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CERTIFICATION OF SUITABILITY OF MONOGRAPHS OF THE EUROPEAN PHARMACOPOEIA 5TH EDITION WORKSHOP SESSION: An outline of the main deficiencies in dossiers and how to avoid them Istanbul October 2005
The main deficiencies found in dossiers for chemical purity Dr P.Poukens-Renwart and Dr D. Byrne Scientific officers Certification Unit, EDQM
Istanbul October 2005
Summary: • • • • • •
Figures Deficiencies at receipt Top ten deficiencies Other deficiencies (new development) Presentation of data Conclusions Istanbul October 2005
Average time to get a CEP: 21 months (min 6 months, max 6 years)
Istanbul October 2005
Number of assessments for CEP
Istanbul October 2005
Requests for add info after 1st assessment: Average number of questions: 11 (min 0, max 25)
Istanbul October 2005
(9 in 2004)
Content of the dossier • PA/PH/CEP (04) 1, 3R: Content of dossier for chemical purity: Revision of annex 1 of the Resolution APCSP (99) 4: CTD format • Application form (declarations)
Istanbul October 2005
Dossiers blocked at receipt 9% of applications received in 2004 (24% in 2002) • ADMINISTRATIVE REASONS: Missing application form/declarations/samples/ QOS
• TECHNICAL REASONS: 2 processes / incomplete documentation / Class I solvents / Referred monograph ≠ current Ph. Eur monograph / related substances controlled by TLC Istanbul October 2005
Application form – – – – –
Details on holder, manuf. site: on the CEP Details on contact person/company for correspondence History of the substance Retest period Declarations (templates): GMP, willingness to be inspected, absence / presence of material of animal/human origin
NB: 2 different forms: new requests and revisions Istanbul October 2005
CTD format • • • • •
(3.2.S.1) General information (3.2.S.2.2) Manufacturing process (3.2.S.2.3) QC of Starting materials (3.2.S.3.2) Impurities / solvents / catalysts (3.2.S.4.1) Specifications and routine tests
Istanbul October 2005
CTD format (cont) • (3.2.S.4.3) Analytical validation / suitability of the monograph • (3.2.S.4.4) Batch results • (3.2.S.5) Packaging material • (3.2.S.7) Stability
Istanbul October 2005
Repartition of questions after the first evaluation
Istanbul October 2005
TOP TEN of deficiencies 1. (3.2.S.2.3) Description of the route of synthesis of the declared starting material(s), description of impurity profile (related subst, reagents, solvents, catalysts), and carry-over of impurities to the final substance : 83.5% of dossiers (58% in 2004) 2. (3.2.S.2.3) Specification for all reagents, solvents and water. Include purity tests: 64.6% (38% in 2004) Istanbul October 2005
TOP TEN deficiencies (cont) 3. (3.2.S.2.3) Specification of the starting materials should include suitable limits for impurities and solvents: 48.1% (29% in 2004). 4. (3.2.S.2.2) Detailed description of each step of the manufacturing process: quantities of starting materials, reagents, solvents,…operating conditions: 35.4%
Istanbul October 2005
TOP TEN deficiencies (cont) 4. Limits for impurities should be in accordance with the specific monograph + general monograph 2034 (unspecified imp: 0.10%): 35.4% (38% in 2004). 5. Demonstration that all solvents used are removed or suitably limited (validated method): 34.2% (42% in 2004)
Istanbul October 2005
TOP TEN deficiencies (cont) 6. (3.2.S.2.2) Maximum/typical batch size: 29.1% (38% in 2004) 6. (3.2.S.5) Characterisation of reference standards: 29.1% 7. (3.2.S.2.3) Proof of absence of particular reagents in the final substance (catalysts, alkylating agents, …): 27.8 % (42% in 2004) Istanbul October 2005
TOP TEN deficiencies (cont) 8. (3.2.S.3.2) Illustration of the impurity profile based on typical chromatograms : 26.6% 9.(3.2.S.3.2) Detailed discussion on impurities: - origin, correspondence with transparency list : 22.8% - levels found, setting of limits: 22.8%
Istanbul October 2005
TOP TEN deficiencies (cont) 9. (3.2.S.4.4) Results on 3 batches (size + manufacturing date) : 22.8% 10.(3.2.S.1) History of the substance : 21.5% (29% in 2004)
Istanbul October 2005
Deficiencies linked to the new developments of the procedure • General monograph for substances for pharmaceutical use (2034) =>Quantitative methods should be used for the control of related substances: TLC IS NO LONGER ACCEPTABLE !!!
Istanbul October 2005
Deficiencies linked to new developments of the procedure (cont) • Implementation PA/PH/CEP (04) 1, 3R: Content of dossier for chemical purity: Revision of annex 1 of the Resolution AP-CSP (99) 4: - CTD format - Declaration of the absence of any material of human / animal origin
Istanbul October 2005
Data presentation • Data given in the dossier should be : – Clear – Concise – Readable – Obtained from recent analysis
Istanbul October 2005
Conclusions: how to avoid deficiencies ? • Revised annex 1 to resolution « content of the dossier » (including CTD format) • Top ten deficiencies • Implementation of recent developments Istanbul October 2005
THANK YOU! • EDQM Internet site www.pheur.org • for questions on the procedure [email protected]
Istanbul October 2005
CERTIFICATION OF SUITABILITY OF MONOGRAPHS OF THE EUROPEAN PHARMACOPOEIA 5TH EDITION WORKSHOP SESSION: An outline of the main deficiencies in dossiers and how to avoid them Istanbul October 2005
Deficiencies related to manufacturing process, control of drug substance and stability Dr. Samuel Steiner Cantonal Pharmacist of the Canton of Berne Switzerland
3.2.S.2.2. Manufacturing Method • Brief outline and flow chart • Detailed description, including - typical / maximum batch size - narrative description, including explanation of chemical reactions - all materials and reagents introduced and typical quantities, yields - operating conditions (ranges of T°C, time, pH..) - structure of isolated intermediates
Certification Conference, Istanbul, 27-28 October 2005
2
3.2.S.2.2. Manufacturing Method - re-processing, re-working, recovery (where, how)
typical quantities, yields operating conditions (ranges of T°C, time, pH..) - IPC (in process controls) : where, how, methods, specifications - options (alternatives) - Blending, mixing sub batches (QC where?) Certification Conference, Istanbul, 27-28 October 2005
3
3.2.S.2.2. Manufacturing Method • Semi-synthetic products: Fermentation steps involved in synthesis of starting material ? - Characterisation of fermented starting material, incl. detailed impurity profile - Compliance with general monograph Products of Fermentation 1468 - Carry over of fermentation impurities - TSE risk substances!
