of flaws of products and other type of problems, a root-cause analysis should be performed. This analysis may be determined based on principle of risk management. When the root-cause cannot be determined, the most likely cause should be considered to be investigated. Corrective and/or preventive actions (CAPA) should be identified and adopted in response to the performed investigations. The effectiveness of these actions must be followed and assessed, in line with the principles of quality risk management.

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5.1.4.14 No drug product is sold or supplied without the previous certification of a qualified person that each batch of manufacture has been produced and controlled according to the established requirements in the Marketing Authorization and any other regulation related with production, control and release of drug products. 5.1.4.15 Measures are adopted to ensure that medication is stored and distributed so that the quality is maintained during the whole period. 5.1.4.16 There is in place a procedure for self-inspections and/or audits of quality which assess regularly the efficacy and application of the Quality Management System. 5.1.4.17 The minimum elements that the Quality Management System should have are the following: 5.1.4.17.1 Quality Manual 5.1.4.17.2 Audit System 5.1.4.17.3 Complaint management 5.1.4.17.4 Management of product out of specifications or nonconforming 5.1.4.17.5 Management of deviations and CAPA system 5.1.4.17.6 Recall 5.1.4.17.7 Change control 5.1.4.17.8 PMV 5.1.4.17.9 RAP 5.1.4.17.10 Technology transfer 5.1.4.17.11 Risk management 5.1.4.17.12 Control of documents 5.1.4.17.13 Returns 5.2 Documentation 5.2.1 Generation of documentation 5.2.1.1 Documents must be defined and must adhere to the provisions. The requirements apply equally to all forms of documentation media. Electronic systems to generate documents must be understood, well documented, validated, and with adequate controls 5.2.1.2 The documents of the system should be written in Spanish language. If documents are written in two languages or more, always will include the Spanish version. Some documents may exist as hybrid, e.g., part in electronic format and part in paper. The documents containing instructions should be edited in order and be easy to check. The style and language of documents must be concordant with the intended use. 5.2.2 Control of documentation 5.2.2.1 The relations and control measures for master documents, the official copies, the management of data and registrations must be established for both, hybrid systems and the homogeneous system. 5.2.2.2 Adequate controls should be implemented for electronic documents just as templates, forms, and master documents. Adequate controls should be available to ensure the integrity of records throughout the retention period. 5.2.2.3 Documents should be designed, prepared, reviewed and distributed according to that established in the Quality Management System. 5.2.2.4 The documents must comply with the parts applicable of product specification, the files of authorization of manufacture and marketing. The reproduction of working documents derived from the original ones should not allow the introduction of some error in the reproduction process. 5.2.3 Secure document storage 5.2.3.1 The place for a secure storage of documents related with the manufacture of products must be clearly defined. Control measures should be in place to ensure the integrity of documents during the secure storage and such measures must be assessed.

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5.2.3.2 The manufacturing record of each lot produced must be maintained on safeguard at least one year after its expiration date or five years after the batch was released by the Health Manager or the equivalent abroad. In this case, it must be preserved during the longest period. 5.2.3.3 For another type of documents, the preservation period will depend on the activity that the documentation supports. Critical documentation, including raw data (e.g, related to validation or stability), which support the information of the Health Registry or marketing authorization must be preserved as long as the authorization remains valid. It may be acceptable remove certain documentation (e.g., raw data to support a validation report or stability data), .when data have been replaced for a new complete package of data. 5.2.3.4 A justification should be documented for the above and take into account the conservation requirements of batch documentation; for example, in the case of data validation processes, accompanying raw data must be retained for a period at least as extensive as the records of all lots whose release is based on the validation exercise. 5.2.3.5 For investigational products, the documentation must be preserved on safeguard at least 5 years after the company has registered the product in the last country. 5.2.3.6 Any type of preservation different to the time mentioned must be based on legal dispositions applicable 5.2.4 BPD 5.2.4.1 Documents containing instructions must be approved, signed and dated. All types of documents should be defined and must adhere to that established. The requirements apply in the same way to all forms of documentation media. 5.2.4.2 All documents of the Quality Management System must be periodically reviewed and updated. 5.2.4.3 Documents should not be handwritten; however, when documents require the introduction of data, there must be enough space for them. The handwritten registries in documents, must be clear, readable and unerasable. The registry of activities must be performed at the same time as the activity, respecting the chronologic order. 5.2.4.4 Any correction to the registry of an activity or to a document must be signed and dated taking care to avoid cover the original data. 5.2.4.5 If an explanation is necessary about the correction, it must be documented; these registries must be dated and must identify who performed the activity. 5.2.4.6 There must be a mechanism which allows the identification of firms and rubric of the personnel that executes the operation. 5.2.5 Types of documents The documents that are part of the documentation system include, but not limited to: 5.2.5.1 Quality Manual There must be a Quality Manual or document containing the description of the Quality Management System, including the responsibilities of the Direction. The Manual must ensure the periodic review of the Quality Management System. 5.2.5.2 EMSF There must be an EMSF, describing the activities related with the compliance of the BPF. To provide the contents of EMSF, besides of that described in this clause, the following web page is available to prepare the EMSF: http://www.cofepris.gob.mx/AS/Paginas/Establecimiento%20y%20productos%20biologicos/Certificado BuenasPracticasFabricacion.aspx where are included the explanation notes for pharmaceutical manufacturers about the preparation of the EMSF, established by PIC/S. 5.2.5.2.1 It is mandatory to present the EMSF for all those establishments having a health license with activities of Manufacturing or Drug Products Laboratory or Biological Products for human use; Storage of Medicinal products or Biological Products for human use, that their license includes the authorization to perform primary packaging and/or with a quality control lab and is a Legal Representative and affiliate in Mexico of the holder or applicant of the Sanitary Registry; Warehouses for the Distribution of Drug Products or Biological Products for human use, and having a quality control lab and is legal Representative and affiliate in Mexico of

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the holder or applicant of the Sanitary Registry in Mexico; Laboratory of chemical, biological, pharmaceutical or toxicological control for the study and experimentation of drug products and raw materials, that is Legal Representative and affiliate in Mexico of the holder or applicant of the medication registry . In the case of a conditioning warehouse or a quality control lab, which are part of a Factory or Medicinal Products Laboratory or Biological products for human use, and due to space issues are located in a different address, the responsible to deliver the EMSF will be the one with sanitary license as manufacturer including the information of the site(s) located in other address. 5.2.5.2.2 EMSF Maintenance Any technical change to the EMSF contents should be assessed through the Change Control System. If it is a major change, the EMSF should be updated and notify to COFEPRIS by means of the document updating. 5.2.5.2.2.1 Major changes are those described below (denunciative, not limited): 5.2.5.2.2.1.1 Change of the Sanitary Responsible, of the responsible of the production unit and/or responsible of the quality unit. 5.2.5.2.2.1.2 Change on critical systems. 5.2.5.2.2.1.3 Modifications to manufacturing lines. 5.2.5.2.2.1.4 Modifications on facilities with an impact on the quality of products. 5.2.5.2.2.1.5 Inclusion of new molecules deserving a new cleaning validation 5.2.5.2.2.2 If there are minor changes, the EMSF should be updated at least every 2 years and COFEPRIS should be notified. 5.2.5.3 Specifications and Certificate(s) of Analysis. 5.2.5.3.1 There must exist specifications for inputs, bulk product and finished product and the certificate of analysis must comply with the characteristics indicated in clause 3.33 of this Norm. 5.2.5.3.2 Specifications for raw materials, packaging materials and materials for conditioning must include, at least: 5.2.5.3.2.1 A description of materials: Name, internal code, reference (FEUM, if applicable) 5.2.5.3.2.2 Approved manufacturer for the drug 5.2.5.3.2.3 Approved manufacturer of additives and primary package. 5.2.5.3.2.4 Approved supplier(s) of the other inputs 5.2.5.3.2.5 A sample of printed materials 5.2.5.3.2.6 Instructions for sampling and tests to be performed 5.2.5.3.2.7 Acceptance limits for quail and quantitative determinations 5.2.5.3.2.8 Storage conditions 5.2.5.3.2.9 Period for reanalysis and number of reanalysis 5.2.5.3.2.10 Precautions for handling of materials 5.2.5.3.3 There must exist specifications for intermediate product and bulk, including maximum time and storage conditions. 5.2.5.3.4 The specifications for finished product must include at least the following: 5.2.5.3.4.1 Generic name of the product and internal code assigned 5.2.5.3.4.2 Dosage form and primary packaging. 5.2.5.3.4.3 Instructions for sampling 5.2.5.3.4.4 Method of analysis 5.2.5.3.4.5 Acceptance limits for quali and quantitative determinations 5.2.5.3.4.6 Storage conditions 5.2.5.3.4.7 Expiry period of the product

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5.2.5.3.4.8 Precautions for handling the product 5.2.5.4 Production master order 5.2.5.4.1 There must be written an order and master instructions of production for each product and batch size to be manufactured; these master documents will generate the working documents. 5.2.5.4.2 The production order must include at least: 5.2.5.4.2.1 Generic name of the product and an internal code assigned 5.2.5.4.2.2 Dosage form 5.2.5.4.2.3 Concentration 5.2.5.4.2.4 Batch size 5.2.5.4.2.5 The formula with the list of raw materials, materials, code and quantities, including those that are not present in finished product. 5.2.5.4.2.6 Expected yield with the acceptance limits for each step of process. 5.2.5.4.3 The production instructions must include, at least: 5.2.5.4.3.1 The area where each process step is performed 5.2.5.4.3.2 Equipment to be used 5.2.5.4.3.3 Methods or cross references for the preparation of critical equipment of the production process such as cleaning operations, assembly, calibration, sterilization, among others. 5.2.5.4.3.4 Clearance of the area to be used ensuring that is free of previous products, equipment and unnecessary materials 5.2.5.4.3.5 Verification of the area to confirm cleaning conditions to start the production of the product. 5.2.5.4.3.6 Detailed instructions of each step of process, the critical parameters of the process, such as time, temperature, speed, etc. 5.2.5.4.3.7 In-process controls, frequency and acceptance limits 5.2.5.4.3.8 Specific conditions needed for handling and storing, according to the product. 5.2.5.5 Conditioning master order 5.2.5.5.1 There must be written an order and master instructions of conditioning for each product and for an estimated batch size; these master documents will generate the working documents. 5.2.5.5.2 The master order for conditioning must include at least the following: 5.2.5.5.2.1 Generic name of the product and, if it is the case, the distinctive denomination, internal code assigned. 5.2.5.5.2.2 Batch of bulk product 5.2.5.5.2.3 Dosage form 5.2.5.5.2.4 Final presentation. 5.2.5.5.2.5 Description and size of primary package. 5.2.5.5.2.6 The entire list of all materials needed for product conditioning and their package, including codes, amounts, and, if applicable, the cross reference to their specifications 5.2.5.5.2.7 Expected yield with the acceptance limits for each process step. 5.2.5.5.3 The conditioning order must include at least the following: 5.2.5.5.3.1 Graphical representation of the package or the cross reference to consult. 5.2.5.5.3.2 Clearance of the area to be used ensuring that is free of previous products, equipment and unnecessary materials. 5.2.5.5.3.3 Verification of the area to confirm cleaning conditions to start the conditioning of the product. 5.2.5.5.3.4 Detailed instructions of each step of process and equipment, including the critical parameters of the process.

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5.2.5.5.3.5 In-process controls to be performed, instructions for sampling and storage, according the product 5.2.5.5.3.6 Instructions for conciliation of printed materials. 5.2.5.5.3.7 Storage conditions for finished product 5.2.5.5.3.8 Necessary specific conditions for handling and storage, according to product. 5.2.5.6 Product manufacturing file 5.2.5.6.1 There must exist a manufacturing file for each lot of product, consistent with authorized conditions in Sanitary Registry and containing the order and instructions for production and conditioning with the registry of activities. 5.2.5.6.2 This file must contain at least the following: 5.2.5.6.2.1 Order and instructions for production. 5.2.5.6.2.2 Lot number of the product 5.2.5.6.2.3 Lot numbers and amounts dispensed from all materials included in the formula. 5.2.5.6.2.4 Dates and times of start-up and termination of the most important steps of the production. 5.2.5.6.2.5 Identification of the person who executed the operation, with the first letter of the name and first surname; this information must be traceable to an operators and supervisors registry of production areas. 5.2.5.6.2.6 Registries of supervision. 5.2.5.6.2.7 Registry of in-process controls with the results obtained and individuals who performed it (initial letter of name and first surname). 5.2.5.6.2.8 Yields obtained during the different stages of production. 5.2.5.6.2.9 Any deviation to the instructions must be registered, investigated and assessed. The investigation must be concluded to release the lot. 5.2.5.6.2.10 every file of production must be signed for conformity by the Sanitary Responsible or qualified person who certifies that product has been produced in compliance with GMPs. 5.2.5.6.3 Conditioning file 5.2.5.6.3.1 There must be a conditioning file for each lot of product and it must correspond with the authorized conditions in Sanitary Registry, contain the instructions and the registry of activities performed for conditioning. 5.2.5.6.3.2 The conditioning file must be integrated to the manufacturing file of the lot and must contain at least the following: 5.2.5.6.3.2.1 Order and conditioning instructions 5.2.5.6.3.2.2 Number of the lot of product 5.2.5.6.3.2.3 Number of lot and amount of bulk product. 5.2.5.6.3.2.4 Numbers of lot and amounts of the packaging materials 5.2.5.6.3.2.5 Conciliation of packaging materials to determine the amount used, sent to destruction and the returned materials. 5.2.5.6.3.2.6 Date and time for start-up and termination of the conditioning stages. 5.2.5.6.3.2.7 Identification of the person who executed the operation, with the first letter of the name and first surname; this information must be traceable to an operators and supervisors registry of conditioning areas. 5.2.5.6.3.2.8 Registries of the supervision. 5.2.5.6.3.2.9 Registry of in-process controls with the results obtained and individuals who performed it (initial letter of name and first surname). 5.2.5.6.3.2.10 Yields obtained for the different stages of conditioning. 5.2.5.6.3.2.11 Any deviation to the instructions must be registered, investigated and assessed. The investigation must be concluded to release the lot. 5.2.5.6.3.2.12 Every file of conditioning must be signed for conformity by the Sanitary Responsible or qualified person who certifies that product has been produced in compliance with GMPs

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5.2.5.7 Analytical and test methods 5.2.5.7.1 There must exist written procedures describing methods, equipment and instruments used for the analysis or evaluation of the inputs and product in the different stages of production. 5.2.5.7.2 The registry of analysis and evaluations performed must be preserved. 5.2.5.8 Other documents related with GMP compliance. 5.2.5.8.1 It must be available the written documentation related to GMP compliance for the personnel responsible of activities described in the documents; this documentation should correspond to the level assigned in the Quality Management System and may be as policies, SOPs, protocols, working instructions, reports, agreements, among others. 5.2.5.8.2 There must exist the documented evidence of the use of these documents or the activities described in them. 5.2.5.8.3 There must exist written documentation for the following activities or processes; this list is not limited and may exist more documents related. 5.2.5.8.3.1 Cleaning and sanitization of areas, equipment and instruments. 5.2.5.8.3.2 Operation and maintenance of equipment and instruments. 5.2.5.8.3.3 Qualification of equipment and systems and process validation. 5.2.3.8.3.4 Training, qualification, and verification of the effectiveness of the personnel training in GMP, hygiene, clothing, and technical topics related with their activity. 5.2.3.8.3.5 List of signatures with the first letter of the name and the first surname and/or initials of the personnel involved in manufacturing of drug products in all stages. 5.2.3.8.3.6 Technology transfer 5.2.3.8.3.7 Environmental monitoring 5.2.3.8.3.8 Plague control 5.2.3.8.3.9 Deviation or non-conformities investigation 5.2.3.8.3.10 Complaint report 5.2.3.8.3.11 Change control report 5.2.3.8.3.12 Return of products 5.2.3.8.3.13 Recalls 5.2.3.8.3.14 Report of self-inspections, audits to suppliers, audits from regulatory entities, audits from customer. 5.2.3.8.3.15 Purchase of inputs and purchasing orders of imported products, invoices, and import/export permits. 5.2.3.8.3.16 Supplies reception 5.2.3.8.3.17 Storage 5.2.3.8.3.18 Distribution 5.2.3.8.3.19 Report of annual review for each registered product 5.2.3.8.3.20 Sampling registries. 5.2.3.8.3.21 Technical agreements of manufacture, distribution and quality. 5.2.3.8.3.22 Registries of the product release 5.2.3.8.3.23 Each establishment in the country must have the following legal documents: 5.2.3.8.3.23.1 Original of the Sanitary License or Notice of functioning 5.2.3.8.3.23.2 Notification of Sanitary Responsible. 5.2.3.8.3.23.3 Current GMPs Certificate 5.2.3.8.3.23.4 Current copy of the FEUM and the corresponding supplements

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5.2.3.8.3.23.5 A file for each registered product containing: 5.2.3.8.3.23.5.1 Original of the Sanitary registry 5.2.3.8.3.23.5.2 Labeling projects (IPP and leaflets) authorized by COFEPRIS 5.2.3.8.3.23.5.3 File of registry and modifications (quality information, pre-clinical and clinical studies, among others) 5.2.3.8.3.24 For establishments located abroad, and are the owners of the registry: The Legal Representative in Mexico should have the documents listed at 5.2.5.8.3.23 of this Norm and the registry holder must have an apostilled or legalized letter of the current sanitary registry. 5.3 Audits 5.3.1 There must be procedures establishing the execution process of an audit, containing at least: 5.3.1.1 The scope of each type of audit 5.3.1.2 The qualification of the auditing group, including: 5.3.1.2.1 Experience, training, skills, availability and independence 5.3.1.2.2 Execution process: planning, responsibilities, requirements, registries, report. 5.3.1.2.3 The frequency of the audits and the establishment of a permanent program for audits. 5.3.2 For the purpose of this Norm, the audits are classified as: internal audits (self-inspections), audits to suppliers, and audits from regulatory authorities. 5.3.2.1 Internal audits (self-inspections) There must exist a system for self-inspection for the assessment of the Quality Management System and the compliance level for GMPs. 5.3.2.1.1 Self-inspection audits must be conducted by personnel independent of the audited area. These audits can also be performed by external personnel. 5.3.2.1.2 The following aspects should be evaluated following a pre-established program to verify the conformity with the principles of the Quality Management System: 5.3.2.1.2.1 All self-inspections must be registered. The reports should include all observations performed during the inspections and, if necessary, the proposals of corrective and/or preventive actions should be registered in the CAPA system of the facility. 5.3.2.1.2.2 Results from self-inspections should be communicated to the involved personnel 5.3.2.2 Audits to suppliers: 5.3.2.2.1 The establishments must determine, based on a risk evaluation, which suppliers of inputs have an impact on quality, safety and efficacy of the drug product. 5.3.2.2.2 There must be a procedure for the execution of audits to input suppliers, analytical services, services to critical systems and equipment and manufacturers outsourced. 5.3.2.2.3 There must exist a program of periodical audits as well as documented evidence to demonstrate compliance. The periodicity of the audits should be established based on the risk level in process, the impact and on the previous qualification reports. 5.3.2.2.4 The audit report of suppliers should be part of the qualification file of the supplier. 5.3.2.3 Audits from regulatory authorities 5.3.2.3.1 There must be a procedure for the attention of audits from Regulatory authorities, including, but not limited to: 5.3.2.3.1.1 Reception of the audit by the sanitary responsible or a designated person, according to clause 7.1.6 in this Norm. 5.3.2.3.1.2 Preparation of the information to be presented. 5.3.2.3.1.3 Registry, evaluation and closure of non-conformities during the audit from Regulatory authorities.

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5.3.2.3.2 The results of the audits from Regulatory authorities must be communicated to the personnel involved in the execution of the actions as well as to the General Direction. 5.4 Complaint management 5.4.1 There must exist a responsible for the complaint management. 5.4.2 There must exist a procedure for complaint management, which must include: 5.4.2.1 The mandatory nature for the attention and documentation of all complaints. 5.4.2.2 The investigation process, including the impact on quality, safety and efficacy of product. 5.4.2.3 Definition of the CAPA to be performed with regard to the issue. 5.4.2.4 The form and the time of response to the customer. 5.4.2.5 Indicate in what cases proceeds a recall and notify to the Ministry through the COFEPRIS. 5.4.3 As part of the investigation of a complaint from one lot of defective product, the prospective and retrospective evaluation must be extended to other lots in order to determine if are also affected. 5.4.4 The registries of complaints should have, as a minimum the following: 5.4.4.1 Name of product, presentation and lot number. 5.4.4.2 Amount involved 5.4.4.3 Reason 5.4.4.4 Name and location of who generates it 5.4.4.5 Result of the investigation 5.4.4.6 Actions taken 5.4.4.7 All complaints must be registered crossed with investigation reports and make reference to the corresponding registries of the involved lot. 5.4.5 A periodic review of complaints must be effected to identify specific or recurrent problems and take the necessary measures. 5.5 Product out of specifications and/or non-conforming 5.5.1 The products in any stage which do not comply the established specifications or are manufactured out of the established procedures must be identified and placed in temporary retention or quarantine. 5.5.2 A report of deviation or non-conformity must be issued to define the level and extension of nonconformity as well as to establish the corrective actions such as if the product may be repackaged, recovered, reprocessed, reworked or rejected. 5.5.3 Recovery, reprocessing or reworking processes must be approved by the Sanitary Responsible or the designed person n the terms of clause 7.1.6 of this Norm. 5.5.4 A procedure must exist describing: 5.5.4.1 The identification of the non-conform product. 5.5.4.2 The control of the non-conform product including segregation and prevention of accidental use of the product or the facility where it was processed. 5.5.4.3 Actions to be taken in cases of re-packaging, recovering, reprocessing or reworking of lots. 5.5.4.4 The Sanitary Responsible or the authorized person must establish the final disposition of product. 5.5.5 Recovery of the product in the primary package is only allowed for solid dosage forms 5.5.6 Re-working or re-processing are not allowed in sterile products dosed in its primary package. 5.5.7 Recovered lots must be subjected to quality analysis and documentation must show that the quality of the recovered lot is equivalent to that of the original process. 5.5.8 Re-processing in drug products are permitted just once. If the cause of the re-processing is repeated, then the process should be validated.

