Pharmeng Pat

IDA Industrial Estate, Little Island, Co. Cork, Ireland Tel: 353 (0)21 4297900 Fax: 353 (0)21 4297943 E-mail: [email protected] WWW: www.PharmEng.ie

Process Analytical Technology

Process Analytical Technology Process Analytical Technology (PAT) PAT has been defined by the FDA as: “Process Analytical Technologies are: systems for analysis and control of manufacturing processes based on timely measurements of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process. Process Analytical Technologies involve: optimal applications of process analytical chemistry tools, feedback process control strategies, information management tools, and/or

product/process

optimization

strategies

to

the

manufacture

of

pharmaceuticals.” i

www.fda.gov/cder/gmp/gmp2004/manufsciWP

The FDA’s & EMEA’s Process Analytical Technology (PAT) initiative is an effort to facilitate the introduction of new manufacturing tools & technologies in the pharmaceutical industry in order to achieve more efficient processes. Process Analytical Technologies are systems that enhance process understanding and assist in identifying and controlling critical points in a process. These include appropriate measurements devices that can be placed at/in- or on-line, statistical and information technology tools, and scientific systems approach for data analysis to control processes to ensure production of in-process materials and final products of desired quality. Process Analytical Technology (PAT) is really the implementation of measurement systems to the process – moving the point of analysis from the lab to the process where it can be performed automatically or by non-expert users. It can be used as tool for process control & development, providing essential information that is not readily attainable by other means. By following the process more closely we can figure out more about what makes a product ‘tick’… by gaining better understanding from this knowledge improvements to process and products can be made. PAT approaches include the use of Multivariate Statistical Process Control (MSPC) to interrogate new and existing process data more effectively allowing better extraction of information from available data. The advantages of MSPC over standard Statistical Process Control (SPC) lie in the enhanced diagnostic capability

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Process Analytical Technology in considering a multivariate method of differentiation over a univariate one. That is, considering more than one type of measurement at any given time simultaneously in combination versus following the variance of the process using a single measurement type and value. The example in Figure 1 below illustrates this well. The outlier detected in the direction of Principle Component 1 (PC1) is in the direction of normal variance for the process, i.e. the outlier is outside the range of usually observed variation in the process but is out of range in a mode that is the norm. An outlier is a statistical term. It refers to observations in a distribution of data that deviates so much from the other observations as to arouse suspicions that it was generated by a different mechanism. This type of variance could be for example the thickness measurement value from a tablet run and would be detected by using a univariate approach. The outlier that is detected in the other case illustrated is detected by considering all three available measurements in combination. In this instance the variation in the process that has been detected is very different from the norm, indicating a serious deviation in the process. What is worthy of note is the fact that had a univariate approach been employed this sample would lie within the normal population for the process and hence would not have been detected at all.

Sample with unusual variation inside the model but with a different (more significant) variance type from the model.

Variable 1 PC1

Sample with unusual variation outside the model but with the same variance type as the model.

Variable 3

Variable 2 PC2

Figure 1 Principle Component Analysis (PCA)

PAT is the enabling toolkit for a lot of other initiatives and will play a major part in Right First Time and the continuous improvement concept. In many cases the information attained utilising PAT can assist greatly in any process development and validation of equipment as the information is more descriptive of the process than

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Process Analytical Technology traditional off-line measurements or analyses. The same also applies to deviation investigations as automated logging information provided by PAT produces a more detailed audit trail of a batch’s lifecycle in production and as a result regulatory compliance is more readily demonstrable. In addition there will be a safety impact as the implementation of these approaches will result in less operator/lab personnel exposure to potent API’s and drug products. Benefits of PAT: 1. Better process understanding. 2. Introduction of real time release (RTR). 3. Cycle time reduction. 4. Less batch failure. 5. Regulatory relief. 6. Better management of change controls. PAT offers many advantages such as: •

Increased process knowledge through the use of highly sensitive measurement systems for both chemical and physical attributes.