Certification Conference, Istanbul, 27-28 October 2005
4
3.2.S.2.3. Quality Control of Materials •
Definition of starting material(s) - manufactured in-house or purchased? - few steps synthesis: details of the synthesis of the starting materials (flow chart)
detailed specifications for impurities
• Suitable specification for all materials used - incl. purity tests for solvents, quality of water.. Compliance with EP requirements for starting material/key intermediates/solvents => cannot be imposed 3.2.S.2.4. Control of Critical Steps and intermediates Certification Conference, Istanbul, 27-28 October 2005
5
3.2.S.4. Control of the Drug Substance • Reference to the right (EP) monograph and its tests • Include additional/alternative tests (if necessary) • Appropriate limits for impurities, solvents,... in accordance with the process and relevant guidelines => General monograph 2034 • Adequate methods description => format to be appended to the CEP • Biological substances – information on inactivation/removal infectious material when required? Certification Conference, Istanbul, 27-28 October 2005
6
3.2.S.4.3 Validation of analytical procedures • All in-house methods should be validated (incl. non-routine methods) - ICH Q2B for methodology - Typical chromatograms (selection, illustration of the chromatograms) • Cross-validation against Ph.Eur. - comparative results from the same samples
Certification Conference, Istanbul, 27-28 October 2005
7
Other requirements • 3.2.S.4.4 Batch data (3 batches) - in line with specification (methods used?) - Details on batches tested (batch nr., size, date of manufacture, date of analyses) - Numerical figures (adequate digits, “complies” not appropriate)
Certification Conference, Istanbul, 27-28 October 2005
8
Other requirements • 3.2.S.5 Reference substances:
Characterisation of reference standards Ph.Eur. Standards (CRS)
• 3.2.S.6 Packaging Material: - Description + specifications of materials - compliance with foodstuff legislation should be declared. Certification Conference, Istanbul, 27-28 October 2005
9
3.2.S.7 Stability When a retest period is to be stated on the certificate: Guideline on Stability testing: Stability testing of existing active substances and related finished products CPMP/QWP/122/02 rev 1) • ICH conditions (long-term + accelerated) + Fit the monograph statements • Study description – relevant parameters (incl. reference to methods used) • Detailed results (figures) - Impurities • Validation of in-house methods (stability indicating) • Proposed retest period, packaging material and storage conditions Certification Conference, Istanbul, 27-28 October 2005
10
3.2.S.7 Stability (cont.) • Quality specifications in accordance with the General Monograph „Substances for Pharmaceutical use“ • Proposed retest period and storage conditions: - in accordance with stability results - Extrapolation: see Guideline Note for guidance on declaration of storage conditions (CPMP/QWP/96/Rev 1)
Certification Conference, Istanbul, 27-28 October 2005
11
Thank you
Questions?
Certification Conference, Istanbul, 27-28 October 2005
12
Safeguarding public health
Deficiencies: Impurities
Related Substances, Residual Solvents and Catalysts Sean Jones Pharmaceutical Assessor Medicines and Healthcare products Regulatory Agency, UK
©
Introduction • The Regulatory Framework • Top 10 Deficiencies: Impurities • Control of Starting Materials (3.2.S.2.3
and 2.4) • Impurities (3.2.S.3.2) - Impurity Profiling
• Control of Active Substance (3.2.S.4) • Summary • NfGs, Bibliography, Websites Deficiencies: Impurities Sean Jones
Slide 2
October 2005 ©
1
Regulatory Framework • EU Directives - Medicines, Plastics, TSE. • Notes for Guidance - EU and ICH • European Pharmacopoeia - General Monograph “Substances for Pharmaceutical Use” - Specific Monographs Deficiencies: Impurities Sean Jones
Slide 3
October 2005 ©
General Monograph: Impurities SUBSTANCES FOR PHARMACEUTICAL USE Organic Impurity Threshold Limits
• All Impurities to be reported, identified wherever possible, and
qualified, (in line with Q3A).
• New impurities to be investigated and controlled. • Limits for single unknown and total impurities should also be
controlled.
Quantitative Techniques Required
• HPLC to replace semi-quantitative TLC • System Suitability Testing
Unusually Toxic Impurities
• Specific limits may be applied for impurities known to be
unusually potent or to produce toxic or unexpected pharmacological effects.
Deficiencies: Impurities Sean Jones
Slide 4
October 2005 ©
2
Impurity Threshold Limits Maximum daily dose
Reporting threshold
Identification threshold
Qualification threshold
≤ 2 g/day
> 0.05%
> 0.10% or > 1.0 mg/day
> 0.15% or >1.0 mg/day
(whichever the lower)
(whichever the lower)
> 0.05%
> 0.05%
> 2 g/day
> 0.03%
EXEMPT: Less stringent limits possible, if justified Biologicals, biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, products of fermentation and semi-synthetic products derived therefrom, herbal products and crude products of animal or plant origin. Deficiencies: Impurities Sean Jones
Slide 5
October 2005 ©
Ph Eur 5.10 Control of Impurities (1) • Drug Monograph covers organic and inorganic
impurities
• The ‘Related substances’ test is a general test, which
covers relevant organic impurities
- May be supplemented by specific tests to control a specific impurity - If only specific tests, control of organic impurities is still required
• Different impurity profiles: one test or several tests to
control all known profiles
• Only the tests necessary for a known profile for the
source need be performed to establish compliance.
• Residual solvents to be controlled (Ph Eur 5.4 and
2.4.24).
Deficiencies: Impurities Sean Jones
Slide 6
October 2005 ©
3
Ph Eur 5.10 Control of Impurities (2) • The active substance monograph is based on • • • •
information at time of preparation May not be exhaustive Specified impurities and Other detectable impurities New Impurities / Specified impurities above set limit New impurities may require new analytical techniques - To be controlled according to the General monograph - To be qualified according to the General monograph - Revision of the monograph initiated
Deficiencies: Impurities Sean Jones
Slide 7
October 2005 ©
Drug Substance Specification Drug Substance Specification = • Drug Substance Monograph plus • General Monograph (2034) “Substances for
Pharmaceutical Use” plus • General Text (5.10) “Impurities in Substances for Pharmaceutical Use” plus • General Text (5.4) “Residual Solvents” The joint application of these monographs provide an assurance of quality and safety Deficiencies: Impurities Sean Jones
Slide 8
October 2005 ©
4
Top 10 Deficiencies: Impurities CONTROL OF STARTING MATERIALS (3.2.S.2.3 and 2.4) 1 Absent, insufficient or unjustified impurity profile for starting materials. No discussion of carry-over to the final substance 2 Specification for all reagents, solvents and water. Include purity tests 3 Specification for the starting materials should include suitable limits for impurities and solvents IMPURITIES (3.2.S.3.2) 8 Detailed discussion on impurities: origin, correspondence with transparency statement. CONTROL OF ACTIVE SUBSTANCE (3.2.S.4) 4 Limits for impurities should be in accordance with the specific and general monographs Slide 9
Deficiencies: Impurities Sean Jones
October 2005 ©
Simple Synthesis Scheme A+B (B’)
C (C’)
Starting Materials
Intermediate
By products
~D (~D’) Crude Active
By products
D (D’) Pure Active
Degradants
Organic Impurities Reagents Solvents
Deficiencies: Impurities Sean Jones
------------------------------------------
Slide 10 October 2005 ©
5
Control Of Starting Materials (Sections 3.2.S.2.3 and 2.4 of the Dossier) • Information demonstrating that the materials meet
• •
• •
standards appropriate for their intended use should be provided. Specifications should be justified, supported by appropriate details of the materials’ synthesis and batch data. Potentially reactive and isomeric impurities, which may carry through, unchanged or as derivatives, should be fully discussed and controlled. For critical attributes, tested by non-pharmacopoeial methods, then validation data may be required. The specifications for intermediates should be similarly addressed.