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5.5.9 Reprocessed or reworked lots should be subjected to quality analysis and to stability studies according with the Official Mexican Norm NOM-073-SSA1-2005, Stability of drugs and drug products, Number 8, Known medication, and the documentation should demonstrate the compliance with specifications of the original product. 5.5.10 Rejected products must be identified and segregated until disposition or final destiny. This is performed according to the established procedure. 5.5.11 An order or instructions of rework, recovery or reprocess specific for each lot must be issued. 5.5.12 In the case of re-processes, a different lot number than the original should be assigned, which must be authorized by the Sanitary Responsible. 5.5.13 the release of a reworked, recovered o reprocessed lot must follow the steps described in clause 12 of this Norm and have the authorization of the Sanitary Responsible. 5.6 CAPA 5.6.1 There must be a system for the implementation of resulting CAPAs of non-conformities, complaints, returns, out of specifications, audits, trends and those defined by the system. 5.6.2 A methodology should be established for the investigation of deviations or non-conformities that include the use of technical and/or statistical tools to determine the root-cause, the definition of people responsible and the commitment dates. 5.6.3 Implemented CAPAs should be followed to check their efficiency. 5.7 Control Change 5.7.1 There must exist a documented system of control change including the risk management for evaluation and impact of the proposed change over processes, suppliers, critical systems, computational systems, areas, services, equipment, analytical methods, specifications, documentation, regulatory dispositions and quality of product. 5.7.2 Unplanned changes should be considered as deviations or non-conformities. 5.7.3 A Committee or Technical Group should be formed, integrated by representatives of the areas involved and the responsible of the quality unit, who will review, assess and approve the proposed change. 5.7.4 The implementation of the approved changes must be followed and ensure its closure according to previously established. 5.8 Returns 5.8.1 There should be a procedure for control of returned products, indicating: 5.8.2 That they must be placed in temporary retention/quarantine and be assessed by the Quality Unit in order to determine if they can be released or destroyed. 5.8.3 Reception registries, identification, evaluation and destiny. The report must contain the following at minimum: 5.8.3.1 Name of the product, presentation, lot number and expiry date. 5.8.3.2 Date of return, amount returned 5.8.3.3 Date and reason to return 5.8.3.4 Name and location of who returns 5.8.3.5 The assessment to demonstrate that the product complies with specifications, integrity standards, safety, identity, quality and purity must include: the analysis of the distribution route, storage conditions of the returned product, labeling conditions, decision and final destiny of product. 5.8.3.5.1 The recovery of the returned product is not allowed if during evaluation there are doubts about the condition of the container, cases or cartons, or the text of labeling which raise concerns of integrity, safety, identity, strength, quality or purity of the product. 5.9 Annual Review of Product

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5.9.1 A systematic annual review must be in place of the quality of each product. The Sanitary Responsible must ensure the implementation of the system RAP (annual review of product) and designate the person responsible of its execution and diffusion. 5.9.1.1 The objective of RAP is to check the product performance, the consistency of the manufacturing process and the determination of the need to revalidate the manufacturing processes. With the RAP the necessity to conduct changes in manufacturing process, in-process controls and in the specifications is determined. These changes include to identify improvements for product and for manufacturing process, based on the trending analysis and risk assessment. 5.9.1.2 It is not allowed the grouping of products, irrespective of that during the production processes and similar equipment are used. 5.9.1.3 For drug products imported, the RAP report is a requirement and it must include the information generated by the manufacturer and must be complemented with the information generated by the processes performed in the country. 5.9.2 There must exist a procedure to accomplish the RAP containing to determine and justify the selected areas in the review, as well as the possible extension of the review. The results of RAP must be summarized in the form of the Appendix B Normative annexed in this Norm. 5.9.3 Annual Review of Product for orphan drug products In addition to that specified in Appendix B Normative of this Norm, the following information must be included for the case of RAP for orphan drugs. 5.9.3.1 Listing of the countries where the drug product has been registered or recognized (including date and number of registry). 5.10 Technology transfer 5.10.1 The technology transfer should have a planned and documented approach, which considers trained personnel, requirements of qualification and validation, manufacturing systems and quality control and must be formalized through a protocol and the corresponding report. 5.10.2 The batches from technology transfer cannot be commercialized. 6. Quality risk management 6.1 There should be in place a System of Quality Risk Management which ensures scientifically and systematically the actions to identify, mitigate and control the potential failures in systems, operations and processes which affect the quality of products. 6.2 The methodology for Risk Analysis on systems, operations and processes should be supported by tools of analysis proven to ensure the effective and logic management of priorities and strategies for the quality risk management. 6.3 There must exist a set of procedures which evidence the implementation, training, and qualification of the personnel in charge of the System of quality risk management and its application. 6.4 The risk evaluation performed should be documented such that they be the basis for the preparation of the Master Plan of Validation, as well as the technical evidence for deviations and critical changes of systems, operations and processes and to be the support of the assessment of Preventive and Corrective Actions. 6.5 There must exist an efficient communication media which ensures that analysis and documented actions in the Risk Methodology is known in the organization as part of the Quality Management System. 6.6 Must be established a continuous verification of the result from the process of Quality Risk Management which ensures the validity and robustness of the Quality Management System. 6.7 To implement the Quality Risk Management you may consult the following web site where you will find in Spanish language the Annex 20 of the guideline for GMPs of drug products http://www.cofepris.gob.mx/AS/Paginas/Establecimientos %20y%20productos%20biologicos/Certificado BuenasPracticasFabricacion.aspx 7. Personnel 7.1 Generals

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7.1.1 The most important element for safety, efficacy and quality of drug products is the personnel, so it is the manufacturer responsibility to have the amount of qualified personnel enough to perform all activities required for the manufacture of drug products. The personnel must receive an induction on GMPs since he is hired, receives also a training on the activities he is going to perform and continuous training. 7.1.2 Personnel that participate on any aspect of the manufacture with an impact on the quality of the product must have the required profile and be continuously trained and qualified. 7.1.2.1 Besides the basic training on theory and practice in the Quality Management System and in GMPs, the personnel recently hired must receive an adequate training previous to the execution of the assigned tasks. 7.1.2.2 Personnel who works in areas with a risk of contamination, such as the clean zones or zones where highly active, toxic, infectious or sensitiveness substances are handled, must receive a specific training. 7.1.3 There must exist an organization chart, authorized and updated, where the authority levels and interrelations of different departments or areas are clearly established. Responsibilities should be clearly indicated in the description of the position. 7.1.4 There must exist a Sanitary Responsible according with the legal dispositions applicable, who must occupy the greater hierarchical level of the Quality Unit and report to the maximum authority of the organization. 7.1.5 The Sanitary Responsible is the responsible of the quality of products, along with the maximum authority of the organization, to ensure that a Quality Management System is in place. The Sanitary Responsible must have an academic formation, the knowledge and experience enough for decision making on different aspects of GMPs. 7.1.6 Delegation of functions When the Sanitary Responsible is absent or under special circumstances, e.g., concurrent projects, work load, he/she may designate in writing the person(s) that will assist with several tasks, including the signature of operative documents. Designated person(s) must comply with the requirements established in the legal dispositions applicable to Sanitary Responsible. The equivalent to Sanitary Responsible in plants located abroad is the Authorized Person, Technical Director or Representative of the Quality Unit. 7.1.7 The Sanitary Responsible must authorize the master documents which ensure the compliance of GMPs and the basic documents of the Quality Management System, the documents generated from these, may be signed according to the statement in the documentation system. 7.1.8 For those plants based on Mexico, the owner of the establishment will be the responsible solidary with Sanitary Responsible for compliance of this Norm and other legal dispositions applicable. 7.1.8.1 Legal representatives of the holder of the sanitary registry abroad must have a Sanitary Responsible in Mexico. 7.1.8.2 For manufacturing plants based on another country, the legal representative in Mexico along with the Sanitary Responsible (responsible of the quality unit) is the responsible solidary for the compliance of this Norm. 7.1.9 The manufacturing unit and the quality unit must be completely independent within the organization structure, without reporting or with dependence each other. 7.2 Resources management 7.2.1 Generals Personnel must know and understand clearly their responsibilities and functions, as well as the principles of current GMP applicable. 7.2.2 It should be established in written the profile, description, and the responsibilities of each position and these must be congruent with operations and the application of GMPs. 7.2.3 There must exist a system of selection, training, assessment and qualification, which ensures that the personnel have the academic preparation, knowledge, and experience needed to perform their functions and responsibilities according to the profile. 7.2.4 There must exist an annual program of training, including GMPs, specific operations for the position, hygiene and safety; it must be preserved the evidence of the application. Training must include specific topics

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for the personnel who works in areas where exist contamination risks or handling of materials or products highly active, toxic, or sensitive. 7.2.5 Effectiveness of training must be evaluated periodically through competence tests, which demonstrate the expertise of the personnel in the assigned tasks. 7.2.6 Personnel who exerts positions of responsibility must have enough authority to comply their responsibilities, and for this reason must have the preparation and knowledge technical-scientific and the practical experience in manufacture, in quality control and assurance of drug products, having a professional criteria independent, based on the application of scientific principles to solve practical problems that could occur in manufacturing and control of drug products. 7.2.7 Personnel that is responsible of production and quality units must be professionals in the pharmaceutical, chemical, and/or biological fields, authorized to exert in terms of the legal dispositions applicable. The responsible of the quality unit must comply with the dispositions applicable to sanitary responsible. 7.3 The responsible of the manufacturing unit must: 7.3.1 Ensure that products are manufactured according to written instructions in order to obtain the preestablished quality. 7.3.2 Approve the instructions related to the operations of manufacture and ensure their compliance. 7.3.3 To ensure that the manufacturing file of each lot of product include all registries related to manufacture and product control. 7.3.4 To check that maintenance of areas, equipment and services related to the manufacture, including the calibration of instruments, has been performed. 7.3.5 To ensure that qualifications and scheduled validations are performed on systems, processes, equipment and services. 7.3.6 To ensure that personnel has received the training for induction and the periodical training needed for the execution of their functions. 7.4 The responsible of the quality unit must: 7.4.1 Approve or reject inputs, intermediate products, bulk products and finished products. 7.4.2 To ensure that all determinations and established tests be performed. 7.4.3 To ensure the assessment of the manufacturing file of each lot of product before release. 7.4.4 To approve specifications, sampling instructions, test methods and analytical determinations. 7.4.5 To ensure that analyses performed by outsourcing are reliable. 7.4.6 To check that maintenance of facilities, equipment and instruments of analytical areas is performed. 7.4.7 To ensure that the following takes place: validation and transfer of non-pharmacopeial analytical methods, the studies of applicability of pharmacopeial methods, the qualification of equipment and calibration of analytical instruments. 7.4.8 To ensure that personnel has received the training for induction and the periodic training needed for the execution of their functions. 7.5 Consultants The consultants who advice about manufacturing and control must have a proven level of their academic formation, the knowledge and the experience which allows them to advice on the specific topic for which they were outsourced. Registries must be kept, showing the name, address, qualifications and the type of service delivered by these consultants. 7.6 Hygiene and Safety 7.6.1 There must be established training programs on hygiene practices, safety and clothing of the personnel who enters to manufacturing areas and quality control.

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7.6.2 All personnel must be submitted to medical examination at the time of incorporation. It is the responsibility of the manufacturer to ensure that personnel should have the knowledge of the health states with a potential impact on the quality of products. After the first medical examination, others should be performed whenever necessary for the work and the health of personnel. Personnel that performs visual inspections must submit to tests of visual acuity periodically. 7.6.3 Personnel with an infectious disease or wounds exposed on skin, being determined by a medical examination or observation, should suspend their activities until the condition is corrected or the medical personnel qualified determine that the person does not jeopardize his /her own safety and the quality of products. The personnel must be instructed to report this condition. 7.6.4 The personnel must bear clean and adequate clothes for the activity to be executed, with characteristics required for the protection of the personnel and product. 7.6.5 The requirements of clothing for each manufacturing area, warehouses and quality control should be defined in written. 7.6.6 There must be written instructions about washing of garments, including those used in manufacturing areas of high-risk products, where is indicated their treatment and/or final disposition. 7.6.7 In the case of use of disposable garments, there must be a procedure for their final disposition. 7.6.8 Personnel is not allowed to smoke, eat, drink, chew and store foods and medications in manufacturing areas, warehouses and quality control laboratory. 7.6.9 The personnel should not use jewels or cosmetics in manufacturing areas, including labs and biotery. 7.6.10 The personnel must be instructed to wash their hands before enter to production areas and after they leaving. 7.6.11 The entry of visitors to the areas of manufacturing and quality control must be controlled and not compromise the product quality. Visitors should follow the instructions related with hygiene and personal safety, including the use of garments; these dispositions also apply to employees, contractors, auditors, or any other person previously authorized to enter to areas. These visitors must be closely supervised. 8. Facilities and equipment 8.1 Generals 8.1.1 The areas and equipment must be located, designed, constructed, installed and maintained in such conditions to allow their correct operation. 8.1.2 Areas, manufacturing equipment and critical systems that directly impact product quality must be qualified and validated. 8.1.3 Alternative energy supply systems are required in order to maintain the conditions of the critical operations of the manufacturing process. 8.1.3.1 All operations involved in the aseptic processing must rely on alternative energy supply systems. 8.1.4 Areas and manufacturing equipment to develop products belonging to the penicillin and cephalosporin groups, steroid hormones of androgenic, estrogenic and progestagenic groups, blood products, and viral biological, bacterial biological and biopharmaceutical products must be dedicated. 8.1.5 The manufacturing areas shall be classified based on the Regulatory Appendix A of this Standard. 8.2 Facilities. 8.2.1 Considerations. 8.2.1.1 The design and construction of the manufacturing areas, laboratories and other rooms that are involved in the production process (including areas intended for animal handling) must be made of materials that can be cleaned, kept free of dust, insects, pests and of easy maintenance, in order to minimize the risk of contamination. 8.2.1.2 Maintenance activities should be carried out in facilities and buildings following a program to ensure that the maintenance and repair operations do not represent a risk to the quality of the product 8.2.1.3 All facilities and buildings should be subject to written instructions for their cleaning and sanitization. 8.2.1.4 The lighting, temperature, humidity and ventilation should be appropriate to the activities to be carried out on each one of them and should not affect directly or indirectly to the product, equipment and personnel.

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8.2.1.5 Staff entrance to the facilities or areas should be controlled according to the activities being performed therein. The production and packaging areas should not be used as passageways for personnel and supplies. 8.2.2 Production areas. 8.2.2.1 The production areas must have a sanitary finish; all services such as: lamps and plumbing, ventilation and extraction points and power supply must be designed and installed to avoid dust accumulation and to facilitate the cleaning. 8.2.2.2 The design and location of the areas must be such that the flow of staff, inputs, product in process, finished products and wastes is carried out in a logical and sequential order in accordance with the manufacturing process; avoiding cross flows, minimizing the risk of contamination of the product and considering the appropriate cleaning levels. 8.2.2.3 It must be demonstrated that the size and number of areas is consistent with the manufacturing capacity, equipment, product variety and type of activities to be carried out on each one of them. 8.2.2.4 The design of the manufacturing areas should include rooms for personnel access and clothes changing area, according to the classification of Appendix A of this Standard Standards. 8.2.2.5 The pipes must be identified, according to the code of NOM-026-STPS-2008, Colors and signs of safety and hygiene, and identification of risks of fluids contained in pipes and the flow direction of the fluids if applicable. 8.2.2.6 The pipes through which raw materials, intermediate or bulk products are transferred must be made of an inert non-contaminating material and these must be identified. 8.2.2.7 Drains must have traps or any other device that prevents backflow and contamination. Drains are prohibited in the class A/B areas used for aseptic production. 8.2.2.8 Storage areas for accessories manufacturing equipment are required. 8.2.2.9 There must be specific areas or cabinets for storing tools, substances or materials needed for the maintenance of the manufacturing equipment, and these must meet the same sanitary conditions according to the area in which they are located. 8.2.2.10 There must be separate areas for each one of the manufacturing processes; in cases of processes in which more than a unitary operation is carried out continuously, the management of risk and justification of the design of the areas must be performed. 8.2.2.11 The weighing of raw materials must be carried out in separate areas designed for this purpose. 8.2.2.12 The weighing and sampling of high-risk and sterile medications must be carried out in a specific area of the production area. 8.2.2.13 There should be a specific area for assorted orders to ensure the quality of the inputs. 8.2.2.14 Areas, manufacturing equipment and processes must count with the required critical systems such as: HVAC, compressed air, water for pharmaceutical use, pure steam, among others. 8.2.2.15 The installation and access for maintenance to the HVAC, water and support systems must be prevented from being a source of contamination of the product. 8.2.2.16 Production areas must have all their critical systems and services used properly identified. 8.2.2.17 The HVAC system must be designed and shaped according to the minimum considerations set out in the FEUM in order for it to comply with the classification of the required area in accordance with the Regulatory Appendix A of this Standard. 8.2.2.18 The areas where viable pathogenic organisms are processed must use dedicated ventilation systems without possibility of recirculation and with adjacent areas where no viable pathogens are handled. In addition, their release into the environment must be avoided. 8.2.2.19 There must be a system for monitoring the critical variables according to the FEUM in order to comply with the classification of the Regulatory Appendix A of this Standard. 8.2.2.20 The production areas in which dusts (sampling, weighing, mixing or other process) are generated must have extraction systems and dust collection by design to avoid cross and environmental contamination. 8.2.2.21 The critical operations for the manufacturing of sterile products, such as the preparation of materials, processes of sterilization, depyrogenated and filling must be carried out in controlled and physically separated areas. 8.2.2.22 The areas where visual inspection tests take place must be provided with the necessary lighting requirements. 8.2.2.23 For aseptic processes, facilities must also consider the following:

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8.2.2.23.1 In the aseptic areas, false ceilings must be sealed to prevent contamination from the space above them. 8.2.2.23.2 There must be systems to avoid that two consecutive doors are open simultaneously, so there must be an interlock system and a visual and/or hearing alarm system. 8.2.2.23.3 It must be demonstrated that the pattern of air flow does not represent a risk of contamination. 8.2.2.23.4 There must be an alarm system to indicate any failure on the air system. Differential pressure indicators must be appropriate between areas where this difference is important, and the differential pressure must always be recorded. 8.2.2.23.5 The changing rooms before the entrance to the aseptic processing areas must be designed as airlocks and must provide physical separation of the different stages of changing. The final stage of the changing rooms, in static conditions, must comply with the same classification of the area to which it leads. You must have separate changing rooms for the entry and exit of staff. 8.2.2.24 Production, sampling, weighing, primary packaging and all those where areas exposed to components, products and their inherent services (particularly air systems), products belonging to the penicillin and cephalosporin groups, steroid hormones of androgenic, estrogenic and progestagenic groups, blood products, and viral biological, bacterial biological and biopharmaceutical products and those with high pharmacological activity or high toxicity, should be completely independent and self-contained. 8.2.2.25 Those drug products that are demonstrated to not having high pharmacological activity or high toxicity, may be manufactured in common areas, prior approval of the Ministry, which will be based on the risk assessment of the products, implementing specific precautions for common handling of products, manufacturing campaign and corresponding cleaning validation. 8.2.2.26 The formulation and filling of biotechnological products may be carried out in areas of manufacturing of common sterile products, prior approval of the Secretariat, which will be based on the risk assessment of the products, implementing specific precautions for common handling of products, manufacturing campaign and corresponding cleaning validation. 8.2.2.27 Other penicillin products such as carbapenems, may be manufactured in the areas of cephalosporins, prior authorization of the Secretariat, which will be based on the risk assessment of the products, implementing specific precautions for common handling of products, manufacturing campaign and corresponding cleaning validation. 8.2.2.27.1 When lactamase inhibitors are formulated with penicillin, they may be manufactured in the areas of penicillin products. 8.2.2.28 The containment of areas where products containing pathogens, highly toxic, live bacteria or viruses are handled must be specially ensured. 8.2.2.29 The use of isolators must meet the air quality required for the processes and products to be handled within them. 8.2.2.29.1 The classification of the area where you place the isolator depends on the design of the isolator and its implementation; however, it must be placed in a Class D area as a minimum. 8.2.2.29.2 There must be a system of monitoring of the critical variables including the leak test of the isolator and gloves. 8.2.2.30 It must be ensured that the equipment and instruments as well as the sampling methods used to carry out the process controls are not affected directly or indirectly by the processes and vice versa. 8.2.2.31 The packaging operations must be performed in a specific area, designed and located so that the flow of personnel, supplies and work in process does not allow contamination, confusion and mix of products and inputs. 8.2.3 Storage Areas. 8.2.3.1 Storage areas should be designed and constructed to ensure the BPAD, and they must meet conditions of cleanliness, temperature and relative humidity required by the type of inputs and/or products, and to carry out their monitoring and verification. 8.2.3.1.1 For inputs and/or products that require cold chain, the infrastructure and equipment needed to meet the requirements and to carry out its control, continuous monitoring and verification is a must. 8.2.3.2 The reception area of inputs and outputs must be designed and constructed in such a way that protects them from the external environment, allowing inspection and cleaning. 8.2.3.3 There must be an area for the sampling of raw materials, dedicated and independent and that meets the same conditions of a production area. 8.2.3.4 There must be a boarding area that ensures the conservation of the properties of the drug products and supplies.

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8.2.3.5 There must be bounded areas for the storage of inputs and products, recovered or returned. Rejected products shall be kept in segregated and identified areas. 8.2.3.6 The inputs or products classified as narcotics and psychotropic substances (controlled) must have a segregated, safe area with controlled and restricted access. 8.2.3.7 Printed materials for packaging should be stored in an area with controlled and restricted access. 8.2.4 Areas of quality control. 8.2.4.1 The quality control laboratory must be physically separated from the production areas and warehouses. 8.2.4.1.1 There must be an air injection system to have positive pressure relative to the external environment. 8.2.4.2 The design and construction of the quality control laboratory must have the facilities and enough space for the tests and analysis carried out in them, to prevent mixing and contamination. 8.2.4.2.1 In the case of high-risk products, there must facilities for the safe handling of samples in order to avoid staff exposure and the contamination of the environment. 8.2.4.3 The areas for biological, microbiological and instrumental tests must be physically separated from each other. 8.2.4.4 If the instrumental area contains instruments sensitive to vibration, electrical interference, humidity or that require special conditions, you must have them in separate rooms or in areas that ensure the conditions recommended by the manufacturer for their protection. 8.2.4.5 There must be a specific area for retention samples of finished product that meets the conditions set out in the label. 8.2.4.6 There must be a specific area for retention samples of inputs and products that meets the conditions of conservation of their properties 8.2.4.7 There must be a specific and independent area for the handling of samples for analysis of drug products, in process products and finished products considered as high-risk. 8.2.5 Support areas. 8.2.5.1 The areas destined to the medical service and dining rooms should be separated from the manufacturing areas. 8.2.5.2 The areas destined for changing rooms, lockers, washing, showers and toilets must be in easily accessible locations and its size must be in correspondence with the number of workers. 8.2.5.3 Health services should not communicate directly, nor be located in passageways with the manufacturing areas 8.2.5.4 The maintenance areas must be separated and out of the manufacturing areas. If a maintenance area is required within the areas of production, it must meet the sanitary conditions of the area where it is located. 8.2.5.5 The facilities designed for handling laboratory animals must be isolated from the manufacturing areas and comply with the applicable legal provisions. 8.2.5.6 There must be a specific area with security conditions for records storage and manufacturing. 8.2.5.7 There must be a specific area separated from the manufacturing areas, to store the waste generated during manufacture and/or analysis of products. 8.2.5.8 For the treatment of the waste generated during the manufacture of high-risk products there must be a containment and inactivation system that shall comply with the applicable legal provisions for ecological and health for the final destination of the waste. 8.3 Equipment. 8.3.1 The manufacturing equipment should be designed and located to comply with its intended use and to avoid risk of contamination, its disassembly/assembly, cleaning, maintenance and sterilization, if applicable, must be permitted. 8.3.2 The location of the manufacturing equipment must not hinder the movements of staff nor block the grilles of the ventilation system; they must facilitate the flow of materials to ensure the order of the processes to control the risk of confusion or mixture of any stage of the process. 8.3.3 Control systems must be easily accessible and consistent with the type of area in which it will be operated. 8.3.4 The washing, cleaning and maintenance of the manufacturing equipment should not put at risk the quality of the products or be a source of contamination.

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8.3.5 The materials considered for the design and construction of manufacturing equipment and accessories that are in direct contact with the product must be inert and not be absorbent or adsorbent. 8.3.6 Lubricants, coolants or other substances required for the operation of the manufacturing equipment should not be in direct contact with the product or with the primary packaging. In cases where the lubricants or other substances required for the operation of the manufacturing equipment that could are in contact with the product, these must be at least food grade, purchased under a specification and get its correct handling established. 8.3.7 The manufacturing equipment out of use must be removed from the production areas. 8.3.8 The damaged equipment or awaiting maintenance should be identified and not represent a risk for the staff and the operation. 8.3.9 The manufacturing equipment, accessories, utensils and all pipes must be cleaned and maintained in accordance with written procedures detailing the activities to be performed. 8.3.10 The filters used in the production or the primary packaging of the products must be made of materials that do not release fibers or other foreign bodies. 8.3.11 When the sterile processes are in line, equipment (band conveyor) should not move from an ISO 5 or ISO 6 area to another of lesser classification, unless the equipment has its own system of ambient air and/or performs a continuous sterilization (eg. depyrogenization tunnel). 8.4 Critical Systems. 8.4.1 The system of generation and distribution of water for pharmaceutical use must be designed, constructed and maintained to ensure water quality, in accordance with the FEUM. 8.4.2 The HVAC system must be designed, constructed and maintained in accordance with the FEUM, to ensure the required classification in the Regulatory Appendix A of this Standard. 8.4.2.1 Those corresponding to Class A, B and C must have at least terminal HEPA filters of 99.97% of 0.3 µm. In the case of Class D there must be a filter efficiency of at least 95% and for class ISO 9 filters must have a minimum efficiency of 85%. 9. Qualification and validation 9.1 Generais. An essential element for the BPF (GMP) compliance is the qualification and validation, which allows the demonstration that the manufacture of medicinal products meets the fundamental characteristics of functionality, consistency and robustness, to ensure the quality of the medicines. The process validation is not an event in time, but that involves a focus related to the life cycle of the product, which should consider that the variability is an intrinsic characteristic of the processes of manufacture; know this variability, control and analyze the impact on the quality, safety and efficacy of medicines should lead to the processes of continuous improvement. 9.2 Impact of validation. The manufacturer must determine the impact of the elements of manufacturing in the quality of the product, using risk management as a tool to determine the extent of qualification and validation. 9.3 Qualification and validation. An essential requirement for validation is the qualification of all the elements involved in the process, system or method to validate. 9.4 PMV. 9.4.1 There must be a written plan for the development of the activities of qualification and validation, which must be authorized by the higher hierarchical level of the organization and the Health Responsible, and in which the scope, responsibilities and priorities of the qualification and validation must be established. 9.4.2 The PMV must contain: 9.4.2.1 Validation policy. 9.4.2.2 Organizational structure for validation activities. 9.4.2.3 Responsibilities. 9.4.2.4 Validation committee or its equivalent. 9.4.2.5 List of facilities, equipment, systems, methods and processes to qualify and/or validate. 9.4.2.6 Formats to be used for the protocols and reports. 9.4.2.7 Training matrix and qualification of staff. 9.4.2.8 Change control.

