Process Validation.pdf
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The document outlines the training on process validation led by MD Zakaria Faruki, emphasizing the importance of establishing documented evidence to ensure pharmaceutical processes produce quality products consistently. It details the four types of process validation—prospective, concurrent, retrospective, and re-validation—as well as the stages involved in the validation process. The FDA and EMA approaches to process validation are discussed, highlighting the need for ongoing monitoring and risk management to maintain product quality throughout its lifecycle.
Process Validation.pdf
- 1. TRAINING ON PROCESS VALIDATION Presented by: MD ZAKARIA FARUKI Manager, Quality Assurance Silva Pharmaceuticals Limited Date of Training January 25, 2023 Slide 1 of 26
- 2. Process Validation in Brief… • Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics. • According to the FDA, assurance of product quality is derived from careful and systemic attention to a number of important factors, including: selection of quality components and materials, adequate product and process design, and (statistical) control of the process through in-process and end-product testing. Slide 2 of 26
- 3. Process Validation in Brief… • Thus, it is through careful design (qualification) and validation of both the process and its control systems that a high degree of confidence can be established that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable. • According to the FDA’s Current Good Manufacturing Practices (CGMPs) 21CFR 211.110 a: Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Slide 3 of 26
- 4. Types of Process Validation There are 4 types of Process Validation which are as follows- 1. Prospective Process Validation: This approach to validation is normally undertaken whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences. In fact, validation of a process by this approach often leads to transfer of the manufacturing process from the development function to production. 2. Concurrent Process Validation: Establishing documented evidence that the process is in a state of control during the actual implementation of the process. This is normally performed by conducting in-process testing and/or monitoring of critical operations during the manufacture of each production batch. 3. Retrospective Process Validation: Where historic data taken from the records of the completed production batches are used to provide documented evidence that the process has been in a state of control prior to the request for such evidence. 4. Re-validation: Revalidation is required based on the assessment in the change request whenever there are changes in the process, components, equipment/ facilities or the stating materials, which could impact on product effectiveness or product characteristics and whenever it is necessary. Slide 4 of 26
- 5. Process Validation Stages • Stage 1 – Process Design: The process is defined during this stage based on knowledge gained through development and scale-up activities. Identify sources of Variability • Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Control of Variability • Stage 3 – Continued Process Verification: On going assurance is gained during routine production that the process remains in a state of control. Monitoring Variability - remains “in control” Slide 5 of 26
- 6. EMA Approach to Process Validation “A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of qualification and validation should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes.” A robust product development process is required to enable successful process validation. Before product is released to the market, the process must be shown to be robust and ensure consistent product quality irrespective of the approach used. Retrospective validation no longer acceptable by EMA. Concurrent validation only acceptable where there is a strong benefit-risk ration for the patient. Appropriate quality oversight over the whole validation life cycle is essential. Slide 6 of 26
- 7. FDA Approach to Process Validation Process Validation is “the collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product.” Objective of PV To understand and control input variability impact and manufacturing process to assure consistent product quality and reliable supply. Science and Risk based PV / PPQ – product and process understanding, good science, statistical confidence. - Statistically based sampling plans and acceptance criteria for PPQ / PV and release. Understanding the impact of variability and demonstrating control strategy is robust beyond the variability – Variability in raw materials / excipients, parameter control, operators, shifts, equipment sets, etc. Slide 7 of 26
- 8. FDA Approach to Process Validation PV Stage 3a (Establishing initial process variability) • “We recommend continued monitoring and sampling of process parameters and quality attributes at the level established during the process qualification stage until sufficient data are available to generate significant variability estimates.” PV Stage 3b (After variability established) • “Monitoring can then be adjusted to a statistically appropriate and representative level.” Slide 8 of 26
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- 13. Process Validation Demonstrates- The validity of the process design and the suitability of the process control strategy At full-scale (commercial manufacture) Provides confidence (documented evidence) that systems of monitoring, control and SOPs in production are capable of detecting and compensating for potential sources of process variability over the product lifecycle The number of PV batches to be produced should be justified Slide 13 of 26