Deficiencies: Impurities Sean Jones
Slide 11
October 2005 ©
Control Of Solvents and Reagents (Section 3.2.S.2.3 of the Dossier) • Water should comply with NfG on Quality of Water for •
• • • •
Pharmaceutical Use Solvents used at the final stages of the synthesis require more stringent control than those used in earlier stages. - Class I solvents to be avoided. Specifications for all reagents should be provided. - Novel reagents should be fully discussed Identification tests and an assay should be specified Reactive and toxic impurities should be specified Important performance attributes should be specified e.g. Adsorption Power for Activated Charcoal
Deficiencies: Impurities Sean Jones
Slide 12
October 2005 ©
6
Impurities (Section 3.2.S.3.2 of the Dossier)
Information on impurities should be provided: • Potential impurities should be discussed arising from synthesis and degradation • Data for impurities found should be provided • Data to support the absence of toxic impurities (and absence of control in the Drug Substance Specification) should be provided • Analytical systems should be fully described and appropriate validation data provided. • Easier said than done! Slide 13
Deficiencies: Impurities Sean Jones
October 2005 ©
Impurity Profiling Id of all significant impurities Absence of possible impurities
Qualify, if necessary. Control: Revise DSS
Determine Origin
Minimise and / or Eliminate Revise Synthesis and / or Storage Deficiencies: Impurities Sean Jones
Slide 14
October 2005 ©
7
Impurity Profiling: Getting Started • Literature Review • New vs. Well Established Synthesis • New vs. Known Impurities • Development, Optimisation and Scale up,
Validation Data
Deficiencies: Impurities Sean Jones
Slide 15
October 2005 ©
Impurity Profiling: General Cues • General Properties and Characterisation Cues
- Appearance / Crystalinity / Colour and Clarity of Solution / Odour - Additional spectral peaks, - Specific Absorbance - Optical Rotation - Acidity / Alkalinity and pH - Thermal Analysis, including Melting Point •Assay - Sensitivity and Specificity • Compare with Certificated Reference Standard
Deficiencies: Impurities Sean Jones
Slide 16
October 2005 ©
8
Impurity Profiling: Potential Organic Impurities • The Starting Materials and Intermediates • By-Products
- Under and over reactants - Side reactions with reagents and solvents • Impurities from Starting Materials and
Intermediates • Chiral Products
Deficiencies: Impurities Sean Jones
Slide 17
October 2005 ©
Impurity Profiling: Known Impurities • Ph Eur quantitative method is available • • • •
(not TLC) System Suitability Testing to assure resolution and sensitivity Specified Impurity Reference standards Defined chromatographic characterisation of known impurities Peak purity measurements in case of new impurities
Deficiencies: Impurities Sean Jones
Slide 18
October 2005 ©
9
Impurity Profiling: New Impurities • Validation data required to show suitability of • • • •
Ph Eur method New method may be required - development and optimisation to be discussed Potential of coupled techniques Reference standards Degradation of new impurities
Deficiencies: Impurities Sean Jones
Slide 19
October 2005 ©
Impurity Profiling: New Impurity
Int.J.Tox, (2004), 23, 41-45
Deficiencies: Impurities Sean Jones
Slide 20
October 2005 ©
10
Impurity Profiling: By-Products
Scheme for the formation of some impurities in ethynodiol diacetate Anal.Bioanal.Chem.(2003), 317, 852-862 Deficiencies: Impurities Sean Jones
Slide 21
October 2005 ©
Impurity Profiling: Reagents and Catalysts • The description of the synthesis should be explicit. - How each reagent and solvent is removed, especially toxic materials, should be clearly described. • Toxic reagents should be controlled, using specific tests,
in the specifications for intermediates and / or the drug substance. - unless justified by provision of development and validation data that show successful removal, using a validated and sensitive analytical method. - Catalysts should be similarly addressed. - See NfG Specification Limits for Residues of Metal Catalysts • Role of General tests methods e.g. Heavy Metals Test, Sulphated Ash, should be discussed Deficiencies: Impurities Sean Jones
Slide 22
October 2005 ©
11
Impurity Profiling: Toxic impurities Specific toxic impurities • Impurity G in Paroxetine, • Chloroacetanilide in Paracetamol • Impurity B in Pethidine (tighter limit for parenteral use) • Dimethylaniline in Semi-synthetic antibiotics Production Section of Monograph • Use of tandem techniques LC –MS (Impurity G) Specific Test Methods in monographs • Dimethylaniline • Impurity F in Ibuprofen General Test Methods • Dimethylaniline • Ethylene oxide and dioxan
Ph Eur 2.4.26 Ph Eur 2.4.25
Deficiencies: Impurities Sean Jones
Slide 23
October 2005 ©
Impurity Profiling: Residual Solvents • Comprehensive guidance available • Toxicity of Solvents
- Class I to be avoided - Class II to be limited - Class III GMP limited (nmt 0.5%) • Fate of solvents and their removal used should be fully discussed • Limits for solvents used in the purification and last steps should be specified.
Deficiencies: Impurities Sean Jones
Slide 24
October 2005 ©
12
Control of Active Substance (Section 3.2.S.4 of the Dossier: Organic Impurities) • Organic Impurities in the Transparency Statement - Specified impurities are limited by the Drug Substance Monograph - Other Detectable impurities, if present, to be limited by the General Monograph • Organic Impurities NOT in the Transparency Statement - New Impurities: To be limited by the General Monograph • Single Unknown Impurities: - To be limited by the General Monograph • Total Impurities: - Limit to be justified by reference to batch data. Slide 25
Deficiencies: Impurities Sean Jones
October 2005 ©
Control Of Active Substance e.g. Ketoprofen MONOGRAPH IMPURITIES Maximum Daily Dose < 2g/day • Specified impurities: • Other detectable impurities:
A, B, C, D, E, F. G, H, I, J, K, L .