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9.4.2.9 Reference to applicable documents. 9.4.2.10 Analytical methods. 9.4.2.11 Computing systems that may impact the quality of the product. 9.4.2.12 Critical systems. 9.4.2.13 Production and conditioning equipment. 9.4.2.14 Procedures or methods of cleaning and/or sanitization. 9.4.2.15 Production and conditioning processes. 9.4.2.16 Maintenance of the validated state. 9.4.2.17 It should include a program of activities, which must be updated with the required frequency. 9.5 Protocols of qualification and validation. There should be written protocols where it is specified how the qualification and validation will be performed, these must specify the critical stages and include the acceptance criteria. 9.5.1 Reports of qualification and validation. There should be written reports of qualification and validation demonstrating the traceability to the corresponding protocol, these should include the results obtained, the deviations observed and the conclusions. Any change made to the protocol during the implementation must be documented and justified. 9.6 Qualification. The qualification must be carried out using the following four consecutive stages: 9.6.1 There must be a design qualification based on user requirements, including functional and regulatory requirements. 9.6.2 There must be facility qualification according to the design qualification and the manufacturer requirements. 9.6.3 There must be an operational qualification based on the operating conditions and intervals set by the manufacturer and user. 9.6.4 There must be a performance qualification demonstrating that the equipment and system meets the requirements previously established under routine conditions of use and within the work ranges allowed for each product. 9.6.5 To continue to the next stage of qualification the precedent must be concluded successfully. Next stage may be started only after it is demonstrated that there are no major non-conformities open and there is a documented assessment proving there is not a significant impact in the next stage. 9.6.5.1 The measuring instruments involved in the qualification must be calibrated with traceability to the national standards. 9.7 Qualification of the HVAC system. 9.7.1 The HVAC system must be qualified in accordance with the FEUM, taking into account at least the following parameters: temperature and RH of the areas it feeds, air injection volume, pressure differentials between areas, number of air changes , particle counting, airflows, cleaning levels, flow rate and integrity tests of the HEPA filters. 9.8 Qualification of the water systems. 9.8.1 The classification of water systems for pharmaceutical use must be in accordance with FEUM and its supplements. 9.9 Process validation. 9.9.1 The validation of the processes should be done with a risk management approach to quality. 9.9.1.1 There must be a documentary system supporting the knowledge and continuous improvement of the process throughout the life cycle of a product, from its development to its discontinuation in the market. 9.9.1.2 The approach taken must be based on sound science and the level of understanding and demonstrable control of the manufacturer. 9.9.2 Stages of process validation. The process validation consists of three stages in the life cycle of the product: 9.9.2.1 Process design (Stage 1) 9.9.2.1.1 Based on scientific principles and solidly methods, including BPD, the manufacturing processes and control registers are defined. 9.9.2.1.2 At this stage the strategy for process control must be defined and must be documented. This should include the quality of materials, the monitoring of the Critical Parameters of the Process and the Critical Quality

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Attributes that have been identified, including the results obtained during the implementation of the protocol for the transfer of technology. 9.9.2.1.3 Records planned for Production and Control containing the operating limits and overall control strategy must be confirmed in the next stage. 9.9.2.2 Process qualification (Stage 2) This stage can be carried out with prospective or concurrent release approach, and consists of two elements: 9.9.2.2.1 Facility design and qualification of equipment and services. 9.9.2.2.1.1 The facilities, equipment and services should be qualified. 9.9.2.2.1.2 Each of these elements may be qualified with individual plans or all together with general plan. 9.9.2.2.2 Qualification of Process Performance 9.9.2.2.2.1 At this stage the conditions of manufacture must be defined and confirmed. It is the combination, along with the manufacturing process for the production of commercial batches, of all the previously qualified constituent elements, including the qualified staff, control procedures and inputs. 9.9.2.2.2.2 Objective methods of applying statistical measurement tools must be established. 9.9.2.2.2.3 During this stage sampling, additional testing and greater scrutiny of process performance than would be typical in commercial production must be performed. 9.9.2.2.2.4 The level of monitoring and testing should be sufficient to confirm the uniformity of product quality throughout the lot. 9.9.2.2.3 Process qualification must be performed with commercial size lots using at least three consecutive lots in a defined time period, which should provide enough data to show that the process is capable, stable and consistent. 9.9.2.2.4 The lots produced for this purpose may be marketed if they comply with: all the requirements of the BPF, the established acceptance criteria, if the findings are satisfactory and the previously established release specifications. 9.9.2.2.5 Concurrent Release of lots of process qualification. 9.9.2.2.5.1 The concurrent release in the qualification stage of the process is only acceptable in cases such as: limited demand, short half-lives, health emergency, among others; this decision must be justified and approved previously from protocol by the Health Responsible or Authorized Person. Documentation requirements should be the same as for prospective validation. 9.9.2.2.5.2 Even if the validation of the lot with the minimum data required has not been completed, this allows it to be released if it meets all the Critical Quality Attributes. 9.9.2.2.5.3 Lots manufactured under this condition may be released and marketed if they comply with: all the requirements of BPF, the acceptance criteria set out in the protocol of validation, the satisfactory conclusions of the validation reports of each lot and the previously established release specifications. 9.9.2.2.5.4 Any non-conformities or events reported by the customer must be investigated immediately to determine the root cause and correct it. 9.9.2.2.5.5 Lots released concurrently must be included in the program of stabilities. 9.9.2.2.5.6 Concurrent release of lots of process qualification must be an exceptional practice in the validation process. 9.9.2.3 Process Continuous Verification (Stage 3) 9.9.2.3.1 It must be continuously ensured that the process remains in a state of control during the commercial manufacture. 9.9.2.3.2 Control systems should be established to detect changes in the variability of the processes in order to be able to correct them immediately and bring them back to their validated operation conditions. These must be defined in procedures that include the data to be collected, the frequency of collection, the calculations and the interpretation of the results obtained as well as the actions resulting from them. Statistical tools must be used when the nature of the measurement allows it. 9.9.2.3.3 The variability can also be detected by the timely evaluation of complaints related to the process and the product, reports of non-conformity, reports of diversion, variations in yields, revisions of the case files of the lots, records of reception of inputs and reports of adverse events. 9.9.2.3.4 All this information should contribute to the continuous improvement of processes. 9.9.2.3.5 Once the qualification status of a process is established, it must be maintained by defining preventive maintenance programs for facilities, equipment and services as well as for the periodic calibration of

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critical measuring instruments. These aspects will also contribute to the maintenance of the validated state of the process. 9.10 Aseptic process validation. 9.10.1 In products intended to be sterile and that are not subject to terminal sterilization, each of the unit operations involved should be validated independently and confirmed as a whole. 9.10.2 The validation of aseptic processes must be in accordance with FEUM and its supplements. 9.11 Cleaning validation. 9.11.1 Cleaning validation must be performed in order to demonstrate the effectiveness of the cleaning procedures. 9.11.2 The cleaning methods should be appropriate to the nature of the products. 9.11.2.1 There must be a program for the use of sanitizers which must include a sporicidal agent. 9.11.2.3 When the cleaning method includes processes of sanitization, sterilization and/or decontamination, they must be validated. 9.11.2.4 Interactions between different sanitizing agents should be evaluated and included in the validation. 9.11.3 Validated analytical methods considering the sampling technique to detect traces of contaminants, detergents and/or sanitizers must be used. 9.11.4 The cleaning procedures of the surfaces in contact with the product must be validated. 9.11.5 If multiple products are processed on the same equipment, and it uses the same cleaning procedure, a representative product can be used for the validation or the "worst case" criterion. This selection can be based on the solubility and difficulty of cleaning and the calculation of residue limits based on a combination of concentration and toxicity. 9.11.6 The cleaning validation must be carried out in three consecutive applications of the cleaning procedure with satisfactory results. 9.11.7 The effectiveness of the cleaning of the manufacturing equipment, accessories, utensils and all pipes must be established based on the results of the validation. 9.11.8 A regular program for the determination of traces of products included in the cleaning validation must be established. This periodicity should be established based on risk assessment. 9.12 Validation of analytical methods. 9.12.1 The analytical methods not in the pharmacopeia must be validated in accordance with their protocols considering what is indicated in the FEUM. 9.12.2 When pharmacopeia methods are used, they must demonstrate the applicability to the product under the operating conditions of the laboratory and according to the desired analytical method. 9.13 Validation of computer systems. 9.13.1 The computer systems that impact product quality and data integrity must be validated. 9.13.2 There must be an inventory of all computer systems. 9.13.3 Computer systems should consider software components, tools, equipment and infrastructure of information technology, among others. 9.13.3.1 There must be a system of protection, integrity and backing of the information, which should be determined based on the documentation of risk assessment of the computational system. The access and readability of the data must be secured during the entire retention time. 9.13.3.2 Access to these must be controlled. 9.13.3.2.1 Physical and/or logical checks to restrict access to users with different levels of authorization must be applied. The security codes must be defined according to the predetermined criteria and must be modified periodically. 9.13.3.2.1 The system must block the user after a defined number of failed login attempts. 9.13.3.3 When a computerized system generates electronic records and/or uses electronic signatures, these must be considered in the validation: 9.13.3.3.1 All the documents and records that are created, modified, maintained, archived, recovered and/or transmitted through electronic systems are considered electronic records. 9.13.3.3.2 If it is determined that a system generates and maintains regulated electronic data, documentary evidence must exist to ensure traceability, easy access and integrity. 9.13.3.4 If critical data is captured manually there must be an additional revision of the accuracy of the data that can be carried out by a second person or through electronic validated equipment.

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9.13.3.5 Data should be protected by tools such as backups made with the frequencies defined according to a procedure. 9.13.3.6 The ability to restore the data, as well as the integrity and accuracy of its support must be verified during the validation and must be monitored on a regular basis. 9.13.3.7 Based on a risk assessment, determine the need for the system to include an audit system data, scheduled to record regardless the date and time of entry of the users, as well as the actions to create, modify, or delete electronic records. 9.13.3.7.1 The data audit (audit trail) will prevent spoilage and must be available and convertible in an understandable way, during its retention period, to permit the evidence in the chain of events. 9.13.4 The validation process must include all relevant phases of the life cycle according to the category and construction of the system, to ensure the accuracy, completeness and consistency of the expected performance of the Computer Systems. 9.13.4.1 Risk management should be applied to the full validation cycle, including the phases of planning, specifications, testing, System release, and maintenance and system removal. 9.13.4.2 The components of the infrastructure of information technology and any relevant instrument or equipment must be qualified. 9.13.4.3 For the validation process, tests executed by the supplier may be used; however, the acceptance of test records delivered by the supplier must not replace the validation tests carried out in its facilities, equipment and staff such as the Validation Plan, user requirements, Risk Analysis, Performance Qualification, Validation Report, among others. 9.13.4.4 If a centralized system is used at multiple sites, the validation process should include the verification of the processes executed through the system at each individual site. 9.13.5 There must be a traceability matrix documenting the multiple stages of the specifications (including the revisions) and tests once they have been satisfactorily fulfilled. 9.13.5.1 Any change made to a Computer system must be performed according to the system control of changes, including system configurations, must be implemented according to a predefined and controlled process which involves defining the impact of the change and results in the verification of the activities, including regressive testing. 9.13.5.2 Control procedures should be implemented to ensure the revision of the audit of data on a regular basis; the frequency and the method will be determined according to the risk. 9.13.5.3 Systems with data audit function must issue information to verify if any data has been altered from its original record. 9.13.5.4 If data is transferred to another data format or system, validation should include reviewing the data are not altered in value and / or definition during the migration process. 9.13.6 For electronic signatures: 9.13.6.1 These must be unique for each person and non-transferable. 9.13.6.2 When the use of electronic signatures gets implemented, the date from which the electronic signatures will be valid and equivalent to handwritten signatures must be established. 9.13.6.3 Electronic signatures must have at least two different elements such as an identification code and password. 9.13.6.4 Electronic signatures must be linked to their respective electronic records to ensure that signatures have not been altered, copied or in any way transferred to an electronic record that may be falsified by ordinary means. 9.13.6.5 If the electronic signature is carried by tokens or biometric devices, the system must ensure that another person cannot use it and that it has the necessary control measures implemented. 9.14 Maintenance of the validated state. 9.14.1 The maintenance of the facilities, equipment and systems is another important aspect to ensure that the process is kept under control. Once the qualified/validated status has been achieved, it should be maintained through routine monitoring, maintenance, calibration procedures and programs. 9.14.2 There must be a periodic review of the facilities, systems and equipment, in order to determine whether it is necessary to make a new qualification. This should be documented as part of the maintenance of the validated state. 9.14.2.1 If the facilities, systems and equipment have not had significant changes, documentary evidence that they meet the pre-defined requirements is sufficient as evidence of the maintenance of the validated state.

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9.14.3 When a change affects the quality or characteristics of the product, or its components and/or process, a new qualification and/or validation must be carried out. 9.14.4 The maintenance of the validated state of manufacturing processes must be carried out according to what is established in the continuous verification of the process (phase 3), see point 9.9.2.3 of this Standard. 9.15 Guides for the qualification and validation. 9.15.1 They may be used as a support for the qualification and validation; national and international guides are described in the literature of this Standard. 10. Manufacturing systems Pharmaceutical manufacturing systems must follow written procedures to ensure compliance with the BPF. The characteristics of each system shall be conditioned, among other things, by the nature of the processes, the pharmaceutical form and the quality specifications of each product. 10.1 Control of inputs. 10.1.1 General. 10.1.1.1 There must be written procedures for the reception, identification, storage, control and management of all the inputs that are used in the manufacture of medicines. 10.1.1.2 Inputs should be purchased, when possible, directly from the manufacturer. 10.1.1.2.1 It must be ensured that the certificates of analysis inputs are those issued by the manufacturer. 10.1.1.2.2 The qualification and approval of suppliers must be made before purchasing any input. 10.1.1.3 Inputs in any of the stages of manufacture should be handled and stored in such a way as to prevent their contamination and alteration. 10.1.1.4 Inputs and products in any of the stages of manufacture should not be placed directly on the floor. 10.1.1.4.1 Pallets and containers used within the areas of production must be easy to clean and easy to prevent particle detachment. 10.1.1.5 Inputs must be identified with an internal lot number according to each shipment received. 10.1.1.5.1 When various lots are received in a shipment, each lot must be considered separately for its sampling, analysis and release. 10.1.1.5.2 When it comes to the shipping of an already received lot, the criteria to evaluate or analyze the inputs must be should establish. 10.1.1.6 The lot number must be used to record the use of each input. Each lot must be identified with its status: quarantine, approved or rejected. 10.1.1.7 There must be a system to ensure that inputs are used at the criterion of First in Expiration-First in Departure or First in Receipt-First in Issue. 10.1.1.8 When computerized systems are used to control inputs, they must be validated and managed through identification with tags or codes. 10.1.1.9 Inputs whose validity of approval has finished must be quarantined for their reanalysis or final disposal. 10.1.1.10 Rejected inputs must be identified and segregated to prevent their use in manufacturing. 10.1.2 Reception. 10.1.2.1 When receiving inputs it must be ensured that each container or group of containers is intact, and identified with at least name, quantity and lot number. 10.1.2.2 Inputs should be identified for storage indicating at least the following information: 10.1.2.2.1 The name and the international designation, when applicable. 10.1.2.2.2 The internal lot number. 10.1.2.2.3 Quantity and number of containers. 10.1.2.2.4 Status. 10.1.2.2.5 The expiry or reanalysis date. 10.1.3 Sampling. 10.1.3.1 Inputs, must be stored in quarantine, until they have been sampled, analyzed or evaluated and released by the Quality Unit for their use. 10.1.3.2 The identity of a complete lot of active ingredients or additives can only be guaranteed if individual samples are taken in all containers and an identity test is performed to each sample. Only a part of the containers

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can be sampled, as long as there is an established validated procedure to ensure that none of the packages of these materials will be incorrectly identified on its label. 10.1.3.2.1 This validation should consider at least the following: 10.1.3.2.1.1 Type of manufacturer and supplier of the input and their level of compliance with the BPF. 10.1.3.2.1.2 The Quality Management System of the manufacturer of the active ingredients or additives. 10.1.3.2.1.3 Manufacturing condition in which the active ingredient or additive is produced and controlled. 10.1.3.2.1.4 Nature of the active ingredients or additives and medicinal products in which it will be used. 10.1.3.2.2 They identity tests may be exempt in each container of active ingredients or additives in cases where the following is true: 10.1.3.2.2.1 They come directly from the manufacturer and have a single origin site. 10.1.3.2.2.2 The original container is maintained from the source to the receiver end without being opened. 10.1.3.2.2.3 The manufacturer of the active substance or additive is periodically audited by the manufacturer of the medicinal product. 10.1.3.2.2.4 The manufacturer of the active ingredient or additive has a reliable track record, based on a statistical analysis and compliance to good manufacturing practices. 10.1.3.2.3 They identity tests cannot be exempt in each container of active ingredients or additives in the following cases: 10.1.3.2.3.1 When the active principles or additives are supplied by an intermediary (broker) and the manufacturer of the active substance or the additive has not been audited. 10.1.3.2.3.2 When the active principles or additives are used for parenteral drugs. 10.1.3.2.3.2.1 For additives and when it is justified through a risk assessment, only a part of the container may be sampled if the point 10.1.3.2.1 of this Standard is met. 10.1.3.3 Representative samples of each batch and departure must be taken. 10.1.3.3.1 The samples taken for identity testing must be analyzed individually. 10.1.3.4 The number of containers to be sampled and the quantity of material taken from each container should be based on statistical criteria of variability of the input, confidence levels, history of quality of the supplier, and the amount needed for analysis and retention sample required. 10.1.3.5 Sampling must be performed considering the following: 10.1.3.5.1 Containers must be cleaned and/or sanitized to prevent the introduction of contaminants. 10.1.3.5.2 For sampling of sterile inputs, sterile instrumental and aseptic techniques of sampling must be used. 10.1.3.5.3 It must be established in which cases the individual samples can be mixed to form a composite sample, taking into account the nature of the material, knowledge of the supplier and the homogeneity of the composite sample. 10.1.3.5.4 The samples taken must be identified. 10.1.3.5.5 Containers sampled must indicate this on their identification. 10.1.4 Assortment. 10.1.4.1 Lot traceability of the amounts received against the assorted amounts must be ensured. 10.1.4.2 Inputs should be weighed or measured in accordance with the written procedures and this activity must be verified by a second person. 10.1.4.2.1 It should be verified that inputs assortments have been previously approved by the Quality Unit and have the expiration or reanalysis date still in force. 10.1.4.3 The amounts to be dispensed must correspond to the production or conditioning order. 10.1.4.4 If an input is removed from the original container to another, the new container must be identified as well. 10.1.4.5 Printed materials must be stored and transported separately in closed containers to prevent mixing. 10.1.4.6 Assorted inputs for manufacturing must be separated by the lot of product in which it is to be used. 10.2 Control of Manufacturing Operations. 10.2.1 Manufacturing operations must be performed by qualified personnel and supervised by staff with experience, knowledge and academic training corresponding to the activity they supervises.

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10.2.2 Access to manufacturing areas should be restricted and controlled. 10.2.2.1 When products containing narcotic drugs and psychotropic substances are manufactured, specific controls must be set for staff and handling of the product. 10.2.3 Before starting the manufacture the cleanliness of areas and equipment must be verify and also that there is no raw material, product, product residue or documents from the previous operation and which are not required for the operation. 10.2.4 The medicine manufacturing areas should maintain the conditions that correspond to their classification in accordance with the Regulatory Appendix A of this Standard. 10.2.5 The operations of different products or lots should not be carried out simultaneously or consecutively in the same room, except when there is no risk of cross contamination. 10.2.6. The flow of inputs must be done in a logical sequence so that the risk of cross contamination is prevented. 10.2.7 Measures must be established during manufacturing operations to minimize the risk of cross contamination. 10.2.8 Products and/or materials must be protected from microbial or other kinds of contamination at each stage of the process. 10.2.9 There must be established controls to ensure that products manufactured do not contain residues of metals from the process. 10.2.10 The primary packaging must be used clean. 10.2.10.1 Washing and sputter operations must be set or referenced in the production and control instructions. 10.2.11 When working with dry materials and products, care must be taken to prevent the generation and dissemination of dust. 10.2.12 All materials, containers, equipment and areas used, should be identified with product data, lot number and manufacturing stage. 10.2.13 Each lot of product must be controlled from its assortment by the production or conditioning order. 10.2.14 When adjustments to the assorted quantity need to be made, based on the potency of the drug product, they must be calculated and approved by the authorized personnel and documented in the production order. 10.2.15 The use of documents within the production areas should not represent a risk to product quality and the staff. 10.2.16 The addition and order of inputs during production must be carried out and verified according to the instructions of manufacture. 10.2.17 The implementation of controls in the process during the production should not affect the process nor put at risk the product quality and the staff. 10.2.18 The results of the tests and analyzes for process control should be recorded or attached to the production or packaging files. 10.2.19 Any deviation in the yields indicated in the order of production or packaging must be investigated before the release of the lot. 10.2.20 Times for each critical stage of the production process must be established and when the product is not immediately taken to the next step, the conditions and maximum storage or wait periods must be specified. 10.2.21 In case of requiring maintenance during the manufacture, the procedures describing the measures taken to prevent the impairment of the quality characteristics of the inputs, outputs and conditions of the areas must be established. 10.2.22 The finished product is considered quarantined until all analyzes are carried out and it can be released by the Quality Unit. 10.3 Production systems of non-sterile products. 10.3.1 Controls to prevent cross contamination in accessories such as sleeves, matrices and filter equipment in contact with the product must exist. Based on a risk assessment and cleaning validation, determine their dedicated use is determined. 10.3.2 To maintain traceability and functionality there must be a record of usage and inspection of the state of the sieves, feeders, punches and matrices. 10.3.3 Feeding and metering systems should be designed in such a way to minimize the exposure of inputs to the environment.

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10.3.4 Hoppers, tanks or pots must have lids, and, when required, they must be jacketed and with agitation control systems. 10.3.7 The final rinse of equipment, accessories and utensils which are in contact with the product must be made with purified water level 1 or level 2 according to the process requirements. 10.3.6 The quality of water used in production must comply with the provisions of the FEUM and its supplements. 10.3.7 For heterogeneous mixtures, as suspensions, homogeneity should be maintained throughout the filling process, even after line stoppages. 10.4 Production systems of sterile products. 10.4.1 The production of sterile dosage forms should be carried out in controlled areas according to the Regulatory Appendix A of this Standard. 10.4.2 The routine for microbiological monitoring must be established and the sampling points must be supported in validation studies. 10.4.3 The loading and unloading operations for sterilization and depyrogenation of equipment and materials must be done in an environment that ensures their condition of sterility and avoids confusion. 10.4.4 Any gas is used to purge a solution or to displace the air of a product must pass through a filter of sterilization. 10.4.5 The routine operation must be carried out with a minimum number of people. 10.4.6 The supervision of the aseptic operations should be performed from outside the area where they take place. 10.4.7 The personnel involved in the production and control of sterile products must receive training on basic to specific concepts of microbiology, aseptic techniques and clothing, hygiene rules and other rules applicable to sterile products and they must be qualified for that purpose. 10.4.8 The clothing used in aseptic areas must be made of materials that minimize particle contamination and have comfortable features. 10.4.9 Specific procedures for washing, preparation and sterilization must be established. 10.4.10 Time limits must be set and registered: 10.4.10.1 From the sterilization to the use of the materials. 10.4.10.2 Of storage of water for the production of sterile products. 10.4.10.3 From the preparation to the filling of the product. 10.4.10.4 From the filling to the sterilization of the product (for terminal sterilization products). 10.4.10.5 From the beginning to the end of the filling process. 10.4.10.6 Of permanence of the staff performing the aseptic filling. 10.4.11 The bioburden must be monitored before sterilization. There must be limits on the bioburden prior to sterilization, which must be related to the efficiency of the method to be used. The determination of the bioburden should be performed in each lot, both for aseptically filled products and those requiring terminal sterilization. When the parameters on death (overkill) for terminally sterilized products are stablished, the bioburden can be monitored at intervals, these intervals will have to be based on a risk analysis. 10.4.11.1 For parametric release systems, bioburden determination should be performed on each lot and considered as a control test in the process. When deemed appropriate, the level of endotoxins must be monitored.. 10.4.11.2 All solutions, in particular infusion fluids of great volume, must pass through a filter of retention of microorganisms located immediately before the filling if possible. 10.4.12 The final rinse of equipment, accessories and utensils which are in contact with the product must be carried out with water for the manufacture of injectables. 10.4.13 There must be an established program to verify the maintenance of the validated state that includes at least the frequency, number of units and presentation. 10.4.14 When including a new presentation or if there are significant changes in the process or equipment a new validation must be carried out. 10.4.15 Injectable solutions must be inspected to 100% for the detection of particles and other defects. 10.4.15.1 When the inspection for particle detection is performed visually, the personnel performing it must undergo regular checks of visual acuity, indicating the maximum time this operation can be performed on a continuous basis, and they must be qualified.