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The ability to control key to quality attributes of a process via direct feedback from PAT measurements.

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Real time results/rapid turn around of results.

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Large sampling of a particular process.

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Improved Health and safety.

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Reject avoidance/Quality Improvement/Yield Improvement.

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Improved Regulatory Compliance.

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Controlled Processes as well as Products.

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Product cost reduction.

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Ability to manage variability.

Potential Barriers to PAT: The potential barriers to PAT are from the misconceptions that people have and these include the following: •

Misconception that it technology based and therefore expensive.

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Bleeding Edge technology-not invented here syndrome.

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Process Analytical Technology •

“There is no pressure to change from FDA, so let’s stay the same”.

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Parametric release will never happen in my life time.

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PAT has only value in new formulations.

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Not enough expertise in this company.

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Amount/level of information required to be presented to the regulators (Chemometrics/Statistical) is too great. There are challenges to the regulators also.

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Correlation between measurements during the process and release testing specifications (basis for the relief of the batch) cannot be made.

The PharmEng approach We at PharmEng Ltd. carry out a systematic approach to P.A.T which can be carried out on any process. We can draw up current process flow diagram as it is now, define the areas where PAT can add value/process knowledge /monitoring or control to your process and develop a future state map which can be used as a blueprint for a more efficient process. The steps we take are: 1. Conduct a kick off meeting and identify what client wants from PAT and reasons for using PAT. 2. PharmEng presents possible technologies / techniques & solutions available 3. Perform a detailed analysis of process, existing data and identify critical to quality parameters (CTQ). 4. Present the results of the above analysis (with recommendations for detailed investigations). 5. Perform detailed investigations / research on agreed areas. 6. Perform cost / benefit analysis. 7. Present final results.

The preliminary investigation is carried out in such a way as to gain as much relevant information in the time assigned to this phase of the project. The results of the preliminary investigation enable an assessment to be made as well as prioritisation

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Process Analytical Technology of the areas for further more detailed investigation. This approach will provide the following benefits: •

Firstly, it will ensure that any other possible areas of investigation could be identified in advance of executing the detailed investigations.

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It would prevent time and effort possibly being expended on items that are not feasible or practical.

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It would allow prioritisation based on potential benefits to be gained.

Resources: •

Full time personnel with over five years experience in P.A.T applications integration.

•

To

date

PharmEng

have

successfully

completed

various

material

assessments and pharmaceutical investigations. •

Pharmeng have access to resources from various vendors and other partnerships including UCC (Tyndall National Institute).

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PharmEng has a mutual relationship with PAT technology & software suppliers who provide robust solutions for the pharmaceutical industry and meet all regulatory compliance such as 21CFR & material of construction requirements.

Applications for solid oral dosage manufacturing: •

Raw Materials Assessment using NIR o Lot to lot comparison o Chemical & Physical attributes

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Blending o On line Homogeneity of powder/granulate o Blend end point determination o Moisture content on line o Multi-Variate Analysis

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Granulation o Granulation end point determination o Granulation particle size growth monitoring o Binder addition rates o Moisture content tracking

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Process Analytical Technology

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•

o o

Flow characteristics e.g. bulk densities Batch to batch monitoring/comparison

o o

Granulation binder manufacturing Multi-Variate Analysis

Drying o o o o o

Moisture content-on line Physical drying dynamics On-line Particle size characterisation Batch to batch monitoring/comparison Multi-Variate Analysis

Milling o o o o

Particle size tracking Batch to batch monitoring/comparison Transfer rate monitoring Multi-Variate Analysis

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Tabletting o Potency o Content Uniformity o Assay o Multi-Variate Analysis

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Coating o Coating Thickness o Spray pattern visualisation o Multi-Variate Analysis

How to contact us: Office PharmEng Ltd IDA Industrial Estate, Little Island Co.Cork Tel: Fax: Email:

+353 (0)21 4297900 +353 (0)21 4297943 [email protected]

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