• Organic Impurity Acceptance criteria: • Related Substances (HPLC):
Impurities A and C: Any other impurity: • Total impurities (excluding Impurities A and C) • Disregard limit:
0.2%, 0.2% 0.4% 0.02%
• Method includes system suitability test and relative
retention times for all Impurities A to L.
Deficiencies: Impurities Sean Jones
Slide 26
October 2005 ©
13
Control Of Active Substance e.g. Ketoprofen IMPURITIES FOUND Specified impurities : A, C, E. (use specific monograph) Other detectable impurities: G, H. (use general monograph) Unidentified impurities: > 0.05% - < 0.10% (use general monograph)
DRUG SUBSTANCE SPECIFICATION: Related substances (HPLC Ph Eur method) Impurities A, C and E: ≤ 0.2% Impurities G and H: ≤ 0.15% (added to EDQM certificate) Any other impurity (not specified in the monograph): ≤ 0.10% (added to EDQM certificate) Total impurities (excluding Impurities A and C): ≤ 0.4% Deficiencies: Impurities Sean Jones
Slide 27
October 2005 ©
Control Of Active Substance e.g. Sulfadiazine MONOGRAPH IMPURITIES Maximum Daily Dose > 2g/day • No transparency statement • Organic Impurity Acceptance criteria: • Related Substances (TLC):
Any impurity: 0.5%
•The impurity investigation to be undertaken using
a quantitative and validated method e.g. HPLC Deficiencies: Impurities Sean Jones
Slide 28
October 2005 ©
14
Control Of Active Substance e.g. Sulfadiazine IMPURITIES FOUND
Sulfanilamide: up to 0.3% (use general monograph) 2-hydroxypyrimidine up to 0.1% (use general monograph) Unidentified impurities > 0.03% - < 0.05% (use general monograph) Both known impurities qualified, by reference to published data. MONOGRAPH Test for Related substances
TLC test superseded by HPLC method
(use Chapter 5.10).
DRUG SUBSTANCE SPECIFICATION:
Related substances
(HPLC method to be annexed to certificate replacing TLC in monograph)
Sulfanilamide: 2-hydroxypyrimidine Single unknown impurity: certificate) Total Impurities: Deficiencies: Impurities
≤ 0.3% ≤ 0.1% ≤ 0.05%
(added to EDQM certificate) (added to EDQM certificate) (added to EDQM
≤ 0.5%
Sean Jones
Slide 29
October 2005 ©
Summary The Regulatory Framework • DSS = General Monograph + Specific monograph • Quantitative methods required Top 10 Deficiencies: Impurities • Control of Starting Materials (3.2.S.2.3 and 2.4) • Impurities (3.2.S.3.2) - Impurity Profiling • Control of Active Substance (3.2.S.4) Further Information • Directives, NfG, Bibliography and Websites Deficiencies: Impurities Sean Jones
Slide 30
October 2005 ©
15
EU Directives Medicines DIRECTIVE 2001/83/EC relating to medicinal products for human use. Amended by Directives 2002/98/EC, 2003/63/EC, 2004/24/EC and 2004/27/EC. TSE EMEA/410/01 Rev. 2 NfG on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (has force of law by reference to Annex 1 of Medicines Directive)
Plastics DIRECTIVE 2002/72/EC relating to plastic materials and articles intended to come into contact with foodstuffs Deficiencies: Impurities Sean Jones
Slide 31
October 2005 ©
Notes for Guidance CHEMISTRY OF ACTIVE SUBSTANCE
• CHMP/QWP/297/93 Rev. 1 corr Guideline on Summary of
Requirements for Active Substances in the Quality Part of the Dossier • CPMP/QWP/130/96 Rev. 1 Note for guidance on Chemistry of the New Active Substance • 3CC29A Investigation of Chiral Active Substances
IMPURITIES OF ACTIVE SUBSTANCE
• CPMP/QWP/1529/04 Guideline on Control of Impurities of
Pharmaceutical Substances: Compliance with the European Pharmacopoeia General monograph “Substances for Pharmaceutical Use” and General Chapter “Control of Impurities in Substances for Pharmaceutical Use” • CPMP/QWP/1529/04 Guideline on Control of Impurities of Pharmacopoeial Substances • Topic Q3A, NfG on Impurities Testing: Impurities in New Drug Substances Deficiencies: Impurities Sean Jones
Slide 32
October 2005 ©
16
Notes for Guidance SPECIFICATIONS, METHODOLOGY AND VALIDATION • Topic Q6A, NfG Specifications: Test procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances • Topic Q2B NfG on Validation of Analytical Procedures: Methodology • Topic Q2A NfG on Validation of Analytical Methods: Definitions and Terminology STABILITY TESTIG OF THE ACTIVE SUBSTANCE • CPMP/QWP/122/02 Rev. 1 Note for guidance on Stability Testing of Existing Active Substances and Related Finished products WATER • CPMP/QWP/158/01Note For Guidance on Quality of Water for Pharmaceutical Use Deficiencies: Impurities Sean Jones
Slide 33
October 2005 ©
Notes for Guidance RESIDUAL SOLVENTS • Topic Q3C NfG on Impurities: Residual Solvents • CPMP/QWP/450/03: Annexes to Specifications for class 1 and class 2 residual solvents in active substances • Topic Q3C(M) NfG on Impurities: Residual Solvents Permissible Daily Exposure (TDE) for Tetrahydrofuran and N. Methylpyyrolidone • Topic Q3C(M) Maintenance for NfG on Impurities:Residual Solvents - Type of Maintenance: Updating based on new information CATAYLSTS AND GENOTOXIC IMPURITIES • CPMP/SWP/QWP/44446/00 Draft Note for Guidance on Specification Limits for Residues of Metal Catalysts • CPMP/SWP/5199/02 Draft Guideline on the Limits of Genotoxic Impurities
Deficiencies: Impurities Sean Jones
Slide 34
October 2005 ©
17
Bibliography • Handbook of Isolation and Characterisation of Impurities
in Pharmaceuticals. Eds: A Aahuja and K Mills Alsante. Academic Press, 2003, ISBN 012044982X
• Identification and Determination of Impurities in Drugs
Editor: S. Görög. Elsevier, 2000, ISBN 0444828990
• Impurities Evaluation of Pharmaceuticals.