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10.4.15.2 If because of the nature of the packaging and the product, the inspection is not effective controls to ensure product quality must be set. 10.4.16 Integrity tests the product as a container-closure system must be conducted. 10.4.16.1 Containers closed by fusion, for example glass or plastic vials must be inspected in its entirety to one hundred percent. For other types of containers, samples should be checked by pharmacopoeia procedures. 10.4.17 Manufacturing operations are divided into two categories: those in which the product is sterilized terminally; and those performed aseptically at some or all stages. 10.4.18 When the products require terminal sterilization there must be physical barriers and indicators to differentiate between non-sterile and sterile, in order to avoid confusion. 10.4.19.1 A conciliation of the product before and after sterilization must be conducted. 10.4.19.2 Controls must be set for the handling of samples for quality control. 10.4.20 The preparation of products that require terminal sterilization must be carried out in areas classified as Class C minimum. 10.4.21 The purpose of aseptic processing is to maintain the sterility of a product that is assembled from its components, each of which has been sterilized. 10.4.22 The manufacture of products through the aseptic process is only allowed when the terminal sterilization process is not compatible with the product. 10.4.23 The maximum number of persons in the areas of aseptic processes must be established based on the process validation. 10.4.24 The handling and filling of aseptic preparations must be carried out in a Class A area, surrounded by a Class B environment. 10.4.25 When the container-closure system is not sealed, the product must be handled in a Class A. 10.4.26 When using mobile systems of laminar flow, these must be qualified and the operations must be a part of the validation of the process. 10.4.27 The monitoring of particles must be carried out throughout the aseptic process, including the assembly of equipment, analyzing the trends and verifying the compliance with the established warning limits and actions. 10.4.28 The sanitizers and detergents used in aseptic areas must be monitored for microbial contamination; preparations must be stored in containers that have been cleaned and must only be stored for defined periods unless they have been sterilized. Sanitizers and detergents used in Class A and B areas must be sterilized before their use. 10.4.29 The sanitation program of Class A and B areas should include a sporicidal agent. It should demonstrate the effectiveness of the cleaning and sanitizing procedures. 10.4.30 Each unit operation involved in the aseptic process must be validated individually. 10.4.31 The filter usage time must be established considered in the validation. 10.4.32 Integrity tests should be performed to the filters used in the filtration process before and after use. 10.4.33 The validation of aseptic processes must include the simulated filling test using a culture medium. The selection of the nutrient medium should be made based on the type of product dosage, selectivity, clarity, concentration and suitability for sterilization of the medium. 10.4.33.1 Simulated filling tests must be performed as part of the validation through the execution of three consecutive runs that meet the acceptance criteria specified in the FEUM. 10.4.33.2 These tests should be repeated at defined intervals with a frequency of at least once every six months and after any significant change in the air conditioning system (HVAC), installations, equipment or process. 10.4.33.3 Tests of simulated filling must include all the activities and interventions carried out during the normal production, as well as periodical simulation of situations of worst-case situations. 10.4.33.4 Processes of tests of simulated filling must be representative of each shift and shift change, to cover the functions related to time and process operations. 10.4.34 The number of pieces filled in the simulated filling study should be sufficient to be considered valid according to the criteria of the FEUM. 10.4.34.1 For lots of less than 5000 units, the number of filled parts must be at least equal to the size of the product lot. 10.4.35 For any run size, intermittent incidents of microbial contamination may be indicatives of low-level contamination, which should be investigated.

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10.4.35.1 The investigation of failures must include the potential impact on sterility assurance of the lots manufactured since the last successful simulated filling study. 10.4.36 The sterilization methods used must adhere to the provisions of the FEUM. 10.4.37 Blow/fill/seal technology (Blow/fill/seal) 10.4.37.1 For this technology, attention must be in at least the following: 10.4.37.1.1 Equipment design and qualification; 10.4.37.1.2 Validation of cleaning and sterilization; 10.4.37.1.3 Environment in which the equipment is located; 10.4.37.1.4 Training of operators; and 10.4.37.1.5 Interventions in the critical area of the equipment, including any aseptic assembly prior to the beginning of the filling. 10.5 Biological and Biotechnological. 10.5.1 General. 10.5.1.1 The manufacture of biological and biotechnological products involves additional precautions and conditions based on the nature and risk of the biological material involved, coupled with the implicit biological variability. 10.5.1.2 Vaccines, toxoids, toxins, macromolecular hormones, enzymes, serums and antitoxins of animal origin, and blood products are considered biological products; and any substance that has been produced by molecular biotechnology, such as recombinant proteins, monoclonal antibodies and others is considered a biotechnological product. 10.5.1.3 Biological products can be obtained by extraction from biological tissues, propagation of live agents in embryos or animals, microbial or cellular cultures not involving a genetic recombination process. The vaccines that have been produced by molecular biotechnology involving genetic recombination of one cell or microorganism must be treated as biotechnological products in the scope of this Standard. 10.5.1.4 The implementation of points 10.5.1 to 10.5.5.3.11 of this Standard is a requirement that applies generally to the manufacture of biological and biotechnological products. The specific requirements for blood products are described in point 10.5.6 and its sub-sections and the specific requirements for biotechnological products are described in point 10.5.7 and its sub-sections. 10.5.1.5 In addition to what is stated in point 10.5 and its sub-sections of this Standard, what is established in the current FEUM must be complied. 10.5.2 Staff. 10.5.2.1 All personnel involved in the manufacture of these products should receive specific training on the processes involved and hygiene and microbiology techniques, including the staff not directly involved in the production of the medicine, such as: the cleaning staff, maintenance and quality control. 10.5.2.2 The staff will be under the authority of a person who is skilled in the techniques used in the manufacture of these products and possesses scientific knowledge in their manufacturing and handling. The staff will include specialists in immunology, bacteriology, virology, molecular biology, genetics or other areas of knowledge that are required according to the nature of the product and processes. 10.5.2.3 The personnel involved in the manufacture of vaccines must be immunized and monitored in accordance with the nature of the biological agent used. 10.5.2.3.1 The personnel involved in the production and management of animals shall be immunized and be monitored according to risk and nature of the product. 10.5.2.3.2 Equivalent measures should be implemented for temporary employees, contractors, auditors or any other person previously authorized to enter these areas. 10.5.2.3.3 The personnel involved in the manufacture of the BCG vaccine should be subject to periodic medical control, including active tuberculosis tests and X-rays of the chest. 10.5.2.4 During the working, staff must not go from areas where microorganisms or animals are handled to any other area, unless there are effective decontamination measures, including the complete change of clothing. 10.5.2.4.1 All the transit restrictions of the staff to other areas and the control measures to avoid contamination of the product must be based on the risk assessment. 10.5.2.5 There must be a program of staff training in biosafety practices and biological containment; the program must include direct and indirect staff, and permanent or temporarily contracted personnel.

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10.5.3 Facilities and equipment. 10.5.3.1 The areas dedicated to the production of vaccines or biotechnological products containing live or attenuated agents should be designed with the appropriate level of biocontainment. 10.5.3.2 Production with live or attenuated microorganisms should be performed in dedicated areas. 10.5.3.3 There must be production areas dedicated to handle the microorganisms able to survive in the environment and the pathogenic microorganisms (biosafety level 3 and 4) to the completion and verification of the process of inactivation. For Bacillus anthracis, Clostridium tetani and Clostridium botulinum production plants strictly dedicated for each type of product must be used. 10.5.3.4 The Production areas of the BCG vaccine must be dedicated and independent. 10.5.3.5 The air systems of the areas where vaccines with live or attenuated microorganisms are handled must be designed to allow decontamination and this process must be validated. 10.5.3.6 Some stages of the manufacturing process, especially those were living microorganisms are used, may be carried out using dedicated facilities, equipment and utensils, and production by campaign or closed systems to avoid risks of cross contamination. 10.5.3.7 After the process of inactivation of vaccines of recombinant DNA origin, the toxoids and bacterial extracts may be formulated and filled in the same areas and with the equipment of other sterile products, considering the validated cleaning and decontamination methods and the assessment of the corresponding risk. 10.5.3.8 When manufacturing is done by campaign, the design and layout of the areas, services and equipment must permit effective decontamination. 10.5.3.9 The areas used for processing biological materials, tissue and cell cultures must be separated from the other activities considered less risky. 10.5.3.10 There must exist procedures in which there are planned actions established in case of accidental exposure or spillage of biological material. 10.5.3.11 The HVAC system, including air handling units must be designed, constructed and maintained to minimize the risk of cross contamination between the different areas of manufacture. 10.5.3.11.1 When handling microorganisms with biosafety levels 1 and 2, air may be recirculated considering the use of biosafety cabinets and based on the risk assessment. In the case of microorganisms of a biosafety level greater than 2, it won’t be allowed to recirculate the air and it must be previously treated with HEPA filters before being expelled to the outside, the performance of these filters should be checked periodically. 10.5.3.12 Areas, equipment, materials and equipment used must undergo a validated inactivation process. Precautionary measures to avoid contamination of the drainage system effluents containing infectious agents must be taken. 10.5.3.13 The equipment used during the handling of live organisms should be designed so as to maintain crops in pure and in an unpolluted state. 10.5.3.14 Pipeline systems, valves and filters for venting must be designed in a way to facilitate cleaning, decontamination and, in their case, sterilization. There preferably should be systems of cleaning and sterilization in place. 10.5.3.15 When the production processes are not carried out in closed systems and require the addition of supplements, media, buffers, gases, among others, the measures to avoid contamination of the product and the environment must be establishes based on the assessment of the risk. 10.5.4 Animal facilities. 10.5.4.1 The animal facilities must be physically separates and independent from other areas. Effective decontamination measures must exist, including the complete change of clothing. 10.5.4.2 The animal facilities must count with specific areas for dressing and changing clothes. 10.5.4.3 The technical specifications for the production, care and handling of animals used for the production and control of biological products must comply with the applicable legal provisions. 10.5.4.3.1 In the manufacture of biological products in which the use of transgenic animals is required, traceability from the reception of the animals to the production lot in which they were used in must be ensured. 10.5.4.3.2 For different animal species, the criteria for acceptance must be defined and it should include the age, weight and health status of the animals. These criteria should be monitored and recorded. 10.5.5 Production. 10.5.5.1 Control of inputs. 10.5.5.1.1 Growth promotion testing must be performed to the culture media used in manufacturing.

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10.5.5.1.2 In the case of inputs of animal origin there must be microbiological controls and adventitious agents to ensure the safety in use. 10.5.5.1.3 Living organisms must be handled and stored so that their viability, purity and genetic stability is maintained. 10.5.5.1.4 The inputs of animal origin or those used for manufacturing derivatives of animal origin, must present a certificate indicating that they are free from risk of TSE, BSE, foot and mouth disease, bovine leucosis and other agents representing a risk to health. 10.5.5.1.5 When the time required to run an analysis is very long, the use of raw material of biological origin may be authorized prior to obtaining the results of the corresponding tests for the release. In such cases, the release of the finished product must be conditional upon obtaining the satisfactory results of all the pending tests of its raw materials. 10.5.5.2 Cell bank and seed lot. 10.5.5.2.1 The specifications of the inputs used for the preparation of the master and working cell banks, must include their source, origin and the necessary controls to ensure they are suitable for use. 10.5.5.2.2 The production of medicines of biological origin obtained by microbial culture, cell culture or propagation in embryos and animals should be made based on master and working cell banks, and, if applicable depending on the design of the process, on the basis of master and working seed lots. 10.5.5.2.3 The number of passages or population doublings between the master cell bank and cell culture of the production lot at the time of harvest must correspond to the authorized condition. 10.5.5.2.4 There must be a documentation of the origin of the cell banks, the construction of the vector-host system for the protein of interest, along with the characterization of the genotype and phenotype and the number of cellular passages that guarantees the stability under the evaluated conditions. The origin and cell passage of the master and working seed lot must be documented. 10.5.5.2.5 There must be documented information on the genetic stability of the master and working cell banks. In case a master and working seed lot is used, its stability must also be documented. Some of the parameters to be considered are the retention of the gene segment of interest and its purity, using controls to demonstrate that they are free of adventitious microbial agents and other cellular contaminants outside the crop object. 10.5.5.2.6 There must be records of the use of the vials of the master and working cell banks and the conditions for their storage. If master and working seed lots are used, the conditions for their storage must be documented. 10.5.5.2.7 The cell banks and/or seed lots must be kept separately from other materials, under storage conditions designed with the aim of maintaining their viability and prevent their contamination. 10.5.5.2.8 Storage containers of cell banks and/or seed lots must be hermetically sealed, labeled and maintained at the set temperature. The storage temperature must be recorded continuously. Any deviation from the established limits and any corrective actions taken must be registered. Also there must be a contingency plan in case of a failure of the cryopreservation systems. 10.5.5.2.9 Access to cell banks and / or seed lots must be limited to authorized personnel. 10.5.5.2.10 There must be a procedure that ensures control of usage, handling and maintenance of the cell banks and/or seed lots. 10.5.5.2.11 The characterization of the cell banks must include: 10.5.5.2.11.1 Identification in terms of species, retention of plasmid and expression of the protein of interest, if applicable. 10.5.5.2.11.2 Growth characteristics and morphology (microscopic techniques). 10.5.5.2.11.3 Karyotype of cell lines. 10.5.5.2.11.4 Number of passages. 10.5.5.2.12 The handling of the seed lots and cell banks must be performed in environments that ensure their stability and purity. 10.5.5.2.13 There must be a periodical revision of the cell banks to determine if they are suitable for use. 10.5.5.3 Control of production. 10.5.5.3.1 Products and biological materials must be inactivated prior to disposal and in some cases they must be neutralized before the final disposal, in accordance with the applicable legal provisions. 10.5.5.3.2 The addition of inputs or culture medium in fermentation or propagation processes must be done under controlled conditions to ensure there is no contamination.

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10.5.5.3.3 Condensates or gases with live microorganisms that can form in the manufacturing process must be contained and treated to prevent their transfer to the environment. 10.5.5.3.4 The addition of substrates, buffers, defoamers, solutions for adjustment of acidity or alkalinity must be done through a sterile port to ensure the transfer of these components or through filters of sterilization of these components. 10.5.5.3.5 There must be a system that includes facilities, equipment and services and that allows to separate and clearly distinguish between products subject to a process of viral clearance or inactivation from those that have not received this treatment. 10.5.5.3.6 Processes of viral clearance and inactivation shall be validated. 10.5.5.3.6.1 The validation of these processes must be performed outside the areas of manufacturing, if applicable. 10.5.5.3.6.2 There should be decontamination measures validated with a strain for each organism or group of related organisms. In the case of different strains of the same bacteria or similar viruses, the decontamination process can be validated with a representative strain, unless there is significant variability in the resistance to the decontaminating agent involved. 10.5.5.3.6.3 Any deviation in these processes must be investigated and the impact on the safety of the finished product must be evaluated prior to its release. 10.5.5.3.6.4 A potential viral contamination must be avoided from the viral pre-inactivation, removal and postinactivation stages. The implementation of appropriate environmental and monitoring controls, and if applicable, the in-situ cleaning and sterilization systems, along with the use of closed systems can significantly reduce the risk of accidental contamination and cross contamination. 10.5.5.3.7 There must be an established method used for the separation of biomass from the liquid phase, including the control parameters for producing crops, as well as the yields obtained. 10.5.5.3.8 There must be a validated purification process by which it is shown that residual contaminants are systematically reduced to a set level that does not represent a risk of toxicity or affects the safety of the product. 10.5.5.3.9 Reusing the same column at different stages of processing of a product is not recommended and reusing the same column for different products is not acceptable. The acceptance criteria, the operating conditions, the regeneration methods, the lifespan and the sanitization or sterilization methods for the columns must be defined and validated. 10.5.5.3.10 A record should be kept of the use of the chromatography columns and their lifespan must be determined based on the established criteria. 10.5.5.3.11 Wastewater that may contain pathogenic microorganisms should be decontaminated prior to its treatment and final disposal. 10.5.6 Blood Products 10.5.6.1 General 10.5.6.2 All the products obtained from some blood components, especially plasma by physicochemical or biological processes, for therapeutic applications, diagnostic, prevention or research are considered blood products. Including: 10.5.6.2.1 Coagulation factors. 10.5.6.2.2 Immunoglobulins. 10.5.6.2.3 Albumin and plasma protein solutions. 10.5.6.2.4 Other fractions from the isolated plasma or combinations of them. 10.5.6.2.5 Dialyzable extract of human leukocytes (transfer factor). 10.5.6.3 The requirements for the selection of blood donors are generally established in NOM-253-SSA12012 as well as the requirements of human plasma for fractionation in the FEUM. 10.5.6.4 For the use of plasma or imported intermediate products, the criteria set out in this Standard must be met. 10.5.6.5 Starting material 10.5.6.6 The plasma used for the manufacture of blood products must come from blood fractions, from individual donations of whole blood or non-therapeutic plasmapheresis donors who are healthy and have met the requirements of selection of donors and the times of quarantine established according to the types of donation described in the NOM-253-SSA1-2012 and the FEUM.

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10.5.6.6.1 Leukocyte concentrates used in the manufacture of transfer factor must come from fractionated blood, individual whole blood from regular or repetition donors who are healthy and have an accumulate of two clinical evaluations documented in a year and at the same center and have complied with the requirements of Selection of Donors described in the NOM-253-SSA1-2012 and the FEUM. 10.5.6.6.1.1 The final release of the product Transfer Factor will proceed after the units have completed the serological screening and all tests relevant to the assessment of viruses mentioned in paragraph 10.5.6.18 of this Standard have been completed. 10.5.6.6.2 The Blood Bank will submit the documentation supporting compliance with the above. 10.5.6.7 The plasma used for the manufacture of blood products must be collected in establishments that have the authorization of the Secretariat or the competent authority fin case of establishments located abroad, and they must have been audited and approved by the manufacturer of the medicinal product. 10.5.6.8 Establishments proposed for the use of residual plasma for blood products must be evaluated by the Secretariat in accordance with the Official Mexican Standard NOM-253-SSA1-2012, for the disposal of human blood and blood components for therapeutic purposes. And, with regard to the infrastructure for the handling and storage of the plasma, they must comply with the applicable legal framework. 10.5.6.8.1 To obtain the release permit for products from human beings (plasma), evidence of compliance with the previous point and a copy of the sanitary license of the blood banks from which the plasma was obtained must be submitted. 10.5.6.8.2 Prior to the date of application of the permit for the internment of blood products obtained under the under the agreement for the use of plasma, the plasma-blood product balance must be submitted to the COFEPRIS. 10.5.6.9 Establishments receiving the residual plasma must submit The Plasma Master File to the Secretariat and keep it updated annually. 10.5.6.10 There must be a subscription of a technical contract between the manufacturer and the establishment of collection and initial fractionation of blood for the compliance with the Good Manufacturing Practices and those concerning the storage and transport of the plasma for fractionation in compliance with the measures to ensure the recovery of labile and non-labile proteins in the plasma, as specified in the FEUM. 10.5.6.10.1 The compliance with these contracts will be verified periodically, under the system of approval of suppliers. 10.5.6.11 The individual units of blood/plasma must be labeled according to the recommended specifications in the NOM-253-SSA1-2012 and at least indicate: 10.5.6.11.1 Product name 10.5.6.11.2 Volume or weight 10.5.6.11.3 Donor identification 10.5.6.11.4 Establishment of collection 10.5.6.11.5 Expiration 10.5.6.11.6 Storage temperature 10.5.6.11.7 Name, content and volume of anticoagulant 10.5.6.11.8 Results of serological tests 10.5.6.11.9 Blood type 10.5.6.12 The manufacture of blood products will be made from pooled plasma loads defined with a maximum of 15,000 donations of which data of the plasma units composing them are known in detail. 10.5.6.13 Retention samples of each donation will be identified so that information is traceable to the donation and will be kept at a temperature of at least -30 °C. 10.5.6.13.1 These retention samples must be kept up to one year after the expiry date of the product with the longest useful life obtained from the mixture in which the plasma was used. 10.5.6.14 The human leukocyte dialyzable extract or plasma used for the manufacture of blood products must have the consistency of all the analysis, including the tests conducted by the establishment that made the collection as indicated in the NOM-253-SSA1-2012 and the FEUM. 10.5.6.15 The plasma fractionation facility should assess the presence of nucleic acids (by NAT) of the Human Immunodeficiency Virus (HIV) 1 and 2, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and parvovirus B19 (e.g. by polymerase chain reaction) in mini-mixtures of plasma before the units (bags or bottles) are released for the creation of the mixtures or loads of fractionation. 10.5.6.16 The evaluation of nucleic acids must be repeated in the mixtures for fractionation.

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10.5.6.17 It is the obligation of the Health Responsible of the establishment to release the plasma used in the manufacture of blood products and to ensure that it meets the requirements and specifications set. 10.5.6.18 Only the utilization of mixtures of plasma with negative results of Serological Markers for HIV, HBV and HCV and negative for Nucleic Acids of HIV 1 and 2, HAV, HBV, HCV [<100 IU / L], PVB19 [<104 IU viral/mL DNA]), total proteins (50 g/L) and FVIII (= 0.7 IU/mL)) may be released in accordance with the NOM253-SSA1-2012, the FEUM and the WHO recommendations. 10.5.6.19 Procedures for the visual inspection of the bags or individual bottles before mixing, thawing plasma process and the opening and elaboration of the mixture must be established. 10.5.6.20 The size of the plasma mixture will be reported in number of donations and in liters. 10.5.6.21 Records shall be kept to allow the traceability of the origin and controls to which each donation was subjected to. These records shall be kept for at least one year after the date of expiration of the finished product with the longest useful life. 10.5.6.22 Retention of each mixture of plasma will be kept for the same period that the records will be retained. Retention samples will be stored at temperatures of at least -30 °C. 10.5.6.23 Plasma Master File (EMP). 10.5.6.24 The Plasma Master File (EMP) will be jointly designed by the manufacturer of blood products and the Blood Banks suppliers of plasma and will contain common information about the plasma, from the collection to mixing of the plasma. This will include all information relating to the production of all the intermediate fractions including the components of the excipients and active principles. 10.5.6.25 The EMP should contain as a minimum: 10.5.6.25.1 Identification and addresses of collection centers and Blood Banks suppliers of blood and plasma, including any subcontractors and any separate site for testing individual donations for each Blood Bank. 10.5.6.25.2 Demonstration of evaluation and acceptance of suppliers of pharmaceutical raw material plasma. 10.5.6.25.3 Evidence that blood banks are authorized by COFEPRIS and they are regularly inspected by COFEPRIS in coordination with the National Blood Transfusion Center (CNTS), in accordance with the consensual instruments subscribed for this purpose. 10.5.6.25.4 Information on audits conducted by or on behalf of the applicant/holder of Drug Product Registration and any certification from other organizations (name and frequency). 10.5.6.25.5 Copy of the agreement or contract between the manufacturer of the blood products and the Blood Banks suppliers of plasma. 10.5.6.25.6 Information on the type of donation, according to the source of the plasma in: fractionated whole blood or blood plasma, and type of donors. 10.5.6.25.7 Records of the plasma donors and its characterization, according to the procedures defined in the selection criteria, the results of the tests for blood-borne infectious diseases and the registers of selection/exclusion of donors according to paragraph 2.14 of the references of this Standard and FEUM. 10.5.6.25.8 Information of the tests used for the detection of infectious agents and their validation, including, as a minimum: trade name, manufacturer, registration number of the diagnostic kit if it is registered in the country, or in its defect, a certification attesting its quality, the levels of detection, the sensitivity and the specificity summarized according to table 1, as well as the criterion of acceptability or rejection, including the policy of retests and confirmatory tests and their algorithms.

Parameter

HBsAg Antibodies Anti-HIV 1 and 2 Antibodies Anti-HCV NAT for RNA Of HCV

Method of Evaluation

Trademark of the diagnostic Manufacturer kit

Used for Individual donations

Minimix/mixtures of plasma

Location of Evaluation

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DNA of PB19 Other evaluations

Table 1 10.5.6.25.9 Report of the results of the evaluations carried out to donations and their acceptance or rejection according to the specifications of the FEUM and the point 10.5.6.18 of this Standard. 10.5.6.25.9.1 When tests are carried out with mini-mixes, details of its rational usage and the method used must be provided, including the number and list of samples included as summarized in Table 2.

Evaluation carried out in:

Parameter Individual donations

Mini-mix (size)

Mixtures of plasma

HBsAg Anti-HIV antibodies 1&2 Anti-HCV antibodies NAT for HCV RNA DNA of PB19 Other evaluations

Table 2. 10.5.6.25.10 Information on the establishment of a post-donation System of Information. 10.5.6.25.11 Information on the procedure by which it will be immediately communicated to the COFEPRIS and the CNTS of any event that occurs in a detected a critical failure in a Blood Bank and the measures taken in this regard. 10.5.6.25.12 Epidemiological information on the incidence and prevalence of confirmed positive donors attending collection facilities and blood banks selected as suppliers, obtained from official sources and the corresponding health authority. 10.5.6.25.13 Report of the incidence of seroconversions and positive infectious particles confirmed in donors (by number of donors and number of donations). 10.5.6.25.14 Description of the procedures used to ensure that the storage and transportation of the plasma are executed in the right conditions, specifying the maximum amount of time and storage temperature of plasma and the time and temperature during transportation, according with the BPF and the specifications of the FEUM. Confirm that the storage and transportation conditions have been validated. 10.5.6.25.15 Information of the maintenance procedures of inventories and the quarantine for the plasma with a provide justification for the chosen period for any retention period of inventory. 10.5.6.26 The blood products manufacturer will verify that the starting material is not obtained from populations that have a high prevalence of blood transmitted infections relating to the relevant markers that are screened routinely. Also, they must verify that the starting material has not been obtained from blood donation campaigns carried out during known outbreaks of infectious diseases, particularly hepatitis A. 10.5.6.27 Information on the technical characteristics of bags used for obtaining blood and / or plasma and the anticoagulant used, describing: 10.5.6.27.1 Bag type, including the description of the specifications of the bag, identity of the involved plastic material and the sterilization procedure and its validation. Evidence of the absence of residual toxic substances. 10.5.6.27.2 Manufacturer 10.5.6.27.3 Composition and quality of the anticoagulant solution. 10.5.6.27.4 Results of a study of stability in real time of storage of the plasma in the container in question. 10.5.6.27.5 Proof of registration issued by COFEPRIS. 10.5.6.28 Epidemiological data from Blood Banks shall be evaluated regularly, jointly by the manufacturer of blood products and the Blood Banks, reporting at least the following information: 10.5.6.28.1 Incidence of confirmed positive seroconversions in donors (by number of donors and number of donations). 10.5.6.28.2 Prevalence of confirmed positive new donors.