- 14. SOP/PD/001/01: Process Validation 1. Purpose : To provide documents evidence and procedure of process validation which confirm that a process is capable of reliably and repeatedly rendering a product of the required quality. 2. Scope: This SOP is applicable for process validation of all products of Silva Pharmaceuticals Limited. Slide 14 of 26
- 15. 3.0 Responsibility 3.1 Product Development department will form a validation team with the help of Production, QA, QC and Engineering Department. 3.2 Product Development Department shall be responsible to prepare the process validation protocol for the batches to be validated, co-ordinate the entire process validation activity related to the protocol, preparation of Report & summary. 3.3 Engineering department shall be responsible to provide the utilities, status of calibration & preventive maintenance. 3.4 Quality Assurance department shall be responsible to review & appropriate the process validation protocol, co-ordinate the entire process validation activity related to the protocol. 3.5 IPQA shall be responsible to arrange the sample for analysis as per protocol. 3.6 Quality Control department shall be responsible for analysis of the finished product as per protocol. 3.7 Head of QA and Head of Product Development are accountable for this SOP. Slide 15 of 26
- 16. 4.0 Abbreviations & Definitions 4.1 Abbreviations PD= Product Development PV= Process Validation IPQA= In-Process Quality Assurance SOP= Standard Operating Procedure STP= Standard Testing Procedure PIC/S= Pharmaceuticals Inspection Co-operation Scheme 4.2 Definition of PV Process Validation is the process of ensuring and providing documentary evidence that process (within their specified design parameters) is capable of repeatedly and reliably producing a finished product of the required quality. Slide 16 of 26
- 17. 5.0 Materials and Equipment 5.1 None 6.0 Precaution / Health and Safety Considerations 6.1 Approved validation protocol before starting the process validation activity. 6.2 Identify critical steps before process validation activity. 6.3 Follow validation protocol strictly during process validation activity. 6.4 Collect data and review against predetermined acceptance criteria, while should be reflected in process validation reports. Slide 17 of 26
- 18. 7.0 Procedure 7.1 Validation Procedure 7.1.1 Product Development department will prepare a validation protocol for three consecutive batches to validate the whole process and get approval from QA. 7.1.2 Product Development department will arrange the necessary materials, manpower, equipment and are to execute the batch manufacturing record and batch packaging record as per protocol. 7.1.3 Product Development department will follow up critical process parameter as per protocol in every stage of process validation activity. 7.1.4 IPQA department will arrange the sample for analysis as per protocol. 7.1.5 Product Development department will analyze bulk and intermediate product as per protocol. 7.1.6 Quality Control department will analyze the finished product as per approved STP. 7.1.7 Quality Assurance will collect and review all analytical reports to release the product. 7.1.8 Product Development department will prepare the validation report on the basis of batch document and process validation report. Slide 18 of 26
- 19. 7.2 Validation Protocol A validation protocol should be prepared before starting the process and the following steps/parameter should be included in the protocol (Annexure-I) as draft/sample. Process description, Master Formula & Flow Chart Details of the equipment/facilities with its calibration status Personnel responsibilities Sampling plan Product Specification & Acceptance limit. Critically assessment for process stages, control variables & measuring response justification 7.3 Critical Process and Testing Parameters The purpose of the critical process parameter is to identify, evaluate and document the critical process parameters, which have a significant effect on the process or the quality of the product and to describe the ranges of the operational parameters that lead to a compliant product (design space), based on actual data generated at lab, pilot and full scale. The process must be validated within a specified range of operational for the identified critical process parameters. 7.0 Procedure (Continued…) Slide 19 of 26
- 20. Example of potentially critical parameters Example of quality characteristics to be monitored - Drug substances specification - Disintegration time - Excipients specification - Dissolution rate - Mixing & choppering speeds times - Content uniformity - Quantity of granulation liquid - Weight uniformity - Sequences and speed of adding components - Friability - Compression/ ejection force during tabletting - Hardness - Spray rate, inlet/out air temperature of the coater - Thickness - Drum rotation speed - Homogeneity (blend uniformity) - Process time - Yield - Amount of used film coating suspension/solution - Loss on drying/ Moisture content Table 1: Example of potentially critical parameters for oral solid dosage form Example of potentially critical parameters Example of quality characteristics to be monitored - Drug substances specification - Homogeneity - Excipients specification - Yield - Packaging material specification - pH - Temperature of solvent - Filling volume weight & sealing - Sequences and speed of adding components - Microbial status - Dissolving time - Viscosity - Stirrer speed time stirring - Particle size dispersed drug - Drum rotation speed - Biological activity - Process time - Stability immediate - Amount of used film coating suspension/solution Table 2: Example of potentially critical parameters for oral liquid dosage form 7.0 Procedure (Continued…) Slide 20 of 26