Author: S Ahuja. Marcel Dekker, 1998, ISBN 0-82479884-8
Deficiencies: Impurities Sean Jones
Slide 35
October 2005 ©
Internet Sites • Ph Eur / EDQM: http://www.pheur.org • EMEA: http://www.emea.eu.int • EU Commission (Pharmaceuticals): • • • •
http://pharmacos.eudra.org/F2/home.html Heads of Agencies: http://heads.medagencies.org ICH: http://www.ich.org FDA: http://www.fda.cder.index.html WHO: http://www.who.int/en/
Deficiencies: Impurities Sean Jones
Slide 36
October 2005 ©
18
The main deficiencies found in dossiers for chemical purity Dr P.Poukens-Renwart and Dr D. Byrne Scientific officers Certification Unit, EDQM
Istanbul October 2005
Summary: • • • • • •
Figures Deficiencies at receipt Top ten deficiencies Other deficiencies (new development) Presentation of data Conclusions Istanbul October 2005
Average time to get a CEP: 21 months (min 6 months, max 6 years)
Istanbul October 2005
Number of assessments for CEP
Istanbul October 2005
Requests for add info after 1st assessment: Average number of questions: 11 (min 0, max 25)
Istanbul October 2005
(9 in 2004)
Content of the dossier • PA/PH/CEP (04) 1, 3R: Content of dossier for chemical purity: Revision of annex 1 of the Resolution APCSP (99) 4: CTD format • Application form (declarations)
Istanbul October 2005
Dossiers blocked at receipt 9% of applications received in 2004 (24% in 2002) • ADMINISTRATIVE REASONS: Missing application form/declarations/samples/ QOS
• TECHNICAL REASONS: 2 processes / incomplete documentation / Class I solvents / Referred monograph ≠ current Ph. Eur monograph / related substances controlled by TLC Istanbul October 2005
Application form – – – – –
Details on holder, manuf. site: on the CEP Details on contact person/company for correspondence History of the substance Retest period Declarations (templates): GMP, willingness to be inspected, absence / presence of material of animal/human origin
NB: 2 different forms: new requests and revisions Istanbul October 2005
CTD format • • • • •
(3.2.S.1) General information (3.2.S.2.2) Manufacturing process (3.2.S.2.3) QC of Starting materials (3.2.S.3.2) Impurities / solvents / catalysts (3.2.S.4.1) Specifications and routine tests
Istanbul October 2005
CTD format (cont) • (3.2.S.4.3) Analytical validation / suitability of the monograph • (3.2.S.4.4) Batch results • (3.2.S.5) Packaging material • (3.2.S.7) Stability
Istanbul October 2005
Repartition of questions after the first evaluation
Istanbul October 2005
TOP TEN of deficiencies 1. (3.2.S.2.3) Description of the route of synthesis of the declared starting material(s), description of impurity profile (related subst, reagents, solvents, catalysts), and carry-over of impurities to the final substance : 83.5% of dossiers (58% in 2004) 2. (3.2.S.2.3) Specification for all reagents, solvents and water. Include purity tests: 64.6% (38% in 2004) Istanbul October 2005
TOP TEN deficiencies (cont) 3. (3.2.S.2.3) Specification of the starting materials should include suitable limits for impurities and solvents: 48.1% (29% in 2004). 4. (3.2.S.2.2) Detailed description of each step of the manufacturing process: quantities of starting materials, reagents, solvents,…operating conditions: 35.4%
Istanbul October 2005
TOP TEN deficiencies (cont) 4. Limits for impurities should be in accordance with the specific monograph + general monograph 2034 (unspecified imp: 0.10%): 35.4% (38% in 2004). 5. Demonstration that all solvents used are removed or suitably limited (validated method): 34.2% (42% in 2004)
Istanbul October 2005
TOP TEN deficiencies (cont) 6. (3.2.S.2.2) Maximum/typical batch size: 29.1% (38% in 2004) 6. (3.2.S.5) Characterisation of reference standards: 29.1% 7. (3.2.S.2.3) Proof of absence of particular reagents in the final substance (catalysts, alkylating agents, …): 27.8 % (42% in 2004) Istanbul October 2005
TOP TEN deficiencies (cont) 8. (3.2.S.3.2) Illustration of the impurity profile based on typical chromatograms : 26.6% 9.(3.2.S.3.2) Detailed discussion on impurities: - origin, correspondence with transparency list : 22.8% - levels found, setting of limits: 22.8%
Istanbul October 2005
TOP TEN deficiencies (cont) 9. (3.2.S.4.4) Results on 3 batches (size + manufacturing date) : 22.8% 10.(3.2.S.1) History of the substance : 21.5% (29% in 2004)
Istanbul October 2005
Deficiencies linked to the new developments of the procedure • General monograph for substances for pharmaceutical use (2034) =>Quantitative methods should be used for the control of related substances: TLC IS NO LONGER ACCEPTABLE !!!
Istanbul October 2005
Deficiencies linked to new developments of the procedure (cont) • Implementation PA/PH/CEP (04) 1, 3R: Content of dossier for chemical purity: Revision of annex 1 of the Resolution AP-CSP (99) 4: - CTD format - Declaration of the absence of any material of human / animal origin
Istanbul October 2005
Data presentation • Data given in the dossier should be : – Clear – Concise – Readable – Obtained from recent analysis
Istanbul October 2005
Conclusions: how to avoid deficiencies ? • Revised annex 1 to resolution « content of the dossier » (including CTD format) • Top ten deficiencies • Implementation of recent developments Istanbul October 2005
THANK YOU! • EDQM Internet site www.pheur.org • for questions on the procedure [email protected]
Istanbul October 2005
CERTIFICATION OF SUITABILITY OF MONOGRAPHS OF THE EUROPEAN PHARMACOPOEIA 5TH EDITION WORKSHOP SESSION: An outline of the main deficiencies in dossiers and how to avoid them Istanbul October 2005
Deficiencies related to manufacturing process, control of drug substance and stability Dr. Samuel Steiner Cantonal Pharmacist of the Canton of Berne Switzerland
3.2.S.2.2. Manufacturing Method • Brief outline and flow chart • Detailed description, including - typical / maximum batch size - narrative description, including explanation of chemical reactions - all materials and reagents introduced and typical quantities, yields - operating conditions (ranges of T°C, time, pH..) - structure of isolated intermediates
Certification Conference, Istanbul, 27-28 October 2005
2
3.2.S.2.2. Manufacturing Method - re-processing, re-working, recovery (where, how)
typical quantities, yields operating conditions (ranges of T°C, time, pH..) - IPC (in process controls) : where, how, methods, specifications - options (alternatives) - Blending, mixing sub batches (QC where?) Certification Conference, Istanbul, 27-28 October 2005
3
3.2.S.2.2. Manufacturing Method • Semi-synthetic products: Fermentation steps involved in synthesis of starting material ? - Characterisation of fermented starting material, incl. detailed impurity profile - Compliance with general monograph Products of Fermentation 1468 - Carry over of fermentation impurities - TSE risk substances!