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10.5.6.29 These reports will be part of the Plasma Master File and shall be updated with the same frequency 10.5.6.30 After donation system information. 10.5.6.31 There must be a documented and easily accessible system to ensure the traceability of the plasma from the donor to the final products and vice versa. This system must comply with the applicable legal provisions regarding personal data. 10.5.6.32 This system will describe the mechanisms of mutual information between the Blood Bank and the manufacturer of blood products, so that they can inform each other, after the donation, when: 10.5.6.32.1 It is found that the plasma is not suitable for use in the manufacturing process of plasma derivatives; 10.5.6.32.2 A subsequent donation from a donor previously found negative for viral markers is found positive for any of these or a viral load is detected by the determination of nucleic acids; 10.5.6.32.3 It is discovered that testing for viral markers has not been carried out in accordance with the approved procedures; 10.5.6.32.4 The donor develops Creutzfeldt-Jacob disease (CJD), in its traditional form or in its variant (vCJD). 10.5.6.32.5 It is detected that the plasma received for the production of blood products comes from a unit or component of blood causing adverse effects to the transfusion. 10.5.6.33 If a maximum time limit preset between the donation and the identification of the post-collection information is established, the information discovered after this period will not trigger further actions. It is required that this limit is clearly established, documented and justified in the system. 10.5.6.34 The system will ensure additional testing samples of individual units or mixtures of plasmas from previous donations (at least until 6 months prior to the last negative donation). In such cases, the donations that have not been processed will be identified and removed 10.5.6.35 A careful evaluation of the information received will be used, in order to determine whether it compromises the security of the distributed lots of product and if its removal is required, as established in the system of recall of products from the manufacturer. 10.5.6.36 A revaluation of all the documentation of the lot or lots involved will be carried out as soon as the information is received. 10.5.6.37 The results of this evaluation will immediately be made available to the COFEPRIS, in order for them to have the information and take the appropriate actions in any case where there is evidence that a donation contributor to a mixture of plasma is found infected with HIV or Hepatitis Virus A, B or C or parvovirus B19, and the manufacturer will provide the arguments the continuation of the production from the mixture involved or the recall of the product(s). 10.5.6.38 With regard to the risk of transmission of CJD (sporadic, familiar or iatrogenic) and its variant CJD (vCJD) and, as a precautionary measure, it is prudent to recall from the market the involved lots of medicinal products derived from plasma if a donor for a pool of plasma is considered highly suspect to present vCJD by a recognized reference center. 10.5.6.39 Production: 10.5.6.39.1 The manufacturing process of plasma derivatives includes stages of process such as thawing, plasma mixture, fractionation, purification, inactivation and clearance of viruses, formulation, filling and conditioning. 10.5.6.39.2 Production areas must be individual and independent of the ones of other products and their classification should be in accordance with the process to be carried out in them according to the Regulatory Appendix A of this Standard. 10.5.6.40 The facilities, equipment and services of the stages of fractionation, inactivation and viral clearance and formulation and filling, should be independent. 10.5.6.41 Blood thinners such as heparin and antithrombin may be added in several stages of the manufacturing process of coagulation factors to minimize activation. The materials, their use and residual concentrations should be documented at each stage and on the final product. 10.5.6.42 The processes specifically designed to inactivate enveloped and non-enveloped viruses and the capacity to remove viruses and other agents with infectivity such as bacteria and parasites are included. 10.5.6.43 The establishment of the blood product manufacturer must implement quality controls to ensure the safe use of these materials. 10.5.6.44 The process of fractionation and purification, through which it is shown that the residual contaminants are reduced systematically, must be validated.

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10.5.6.45 The processes for the production of blood products will be validated to demonstrate their ability to inactivate and/or eliminate known and not well-known viruses potentially contaminating to a maximum total reduction of the infectious load, including worst-case conditions, according to what is established in the FEUM. 10.5.6.45.1 Processes of inactivation and elimination of pathogens must be dedicated processes and independent of the process of purification. 10.5.6.45.2 There must be a consideration of the combination of factors for the calculation and interpretation to determine the effectiveness of the viral inactivation/clearance stage. The effectiveness of the process must be established for a total reduction of the pathogenic load greater than 4 log10. However, the reduction in the number log 10 must not be used individually as an absolute measure to determine the effectiveness of the viral inactivation/clearance stage. Therefore, the sum of these methods should give a final value greater than 10 log 10. 10.5.6.45.3 Validations of processes will be conducted to demonstrate the consistency and quality in the manufacture of various products in guarantee of the integrity and expected biological activity. 10.5.6.46 The material that has been processed in a stage of viral inactivation or clearance will be separated and properly identified from the material non-treated material at all stages of production in order to prevent cross contamination. 10.5.6.47 The manufacturer shall demonstrate the consistency of the manufacturing conditions and the specifications of each product, with at least three consecutive lots that are representative of the full scale production. The lots used for the study of consistency will be from different plasma loads or mixtures. 10.5.6.48 At least the following indicators will be considered in the studies of consistency: 10.5.6.48.1 Yields at different stages. 10.5.6.48.2 Elimination of contaminants. 10.5.6.48.3 Compliance with the quality specifications of the intermediate and final products. 10.5.6.48.4 Evaluation of possible degradation and/or aggregation products, leading to loss of the biological activity of the active ingredient and/or affecting product safety. 10.5.6.49 There must be a summarized protocol of manufacture in accordance with the legal provisions applicable to the stage at which the blood product is received. 10.5.7 Biotechnological products. 10.5.7.1 Facilities and equipment. 10.5.7.1.1 The facilities, equipment and utensils used to manufacture the biopharmaceutical must be dedicated to this type of product. 10.5.7.1.1.1 The manufacture of various biopharmaceuticals in the same facilities and equipment may be made by campaigns and a previous risk assessment. 10.5.7.1.1.2 The classification of the areas of manufacture of biopharmaceuticals may be defined according to the process and after the risk assessment. 10.5.7.1.2 The processes of formulation, filling and conditioning may be carried out at non dedicated facilities and classified according to the Regulatory Appendix A of this Standard, after the risk assessment. 10.5.7.1.3 The cleaning and/or sterilization of accessories and culture fermentation tanks that require it must be done following a validated process. 10.5.7.2 Bioprocess. 10.5.7.2.1 Controls must be established for the following stages of the bioprocess: propagation, fermentation or cell culture, harvesting, purification and inactivation, among others. 10.5.7.2.2 Process controls should take the following into consideration: 10.5.7.2.2.1 Follow-up of the process of cell growth, purity, cell viability and, if applicable, levels of endotoxins and/or pyrogens. 10.5.7.2.2.2 The number of crops in continuous culture must meet established specification. 10.5.7.2.2.3 If applicable, viral safety. 10.5.7.2.2.4 Control of impurities. 10.5.7.2.3 The documentary evidence of the process controls carried out must be a part of the dossier of manufacture. 10.5.7.2.4 There must be a method for detecting contaminants.

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10.5.7.2.5 All contaminants must be identified, investigated, documented, and get their cause(s) and CAPA(s) determined. 10.5.7.2.6 There must be a procedure for the decontamination of the equipment or systems causing the contamination. 10.5.7.3 Cell and/or microbial culture. 10.5.7.3.1 Manipulations made in open containers shall be carried out in a biosafety hood or in controlled environmental conditions. 10.5.7.3.2 Whenever possible, closed or containment systems should be used to allow the aseptic addition of cell substrates, culture media, supplements, buffers and gases. If inoculations of an initial container or subsequent transfers or additions (media, buffers) are performed in open containers, there should be controls and procedures in place to minimize the contamination risks. 10.5.7.3.3 Crop handling should be carried out through containment systems, which, by design, are able to maintain viability, purity and avoid the dispersion. This should be determined according to the corresponding biosafety level. 10.5.7.3.4 Cell viability must be monitored, establishing the controls. 10.5.7.3.5 When continuous culture is used, the quality control requirements that correspond to this type of production method will be especially taken into account. 10.5.7.3.6 When the manufacturing process is not continuous, stability data should be provided to substantiate the conditions and time of storage of the intermediate products stored during the process. 10.5.7.3.7 There need to be a follow up on the critical operating parameters to ensure process consistency established. There must also exist a control of the cell growth, purity, yield, and the renewal of culture medium in the case of continuous cropping. The manufacturing conditions for the preparation of subfragments of antibodies (e.g. Fab, F(ab')2, scFv) and other modifications (for example, radiolabeling, conjugation, chemical bonding) must be in accordance with the validated parameters. 10.5.7.3.8 The culture medium must be sterilized before its use. There must be a procedure that describes the actions taken to detect the possible contamination and the actions to be taken to prevent it. 10.5.7.4 Harvest and purification. 10.5.7.4.1 Processes of harvest, inactivation and/or purification must ensure that the intermediate product or the biopharmaceutical are obtained with consistent quality. 10.5.8 Quality control. 10.5.8.1 The biological reference materials must be traceable to a standard recognized by the World Health Organization or the International Reference Center. 10.5.8.2 When the biological reference materials are not available, appropriately characterized in-house reference materials may be used. 10.5.8.3 The process controls that cannot be carried out on the finished product, like the verification of the absence of viruses, may be carried out at an earlier stage and this must be justified. 10.5.8.4 When it is necessary to keep samples of intermediate products to confirm any quality control test, they shall be kept in appropriate conditions to ensure their integrity. 10.5.8.5 When required, the monitoring of the processes of manufacture as in the case of fermentations, shall be registered and attached to the record of the product. 10.5.9 Cold chain. 10.5.9.1 There must be procedures describing the reception, handling, storage and transport of biological materials, intermediate products, bulk products and finished products, in order to maintain the cold chain. 10.5.9.2 All equipment for storage must be qualified. 10.5.9.3 The cold chain must be validated. 10.5.9.4 There must be a system of continuous temperature monitoring to demonstrate that the cold chain has been maintained and to establish in written all the characteristics of the containers, packaging configuration and responsibilities of those involved in this process. 10.5.9.5 You must set the time that the product can remain outside of cooling with based on stability studies to ensure that is kept within specifications. 10.5.9.6 Temperature excursions should be investigated and the corresponding CAPA should be established.

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10.5.9.7 There must be a system of support and a contingency plan to ensure that in emergency situations the storage conditions required by the product are kept. 10.5.10 Release of the finished product. 10.5.10.1 The release of biological products is subject to what is established on the applicable legal provisions. 10.5.10.2 Biotechnological medicines domestically manufactured must comply with what is stated in paragraph 12 of this Standard. 10.5.10.3 The importation of biotechnological medicines shall comply with point 12 of this Standard, with the exception of the point 12.4, in addition with the following: 10.5.10.3.1 Having the certificate of analysis of manufacturer. 10.5.10.3.2 Having a different analytical certificate to the one of the manufacturer, through the analysis of samples according to the FEUM in force and its supplements or according to the validated analytical methods. 10.5.10.3.2.1 The corresponding analyzes may be made in its quality control laboratory or by an establishment that count with BPF certificate issued by the Secretariat. 10.5.10.3.3 When the manufacturer has a certificate of BPF for the biopharmaceutical and the pharmaceutical products, issued by the Secretariat with scope to the site of analysis of the finished product only the analytical certificate of the manufacturer shall be presented. 10.5.10.3.4 There must be attested that the lot and the sample remained within the appropriate conditions of temperature during transport and that the container closure system was not affected during transportation. 10.6 Medicinal gases. 10.6.1 General. 10.6.1.1 Medicinal gases can be obtained through natural sources or chemical processes, followed by the process of purification and packaging of these. This chapter provides a list of the specific requirements in production, facilities, equipment and services. 10.6.1.2 Medical gases must comply with the provisions of the specific chapter of the FEUM. 10.6.2 Documentation. 10.6.2.1 The traceability of the filling of the medicinal gas containers for each lot must be ensured. 10.6.2.2 There must be a record of each gas lot used to produce the gases in bulk, this record must include at least the following: 10.6.2.2.1 Product name. 10.6.2.2.2 Composition and purity. 10.6.2.2.3 Lot number. 10.6.2.2.4 Reference identification of the tank where the gas is transported. 10.6.2.2.5 Date and time of the filling operation. 10.6.2.2.6 Identification of the person(s) who carry out the tank filling operation. 10.6.2.2.7 Traceability to the tanks used. 10.6.2.2.8 Filling activities. 10.6.2.2.9 Certificate of analysis of finished product that includes the specifications in the FEUM and the results and references of the analytical methods used. 10.6.2.2.10 Cross references to the calibration status of the instruments used. 10.6.2.2.11 Deviations during the process must be documented and investigated before the release of the lot. 10.6.2.3 There must be a register of the filling for each lot of cylinders or thermos (dewar) and it must contain at least the following: 10.6.2.3.1 Product name. 10.6.2.3.2 Composition and purity. 10.6.2.3.3 Lot number. 10.6.2.3.4 Date and time of the filling operation. 10.6.2.3.5 Critical stages and parameters of the filling operation, such as the reception of raw materials, the preparation and cleaning of equipment and filling line, filling indicating the equipment used and who performed each operation.

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10.6.2.3.6 Identification, nominal capacity and serial number of the cylinders or thermos (dewar) before filling. 10.6.2.3.7 Pre-filling activities. 10.6.2.3.8 Process controls for filling. 10.6.2.3.9 A sample of the lot identification label containing product description, container closure, content, production date and expiry date. 10.6.2.3.10 Certificate of analysis of finished product containing the specifications in the FEUM, results and references of the analytical methods used. 10.6.2.3.11 Cross references to the calibration status of the instruments used. 10.6.2.3.12 Number of cylinders or thermos (dewar) rejected and reasons for their rejection. 10.6.2.3.12.1 There must be an inspection report of the cylinders or thermos (dewar) demonstrating that they meet the specifications and requirements established in the FEUM. 10.6.2.3.13 Conciliation of filled cylinders or thermos (dewar), approved or rejected. 10.6.2.3.14 Deviations during the filling process must be documented and investigated before the release of the lot. 10.6.3 Staff. 10.6.3.1 All personnel involved with the manufacture of medicinal gases should receive training on security standards, handling of cylinders subject to pressure, and specific training on the properties of the gas and the type of products involving the staff, including the personnel that does not intervene directly in the production of the medicinal gas, like maintenance, packaging maintenance, quality control and the drivers of the trucks transporting the gas 10.6.3.2 All subcontractors involved in activities that may affect product quality should be trained. 10.6.4 Facilities and equipment. 10.6.4.1 The manufacture of medicinal gases is carried out in a closed circuit, so that their production facilities must be designed in accordance with the requirements of the process, these requirements are not listed in Appendix A (Normative). 10.6.4.2 The areas where the revision, preparation, storage and filling of the cylinders and thermos (dewar) are performed must be independent and specific for the manufacture and/or packaging of medical gases. The shared use of facilities of production of same gases of different grades is possible as long as they meet the same standards of quality and compliance with the BPF and after the risk assessment is made. There must not be a blend of the different grades of product during the filling process. 10.6.4.3 The use of cylinders and thermos (dewar) must be dedicated to the manufacture and/or packaging of medical gases. 10.6.4.4 The facilities must be designed so that there is enough space to carry out manufacturing operations, analysis and storage in order to avoid possible risks of cross contamination. 10.6.4.5 There should be defined areas for the different gases produced and stored. 10.6.4.6 There must be a clear identification, segregation and control system of medical gas containers, including tanks, at the different stages of the process, such as: revision, filling, quarantine, approved, rejected. 10.6.4.7 A control system in the cylinders and thermos (dewar) must be established to identify the different stages of the process. 10.6.4.8 Empty cylinders and thermos (dewar) must be classified, revised, given maintenance in roofed areas, if required, and kept at a level of cleanliness in accordance with the area where they are going to be used. 10.6.4.9 The equipment must be designed so as to avoid the risk of cross contamination between the different gases; the pipes used must prevent connections between the different gases and have anti-return gas flow devices. 10.6.4.10 The connections of multiple heads should be specific for each type of gas, in accordance with what is established in the FEUM. 10.6.4.11 A system for the control and use of adapters of the bypass systems at the various stages of production of medical gases should be established. 10.6.4.12 The tanks must be dedicated to a type of gas and different grade gases may also be transported or stored there as long as they meet the same medicinal gas quality, the BPF and the provisions of the FEUM. 10.6.4.12.1 The storage tanks should be provided with a device to prevent the return of product from the tanks of the client.

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10.6.4.12.2 If the storage tanks of liquefied gases come with a two hoses filling system to balance the pressure between the tank of the client and the storage tank, the first deliveries must be for the medicinal grades and the subsequent deliveries for other applications. 10.6.4.13 There must be common supply systems of gas with multiple heads to deliver medicinal gases and non-medicinal gases in order to prevent cross contamination and return. 10.6.4.14 The use of multiple heads must be dedicated to a single medicinal gas, or mixtures of medicinal gases in different concentrations, the shared use with other grades gases is possible as long as they meet the same standards of quality and compliance with the BPF and after the risk assessment is made. 10.6.4.15 During maintenance, cleaning and purging of equipment, actions must be taken as not to affect the quality of the gases and there must be procedures for these activities. 10.6.4.16 When during the maintenance operation of an equipment, its integrity is broken, this must be documented and actions must be taken to ensure that the equipment returns to operate in closed system conditions. 10.6.4.17 After maintenance, cleaning and purging of the equipment, it must be ensured that it is now free of any contaminants that may affect the quality of the final product. 10.6.4.18 A system must be established to describe the actions to be taken for the control of the storage tanks before filling it again, in order to prevent cross contamination; this must include the analytical controls. 10.6.4.19 The equipment used in the manufacture and/or packaging of medicinal gases such as compressors, filters, heat exchangers, moisture separators, storage tanks, multiple heads, valves, hoses and connections that are in contact with the medicinal gas must be cleaned when the system integrity is broken, using validated techniques. 10.6.4.20 There must be installed measuring devices for the determination of the gas pressure in the filled cylinders. 10.6.4.21 There must be installed vacuum measuring devices so that they can be easily read, and they must be protected against excessive pressurization, and they must return to atmospheric pressure to allow the performance of a review to zero. 10.6.4.22 The revision to zero of the pressure gauges must be done before each use and it must be documented. 10.6.4.23 The temperature measurement of the production lot during the process must be made in the wall of the cylinder with a calibrated instrument. 10.6.5 Production. 10.6.5.1 Control of inputs. 10.6.5.1.1 When using bulk gases for the manufacture or filling of medicinal gases or their mixtures, they must comply with the specifications set in the FEUM for production, as well as those gases extracted from natural sources. When atmospheric air is used as raw material, it must be filtered at the entry point to restrict the admission of solid particles and gas impurities. 10.6.5.1.2 The conservation of retention samples does not apply to inputs used in the manufacture of medicinal gases. 10.6.5.1.3 When a new shipment of gas is received and is transferred into a storage tank containing the same type of input, the mixture generated must be analyzed and it must meet the requirements of the FEUM. 10.6.5.2 Control of production. 10.6.5.2.1 Transfer and delivery of medicinal gas in bulk. 10.6.5.2.1.1 The transfer of medicinal gas in bulk from the primary storage tanks must be validated to avoid cross contamination. Transfer lines must be equipped with valves to prevent the return of the gases. Flexible connections, hoses and connectors must be treated by venting and purging or sweeping. 10.6.5.2.1.2 The hoses and connections used for transferring gases must be specific for each type of gas and must be provided with a protective cap while they are not being used. 10.6.5.2.1.3 When adaptors are used for the connection of storage tanks, these must be dedicated to each type of gas. 10.6.5.2.1.3.1 Medicinal gases in bulk can be stored in the same storage tank of non-medicinal gases as long as the quality of the non-medicinal gas is at least equal to that of the medicinal gases. 10.6.5.2.2 Filling of containers of medicinal gases and labelling of the cylinders and thermos (dewar). 10.6.5.2.2.1 The lot or lots of gas must be determined before the filling and this must be approved prior to its use. The lot number of the gas is defined by the filling operation.

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10.6.5.2.2.2 For the continuous production process controls must be installed in the process to ensure that the gas meets the specifications during the entire filling process. 10.6.5.2.2.3 The containers of medicinal gases, including storage tanks, must be made of materials of characteristics with accordance to the conditions of the Health Registration and these should be dedicated by type of gas or mixture of gases. 10.6.5.2.2.4 To control cylinders and thermos (dewar), a color code in accordance with the provisions of FEUM must be used. 10.6.5.2.2.5 Cylinders, thermos (dewar) and valves should be checked before using them in production and prior to filling to ensure their proper operation and that they do not have visible damage or are contaminated with grease or oils, and in case of not complying with the established, they must be identified, separated and sent to maintenance. 10.6.5.2.2.6 Control or maintenance operations must not affect the production of a medicinal gas or represent a risk to its quality or safety. 10.6.5.2.2.7 The water used for the hydrostatic pressure test applied to cylinders must be at least of potable quality. 10.6.5.2.2.8 Control or maintenance operations of the cylinders should include an internal visual inspection and a drying process before placing the valve, in order to prevent contamination with water or other contaminants. 10.6.5.2.2.9 After the installation of each valve, they must be kept closed to avoid contamination of the cylinder. 10.6.5.2.2.10 There must be an established system to ensure the traceability of the medicinal gas containers, including storage tanks. 10.6.5.2.2.11 Controls must be established prior to filling cylinders: 10.6.5.2.2.12 The cleaning of the cylinders must include validated vacuum and purge methods. 10.6.5.2.2.13 It must be ensured that the labels of previous lots were withdrawn. 10.6.5.2.2.14 It must be verified that the coupling connection of the cylinders or thermos (dewar) corresponds to the type of gas filling them, in accordance with the FEUM. 10.6.5.2.2.15 It must be verified that the valves used are inspected prior and during the filling, and this activity must be registered. 10.6.5.2.2.16 It must be verified that the cylinders are within the period of validity of their periodic revision and that they comply with what is established in the FEUM. 10.6.5.2.2.17 It must be verified that the color code of the cylinder corresponds to the one specified for the gas filling it. 10.6.5.2.2.18 A sweep or purge of the line should be done before the filling process. 10.6.5.2.2.19 There must be an implemented system to prevent risks of cross contamination in the empty cylinders set for a new filling. This system must be validated. 10.6.5.2.2.20 There must be established controls of the process to ensure the correct filling of the cylinders or cryogenic containers. 10.6.5.2.2.21 A leak test must be conducted, by a validated method, to each filled cylinder and thermo (dewar) before placing a seal of guarantee on them. 10.6.5.2.2.22 The outputs of the valves of the cylinders and thermos (dewar) must be protected and must be provided with a seal of guarantee. 10.6.5.2.2.23 Each cylinder and cryogenic container must be labelled. The lot number and expiration date may be added on a separate label. 10.6.5.2.2.24 The process of mixing a medicinal gas produced by the composition of two or more gases, whether it be in line, must be validated before the filling or directly inside the cylinders. 10.6.5.2.2.24.1 When mixture filling is done individually, each cylinder must be analyzed. 10.6.5.2.2.25 There must be design specifications of the labels of the medicinal gases. Labels must be issued by authorized personnel. 10.6.5.2.2.26 The manufacturer/packager of the medical gases, must ensure the contents of the cylinders when the latter are owned by the customer. 10.6.6 Distribution. 10.6.6.1 It is permissible to transport medical gases in the same units of distribution of cylinders or thermos (dewar) of industrial gases, as long as they are properly identified.

