Process validation
- 2. 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.
- 3. According to the FDA, assurance of product quality is derived from careful and systematic attention to a number of important factors, including selection of quality components and materials, adequate product and process design and control of the process through in-process and end product testing.
- 4. Conventional quality control procedures for finished product testing includes 3 basic steps: • Establishment of specifications and performance characteristics. • Selection of appropriate methodology, equipment and instrumentation. • Testing of the final product, using validated analytical and testing methods to ensure that finished product meets specifications
- 5. Qualification of the processing facility and its equipment. Qualification and validation of the manufacturing process through appropriate means Auditing, monitoring, sampling or challenging the key steps in the process for conformance to in- process and final product specifications. Revalidation when there is a significant change in either the product or its manufacturing process.
- 6. Process capability is defined as the studies used to determine the critical process parameters or operating variables that influence process output and the range of numerical data for critical process parameters that result in acceptable process output. Process qualification represents the actual studies or trials conducted to show that all systems or unit operations of a manufacturing process is intended, that all critical process parameters operate within their assigned control limits.
- 7. The strategy selected for process validation should be simple and straight forward. 1.The use of different lots of raw materials should be included. 2. Batches should be run in succession and on different days and shifts. 3.Batches should be manufactured in the equipment and facilities designed for eventual commercial production.
- 8. 4.Critical process variables should be set within their operating ranges and should not exceed their upper and lower control limits during process operation. 5. Failure to meet the requirements of the validation protocol with respect to process input and output control should be subjected to process requalification and subsequent revalidation following an thorough analysis of process data and formal discussion by the validation team.
- 9. Phase I (Process capability Design) Phase II (Process qualification phase) Phase III (Validation Maintainace Phase)
- 10. A. Prospective Process(Pre market) Validation An experimental plan called validation protocol is executed before the process is put into commercial use. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes.
- 11. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily. 1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements(completion of installation qualification). 2. The supervising personnel should have understanding of the process and its requirements 3. The design, selection and optimization of the formula have been completed. 4. The qualification trials using pilot laboratory batches have been completed in which the critical processing steps and process variables have been identified.
- 12. 5. Detailed technical information on the product and manufacturing process have been provided. 6. At least one qualification trial of a pilot production batch has been made and shows there were no significant deviations from expected performance of the process. Validation of the process by this approach often leads to transfer of the manufacturing process from the development function to production
- 13. The retrospective validation option is chosen for established products whose manufacturing processes are considered stable. Prior to undertaking retrospective validation the numerical in process and or end product test data of historic production batches are subjected to statistical analysis, the equipment, facilities and subsystems used in connection with the manufacturing process must be qualified and validated in conformance with CGMP requirements
- 14. Retrospective validation is achieving validation by documenting all the historical information (e.g. release data) for existing products and using that data to support the position that the process is under control.
- 15. 1. Gather the numerical values from the completed batch record and includes assay values, end product test results and in process data. 2. Organize these data in a chronological sequence, according to batch manufacturing data. 3. Include data from at least 20-30 manufacturing batches for analysis. If number of manufactured batches is less than 20 then include all manufactured batches in analysis. 4. Trim the data by eliminating test results from non critical processing steps and delete all numerical information.
- 16. 5.Subject the resultant data to statistical analysis and evaluation. 6. Draw a conclusion as to the state of control of the manufacturing process based upon the analysis of retrospective analysis validation data. 7.Issue a report of your findings (documented evidence)
- 17. 1. Individual assay results from content uniformity test. 2. Individual tablet hardness values 3. Dissolution time. The statistical methods like Basic statistics (mean, S.D.) ,regression analysis etc. may be employed to analyze above data.
- 18. In process monitoring of critical processing steps and end product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources
- 19. Test parameter Data source Content uniformity End product testing Dissolution time End product testing Particle size distribution In-process testing Weight variation In-process testing Tablet Hardness In-process testing Disintegration Time In-process testing
- 20. Not all of the in-process tests enumerated above are required to demonstrate that the process is in state of control. Selection should be made on the basis of the critical Processing variables to be evaluated The critical in process test parameters would be particle or granule size distribution, Tablet hardness etc.
- 21. Conditions requiring revalidation study and documentation are listed Change in a critical component(usually refers to raw materials) change or replacement in a critical piece of modular equipment Change in facility and or plant(usually location or site) Significant increase or decrease in batch size Sequential batches that fail to meet product and process specifications
- 22. Documentation associated with validation includes: — standard operating procedures (SOPs) — specifications — validation master plan (VMP) — qualification protocols and reports — validation protocols and reports.
- 23. Validation master plan (VMP) The VMP is a high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan. Validation protocol (or plan) (VP) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use. Validation report (VR) A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment
- 24. The validation master plan (VMP) should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following: — a validation policy — organizational structure of validation activities — summary of facilities, systems, equipment and processes validated and to be validated — documentation format (e.g. protocol and report format) — planning and scheduling — change control — references to existing documents.
- 25. Validation protocols should include the following significant background information: — the objectives of the study — the site of the study — the responsible personnel — description of SOPs to be followed — equipment to be used; standards and criteria for the relevant products & processes — the type of validation — the processes and/or parameters — sampling, testing and monitoring requirements — predetermined acceptance criteria for drawing conclusions.
- 26. Validation reports •There should be written reports on the qualification and validation performed. •Reports should reflect the protocols followed and include at least the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods. • The results should be evaluated, analysed and compared against the predetermined acceptance criteria. •The departments responsible for the qualification and validation work should approve the completed report. •The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful. •The quality assurance department should approve the report after the final review.
- 27. Process validation result in fewer product recalls and troubleshooting assignments in manufacturing operations and more technically and economically sound batches and their manufacturing processes. Thus through careful design and validation of both the process and its control system can establish a high degree of confidence that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable.
- 28. Nash RA ,Wachter AH , Pharmacutical Process Validation,An International 3rd Edition ,Revised &Expanded,Indian special edition,Informa Healthcare, 2011 ,volume 129. p 607-609 Potdar MA, Pharmaceutical Quality Assurance, 2nd ed., Pune: Nirali Prakashan , 2007 ICH OFFICIAL WEB http://www.ich.org