Certification Conference, Istanbul, 27-28 October 2005
4
3.2.S.2.3. Quality Control of Materials •
Definition of starting material(s) - manufactured in-house or purchased? - few steps synthesis: details of the synthesis of the starting materials (flow chart)
detailed specifications for impurities
• Suitable specification for all materials used - incl. purity tests for solvents, quality of water.. Compliance with EP requirements for starting material/key intermediates/solvents => cannot be imposed 3.2.S.2.4. Control of Critical Steps and intermediates Certification Conference, Istanbul, 27-28 October 2005
5
3.2.S.4. Control of the Drug Substance • Reference to the right (EP) monograph and its tests • Include additional/alternative tests (if necessary) • Appropriate limits for impurities, solvents,... in accordance with the process and relevant guidelines => General monograph 2034 • Adequate methods description => format to be appended to the CEP • Biological substances – information on inactivation/removal infectious material when required? Certification Conference, Istanbul, 27-28 October 2005
6
3.2.S.4.3 Validation of analytical procedures • All in-house methods should be validated (incl. non-routine methods) - ICH Q2B for methodology - Typical chromatograms (selection, illustration of the chromatograms) • Cross-validation against Ph.Eur. - comparative results from the same samples
Certification Conference, Istanbul, 27-28 October 2005
7
Other requirements • 3.2.S.4.4 Batch data (3 batches) - in line with specification (methods used?) - Details on batches tested (batch nr., size, date of manufacture, date of analyses) - Numerical figures (adequate digits, “complies” not appropriate)
Certification Conference, Istanbul, 27-28 October 2005
8
Other requirements • 3.2.S.5 Reference substances:
Characterisation of reference standards Ph.Eur. Standards (CRS)
• 3.2.S.6 Packaging Material: - Description + specifications of materials - compliance with foodstuff legislation should be declared. Certification Conference, Istanbul, 27-28 October 2005
9
3.2.S.7 Stability When a retest period is to be stated on the certificate: Guideline on Stability testing: Stability testing of existing active substances and related finished products CPMP/QWP/122/02 rev 1) • ICH conditions (long-term + accelerated) + Fit the monograph statements • Study description – relevant parameters (incl. reference to methods used) • Detailed results (figures) - Impurities • Validation of in-house methods (stability indicating) • Proposed retest period, packaging material and storage conditions Certification Conference, Istanbul, 27-28 October 2005
10
3.2.S.7 Stability (cont.) • Quality specifications in accordance with the General Monograph „Substances for Pharmaceutical use“ • Proposed retest period and storage conditions: - in accordance with stability results - Extrapolation: see Guideline Note for guidance on declaration of storage conditions (CPMP/QWP/96/Rev 1)
Certification Conference, Istanbul, 27-28 October 2005
11
Thank you
Questions?
Certification Conference, Istanbul, 27-28 October 2005
12
Safeguarding public health
Deficiencies: Impurities
Related Substances, Residual Solvents and Catalysts Sean Jones Pharmaceutical Assessor Medicines and Healthcare products Regulatory Agency, UK
©
Introduction • The Regulatory Framework • Top 10 Deficiencies: Impurities • Control of Starting Materials (3.2.S.2.3
and 2.4) • Impurities (3.2.S.3.2) - Impurity Profiling
• Control of Active Substance (3.2.S.4) • Summary • NfGs, Bibliography, Websites Deficiencies: Impurities Sean Jones
Slide 2
October 2005 ©
1
Regulatory Framework • EU Directives - Medicines, Plastics, TSE. • Notes for Guidance - EU and ICH • European Pharmacopoeia - General Monograph “Substances for Pharmaceutical Use” - Specific Monographs Deficiencies: Impurities Sean Jones
Slide 3
October 2005 ©
General Monograph: Impurities SUBSTANCES FOR PHARMACEUTICAL USE Organic Impurity Threshold Limits
• All Impurities to be reported, identified wherever possible, and
qualified, (in line with Q3A).
• New impurities to be investigated and controlled. • Limits for single unknown and total impurities should also be
controlled.
Quantitative Techniques Required
• HPLC to replace semi-quantitative TLC • System Suitability Testing
Unusually Toxic Impurities
• Specific limits may be applied for impurities known to be
unusually potent or to produce toxic or unexpected pharmacological effects.
Deficiencies: Impurities Sean Jones
Slide 4
October 2005 ©
2
Impurity Threshold Limits Maximum daily dose
Reporting threshold
Identification threshold
Qualification threshold
≤ 2 g/day
> 0.05%
> 0.10% or > 1.0 mg/day
> 0.15% or >1.0 mg/day
(whichever the lower)
(whichever the lower)
> 0.05%
> 0.05%
> 2 g/day
> 0.03%
EXEMPT: Less stringent limits possible, if justified Biologicals, biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, products of fermentation and semi-synthetic products derived therefrom, herbal products and crude products of animal or plant origin. Deficiencies: Impurities Sean Jones
Slide 5
October 2005 ©
Ph Eur 5.10 Control of Impurities (1) • Drug Monograph covers organic and inorganic
impurities
• The ‘Related substances’ test is a general test, which
covers relevant organic impurities
- May be supplemented by specific tests to control a specific impurity - If only specific tests, control of organic impurities is still required
• Different impurity profiles: one test or several tests to
control all known profiles
• Only the tests necessary for a known profile for the
source need be performed to establish compliance.
• Residual solvents to be controlled (Ph Eur 5.4 and
2.4.24).
Deficiencies: Impurities Sean Jones
Slide 6
October 2005 ©
3
Ph Eur 5.10 Control of Impurities (2) • The active substance monograph is based on • • • •
information at time of preparation May not be exhaustive Specified impurities and Other detectable impurities New Impurities / Specified impurities above set limit New impurities may require new analytical techniques - To be controlled according to the General monograph - To be qualified according to the General monograph - Revision of the monograph initiated
Deficiencies: Impurities Sean Jones
Slide 7
October 2005 ©
Drug Substance Specification Drug Substance Specification = • Drug Substance Monograph plus • General Monograph (2034) “Substances for
Pharmaceutical Use” plus • General Text (5.10) “Impurities in Substances for Pharmaceutical Use” plus • General Text (5.4) “Residual Solvents” The joint application of these monographs provide an assurance of quality and safety Deficiencies: Impurities Sean Jones
Slide 8
October 2005 ©
4
Top 10 Deficiencies: Impurities CONTROL OF STARTING MATERIALS (3.2.S.2.3 and 2.4) 1 Absent, insufficient or unjustified impurity profile for starting materials. No discussion of carry-over to the final substance 2 Specification for all reagents, solvents and water. Include purity tests 3 Specification for the starting materials should include suitable limits for impurities and solvents IMPURITIES (3.2.S.3.2) 8 Detailed discussion on impurities: origin, correspondence with transparency statement. CONTROL OF ACTIVE SUBSTANCE (3.2.S.4) 4 Limits for impurities should be in accordance with the specific and general monographs Slide 9
Deficiencies: Impurities Sean Jones
October 2005 ©
Simple Synthesis Scheme A+B (B’)
C (C’)
Starting Materials
Intermediate
By products
~D (~D’) Crude Active
By products
D (D’) Pure Active
Degradants
Organic Impurities Reagents Solvents
Deficiencies: Impurities Sean Jones
------------------------------------------
Slide 10 October 2005 ©
5
Control Of Starting Materials (Sections 3.2.S.2.3 and 2.4 of the Dossier) • Information demonstrating that the materials meet
• •
• •
standards appropriate for their intended use should be provided. Specifications should be justified, supported by appropriate details of the materials’ synthesis and batch data. Potentially reactive and isomeric impurities, which may carry through, unchanged or as derivatives, should be fully discussed and controlled. For critical attributes, tested by non-pharmacopoeial methods, then validation data may be required. The specifications for intermediates should be similarly addressed.