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10.6.6.2 Gas cylinders or thermos (dewar) must be protected during transportation, so that they are delivered to customers in a clean condition consistent with the environment in which they will be used. 10.6.6.3 There must be a system established for the management of devolutions including the reception, inspection, analysis, if applicable, and opinion for final disposal. 10.6.7 Quality control. 10.6.7.1 Each lot of medicinal gas must be analyzed according to the FEUM or the validated methods of the manufacturer. 10.6.7.2 Each lot of medicinal gas must be sampled and analyzed under the following criteria: 10.6.7.2.1 At the start of the production lot, after the maintenance and during the arrival of different lots of raw material. 10.6.7.2.2 By each pumping, gasification and compression system. 10.6.7.2.3 When a mixture of gases is filled individually, its identity must be analyzed and each gas in each cylinder must be tested, if the mixture contains excipients the identity of at least one cylinder per cycle of filling must be analyzed. 10.6.7.2.4 When a mixture of gases is filled simultaneously, the same tests as indicated in points 10.6.7.2.1 or 10.6.7.2.2 of this Standard must be performed. 10.6.7.3 Identity tests and identification assays must be done to every storage tank of bulk gases. 10.6.7.4 It is not necessary to keep retention samples from each lot of medicinal gas. 10.7 Aerosol medications. 10.7.1 General The manufacture of drug products in pressurized aerosols for inhalation with metering valves requires some additional provisions due to the particular nature of this pharmaceutical form. 10.7.1.1 There are two common manufacturing and filling methods: 10.7.1.1.1 Two-phase system (pressure filling). It involves making a suspension of the active substance in a propellant of high boiling point, introducing the dose into the container, adjusting the valve and injecting the propellant of a lower boiling point through the stem of the valve to complete the finished product. The suspension of the active principle in the propellant is kept cold to reduce evaporation losses. 10.7.1.1.2 One phase process (cold filling). The active ingredient is suspended in a propellant mixture and maintained at high pressure and/or low temperature. Subsequently the container is filled directly with the suspension in one single step. 10.7.2 Facilities and equipment 10.7.2.1 The manufacture must be done under conditions that reduce microbial and particle contamination, according to the Regulatory Appendix A of this Standard. 10.7.2.2 When possible, manufacturing and filling must be carried out in a closed system. 10.7.2.3 The areas destined to the filling of aerosols must have all the risk prevention systems for the handling of propellants. 10.7.3 Production and quality control 10.7.3.1 The metering valves of aerosols are more complex engineering devices than most pharmaceutical components, so for the specifications, sampling and testing, this should be taken into account. 10.7.3.1.1 An audit of the quality assurance system must be made to the manufacturer of the valve. 10.7.3.2 All liquid or gaseous propellants must be filtered to remove particles of a size greater than 0.2 . 10.7.3.3 Containers and valves must be cleaned using a validated procedure adapted to the use of the product, in order to ensure the absence of any contaminates, such as adjuvants of the manufacturing process (like lubricants). 10.7.3.3.1 After cleaning, the valves will be kept in closed, clean containers, taking care not to introduce contaminants during the following stages. The containers will be sent to the fill line in clean conditions, or will be cleaned in the line immediately before the filling. 10.7.3.4 The uniformity of the suspensions at the filling point must be ensured throughout the entire process. 10.7.3.5 When a two phases filling process is used, it must be ensures that both phases have the correct weight to achieve an adequate composition. It is therefore necessary to check the 100% of the weight in each stage. 10.7.3.6 Controls after filling should ensure the absence of leaks.

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10.7.3.6.1 All leak tests will be carried out in such a way as to avoid microbial contamination or residual moisture. 10.8 Homeopathic medicines 10.8.1 General 10.8.1.1 The manufacture of homeopathic medicines requires some additional provisions due to the particular nature of these drug products. 10.8.1.2 Homeopathic medicines are substances or mixtures of substances of natural or synthetic origin. 10.8.1.3 Inputs and active ingredients used for homeopathic medicinal products must be analyzed according to what is established in the FEUM and the FHOEUM. 10.8.2 Documentation. 10.8.2.1 The starting points must be mother tinctures and approved triturations and dilutions in accordance with the established in the FHOEUM. 10.8.2.2 The traceability of each lot must be ensured, according to the lot of mother tincture and the corresponding dilution or trituration. 10.8.2.3 There must be a record of manufacture of each dilution or trituration, for the presentations of the homeopathic medicines. 10.8.3 Staff. 10.8.3.1 The personnel associated with the production of homeopathic medicines should receive training in the management of dilutions and triturations. 10.8.4 Production 10.8.4.1 Homeopathic medicines are prepared by dynamization, which is the specific procedure of homeopathy that is used for the preparation of active ingredients from tinctures, aqueous solutions or triturations. 10.8.4.2 The preparation of dynamizations must follow the rules established in the FHOEUM. 10.8.4.3 Trituration consists of the dynamization of an active ingredient with lactose or other solid carrier so that it can be compressed or encapsulated. 10.8.4.4 Solid homeopathic medicines. They are prepared by impregnating inert carriers and/or triturations. For the impregnation of inert vehicles various pharmaceutical forms are used, such as: globules, pills, granulated powders, medicinal soaps and tablets which, through dynamized solutions, were added with the active principle. 10.8.4.5 Liquid homeopathic medicines are prepared through the dynamization of active principles in aqueous, alcoholic or oily solutions for pharmaceutical forms, such as elixir, syrup, lotion, liniment or homeopathic solution. 10.8.4.6 Semisolid homeopathic medicines are prepared by mixing the active ingredient with the corresponding vehicle for pharmaceutical forms, such as ointments, suppositories, gels and creams. 10.8.4.7 For the preparation of sterile homeopathic medicinal products what is indicated in point 10.4 of sterile products in this Standard and the provisions established in the FEUM must be met. 10.8.5 Facilities and equipment. 10.8.5.1 Areas and manufacturing equipment must be used solely for Homeopathic medicines. 10.8.5.2 In the case of the preparation of tinctures, from the reception, processing and storage of the plant, there must be segregated areas and associated documentation to comply with the traceability and the BPF. 10.8.6 Impact of validation. For homeopathic medicines there must be a determination of the impact of the elements of manufacture in the quality of the product, using risk assessment as a tool to establish the scope of the qualification and the validation. 10.9 Medicines for use in clinical studies 10.9.1 General. 10.9.1.1 The manufacture of investigational drug products for use in clinical studies shows greater complexity than the marketed products due to the lack of systematic procedures, to the variety of the clinical trial designs and, consequently, of the conditioning (randomization and masking needed). This is due to several factors linked with the compliance systems typically characterized by the commercial scale production, repeatable and validatable, which in the case of investigational medicinal products is limited. 10.9.1.2 The sponsor must ensure that the reference medicinal products or placebos are contained in the notification/request for authorization to carry out the clinical study and that they are of the appropriate quality

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for the purposes of the clinical study, considering the origin of the materials, whether they have marketing authorization and whether they have been re-conditioned. 10.9.1.3 Drug products for use in research in Mexico must be released in accordance with the Good Clinical Practices and the procedures established by the sponsor. 10.9.2 Documentation. 10.9.2.1 Within the established Quality Management System there must be considered policies and guidelines that apply to medicinal products for use in clinical studies, in order to apply them to the basic principles of BPF and distribution. This system must be described in the clinical protocol or as part of the product monograph for the Researcher. 10.9.2.2 There must be established specifications for inputs and product and instructions and production order, however, they may change during the development of the product so it must be ensured that these changes are documented and are available in the history of the product. 10.9.2.2.1 There must be clear instructions for each stage of manufacture. 10.9.2.2.2 There must be a product file and it must remain updated, ensuring the traceability of previous records. 10.9.2.2.3 The product file must include specifications, reference to the analytical methods used, instructions for production and packaging, control in process, approved labels, reference to the protocols authorized for the clinical trial, technical agreements of the contracted services, results of stability, conditions of storage and distribution records. 10.9.2.2.4 The study sponsor is responsible for storing the file with information related to the manufacture and control of the investigational drug product for at least 5 years after product registration is granted. 10.9.2.2.5 The safeguard of the documentation related to the manufacture and control of the investigational medicinal product may be done in the facilities of the sponsor or in facilities specifically contracted for this purpose. 10.9.3 Staff. 10.9.3.1 There must be a responsible for production and a responsible for quality and they must not be dependent of the other. 10.9.3.2 The staff involved in the production and control of investigational medicinal products must have the necessary experience to handle the drug product undergoing the clinical research and be familiar with the principles of the BPF. 10.9.4 Facilities and equipment. 10.9.4.1 When using the same facilities and equipment for the manufacture of commercial lots, there must be a cleaning validation that includes the product in research. 10.9.4.1.1 The manufacture of high-risk products in research will be subject to the conditions authorized in the sanitary license. 10.9.4.2 When there are facilities and equipment dedicated to manufacture investigational products, measures must be taken to prevent cross contamination according to the level of risk of the product in research and the safety of staff teams; manufacturing campaigns may be used when working with several products in the same facilities and equipment. 10.9.4.2.1 The equipment and instruments must be included in the programs of maintenance, calibration and qualification. 10.9.4.2.2 Manufacturing areas must be classified according to what is described in the Regulatory Appendix A of this Standard. 10.9.5 Quality control. 10.9.5.1 As the manufacturing process may not be validated, quality control is important to ensure that each lot of investigational product meets the specifications. 10.9.5.2 There must be establishes responsibilities of quality control for assessing the inputs used in the manufacture of a medicinal product in the research phase, to ensure they are appropriate and comply with the expected quality characteristics. 10.9.5.2.1 There may be a specific Quality Unit for investigational products. 10.9.5.3 There must be retention samples of investigational products manufactured in quantities that may be checked for identity and quality.

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10.9.5.3.1 These samples must be stored in conditions that ensure their integrity for at least two years after clinical study in which it was used has concluded or up to the expiration date of the investigational medicinal product. 10.9.6 Release of investigational products. 10.9.6.1 There must be a system for the release of each lot of investigational medicinal product. The system of release may be based and not be limited to the revision of the manufacture files, process controls, quality control testing, deviations and noncompliance’s. In the case of reference medicinal products or placebos, the release for their use in clinical studies must also be considered and documented. 10.9.6.2 The opinion of release must be supported by a qualified person. 10.9.6.3 The out of specifications results and deviations or nonconformities during manufacture must be investigated. 10.9.7 Stability. 10.9.7.1 If there are no previous stability studies, stability studies must be carried out with representative samples in the phase of the investigational medicinal product, to monitor its quality during the clinical trial and to protect its useful life from the date of manufacture to the date of the last administration. 10.9.8 Packaging, labeling and distribution. 10.9.8.1 Investigational medicinal products should be packaged to protect them from alterations, contamination and damage during storage and shipping. 10.9.8.2 There must be procedures or instructions for the control of the packaging, labelling and distribution operations. 10.9.8.3 The packaging of products for blind clinical studies must ensure that the conciliation of products and inputs is performed at 100% 10.9.8.4 The labelling of medicinal products for clinical use must be subject to the applicable legal provisions. 10.9.8.5 The minimum information that must be contained the label of the investigational medicinal product is: 10.9.8.5.1 Name, address and telephone number of the sponsor or to the main contact. 10.9.8.5.2 Pharmaceutical form and route of administration. 10.9.8.5.3 Lot number. 10.9.8.5.4 The legend "exclusively for clinical studies." 10.9.8.5.5 Expiration date. 10.9.9 Product withdrawal. 10.9.9.1 There must be a procedure for the withdrawal of the investigational product for clinical use, describing the responsibilities of all members from the supply chain up to the team researching the product; this must include the manufacturer, the sponsor, the investigator, the clinical monitor and the head of the research unit. 10.9.9.1.1 The manufacturer and the sponsor must ensure that all the staff involved is trained in this procedure. 10.10 Compatibility of operations. 10.10.1 The authorization from the Secretariat of shared use of the facilities and equipment for the manufacture of medical devices must be requested following the requirements set out in this Standard. 10.10.2 For the shared use of the facilities and equipment for the manufacture of products classified under other operations, the Secretariat will evaluate on a case-by-case basis, at request. 11. Quality Control Lab 11.1 General The activities of Quality Control comprises the organization, documentation, and procedures, to ensure that tests are performed in compliance with the GLPs, according to the methods and current specifications, so that inputs and products cannot be released for use or sale until their quality is assessed. 11.2 Every holder of a Sanitary Registry must have an independent quality control laboratory and under the authority of a qualified person, with an academic formation and the required experience. 11.3 The areas of control lab must meet the requirements set out in section 8.2.4 of this Norm.

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11.4 Personnel, areas and equipment used in control lab must be qualified. 11.5 There must be procedures for cleaning, maintenance and operation of areas, measuring instruments and lab equipment with the corresponding registries. 11.6 There must be a program for calibration of measuring instruments used in the lab. 11.7 Analytical methods should be validated and, if there are changes in methodology, a new validation must be performed. 11.8 There must be specifications, sampling procedures, test procedures and registries, analytical certificates and, when applicable, registries of environmental monitoring. 11.9 The documentation in the lab must meet with that established n clause 5.2 of this Norm. 11.10 Containers for samples must have an identification indicating, at least: name, lot number, sampling date, storing conditions and the container from which the sample was withdrawn. 11.11 Retention samples from each lot of finished product should be preserved at least for one year after the expiry date of the drug product in its final package and stored under conditions shown in label. 11.12 Retention samples of raw materials should be preserved at least one year after the expiry date of the last lot of product where they were used and stored under the conditions shown in label. 11.12.1 Samples from solvents, gases and water, used in drug product manufacture should not be retained. 11.12.2 The retention samples from gases used in the manufacture of drug products and which are not part of the finished product may not be retained, provided they have the manufacturer or gas supplier qualification. 11.12.3 The retention samples of primary packaging material and those contributing to the product integrity must be preserved the same time than the expiry date of the last lot of product where it was used. 11.13 Retention samples from intermediate product or bulk product must be retained when some manufacturing step is carried on a facility distinct from the manufacturing site of the drug product. 11.14 When the site for primary or secondary packaging stated in sanitary registry is different from the manufacturing site of the drug product, the packaging sites must preserve retention samples of the materials used, according to that indicated in this Norm. 11.15 The registries of the tests results should include at least the following: 11.15.1 Name of product, presentation, and if applicable, the concentration 11.15.2 Lot number 11.15.3 Name of the manufacturer or supplier 11.15.4 References to specifications and analytical methods 11.15.5 Results of tests, including observations, calculation, printed output from equipment 11.15.6 When tests are carried on by an authorized external laboratory, the reference of the analysis certificate 11.15.7 Date when tests were performed. 11.15.8 The initials or name of persons that supervise the tests. 11.16 There must be procedures describing the handling and storing of reagents, solutions, strains and culture media used in the lab. 11.17 Reagent solutions and culture media should be prepared according the FEUM and current supplements. 11.18 Expiry date of reagents and culture media should be indicated in the label along with storing conditions. For volumetric solutions, the date of titration, real concentration and the initials of whom prepared must be indicated. 11.19 Primary and secondary reference substances must be dated, stored, handled and used without affecting their quality. At least, origin, lot and identification should be registered. 11.20 When animals for lab tests are used for the analysis of raw materials or products, these should be supplied by qualified providers and placed in quarantine before using.

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11.20.1 The animals should be maintained and controlled so that their suitability for the intended use is ensured. 11.20.2 The animals should be identified since their entry and preserve the registries since the reception, history of use and final disposition. 11.21 All tests of in-process control should be performed according to the methods approved by the Quality Unit. 11.21.1 All tests of in-process control must be performed in the manufacturing site. 11.22 There must exist a procedure indicating the actions to be followed in the case of OOSs results. 11.22.1 A sample analysis should not be repeated when some of the results is out of specification and they cannot be averaged when any of them is out of specifications. 11.22.2 The procedure for analytical results out of specifications must involve at least the following: 11.22.2.1 The verification that the results to discard analytical errors is clearly identified; this investigation must be documented and reported. 11.22.2.2 If an analytical error is discarded, it must be justified as part of the investigation. 11.22.2.2.1 An investigation should be started involving all areas related to the manufacture of product, and establishing a plan of tests considering re-sampling or re-analysis of samples to confirm the result. 11.22.2.3 The evaluation and interpretation of results obtained should be established, taking into account all findings in investigation, re-analysis or re-sampling to determine the acceptance or rejection of the lot being investigated. 11.22.3 Investigations and conclusions of the analytical results out of specification must be approved by the Sanitary Responsible. 11.23 The use of outsourced labs for quality control must meet the clause 14 of this Norm and may be accepted due to special causes, but must be reflected on the registries of quality control. 11.24 The sampling must be performed and registered according with written and approved procedures describing: 11.24.1 Sampling method; 11.24.2 Equipment to be used; 11.24.3 The amount of sample to be taken; 11.24.4 Instructions for the possible subdivision of sample; 11.24.5 Type and conditions of the package that must be used for the sample; 11.24.6 Identification of sampled packages; 11.24.7 Any special precaution to be considered, mainly related with sampling of sterile or noxious materials; 11.24.8 Storing conditions; 11.24.9 Instructions of cleaning and storing of sampling equipment. 11.25 With a previous authorization from the Secretariat, the holder of a Sanitary Registry may perform the reduction in frequency and/or in analytical tests for imported finished products; the analysis referred in this clause is that performed in the country; frequency and analytical tests cannot be reduced in the analysis performed by the manufacturer. 11.25.1 For imported finished product, the holder of the Sanitary Registry must submit to the Secretariat the following information: 11.25.1.1 The RAP of the last three years previous to the application. 11.25.1.1.1 That major changes in manufacturing of drug and drug product do not exist. 11.25.1.1.2 That the manufacturing site of the drug and drug product correspond with the history of the last three years. 11.25.1.2 A copy of the current official communication of Sanitary Registry of the imported drug product.

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11.25.1.3 Current Certificate of Good Manufacturing Practices issued for the product manufacturer through the COFEPRIS or some of the regulatory entities recognized by the COFEPRIS. 11.25.1.4 Qualification report of the drug manufacturer. 11.25.1.5 Assessment of the risk containing the technical and scientific justification supporting the application of frequency and analytical tests to be reduced. 11.25.1.6 Statistical study performed between the results obtained by the manufacturer and those obtained in Mexico, with a minimum of 20 lots commercialized in Mexico, to demonstrate that there is not any significant difference. The corresponding certificates of Analysis supporting the lots of the study must be included. 11.26 With a previous authorization from the Secretariat, the holder of a Sanitary Registry may perform the reduction in frequency and/or in analytical tests for drugs. 11.26.1 For the analytical reduction of a drug, the holder of the Sanitary Registry of the medicinal product manufactured with the drug should submit to the Secretariat the following: 11.26.1.1 A copy of the current official communication of Sanitary Registry of the drug product manufactured with the drug substance. 11.26.1.2 Certificate of current Good Manufacturing Practices from the manufacturing site of the applicant. 11.26.1.3 Certificate of current Good Manufacturing Practices issued to the manufacturer of the drug through the COFEPRIS or some of the regulatory entities recognized by COFEPRIS 11.26.1.4 Qualification report from the manufacturer and from the supplier(s) involved in supply chain. 11.26.1.5 Risk assessment containing the technical and scientific justification supporting the application of frequency and analytical tests to be reduced. 11.26.1.6 Statistical study performed between the results obtained by the manufacturer and those obtained in Mexico, with a minimum of 20 lots of the drug used in drug product manufacturing, to demonstrate that there is not any significant difference. The corresponding certificates of Analysis supporting the lots of the study must be included. 11.27 With a previous authorization from the Secretariat, the holder of a Sanitary Registry may perform the reduction in frequency and/or in analytical tests for additives. 11.27.1 For the analytical reduction of an additive, the holder of the Sanitary Registry of the medicinal product manufactured with the drug should submit to the Secretariat the following: 11.27.1.1 A copy of the current official communication of Sanitary Registry of the drug product manufactured with the additive. 11.27.1.2 Certificate of current Good Manufacturing Practices from the manufacturing site of the applicant. 11.27.1.3 Qualification report from the manufacturer and from the supplier(s) involved in supply chain. 11.27.1.4 Risk assessment containing the technical and scientific justification supporting the application of frequency and analytical tests to be reduced. 11.27.1.5 Statistical study performed between the results obtained by the manufacturer and those obtained in Mexico, with a minimum of 20 lots of the additive used in drug product manufacturing, to demonstrate that there is not any significant difference. The corresponding Certificates of Analysis supporting the lots of the study must be included. 11.28 The use of fast microbiological methods may be approved with a previous authorization of the Secretariat, for which must be presented the validation of the method and a comparative assessment between the fast microbiological method proposed and the microbiological method described in FEUM. 11.29 Transfer of analytical methods 11.29.1 Before transfer of an analytical method, the laboratory who transfers must verify that analytical methods comply with that reported in the corresponding technical dossier. It should be performed the original validation of the method to ensure the compliance of requirements for the transference. 11.29.2 Any modification to the original validation should be documented and assessed before start with the transfer process.

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11.29.3 Types of transfer for analytical methods, being some of them: 11.29.3.1 From the analytical development unit to the quality control lab. 11.29.3.2 From the development unit or from the quality control lab in a facility abroad to the affiliate in Mexico or to an authorized third party. 11.29.3.3 From a registry holder to a third party. 11.29.4 For an analytical transfer the following must be taken into account: 11.29.4.1 The reception unit must have facilities, equipment, instruments and personnel qualified for the methods to be transferred. 11.29.4.2 There must be protocols and analytical methodology of the methods to be transferred. 11.29.4.3 The transfer protocol must include, at least: 11.29.4.3.1 A description of the assay to be performed and the relevant analytical methods transferred; 11.29.4.3.2 Identification of any additional requirement; 11.29.4.3.3 Identification of reference standards and the samples to be analyzed; 11.29.4.3.4 Description and identification of any special condition of transport and preservation of products, standards and reagents to be used; 11.29.4.3.5 The acceptance criteria based on the current validation study of the methodology and regulatory requirements. 12. Release of finished product 12.1 The Person Authorized by the Sanitary Responsible and who determine the release of each batch, must have the academic formation, the knowledge and the experience according to the Sanitary Responsible profile. 12.1.1 The release of imported medication under de scheme of ‘without plant requirement’ must be performed by the Sanitary Responsible designated by the holder of the Sanitary Registry abroad or by its legal representative. 12.2 There must be a procedure to describe the integration process and review of the file of the lot and product release. 12.2.1 The production and packaging procedures, the registries, the analytical results, the labels and other documentation inherent to process, must be reviewed by checking that they comply with the established specification of the process. Only the Quality Unit may approve or reject the product. 12.3 Besides the lot file the following must be considered: 12.3.1 The Change Control System to check that there are not open changes which may impact the lot to be released. 12.3.2 The results of the program for environmental monitoring, to check that there is not impact for the lot to be released. In the case of products manufactured aseptically, the results of the environmental monitoring should be attached in order to check that there is not an impact for the lot to be released. 12.3.3 That the corresponding retention samples were taken. 12.3.4 Any other document or official communication related with the quality of product, including deviations or non-conformity reports. 12.4 For imported products, the analytical control by the importer must be performed following the same releasing procedure described in this Norm. 12.4.1 For product of cold chain there must be evidence of temperature monitoring during the move since the site of origin to the establishment. Excursions should be investigated and evaluated. For lot release, it is necessary to check that the cold chain complies with the acceptance criteria. 12.5 For the case of release finished product of orphan medications, the Sanitary Responsible must integrate a release file, containing, as minimum the following documents: 12.5.1 Certificate of Analysis of the lot to be released issued by the manufacturer and/or by the analytical lab authorized by the sanitary authority in the country of origin. It must be ensured that the approved specifications are met.

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12.5.2 A copy of the primary and secondary packaging material, in order to review and ensure the correspondence with the authorized labels. 12.5.3 In the case of imported medicines, it is necessary the documentation to endorse the correct custom release. 12.6 Parametric release The parametric release only applies to the process of terminal sterilization by wet heat. The parametric release is possible when the sterilization process is deeply understood; when physical parameters of the process are well defined, are predictable, measurable and there is evidence which demonstrates that the process is validated and is under control. 12.6.1 The product release may be performed without the sterility test if there is a previous authorization of the Secretariat. 12.6.2 To request the authorization of parametric release, the following information must be submitted: 12.6.2.1 Evidence that in the manufacturing site and where the sterilization process is performed exist the qualified personnel to perform the supervision of these activities to ensure the sterility of product. 12.6.2.1.1 There must be at least one person qualified in the production area to supervise the sterilization process and another qualified person to supervise the process of parametric release. Personnel must be qualified for terminal sterilization processes and microbiological techniques. 12.6.2.2 The establishment must have a history of compliance in Good Manufacturing Practices and a current certificate issued by COFEPRIS. 12.6.2.3 There must be in place the validation of the sterilization process demonstrating a Sterility Assurance Level (NAE) 1 x 10-6 and that complies with that established on FEUM. 12.6.2.4 There must exist the validation of the container-closure system, in order to ensure the integrity and sterility of the product. 12.6.2.5 There must be a history record of data, including as a minimum data from critical parameters and satisfactory results of the sterility test, obtained at least in 20 lots of the product, as an evidence that the program of sterility assurance is under control. 12.6.2.6 To have a history of commercialization of 3 years at least. 12.6.2.7 Submit the Reports of Product Annual Review of the last 3 years. 12.6.2.8 Implementation of the use of indicators per load. 12.6.2.8.1 The location of indicators must comply with the information obtained with the equipment qualification and validation of the sterilization process. 12.6.2.8.2 Using of indicators of temperature, biological, or chemical must be justified and duly documented. 12.6.2.9 To demonstrate that the performance of the Quality Management System is efficient. 12.6.3 For product release, a review must be conducted of the approval criteria for this kind of release, which must include the following, among others: 12.6.3.1 Review of load patterns used in sterilization and which are in accordance with the validated condition. 12.6.3.2 Review of use and review of indicators used per load. 12.6.3.3 Review of the consistency of the execution of sterilization cycle within the validated limits. 12.6.3.4 Review of the control system implemented in order to verify that the load was exposed to the sterilization process. 12.6.3.5 Review of the results of microbiological monitoring of product, components and environmental air. 12.6.3.6 Review of the closure-container system. 12.6.3.7 Review of the monitoring and control methods. 12.6.3.8 Review of the manufacturing processes. 12.6.3.9 Review of the entire manufacturing file, according to clause 12.2 of this Norm.