- 21. 7.4 Process optimization If required, one or more optimization batches (smaller than the standard batch size) can be produced using the production facilities for detailed assessment of process parameters. Protocol and Report for optimization batches have to be maintained. 7.5 Re-validation Revalidation for non-sterile products has to be performed after two years only for highly regulated market and five years for others market depending on trend, modifications, deviations and/or changes assessed in the annual product review/ product quality review. The documentation for revalidation is to be established in the same way as for the initial validation. A formal change control to initiate which defines how changes are evaluated and managed. In case of planned changes, it has to be considered whether and to what extent a revalidation of the process has to be performed. In case of deviations, resulting in e.g. failing analytical results, the process has to be thoroughly investigated and the root cause determined. The affected process steps have to be reviewed and optimizes process may have to be validated, based on a risk assessment. 7.0 Procedure (Continued…) Slide 21 of 26
- 22. 7.5 Re-validation Contd… Examples of changes: Manufacturing: changes of the manufacturing procedure, specifications, analytical procedures Drug substances: Changes of the route of synthesis, of physical properties, of specifications, of supplies Excipients: Changes of supplier, change of specifications Equipment: Changes of type or size, change in maintenance and/or calibration, change of cleaning procedure Batch size Change in the facility and/ or plant (location or site) Production area support system Accumulation of a number of minor changes 7.0 Procedure (Continued…) 7.6 Validation Report The process validation report documents the validation activities performed. It presents all pertinent findings and conclusion, especially the validation status. It has to contain at least the following (Annexure- II) as draft/sample. The study objective and a reference to be validation protocol. A summary of the performed activities with conclusions and validation status. Any deviations from the protocol, from the process or the acceptance criteria set with short description, evaluation, assessment, corrective/ preventive action as needed and conclusion Slide 22 of 26
- 23. 7.0 Procedure (Continued…) 8.6 Validation Report contd… The starting materials used including batch numbers or a reference to attached batch documentation. Facilities, equipment and control instruments used or a reference to the validation protocol or A detailed summary of all results, as required by the validation protocol from in process controls, final testing and additional testing. The results have to be compared with their acceptance criteria as defined or referenced in the validation protocol. Results of any supplementary studies as defined in the validation protocol. The decision to accept or not accept the validation study and as appropriate the rationale. Anny corrective or follow-up actions needed. As appropriate recommendations with respect to the extent and frequency of monitoring and in-process controls and their limits necessary routine production based on the experience from the validation batches. Final process parameters and their corresponding ranges Actions to be taken in the event of the acceptance limit being exceeded Short assessment/ reference to transport studies and stability reports for bulk holding times and final product as appropriate. The conclusion and recommendation should be incorporated in to the batch manufacturing and the batch packaging documents. Action to be taken in the events of limits being exceeded should be specified. Slide 23 of 26
- 24. 7.7 Release Procedure of Validation Batches After completion of validation of one batch a preliminary release notification documents will be approved by QA intended to be sold or supplied when all raw data has been generated, reviewed and meets the pre-determined acceptance criteria and when all deviations or OOS results have been investigated, evaluated, assessed, resolved documented and approved by QA. On the basis commercial distribution of the drug product will be initiated while the validation report is being completed. 8.0 Reference Document 8.1 As per WHO GMP guideline, Volume 2 8.2 PIC/s; PI 006-3, 25 September 2007 8.3 Book of Pharmaceuticals Process Validation by Robert A. Nash 9.0 Annexes 9.1 Annexure-I: Process Validation Protocol 9.2 Annexure-II: Process Validation Report 9.3 Annexure-III: Re-validation Schedule 7.0 Procedure (Continued…) Slide 24 of 26
- 25. 11.0 Training 11.1 Training is required for Officers to Above of all Departments trained by Head of Product Development department 10.0 Revision History Version No. Brief Reason for the Revision Effective Date Remarks 01 New 04/01/2018 - 02 Revision for after validity of period 26/12/2020 - Slide 25 of 26 Conclusion: Because of resource limitation, it is not always possible to validate an entire company’s product line at once. With the obvious exception that a company’s most profitable products should be given a higher priority, it is advisable to draw up a list of product categories to be validated. Process validation is done by individuals with the necessary training and experience to carry out the assignment.
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