Deficiencies: Impurities Sean Jones
Slide 11
October 2005 ©
Control Of Solvents and Reagents (Section 3.2.S.2.3 of the Dossier) • Water should comply with NfG on Quality of Water for •
• • • •
Pharmaceutical Use Solvents used at the final stages of the synthesis require more stringent control than those used in earlier stages. - Class I solvents to be avoided. Specifications for all reagents should be provided. - Novel reagents should be fully discussed Identification tests and an assay should be specified Reactive and toxic impurities should be specified Important performance attributes should be specified e.g. Adsorption Power for Activated Charcoal
Deficiencies: Impurities Sean Jones
Slide 12
October 2005 ©
6
Impurities (Section 3.2.S.3.2 of the Dossier)
Information on impurities should be provided: • Potential impurities should be discussed arising from synthesis and degradation • Data for impurities found should be provided • Data to support the absence of toxic impurities (and absence of control in the Drug Substance Specification) should be provided • Analytical systems should be fully described and appropriate validation data provided. • Easier said than done! Slide 13
Deficiencies: Impurities Sean Jones
October 2005 ©
Impurity Profiling Id of all significant impurities Absence of possible impurities
Qualify, if necessary. Control: Revise DSS
Determine Origin
Minimise and / or Eliminate Revise Synthesis and / or Storage Deficiencies: Impurities Sean Jones
Slide 14
October 2005 ©
7
Impurity Profiling: Getting Started • Literature Review • New vs. Well Established Synthesis • New vs. Known Impurities • Development, Optimisation and Scale up,
Validation Data
Deficiencies: Impurities Sean Jones
Slide 15
October 2005 ©
Impurity Profiling: General Cues • General Properties and Characterisation Cues
- Appearance / Crystalinity / Colour and Clarity of Solution / Odour - Additional spectral peaks, - Specific Absorbance - Optical Rotation - Acidity / Alkalinity and pH - Thermal Analysis, including Melting Point •Assay - Sensitivity and Specificity • Compare with Certificated Reference Standard
Deficiencies: Impurities Sean Jones
Slide 16
October 2005 ©
8
Impurity Profiling: Potential Organic Impurities • The Starting Materials and Intermediates • By-Products
- Under and over reactants - Side reactions with reagents and solvents • Impurities from Starting Materials and
Intermediates • Chiral Products
Deficiencies: Impurities Sean Jones
Slide 17
October 2005 ©
Impurity Profiling: Known Impurities • Ph Eur quantitative method is available • • • •
(not TLC) System Suitability Testing to assure resolution and sensitivity Specified Impurity Reference standards Defined chromatographic characterisation of known impurities Peak purity measurements in case of new impurities
Deficiencies: Impurities Sean Jones
Slide 18
October 2005 ©
9
Impurity Profiling: New Impurities • Validation data required to show suitability of • • • •
Ph Eur method New method may be required - development and optimisation to be discussed Potential of coupled techniques Reference standards Degradation of new impurities
Deficiencies: Impurities Sean Jones
Slide 19
October 2005 ©
Impurity Profiling: New Impurity
Int.J.Tox, (2004), 23, 41-45
Deficiencies: Impurities Sean Jones
Slide 20
October 2005 ©
10
Impurity Profiling: By-Products
Scheme for the formation of some impurities in ethynodiol diacetate Anal.Bioanal.Chem.(2003), 317, 852-862 Deficiencies: Impurities Sean Jones
Slide 21
October 2005 ©
Impurity Profiling: Reagents and Catalysts • The description of the synthesis should be explicit. - How each reagent and solvent is removed, especially toxic materials, should be clearly described. • Toxic reagents should be controlled, using specific tests,
in the specifications for intermediates and / or the drug substance. - unless justified by provision of development and validation data that show successful removal, using a validated and sensitive analytical method. - Catalysts should be similarly addressed. - See NfG Specification Limits for Residues of Metal Catalysts • Role of General tests methods e.g. Heavy Metals Test, Sulphated Ash, should be discussed Deficiencies: Impurities Sean Jones
Slide 22
October 2005 ©
11
Impurity Profiling: Toxic impurities Specific toxic impurities • Impurity G in Paroxetine, • Chloroacetanilide in Paracetamol • Impurity B in Pethidine (tighter limit for parenteral use) • Dimethylaniline in Semi-synthetic antibiotics Production Section of Monograph • Use of tandem techniques LC –MS (Impurity G) Specific Test Methods in monographs • Dimethylaniline • Impurity F in Ibuprofen General Test Methods • Dimethylaniline • Ethylene oxide and dioxan
Ph Eur 2.4.26 Ph Eur 2.4.25
Deficiencies: Impurities Sean Jones
Slide 23
October 2005 ©
Impurity Profiling: Residual Solvents • Comprehensive guidance available • Toxicity of Solvents
- Class I to be avoided - Class II to be limited - Class III GMP limited (nmt 0.5%) • Fate of solvents and their removal used should be fully discussed • Limits for solvents used in the purification and last steps should be specified.
Deficiencies: Impurities Sean Jones
Slide 24
October 2005 ©
12
Control of Active Substance (Section 3.2.S.4 of the Dossier: Organic Impurities) • Organic Impurities in the Transparency Statement - Specified impurities are limited by the Drug Substance Monograph - Other Detectable impurities, if present, to be limited by the General Monograph • Organic Impurities NOT in the Transparency Statement - New Impurities: To be limited by the General Monograph • Single Unknown Impurities: - To be limited by the General Monograph • Total Impurities: - Limit to be justified by reference to batch data. Slide 25
Deficiencies: Impurities Sean Jones
October 2005 ©
Control Of Active Substance e.g. Ketoprofen MONOGRAPH IMPURITIES Maximum Daily Dose < 2g/day • Specified impurities: • Other detectable impurities:
A, B, C, D, E, F. G, H, I, J, K, L .