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12.6.3.10 The following additional elements must be confirmed before the release of each lot of product: 12.6.3.10.1 All maintenance operations and routine controls scheduled for the sterilizer. 12.6.3.10.2 All measuring instruments of the sterilizer are calibrated. 12.6.3.11 In the case that a critical parameter of the process does not comply, then the sterility test will not be used as an alternate test for the release of the lot. 12.6.3.12 When the lot fails to comply with some of the acceptance criteria, it will be rejected. 12.6.4 It must be implemented a system for the assessment of parametric release program which allows to document and maintain the state of control of the sterility program, including the following, at least: 12.6.4.1 The system of change control should require the review of all changes proposed by means of the personnel of Quality Assurance involved in the process of parametric release. 12.6.4.2 Must effect the review of compliance of the programs and procedures of maintenance and calibration 12.6.4.3 Follow-up of deviations, investigation reports and the implementation of corrective and preventive actions 12.6.4.4 Compliance of the periodic qualification of sterilizers and according to acceptance criteria established initially. 12.6.5 An annual report must be issued for released lots under this system, including the data obtained and an assessment of trends observed during such period. This report must be sent to the Secretariat. 12.6.5.1 When a lot of product is rejected, it must be notified to the Secretariat. 13 Recalls 13.1 There must exist a system to withdraw the product from the market in a timely and effective manner in the case of health warnings, for products that are known or suspected of out of specifications and/or loss of efficacy and safety. 13.2 The holder of the Sanitary Registry, through the Sanitary Responsible or Legal Representative must notify to the Secretariat by means of COFEPRIS about the decision of any recall of product, indicating at least: 13.2.1 Name of product. 13.2.2 Product manufacturer 13.2.3 Lot(s) involved 13.2.4 The reason for the recall, indicating if the product may be hazardous for health and/or considered as a threat for life. 13.2.5 Amount and date of manufacture, amount of product expected from the recall in the market considering the times for the distribution and sale. 13.2.6 Extension of the recall. Listing of customers (making the differentiation for public sector). 13.2.7 Location for gathering. 13.2.8 Name, contact telephone of the responsible or whom coordinates the recall 13.3 There must exist a procedure describing: 13.3.1 Name of the responsible for the execution and coordination of the recall. 13.3.2 The activities of the recall, which allow to be initiated as soon as possible at all levels. 13.3.3 The instructions for consumers or customers as well as the confinement activities for recalled product. 13.3.4 Authorities which must be notified according to product distribution. 13.3.5 The review of distribution registries of product for sale, medical samples or for clinical studies which allow an effective recall of the product. 13.3.6 The continuous evaluation of the recall process. 13.3.7 A final report including a conciliation between the amount distributed and the amount recovered, the actions to be taken to avoid the recurrence, and the product destruction.

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13.4 The effectiveness of the recall process from the market must be assessed annually by simulacrum or in the cases where this have occurred. 14. Outsourced activities Principles Any activity included in this Norm that is outsourced, must be defined, agreed and controlled to avoid ambiguities that may result in a product or operation with an inadequate quality. It must be formalized in a written contract between the contracting party and the contracted agent establishing clearly which the responsibilities of each party. The Quality Management System of the contracting agent must reflect clearly the way in that the Sanitary Responsible or person who authorizes the release of each lot of product, considers the outsourced activities in his/her responsibility. 14.1 Generals 14.1.1 A written contract will be formalized considering the outsourced activities, the products or operations related and any technical agreement related with these. 14.1.2 All agreements for outsourced activities, including any modification of technical type or other agreements proposed should be in line with current legal dispositions and with the conditions authorized in the Sanitary Registry of the product, when applicable. 14.1.3 When the holder of the Sanitary Registry and the manufacturer are not the same, there must be agreements considering the principles described in this chapter. 14.2 Contractor agent 14.2.1 The quality management system of the contractor must include the control and review of any activity outsourced. The contractor agent is the last responsible to warrant that there are established processes to ensure the control of outsourced activities. These processes must incorporate the principles of risk management and particularly include: 14.2.1.1 Previously to the outsourced activities, the contractor is responsible to evaluate the legality, suitability and competence of the outsourced to carry on with success the outsourced activities. The contractor is also responsible to ensure by means of the contract that principles and directives of this Norm are followed. 14.2.1.2 The contractor must provide to the contracted all the information and knowledge needed to perform properly the contracted operations according with legal dispositions applicable and with the conditions authorized in the Sanitary Registry of the product involved. 14.2.1.3 The contractor must control and review the performance of the contracted and the identification, implementation, and control of any improvement effected. 14.2.1.4 The contractor must be responsible of the review and assessment of registries and of the results related with the outsourced activities. 14.3 Contracted agent 14.3.1 The contracted agent must be capable to perform satisfactorily the work delivered by the contractor, having for this the adequate facilities, equipment, knowledge experience, and competent personnel. 14.3.2 The contracted must ensure that all products, materials and knowledge that are delivered to him are the adequate for the intended end. 14.3.3 The contracted should not contract to a third for no part of the work that has been entrusted to him with respect to the contract, unless that the contractor have assessed and approved it in advance. The agreements between the contracted and any third must warrant that the information and knowledge, including that of the evaluation of suitability of the third are available in the same way than between the original contractor and the contracted. 14.3.4 The contracted should not make changes without authorization, outside of the terms of the contract, which might affect in a negative manner the quality of the activities subcontracted by the contractor. 14.3.5 The contracted must understand that the activities subcontracted, including the review of the contract, may be subjected to inspection from the regulatory authorities.

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14.4 Contract 14.4.1 A contract must be drafted between the contractor and the contracted where their respective responsibilities and communication forms are specified with respect to the activities subcontracted. The technical aspects of the contract should be prepared by competent persons with an adequate knowledge with respect with subcontracted activities, it must be conform to current legislation and the conditions authorized in the Sanitary Registry of the product involved and receive the approval of both parties, of Legal representative and of the Sanitary Responsible. 14.4.2 The contract must describe clearly who assumes responsibility of each step of the subcontracted activity, such as: knowledge management, technological transfer, supply chain, subcontracting, quality and acquisition of materials, analysis and release of materials, responsibility of the production and quality controls (including in-process controls, sampling and analysis). 14.4.3 The contractor must keep or have available all registries related with the subcontracted activities, such as: production registries, analysis and distribution, as well as reference samples. Any important data to assess the quality of a product in the case of complaints or suspicion of some defect, or to investigate in the case of suspicion of counterfeit products must be available and specified in the corresponding procedures of the contractor. 14.4.4 The contract must allow the contractor to audit the activities subcontracted by the contracted or by subcontracted in a mutual agreement. 14.5 Subcontracted services 14.5.1 All contractors for third party services of drug products manufacturing processes, analysis lab services, critical systems and equipment services which impact the quality of the product, must be assessed and qualified as suppliers. 14.5.2 There must be a procedure describing the criteria to evaluate the contractors before they be approved. 14.5.3 The contractor should not subcontract services for maquila of manufacturing processes of drug products or services of lab analysis. 14.6 Maquila (third parties) 14.6.1 Third parties for drug products manufacturing practices are required to have a current Certificate of Good Manufacturing Practices, to comply with the Norm and with other legal dispositions applicable, document that will be annexed to the notification of maquila to be presented before COFEPRIS. 14.6.2 The holder of the Sanitary Registry must ensure the technology transfer to the contractor, being this annexed to the notification of maquila to be presented to COFEPRIS. If dosage form so requires, and the subcontracted activities are justified, the dissolution profile of the registered product compared with the profile of the product manufactured in the facilities of contractor should be also annexed. 14.6.3 The stages to be maquiled must be validated at the facilities of the third party. 14.6.4 The quality of the product will be the responsibility of the holder of Sanitary Registry. 14.6.5 The registry holder must monitor the manufacturing of his product and to audit the maquila contractor operations in compliance of this Norm and other legal dispositions applicable. 14.6.6 The maquila contractor must deliver the manufactured product approved by the registry holder together with the original documentation of manufactured stages, including registries of in-process controls. The maquila contractor must keep a copy of this documentation for the time specified in this Mexican Official Norm. 14.6.7 It is the responsibility of the holder of Sanitary Registry to perform the entire analysis to release the product. 14.6.8 The holder of Sanitary Registry must ensure that product to be manufactured by maquila will bw manufactured under the same conditions of the Sanitary Registry. 14.6.9 For biological and biotechnological drug products the steps of manufacture of the biodrug, antigens, monovalent bulks or any previous stage to the formulation and filling cannot be performed by maquila. 14.7 Services of analysis lab 14.7.1 The holder of Sanitary Registry must ensure the technology transfer to the contracted lab. 14.7.2 There must be established a system for transferring samples to ensure the integrity of the same.

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14.8 Services to critical systems and equipment. 14.8.1 The academic formation, technical training and experience of personnel who offer this kind of services must be assessed. 15. Final destination of residues 15.1 There must be a system, documented in a procedure, which ensures the compliance of applicable legal dispositions in ecological and sanitary matter for final destination of residues. 15.2 The competent authorities must be notified about the final destination of residues. 16. Good Storage and Distribution Practices 16.1 Generals and Quality Management System 16.1.1 The distribution of drug products is an important activity in the integral management of supply chain. The net of distribution today is increasingly complex. Having a BPAD helps the distributors to perform their activities, prevents the counterfeited drug products enter to the supply chain, ensures the control of supply chain and maintains the quality and integrity of drug products. This chapter applies to warehouses and distribution of drug products. 16.1.2 Quality Management Distributors should maintain a Quality Management System which establishes responsibilities, processes and principles of risk management related with their activities. All distribution activities must be clearly defined in the procedures and are systematically reviewed. All critical steps of the distribution processes and significant changes must be justified and, if applicable, must be validated. The Quality Management System must be under the responsibility of the direction of the organization and requires a leadership and active participation, as well as the personnel commitment. 16.1.3 Quality Management System 16.1.3.1 The Quality Management System must include the organization structure, procedures, processes and resources, as well as the necessary activities to warrant that delivered product maintains its quality and integrity during storage and/or transport. 16.1.3.2 The Quality Management System must be documented and be monitored its efficacy. All activities related with the Quality Management System must be defined and documented. There must be in place a quality manual with the applicable requirements according to clause 5 in this Norm. 16.1.3.3 The direction must designate to the Sanitary Responsible, who will have the authority to ensure that the Quality Management System is applied and maintained. 16.1.3.4 The direction must ensure that all parts of the Quality Management System have the adequate resources, the competent personnel, the adequate and sufficient installations, as well as equipment according to the size of the organization. 16.1.3.5 To prepare or modify the Quality Management System, the size, structure and complexity of the distributor activities must be taken into account. 16.1.3.6 There must be a system of change control which incorporates the principles of risk management and it be documented and effective. 16.1.3.7 The quality management system must ensure that: 16.1.3.7.1 The drug products should be acquired, preserved, supplied, exported or imported according to the requirements of BPAD. 16.1.3.7.2 The direction responsibilities are clearly specified. 16.1.3.7.3 The products are delivered to their addresses ensuring their quality and preservation conditions. 16.1.3.7.4 Registries must be done when activity is performed. 16.1.3.7.5 Deviations to documented procedures must be documented and investigated. 16.1.3.7.6 The proper corrective and preventive actions (CAPA) should be taken to correct the deviations and prevent them according to principles of quality risk management. 16.2 Outsourced activities management

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16.2.1 The quality management system must enclose control and review of all outsourced activities related with acquisition, preservation, supply, import or export of drug products. These processes must incorporate the quality risk management and include: 16.2.1.1 Assess the suitability and competence of the contractor to carry on the activity, preserve the integrity and safety of drug products. 16.2.1.2 Define the responsibilities and the communication process for the activities related with the quality of the involved parts. 16.2.1.3 Follow-up and revision of the contractor performance and the identification and implementation of necessary improvements. 16.3 Revision and follow-up by the direction 16.3.1 The direction must have a formal process to review the Quality Management System periodically. The revision must include: 16.3.1.1 Measuring of the compliance of objectives of the Quality Management System; 16.3.1.2 The evaluation of performance indicators that can be used to follow the efficacy of processes within the Quality Management System, such as complaints, recalls, returns, deviations, CAPA, change in processes; feedback of contracted activities; self-evaluation processes including risk analysis and audits; and external evaluations, such as inspections, results and audits from customers. 16.3.1.3 Norms, guidelines and quality items which emerge and may have an impact on the Quality Management System. 16.3.1.4 Innovations which may improve the Quality Management System 16.3.1.5 Changes in objectives and in company’s environment. 16.3.2 The result of each revision of the Quality Management System must be timely documented and communicated in an effective manner. 16.4 Quality risk management The quality risk management is a systematic process and must be performed according to the clause 6 of this Norm. 16.5 Personnel 16.5.1 General There must be qualified and enough personnel to carry on all tasks which are the responsibility of the distributor. Personnel must be clear of which are their individual responsibilities and they must be written. 16.5.1.1 There must be a sufficient number of qualified personnel involved in all stages of the distribution activities of drug products. The number of personnel required depends on the volume and extent of the activities. 16.5.1.2 There must be an organization chart of the distributor. 16.5.1.3 Roles, responsibilities and interrelationships of all personnel must be clearly indicated. 16.5.1.4 Must be prepared descriptions of the positions in written form and the responsibilities of the employees who work in key positions, including any agreement of replacement. 16.5.2 Designation of responsibilities 16.5.2.1 The direction must designate a Sanitary Responsible, who must have the competence and experience, as well as the knowledge and the formation on BPAD and his/her profile must comply with the legal framework applicable. 16.5.2.2 The Sanitary Responsible must designate a contact person out of the labor hours in case of emergencies and/or recall of product. 16.5.2.3 There must be a written description of the position of the Sanitary Responsible where his/her authority is defined for decision-making with regard to his/her responsibilities. The owner of the establishment must give to the Sanitary Responsible the authority, the adequate resources and the responsibility needed to meet the functions.

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16.5.2.4 The Sanitary Responsible must perform the functions in order to ensure that the distributor may demonstrate the BPAD compliance. 16.5.2.5 The Sanitary Responsible must, among others: 16.5.2.5.1 To guarantee that the Quality Management System is applied and maintained. 16.5.2.5.2 To ensure that programs of initial and continuous training are maintained. 16.5.2.5.3 To coordinate the recall operations, according to the procedure; 16.5.2.5.4 To ensure that claims or complaints of customers are attended. 16.5.2.5.5 To ensure that suppliers are approved and that customers have the License or Functioning Notification and notification of sanitary responsible. 16.5.2.5.6 To approve all activities subcontracted which can have an impact on the BPAD. 16.5.2.5.7 To ensure that internal audits are performed according to an established program and that the necessary corrective actions are adopted. 16.5.2.5.8 To maintain the registries of any activity delegated according to clause 7.1.6 of this Norm; 16.5.2.5.9 To decide according with the holder of the Registry about the final destination of returned, rejected, recalled or counterfeited products according to that established in quality manual and procedures or, in the case of subcontracted services, according to that established in the legal framework applicable, with the quality and distribution contracts applicable. 16.5.2.5.10 To ensure the compliance of any other additional requirement according to characteristics or classification of drug products, as is the case of management of controlled medications or of biological origin. 16.5.3 Training 16.5.3.1 All personnel involved in distribution activities should be trained and qualified in BPADs. They must have the adequate competence and experience before starting their tasks. 16.5.3.2 The personnel must receive an initial training and continuous according to the role, based on written procedures and according with a documented training program. All personnel must ensure the demonstration of competence in BPADs through a continuous training. 16.5.3.3 The training must include features such as product identification to detect counterfeited medicines and avoid the entrance to the supply chain. 16.5.3.4 Personnel who manages products requiring more strict conditions must receive the specific training, such as cytotoxic and high potency products, products containing psychotropic or narcotics and products sensitive to temperature. 16.5.3.5 Training registries must be preserved. 16.5.4 Hygiene and safety Proper procedures of hygiene and personal safety must be in place, corresponding to the activities performed, covering health, hygiene and clothing. 16.6 Installations and equipment 16.6.1 Generals Distributors should have buildings, facilities and adequate and sufficient equipment to ensure the adequate storage and distribution of drug products. The installations must be clean, dry and maintained within the acceptable limits of temperature and moisture according to the authorized conditions shown in drug product labels. 16.6.2 Installations 16.6.2.1 Installations must be designed to ensure that required storage conditions are maintained. They must be secure, structurally solid and with enough capacity to allow storage and safe handling of drug products. The storage area must be equipped with lighting and ventilation to allow all operations may be performed with precision and safety. 16.6.2.2 When installations are not directly operated by the distributor, a written contract must be established.

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16.6.2.3 Drug products should be stored in segregated areas which are clearly identified and with restricted access only for authorized personnel. Any system of replacement of physical segregation, as is the electronic segregation based on a computerized system should provide an equivalent safety and it must be validated. 16.6.2.4 Products that are awaiting a decision with regard to disposition, or products which have been returned must be separated either physically or through a computerized system equivalent. Physical segregation and storage into a specialized area using a risk-based approach should be evaluated. Counterfeited medication, expired, recalled, rejected and not authorized for commercialization must be physically separated in identified areas. 16.6.2.5 Products presenting a special safety risk of fire or explosion (medicinal gases, combustibles and liquids and solids inflammable) must be stored in one or more special zones, subjected to safety measures and adequate protection. 16.6.2.6 Reception and shipping areas must protect products from the outdoor and there must be an adequate separation between reception, shipping, and storing areas. There must exist with procedures to maintain control of incoming and outgoing products and storing. Reception and shipping areas should be designated, duly equipped to review the processes in them. 16.6.2.7 The non-authorized access to restricted areas must be avoided, by means of an adequate control. Visitors must be escorted all the time by the authorized personnel. 16.6.2.8 Buildings and storing areas must be clean and free of waste and powder. There must be a cleaning procedure including a program, instructions and registries for cleaning. Adequate equipment and cleaning agents must be selected in order they not become a source of contamination. 16.6.2.9 Installations must be designed and equipped so that the entrance of insects, rodents or other animals is avoided. There must be a preventive program of plague control through an authorized supplier by the Ministry. The registries for plague control must be reserved. 16.6.2.10 Resting and dining rooms and the bathrooms for workers must be independent from storing zones. In storing areas, is not permitted to have foods, beverages, tobacco and medications for personal use. 16.6.3 Control and/or monitoring f temperature and environment. 16.6.3.1 There must exist procedures, equipment and instruments adequate to control the environment where drug products are stored. Among the factors to be taken into account are temperature, light, humidity and cleaning. 16.6.3.2 An initial mapping of temperature and humidity in the area of storing must be performed before use, on representative conditions. The equipment for temperature and humidity monitoring must be located according to the results of the mapping, placing them in the zones with major fluctuations. The mapping exercise must be repeated after an exercise of risk assessment or when important modifications have been done in the installations or in equipment for temperature control. 16.6.3.3 A risk assessment must be performed for the installation at room temperature and temperature monitors should be placed based on this assessment. 16.6.3.4 If temperature and humidity mapping results in that conditions of the storing zone do not comply the requirements shown on labels of the drug products, measures for temperature control should be implemented, and this may include to install of a system HVAC. 16.6.4 Equipment 16.6.4.1 All equipment impacting the storing and distribution of drug products must be designed, placed and maintained to an adequate level for the intended purposes. There must be a maintenance program. 16.6.4.2 Instruments used to monitor the environment where the drug products are stored must be calibrated on definite intervals on a risk assessment base. 16.6.4.3 Measuring instruments should be calibrated with traceability to national standards. 16.6.4.4 There must be alarm systems to provide warnings when excursions of the predefined conditions of storing occurs. The alarm levels should be established adequately and must be tested regularly to ensure the correct functioning. 16.6.4.5 Equipment repairs, maintenance and calibration operations, should be performed such that quality and integrity of drug products is not committed.

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16.6.4.6 All registries of repair, maintenance and calibration activities in equipment and instruments must be preserved. 16.6.5 Qualification and validation 16.6.5.1 Distributors must identify the equipment and processes to be qualified and/or validated. The extent and extension of such qualification and/or validation activities (storing, reception, packaging and transport) should be determined by using a risk management approach. 16.6.5.2 The equipment qualification and process validation such as the cold chain should be performed according chapter 9. Qualification and Validation in this Norm. 16.6.5.3 Computerized systems should be validated according to clause 9.13 in this Norm. 16.7 Documentation 16.7.1 Generals A good documentation is essential for the Quality Management System. Written documentation must avoid errors derived of the oral communication and allow the follow-up of relevant operations during the drug product distribution. 16.7.2 The preparation and management of the documentation should be performed according to chapter 5.2 Documentation System in this Norm. The extent of the system will be based on the size and complexity of the organization. 16.7.3 Registries on the drug products transactions must be maintained in the form of invoices of purchasing or sale or any document that support the delivery or reception of the drug product, electronically or any other form. Registries must include the following information: date; name of the drug product; amount received; amount delivered; name and address of the supplier, customer or addressee; lot number and expiry date. Registries must be done in the moment that operation is done. 16.8 Operations 16.8.1 Generals All measures adopted by the distributors must ensure that the identification of the drug product do not get lost and that distribution is performed according to the information in secondary package. The distributor must use all available media to reduce to a minimum the risk of counterfeit medications enter to supply chain. All drug products distributed in the market must show a Sanitary Registry. 16.8.2 Suppliers Qualification 16.8.2.1 Distributors must obtain the drug products from the warehouses and distribution of drug products or from factories or drug products laboratories having a sanitary license or notification of functioning, as applied. 16.8.2.2 Qualification and approval of suppliers must be performed before the acquisition of any drug product. This must be controlled through a procedure, and results must be documented and checked periodically through a risk based approach. 16.8.2.3 When a contract is established with new suppliers, the distributor must perform audits in order to evaluate the suitability, competence and reliability of the other party. 16.8.3 Customer qualification 16.8.3.1 Distributors must ensure that they supply drug products to warehouses or pharmacies that have a notification of functioning or Sanitary License. 16.8.3.2 Distributors must watch their transactions and investigate any irregularity in sale patterns of drug products with risk of deviation (e.g., psychotropic substances, narcotics). Unusual sale patterns which may constitute a deviations or undue use of the drug product must be investigated and denounced to the competent authorities, if necessary. 16.8.4 Drug products reception 16.8.4.1 Generals The purpose of the reception is to ensure that the drug product received is the correct; that they are sourced from approved suppliers and that they have not suffered of visible damage during transport.

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16.8.4.2 Priority must be given to drug products which require special measures for handling, storing or safety and once that revision is conducted, must be moved immediately to the adequate installation of storage. 16.8.4.3 The lots of drug products should not be available for the distribution before to ensure that these were obtained according to written procedures. 16.8.4.4 If there is the suspicion of a counterfeited product, the lot must be segregated and reported to the Ministry. 16.8.5 Storage 16.8.5.1 Drug products must be stored separately from other products which can alter them and must be protected of the noxious effects of light, temperature, humidity and other external factors. Attention must be paid to products requiring specific conditions of storage. 16.8.5.2 Drug product containers must be cleaned on the reception and before storing, if necessary. 16.8.5.3 Storing operations must ensure adequate storing conditions and allow an adequate protection of stocks. 16.8.5.4 The rotation of stock must be performed following the principle of first in/ first out (FIFO) or first expiries first outgoing. Exceptions must be documented. 16.8.5.5 Drug products must be manipulated and stored such that spillages, breakages, contamination and mixes are avoided. 16.8.5.6 There must be precise instructions for the control of inventories when they enter to a remaining useful life of three months and the drug products which enter in his last month of useful life must be removed from the stock available for sale. 16.8.5.7 An inventory of the stock must be periodically performed. Detected irregularities in the stock must be investigated and documented, and in the case of controlled medications, this must be reported to the Ministry. 16.8.6 Destruction of drug products 16.8.6.1 Drug products intended for destruction must be identified, segregated and handled according to a written procedure. 16.8.6.2 The destruction of drug products must be performed through a company authorized by SEMARNAT. 16.8.6.3 The registries of destroyed products must be preserved during a 5 years period. 16.8.6.4 The destruction of controlled drug products requires the authorization from the Ministry. 16.8.7 Dispensing 16.8.7.1 Controls must be established to ensure that the requested medication is dispensed. The product must have a useful remainder life in the moment it is prepared to ensure that can be used without the risk of caducity during the distribution process. 16.8.7.2 The suitability of the drug product dispensing must be assessed with 3 months of useful remainder life. 16.8.8 Supply 16.8.8.1 All dispatches must have a document (e.g., note of delivery/list of package) indicating the date; name and dosage form, lot number, expiry date; amount supplied; name and address of the supplier, name and address of delivery, transport and storing conditions. Registries must be maintained in order to know the real location of the product. 16.8.9 Import and Export 16.8.9.1 Activities of import and export must be performed according with the legal framework applicable. Distributors must take de adequate measures to avoid that non authorized drug products for internal market and to export arrive to internal market. 16.9 Complaints, returns, counterfeited medications and recalls 16.9.1 Introduction All complaints, returns, counterfeits suspected and recalls must be registered and managed according to written procedures and/or to distribution agreements with the holders of the sanitary registry Registries must be

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available for the competent authorities. An evaluation of returned drug products must be performed before any approval for re-sale. A consistent focus is required for all partners in the supply chain in order to be successful in the fight against counterfeit medications. 16.9.2 Complaints 16.9.2.1 The complaints must be registered with all original details. A distinction must be done between complaints related with the quality of a drug product and those related with the distribution. In the case that the complaint is related with the quality of the drug product and a possible failure of the product, the manufacturer and/or holder of the registry must be informed. Any complaint must be thoroughly investigated to identify the origin or reason of the complaint. 16.9.2.2 If a failure related with the medication is discovered or suspected, the investigation should be extended to other lots of the product. 16.9.2.3 A person must be designated for manage of complaints. 16.9.2.4 When necessary, follow-up actions (CAPA) must be taken after the investigation and assessment of the complaint, including, as necessary, the notification to the national competent authorities. 16.9.3 Returns 16.9.3.1 Returned medications must be managed according to a written procedure, based on risk, which takes into account the drug product, as well as specific requirements of storing and the elapsed time since the medication was originally sent. Returns must be performed according with national legislation and the contract agreements between parties. 16.9.3.2 Drug products that have going-out of the distributor installation only will be returned to the stock available for sale if the following is met: 16.9.3.2.1 The drug products are in the secondary package not-opened and without damages and in good conditions; have not expired and have not been recalled; 16.9.3.2.2 If customer demonstrates that the medication has been transported, stored and handled according with specific requirements of storing; 16.9.3.2.3 That have been examined and assessed by a person trained enough and competent, authorized to do this; 16.9.3.2.4 The distributor must have the evidence confirming that the product was supplied to that customer (through copies of the original delivery note or making reference to the invoice numbers, lot numbers, expiry date, etc. as is required by the national legislation), and there is not any motif to think that the medication has been counterfeited. 16.9.3.3 Drug products requiring storing conditions of specific temperature, the return only can be made if exist documented proofs that the product has been stored all time at the storing conditions authorized. If a deviation occurs, a risk assessment must be performed demonstrating the product integrity. The evidence must cover: 16.9.3.3.1 Delivery to the customer; 16.9.3.3.2 Inspection by attributes of product; 16.9.3.3.3 The opening of the package for transport; 16.9.3.3.4 The return of the product to packaging; 16.9.3.3.5 Reception and return to the distributor; 16.9.3.3.6 The registry of the readings of temperature during transport; 16.9.3.3.7 The return to the cold chamber of the distributor. 16.9.3.4 Products returned must be placed following the system of first in/first out (FIFO). 16.9.3.5 Products stolen, which have been recovered cannot be returned to the stock for sale. 16.9.4 Counterfeited medications 16.9.4.1 Sale and distribution of a counterfeited medication must be immediately suspended.