• Organic Impurity Acceptance criteria: • Related Substances (HPLC):
Impurities A and C: Any other impurity: • Total impurities (excluding Impurities A and C) • Disregard limit:
0.2%, 0.2% 0.4% 0.02%
• Method includes system suitability test and relative
retention times for all Impurities A to L.
Deficiencies: Impurities Sean Jones
Slide 26
October 2005 ©
13
Control Of Active Substance e.g. Ketoprofen IMPURITIES FOUND Specified impurities : A, C, E. (use specific monograph) Other detectable impurities: G, H. (use general monograph) Unidentified impurities: > 0.05% - < 0.10% (use general monograph)
DRUG SUBSTANCE SPECIFICATION: Related substances (HPLC Ph Eur method) Impurities A, C and E: ≤ 0.2% Impurities G and H: ≤ 0.15% (added to EDQM certificate) Any other impurity (not specified in the monograph): ≤ 0.10% (added to EDQM certificate) Total impurities (excluding Impurities A and C): ≤ 0.4% Deficiencies: Impurities Sean Jones
Slide 27
October 2005 ©
Control Of Active Substance e.g. Sulfadiazine MONOGRAPH IMPURITIES Maximum Daily Dose > 2g/day • No transparency statement • Organic Impurity Acceptance criteria: • Related Substances (TLC):
Any impurity: 0.5%
•The impurity investigation to be undertaken using
a quantitative and validated method e.g. HPLC Deficiencies: Impurities Sean Jones
Slide 28
October 2005 ©
14
Control Of Active Substance e.g. Sulfadiazine IMPURITIES FOUND
Sulfanilamide: up to 0.3% (use general monograph) 2-hydroxypyrimidine up to 0.1% (use general monograph) Unidentified impurities > 0.03% - < 0.05% (use general monograph) Both known impurities qualified, by reference to published data. MONOGRAPH Test for Related substances
TLC test superseded by HPLC method
(use Chapter 5.10).
DRUG SUBSTANCE SPECIFICATION:
Related substances
(HPLC method to be annexed to certificate replacing TLC in monograph)
Sulfanilamide: 2-hydroxypyrimidine Single unknown impurity: certificate) Total Impurities: Deficiencies: Impurities
≤ 0.3% ≤ 0.1% ≤ 0.05%
(added to EDQM certificate) (added to EDQM certificate) (added to EDQM
≤ 0.5%
Sean Jones
Slide 29
October 2005 ©
Summary The Regulatory Framework • DSS = General Monograph + Specific monograph • Quantitative methods required Top 10 Deficiencies: Impurities • Control of Starting Materials (3.2.S.2.3 and 2.4) • Impurities (3.2.S.3.2) - Impurity Profiling • Control of Active Substance (3.2.S.4) Further Information • Directives, NfG, Bibliography and Websites Deficiencies: Impurities Sean Jones
Slide 30
October 2005 ©
15
EU Directives Medicines DIRECTIVE 2001/83/EC relating to medicinal products for human use. Amended by Directives 2002/98/EC, 2003/63/EC, 2004/24/EC and 2004/27/EC. TSE EMEA/410/01 Rev. 2 NfG on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (has force of law by reference to Annex 1 of Medicines Directive)
Plastics DIRECTIVE 2002/72/EC relating to plastic materials and articles intended to come into contact with foodstuffs Deficiencies: Impurities Sean Jones
Slide 31
October 2005 ©
Notes for Guidance CHEMISTRY OF ACTIVE SUBSTANCE
• CHMP/QWP/297/93 Rev. 1 corr Guideline on Summary of
Requirements for Active Substances in the Quality Part of the Dossier • CPMP/QWP/130/96 Rev. 1 Note for guidance on Chemistry of the New Active Substance • 3CC29A Investigation of Chiral Active Substances
IMPURITIES OF ACTIVE SUBSTANCE
• CPMP/QWP/1529/04 Guideline on Control of Impurities of
Pharmaceutical Substances: Compliance with the European Pharmacopoeia General monograph “Substances for Pharmaceutical Use” and General Chapter “Control of Impurities in Substances for Pharmaceutical Use” • CPMP/QWP/1529/04 Guideline on Control of Impurities of Pharmacopoeial Substances • Topic Q3A, NfG on Impurities Testing: Impurities in New Drug Substances Deficiencies: Impurities Sean Jones
Slide 32
October 2005 ©
16
Notes for Guidance SPECIFICATIONS, METHODOLOGY AND VALIDATION • Topic Q6A, NfG Specifications: Test procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances • Topic Q2B NfG on Validation of Analytical Procedures: Methodology • Topic Q2A NfG on Validation of Analytical Methods: Definitions and Terminology STABILITY TESTIG OF THE ACTIVE SUBSTANCE • CPMP/QWP/122/02 Rev. 1 Note for guidance on Stability Testing of Existing Active Substances and Related Finished products WATER • CPMP/QWP/158/01Note For Guidance on Quality of Water for Pharmaceutical Use Deficiencies: Impurities Sean Jones
Slide 33
October 2005 ©
Notes for Guidance RESIDUAL SOLVENTS • Topic Q3C NfG on Impurities: Residual Solvents • CPMP/QWP/450/03: Annexes to Specifications for class 1 and class 2 residual solvents in active substances • Topic Q3C(M) NfG on Impurities: Residual Solvents Permissible Daily Exposure (TDE) for Tetrahydrofuran and N. Methylpyyrolidone • Topic Q3C(M) Maintenance for NfG on Impurities:Residual Solvents - Type of Maintenance: Updating based on new information CATAYLSTS AND GENOTOXIC IMPURITIES • CPMP/SWP/QWP/44446/00 Draft Note for Guidance on Specification Limits for Residues of Metal Catalysts • CPMP/SWP/5199/02 Draft Guideline on the Limits of Genotoxic Impurities
Deficiencies: Impurities Sean Jones
Slide 34
October 2005 ©
17
Bibliography • Handbook of Isolation and Characterisation of Impurities
in Pharmaceuticals. Eds: A Aahuja and K Mills Alsante. Academic Press, 2003, ISBN 012044982X
• Identification and Determination of Impurities in Drugs
Editor: S. Görög. Elsevier, 2000, ISBN 0444828990
• Impurities Evaluation of Pharmaceuticals.
Author: S Ahuja. Marcel Dekker, 1998, ISBN 0-82479884-8
Deficiencies: Impurities Sean Jones
Slide 35
October 2005 ©
Internet Sites • Ph Eur / EDQM: http://www.pheur.org • EMEA: http://www.emea.eu.int • EU Commission (Pharmaceuticals): • • • •
http://pharmacos.eudra.org/F2/home.html Heads of Agencies: http://heads.medagencies.org ICH: http://www.ich.org FDA: http://www.fda.cder.index.html WHO: http://www.who.int/en/
Deficiencies: Impurities Sean Jones
Slide 36
October 2005 ©
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