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16.9.4.2 There must be a procedure where distributors inform immediately to the authority and to the holder of the Sanitary Registry about any counterfeited medication or suspected to be counterfeited and acting on the instructions as specified by the authority. 16.9.4.3 Any counterfeited medication found in supply chain must be physically separated and stored in a specific area separated of others drug products. All activities relevant with regard to such products must be documented and the registries preserved. 16.9.4.4 After the confirmation that a medication has been counterfeited, the holder of the Sanitary Registry must notify to COFEPRIS to make the decision jointly about the recall. If a recall is determined, it must be ensure that do not enter again to the supply chain, including the retention of samples needed for public health, regulation or legal necessities and dispositions for their destruction. All decisions must be duly documented by the holder of the Sanitary Registry. 16.9.5 Product recall 16.9.5.1 There must be documentation and procedures to ensure the traceability of products received and distributed, in order to make the recall easier. 16.9.5.2 In the case of a recall, all customers who have received the product must be rapidly informed with the appropriate grade of urgency and with clear instructions. 16.9.5.3 The national authority should be informed about the recall. If product is exported, the counterparts abroad and/or to the regulatory authorities must be informed about the recall as national demands. 16.9.5.4 The efficacy of the process for recalls must be assessed, by implementing a simulacrum (at least once in a year) or through the evaluation with indicators established by the distributor over the result of the recall of a true event. 16.9.5.5 The operations of the recall must be capable to start immediately and at any moment. 16.9.5.6 The distributor must follow the instructions of a recall alert, which must be approved, if necessary, by the competent authorities. 16.9.5.7 Any recall operation must be registered in the moment that it happens. Registries must be available for the authorities 16.9.5.8 Distribution registries must be easy to access for the person(s) responsible of the recall and must contain enough information about the distributors and the customers directly supplied (with address, telephone and/or fax numbers within and outside labor hours, lot numbers as required in national legislation and the amounts delivered), including those of the exported products and medical samples (if it is allowed by the national legislation). 16.9.5.9 The progress of the recall should be registered in a final report, including the conciliation of the recalled product. 16.10 Subcontracted activities. 16.10.1 Introduction. Any activity subcontracted and which covers activities of the BPAD must be defined, agreed, and correctly controlled in order to avoid misunderstandings which may affect the integrity of product. There must be a written contract between contractor and contracted establishing clearly the obligations of each part. 16.10.2 Contractor agent 16.10.2.1 The contractor is the responsible of the activities assigned under a contract. 16.10.2.2 The contractor is responsible to evaluate the competence of the contracted to perform successfully the required work and to ensure by means of a contract and by audits that the principles of BPD are followed. An audit of the contracted should be performed before starting activities subcontracted and when a change occurs. The requirement of audit and the periodicity must be defined based on the risk, depending on the nature of subcontracted activities. Audits must be allowed in any time. 16.10.2.3 The contractor must provide the contracted with all necessary information to perform the contracted operations according to the requirements of specific products and other relevant requirements. 16.10.3 Contracted agent

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16.10.3.1 The contracted is responsible to cover all activities of the BPD assigned by the contractor, as well as the form to operate the quality management system including complaint and returns management and product recalls. 16.10.3.2 The contracted must have facilities and adequate equipment, procedures, knowledge, experience and competent personnel to carry on the work required by the other part (contractor). 16.10.3.3 The contracted should not subcontract any work agreed in contract without a previous evaluation of the contractor part, the approval of agreements and an audit by the contractor. The agreements between the contractor and subcontracted must ensure that information of the distribution is available in the same way that between the contractor and the contracted. 16.10.3.4 The contracted must abstain of any activity which can affect negatively the product quality managed by the contractor. 16.10.3.5 The contracted may send any information which can affect the quality of product to the contractor according with the requirements of the contract. 16.10.3.6 The contractor must provide information of the drug products which ensure to the contracted the correct management of the stored products. 16.11 Self-inspections 16.11.1 Introduction There must be self-inspections in order to monitor the implementation and application of the BPD and propose the necessary corrective measures. 16.11.2 Implementation 16.11.2.1 A program of self-inspection must be implemented covering all aspects of BPDs as well as the compliance with Norms, guidelines and procedures within a defined calendar. Auto-inspections may be divided in various individual self-inspections of limited extent. 16.11.2.2 Self-inspections must be performed in an impartial and detailed manner by the personnel of the competent designated company. The audits from external experts can be useful also, but they cannot be used instead the self-inspection. 16.11.2.3 All self-inspections must be documented. The reports must contain all observations during the inspection. A copy of the report must be provided to the Direction of the establishment and other relevant persons. If irregularities and/or deficiencies are observed, the causes must be determined and corrective and preventive actions (CAPA) must be documented. 16.12 Transport 16.12.1 Introduction 16.12.1.1 It is the responsibility of the distributor to protect the drug products against breakage, adulteration, steal, and ensure that temperature conditions are maintained within the acceptable limits during transport. 16.12.1.2 Regardless of the type of transport, it must be shown that drug products have not been exposed to conditions that may be risky for the quality and integrity of drug products. There must be used a risk-based approach for planning transport. 16.12.2 Transport 16.12.2.1 The necessary storing conditions must be maintained during transport of drug products within the limits defined as is described in external package and/or information of relevant package. 16.12.2.2 If a deviation of temperature or a damage to product occurs during transport, the distributor and addressee of the affected drug products must be informed. There must be a procedure for the investigation and management of temperature variations. 16.12.2.3 It is the responsibility of the distributor to guarantee that vehicles and equipment used to distribute, store or handle medications are the adequate for use and are properly equipped to prevent exposition of the products to conditions that may affect the quality and integrity of the package. 16.12.2.4 There must be written procedures for the operation and maintenance of all vehicles and equipment used for distribution process, including the precautions for cleaning and safety,

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16.12.2.5 A risk assessment of the routes for delivery must be used to determine where temperature controls are required. The equipment used to monitor temperature during transport inside the vehicles and/or containers, must be subjected to maintenance and calibration on regular intervals. 16.12.2.6 Whenever possible, vehicles and equipment dedicated to drug products must be used. When using non dedicated vehicles and equipment, there must be procedures to ensure that the quality and integrity of the drug product won’t be committed, establishing controls which must be compliant and the characteristics that they must have. 16.12.2.7 The delivery must be done to the indicated address in the delivery note and in the premises of the addressee. Drug products should not be left in alternate premises. 16.12.2.8 A person must be designated and there must be a procedure for emergency deliveries out of labor hours. 16.12.2.9 When transport is performed by a third party, the contract must include the requirements listed in clause 16.10 in this Norm. Transport providers must be informed by the distributor of the relevant transport conditions applicable to the consignment. Temperature, cleaning and safety of the installations must be watched when the route of transport includes discharge and charge. 16.12.2.10 Duration of crossing platform should be minimized waiting for the next stage of the transport route. 16.12.3 Containers, package and labeling 16.12.3.1 Drug products must be transported in containers that do not have any adverse effect on quality of products, and which offer an adequate protection from external conditions, including contamination. 16.12.3.2 The selection of a container and the package must be based on requirements of storing and transport of drug products; the necessary space for the amount of drug product, the predicted extreme outer temperatures; the maximum time estimated for transport as the storing of transit in the custom; the qualification status of the package and the validation status of the containers of transport. 16.12.3.3 The containers must bear labels to provide sufficient information on requirements and precautions of handling and storing to guarantee that products are manipulated and protected all the time. The recipients must allow the identification of contents into the containers and the source. 16.12.4 Drug products that require controlled conditions 16.12.4.1 With respect to deliveries containing drugs that require special conditions, such as narcotics or psychotropic substances, the dealer must maintain a safe and secure supply chain for these products in accordance with the requirements of national legislation. Additional control systems should be set in place for delivery of these products. There must be a protocol to address the occurrence of theft. 16.12.4.2 Drug products containing highly active and radioactive materials must be transported into containers and safe, dedicated vehicles. The necessary safety measures must be conform to international agreements and the national legislation. 16.12.4.3 For those drug products which are temperature-sensitive must be used qualified equipment (thermal packages, controlled temperature containers, or vehicles with controlled temperature) and must be ensure that the correct transport conditions are maintained between the manufacturer, the distributor and the customer. 16.12.4.4 If vehicles with controlled temperature are used, the equipment for monitoring of temperature used during the transport must be subjected to maintenance and calibration at regular intervals. Mapping of temperature under representative conditions must be performed considering the seasonal variability. 16.12.4.5 If it is requested by the customer, there should be available information to demonstrate that products have met the conditions of temperature of storing. 16.12.4.6 If refrigerants in insulated boxes are used, they must be placed so that the product is not in direct contact with the coolant. Staff should be trained in procedures for packaging of insulated boxes and the reuse of refrigerants. 16.12.4.7 There must be a system to control re-using of refrigerants to ensure that non-cold refrigerants are not used. There must be an adequate physical separation among cold and freeze packages. 16.12.4.8 The delivery process of sensitive products and the control of the variations of seasonal temperatures must be described in a procedure.

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17. Agreement between international and Mexican norms This Norm is partially equivalent with international standards: 17.1 EudraLex. Volume 4, Good manufacturing practice (GMP) Guidelines, Introduction, Part I, Part III and Annexes 1, 2, 6, 8, 9, 11, 13, 14, 15 and 19. 17.2 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. Explanatory notes for Pharmaceutical Manufacturers on the Preparation of a Site Master File. January 2011. 17.3 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. Guide to Good Manufacturing Practice for Medicinal Products Annexes. October 2015. 17.4 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. Guide to Good Manufacturing Practice for Medicinal Products Part I. October de 2015. 17.5 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. Guide to Good Manufacturing Practice for Medicinal Products Part II. October de 2015 17.6 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. PIC/S GMP Guide for Blood Establishments. September 2007. 17.7 Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme. GMP Annex 1 Revision 2008, Interpretation of most important changes for the Manufacture of Sterile Medicinal Products. January 2010. 17.8 World Health Organization. Technical Report Series, No. 961, 2011 Annex 3, good manufacturing practices for pharmaceutical products: main principles y Annex 6, WHO good manufacturing practices for sterile pharmaceutical products. Geneva, 2011. 17.9 World Health Organization. Technical Report Series, No. 961, 2011 Annex 4, guidelines on goodmanufacturing practices for blood establishments. Geneva, 2011. 17.10 World Health Organization. Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks. 2010. 17.11 World Health Organization. Technical Report Series, No. 924, 2004 Annex 4, guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products. Geneva, 2004. 17.12 U.S. Foods and Drug Administration. “Title 21, parts 11 & 211” Code of Federal Regulations, Washington: Government Printing Office, 2012. 17.13 U.S. Foods and Drug Administration. Guidance for Industry Process Validation: General Principles and Practices. Washington, January 2011. 17.14 U.S. Foods and Drug Administration. Guidance for Industry, CGMP for Phase 1 Investigational Drugs. Washington, 2008. 17.15 ICH Q5A (R1): viral safety evaluation of biotechnology products derived from cell lines of human or animal origin (September 1999). 17.16 ICH Q5B: Quality of biotechnological products: analysis of the expression construct in cells used for production of r-DNA derived protein products (November 1995). 17.17 ICH Q5C: Quality of biotechnological products: stability testing of biotechnological/biological products (November 1995). 17.18 ICH Q5D: Derivation and characterization biotechnological/biological products (July 1997).

of cell substrates

used for production of

17.19 ICH Q5E: Comparability of biotechnological/biological products subject to changes in their manufacturing process (November 2004). 17.20 ICH Q8 (R2): Pharmaceutical Development (August 2009). 17.21 ICH Q9: Quality Risk Management (November 2005). 17.22 ICH Q10: Pharmaceutical Quality System (June 2008). 18. Bibliography 18.1 Ley General de Salud. 18.2 Ley Federal sobre Metrología y Normalización. 18.3 Ley General del Equilibrio Ecológico y la Protección al Ambiente. 18.4 Reglamento de Insumos para la Salud.

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18.5 Reglamento de la Ley Federal sobre Metrología y Normalización. 18.6 Reglamento de la Comisión Federal para la Protección contra Riesgos Sanitarios. 18.7 Farmacopea de los Estados Unidos Mexicanos, 11a. Ed. México (2014). 18.8 Suplemento para establecimientos dedicados a la venta y suministro de medicamentos y demás insumos para la salud, 5ª. Ed. (2014). 18.9 Suplemento de la Farmacopea de los Estados Unidos Mexicanos, México (2015). 18.10 Farmacopea Homeopática de los Estados Unidos Mexicanos, 3a. Ed. México (2015). 18.11 ISO 9000:2005 Quality management systems-Fundamentals and vocabulary. 18.12 ISO 9001:2008 Quality management systems-Requirements. 18.13 ISO 9004:2009 Managing for the sustained success of an organization - A quality management approach. 18.14 ISO 14644-1:1999. Cleanrooms and associated controlled environments - Part 1: Classification of air cleanliness. 18.15 ISO 14644-2:2000. Cleanrooms and associated controlled environments - Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1. 18.16 ISO 14644-3:2005. Cleanrooms and associated controlled environments - Part 3: Test methods. 18.17 ISO 14644-4:2001. Cleanrooms and associated controlled environments - Part 4: Design, construction and start-up. 18.18 ISO 14644-5:2004. Cleanrooms and associated controlled environments - Part 5: Operations. 18.19 ISO 31000:2009. Risk management - Principles and Guidelines on Implementation. 18.20 I ISO/IEC 31010:2009, Risk management - Risk assessment techniques. 18.21 ISO Guide 73:2009. Risk management -- Vocabulary. 18.22 Organización Mundial de la Salud. Manual de bioseguridad en el laboratorio, tercera edición. OMS, Ginebra, 2005. 18.23 World Health Organization. Quality Assurance of Pharmaceuticals. A Compendium of guidelines and related materials, Vol. 2, 2a. Edition, 2007. 18.24 Parenteral Drug Association. Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control. Technical Report No. 1 (revisad 2007), Suplement Vol. 61, No. S-1. 2007. 18.25 U.S. Department of Health and Human Services, CDC. Biosafety in Microbiological and Biomedical Laboratories, 5th. Edition. 2009. 18.26 ISPE. GAMP 5, A Risk-Based Approach to Compliant GxP Computerized Systems. 2008. 18.27 Colegio Nacional de Químicos Farmacéuticos Biólogos México. Guía de Validación del Método Analítico. CNQFBM, 2002. 18.28 Health Canada. Laboratory Biosafety Guidelines; 3th. Edition. Canada, 2004. 18.29 James Agalloco, Frederick J. Carleton. Validation of Pharmaceutical Process; 3th edition. Informa Healthcare, 2008. 18.30 Pharmaceutical Production. An engineering guide, Edited by Bill Bennett and Graham Cole; Institution of Chemical Engineers (IChemE), 2003. 18.31 Gary Walsh. Pharmaceutical Biotechnology. Concepts and Applications. Ed. John Wiley and Sons Ltd. 2007. 18.32 Anexo 20 “Buenas Prácticas de Fabricación de Medicamentos” PIC, Marzo 2014. 18.33 Guía de “Prácticas de Correcta Fabricación”, Ministerio de Salud de España “Gestión de Riesgo” 2008. 18.34 FDA (2004) Pharmaceutical CGMPS for the 21st century - A risk-based approach. Final report.

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18.35 ICH (2005) “Quality risk management ICH Harmonised Tripartite Guideline Q9. 18.36 ICH (2008) Pharmaceutical quality system. ICH Harmonised Tripartite Guideline Q10. 18.37 ICH (2009) Pharmaceutical development. ICH Harmonised Tripartite Guideline Q8 (R2). 18.38 ICH (2011). Development and Manufacture of Drug Substances (Chemic al Entities and Biotechnological/Biological Entities). Draft Consensus Guideline Q11. 18.39 Vesper, J. L. (2006) Risk assessment and risk management in the pharmaceutical industry. Clear and simple. PDA/DHI. 18.40 CEI/IEC (1985) Techniques d’analyse de la fiabilité des systèmes. Procédured’analyse des modes de défaillance et de leurseffets (AMDE) / Analysis techniques for system reliability. Procedure for failure mode and effects analysis (FMEA). Norme international/International standard 608121985. 18.41 WHO (2003) Hazard and risk analysis in pharmaceutical products. Technical Report Series, No. 908. Annex 7. 19. Observance The enforcement of this standard corresponds to the Ministry of Health and the governments of the states in the area of their respective powers. 20. Validity The present norm will come in force with mandatory character in 180 natural days from its publishing in the Federation’s Official Bulletin.

TRANSIENT SINGLE. This Norm cancels the Mexican Official Norm NOM-059-SSA1-2013, Good Manufacturing Practices of Drug Products, published in the Official Journal of the Federation on 22 July 2013. Mexico City, January 4th, 2016.- The Federal Commissioner for the Protection against Sanitary Risks and President of the National Consulting Committee on Standardization of Regulations and Sanitary Fostering, MikelAndoni Arriola Peñalosa.- Rubric.

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21. Appendix A Normative. Manufacturing areas

Classification

Class A (ISO-Class 5)

Class B

Class C (ISO-Class 7)

Class D (ISO-Class 8)

ISO-Class 9

Processes examplesa Aseptic filling. Aseptic operations. Sampling , weighing and sterile components supply Environment Class A for sterile products without terminal sterilization. Airlocks to filling room Dressing rooms for Class A areas Filling of products with terminal sterilization. Preparation of solutions for sterilizing filtration, for terminal sterilization and elements of containerclosure systeme Storage of accesories for sterile dosage forms Anvironment Class C Isolators room. Incubatio and cooling rooms (located in production areas). Preparation and primary packaging of non-sterile dosage forms. Sampling, weighing and dispensing of nonsterile inputs Secondary packaging

Maximum allowed number of total particlesh / m3; Static/dynamic Monitoring conditionsg frequency = 0.5 µm 5 µm 3 520 / 3 520

3 520 / 352 000

352 000 / 3 520 000

Viable particlesb

Differential pressure and airflow

Changes of air per houri

Temperature and humidity

Clothing Uniform for sterile aseptic area, mob cap, facial mask, shoe covers, gloves and goggles

(CFU)

Monitoring frequency

20 / 20

CONTINUOUS/ All filling process

< 1/plateb.1 < 1/m3 b.2 < 1/plateb.3 < 1gloveb.4

CONTINUOUS/ All filling process

15 Pa with respect to adjacent rooms, applying a cascade conceptc

n.a.

18°C to 25°C 30 to 65% RHf

29 / 2900

Each 3 monthse

< 5/plateb.1 < 10/m3 b.2 < 5/plateb.3 < 5gloveb.4

Daily / Shift

15 Pa with respect to non aseptic areas, applying a cascade concept

n.a.

18°C to 25°C 30 to 65% RH

Same as ISOClass 5

2 900 / 29 000

Each 6 monts except filling of solutions with terminal sterilization performed every 3 monthsd

< 50/plateb.1 < 100/m3 b.2 < 25/plateb.3 -

20 to 50

18°C to 25°C 30 to 65% RH

Clean plant uniform, hair and beard/mustache covered

3 520 000 / n.a.

29 000 / n.a.

Each 6 months

< 100/plateb.1 < 200/m3 b.2 < 50/plateb.3 -

35 200 000 / n.a.

293 000 / n.a.

Annually

n.a.

Weekly

> 10 Pa

Monthly

>5 Pa Negative pressure where dust is generated regarding adyacent rooms and positive regarding rooms where powder is not generated

10 to 20

18°C to 25°C 30 to 65% RH

Clean plant uniform, hair and beard/mustache covered

Annually

Positive pressure regarding to non classified areas

n.a.

18°C to 25°C

Clean plant uniform, hair covered

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NOTES: a b b.1 b.2 b.3 b.4 c d e f g h i

The examples mentioned here are declarative, but not limiting Microbiological monitoring must be performed using the following methods: Sedimentation plate of 90 mm diameter, exposure not less than 30 minutes and not more than 4 hours. Air sampling Contact plate 55 mm diameter Glove sampling on five fingers The unidirectional flow zone must meet the parameters of flow velocity 0.45 m/s ± 20%. It can be perfomed less frequently according to the maintenance of validated status. May be performed at least in Class D rooms as long as it is supported with validation studies. Class A rooms must meet these parameters, it does not apply for modules with unidirectional flow. Particle limits provided in table for static condition may be achieved after a short period of cleaning of 15 to 20 minutes after ths conclusion of operations and without operators. Sample size taken with monitoring purposes are given as a function of the sampling system used and not necessarily the volume of the moitoring sample will be the same as the amount of air taken during formal classification of the room. This parameter may be an indicator of the adequate design of the system, so if compliance does not exist for the range in table, the technical justification should be investigated to evidence that there are not failures inherent to the design of areas.

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21.2 Appendix B Normative. Annual Product Review Annual review of Product Name of product

Registry No.:

DCI

Concentration:

Review for period from

Until:

Total lots reviewed: Approved Approved with deviation Rejected Total: Only export/country lots: Review of documentation

Made by:

Formula

Information: Modifications on quali quantitative formula:

Review of product specifications

Information: Modifications in specifications and analytical methods of the product

Review of the drug history / biodrugs / additives / primary final package

Information: Review the history of supplies involved in the manufacture of the RAP lots, including change in manufacturers, change on specifications and analytical methods, cross references, reports and programs.

Review of the quality management system

Date:

Made by:

Date:

Deviations and/or non-conforming product

Information: Include cross references, reports and investigation of associated failures and CAPA

Analytical results out of specification (OOS) / analytical results out of trend (OOT)

Information: Include cross references, reports and investigartion of associated failures.

Review of process data Critical parameters

Made by:

Date:

Information: Review of in-process controls, including the modifications

Maintenance of validated status

Made by:

Date:

Validation of process

Information: Review of process validation status, include re-validations.

Validation of analytical methods

Information: Review of analytical methods validation status, include revalidations

Critical systems

Information: Description and review of the validated status

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79

Date:

Information: There not exists adverse observations over a representative sample based on a visual inspection.

Review of stability

Made by:

Date:

Information: The product consistently meets the specification throughout the expiry period. Refer to stability review for trend analyses..

Outsourced activities for analytical and manufacturing process

Made by:

Date:

Modification to registry conditions

Made by:

Date:

Information: Include the technical and administrative conditions of the period along with cross references to request number (total subjected, approved, rejected, and in evaluation with COFEPRIS

Post-marketing commitments acquired with regulatory authorities

Made by:

Date:

Information: Include pharmaceutical surveillance, Phase IV studies, risk management plans, additional stability plans.

Notifications of suspected adverse reactions

Made by:

Date:

Information: Include those related with quality and/or manufacturing process of product..

Actions derived from the previous RAP

Made by:

Date:

RAP conclusion

Made by:

Date:

Information:

Actions derived from RAP conclusions

Made by:

Date:

Information:

Made by:

Summary of Annual Review of Product Date:

Approved by:

Date: