validation and its concepts and its types

validation types

1. TYPES of VALIDATION

2. Product validation Process validation Documentary evidence is based on the test for the quality of the finished (end or manufactured) product. Process validation builds the quality into the product. A set of procedures ensure product validation. Mostly are pharmacopoeial specifications . Process makes a product that meets the quality assurance, through control of manufacturing. It lowers the number of waste products in a batch and reduces the cost of production, due to rigorous testing of products. Often defective products are removed from the batch/lot. It ensures the capabilities of the system and equipment are the major part, to reduce defects and wastage. Process control reduces defects. Vigorous testing is done on the process. It ensures that validated inputs give validated products. Variations in inputs will guarantee a similar output. It assures that the end product works effectively for its intended purpose. Makes the process uniform (of the production) from one site to another site.

3. Process Validation Types of validation models Process controller validations Analytical validation Process validation Cleaning validations Types of validation 2) Retrospective Validation 3) Concurrent Validation 1) Prospective Validation (pre-market validation) 4) Revalidation

4. Types of Process Validation – Four Types Process Validation 2) Retrospective Validation 3) Concurrent Validation 1) Prospective Validation (pre-market validation) 4) Revalidation Types of process validation

5. Prospective process validation In prospective validation, validation protocol is executed before the process is put into the commercial use This is normally carried out in connection with the introduction of new drug products Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the priorities set. 5

6. Features to be considered Process is defined for a series of batches and they should be of same size as production batches. Extensive testing should be made on each batch. A series of experiments are conducted for a defined batch, to determine the criticality of factors in obtaining the finished products. Process robustness is evaluated. Each experiment is planned and documented fully, using an authorized protocol. It is a laborious process. Master batch recommendations are set for testing the critical parameters. Documentation and reporting are made for the batches (under validation). Production environment and analytical methods are validated and qualification are carried out.

7. Retrospective validation: Retrospective validation of a process is carried out for products which are already in distribution. This approach is based upon information accumulated from production, testing and control data. It involves trend analysis (using control chart, etc ) of historical manufacturing and quality control data of the product. 7

8. Product (not previously validated) Candidate for retrospective validation 2) Retrospective Validations Low profile validation Stable manufacturing history Batches (20 to 30 batches) are changes significant? Product to be sold or discontinued Consider prospective validation No No No Yes Yes Yes Selective criteria for validation sub-types

9. Selective criteria for retrospective validation Including process changes (change of approved vendors) If process is changed, no records are available Discontinue for any reason, low profile validation If to continue, retrospective validation If formulation changes, new equipment not equivalent to that previously used Changes in method of mfr that may affect the product attributes Changes in mfg site Current production show that mfg process in state of control, then based on market demand Carried out under a protocol during normal production Prospective validations essential when:

10. Sequence of steps involved 5) Critical data are analysed statistically Numerical data (from completed batches assay values, end-product test results, in-process data) 2) Organize the data in chronological sequence (batch number date) 3) Include at least 20 to 30 mfg batches. 7) Reports of findings are reviewed 4) Results of noncritical parameters are eliminated. 6) Conclusions are drawn (based of analysis) on the state of control

11. Analysis of data for retrospective validation : The in-process tests (data) and/or end-product tests (data) of the historical production batches are correlated statistically. If the in-process tests can derive end-product test results, then, retrospective validation becomes reliable.

12. Concurrent validation: Concurrent validation studies are conducted during routine production by carrying out in-process testing and/or monitoring of critical operations during the course of actual normal process. In concurrent validation, current production batches are used to monitor processing parameters to find the consistency of quality from batch to batch. 12

13. Validation - Introduction A. When a previously validated process is being transferred to a third party contract mfr or to another mfg site B. Where the product is a different strength of a previously validated product, with the same ratio of active/inactive ingredients C. Special case: not possible to complete validation before routine production Urgently required for sale or supply Conditions for concurrent validation

14. Features to be considered : The conventional production process is continued, under CGMP conditions, i.e. p remises and equipment are already validated. Under these conditions, the following procedures are adopted for concurrent validation:-   Validation is performed by authorized people. Protocol and documentation are same as prospective validation. c) In-process and finished products are tested and analyse In the end, protocols and reports are reviewed and if approval criteria are met, then the product is released into the market

15. Revalidation   Revalidation is defined as repeating full/part of the (original) documentation, as in prospective validation . It is attempted to assure that validation status of plant/equipment/manufacturing processes, computer systems, etc. is maintained continuously.

16. When process changes are observed , revalidation studies are permitted, under the following conditions.   Change in equipment (type, function, location, control systems, major repairs). Change in a certain facility (site) and/or plant and transfer of a product from one plant to another plant. Nature and extent of changes affect the product characteristics. Planned changes in the critical components, e.g. starting materials, methods, cleaning process, packaging, etc.

17. Significant changes (increase/decrease) in batch size (usually of the order of magnitude ). Sequential batches failed to meet product and process specifications

18. ii) When the documentation needs to be updated , due to periodic review of routine manufacture, revalidation is permitted under the following conditions.  SOPs being followed or to be updated. Equipment calibration requirements are under control. Preventive maintenance is in accordance with the program. Cleaning and hygiene program is still appropriate (CGMP).  

19. iii) As part of the routine quality assurance , revalidation is permitted, under the following conditions.   Non-sterile processes are low priority than sterile processes. Unplanned changes in the maintenance of equipment or instruments. Conventional equipment requires retrospective validation of a standard process.

20. Control during routine operation The validated systems should be periodically monitored to confirm that they operate within their design specification and produce water and air of acceptable quality Monitored data may compared to product specification Acton and alert levels are set depending on past data or based statistical analysis of data of PQ

21. MANUFACTURING PROCESS MODEL – STAGES OF DEVELOPMENT Process capability is defined as the studies used to determine the critical process parameters or operating variables that influence the process output, the range of numerical data and acceptable criteria.

22. Stages of development of pharmaceutical processes – Validation model.

23. Stages of Validation   The guidance describes the process validation activities in three stages   Process design: Commercial manufacturing process is defined, based on the knowledge gained from the product development and scale-up activities . Process qualification: Process is evaluated to determine, whether the manufacturer is capable of reproducing it commercially or not . Continued process verification: Ongoing assurance is gained that routine (production) process remains in a state of control.  

24. Process design : Product development can be achieved by studying the process in two steps . 1.Building and capturing process knowledge and understanding. 2.Establishing a strategy for process controls.

25. Building and capturing process knowledge and understanding : DOE studies can help in developing process knowledge. Risk analysis can be screened at the DOE studies, to minimize the variability. Computer-based or virtual simulations of certain unit operations can provide process understanding and help in avoiding problems on a commercial scale. Practicality and feasibility of the process design must be established (at a laboratory level), so as to easily transfer to the manufacturing site with minimal problems

26. 2. Establishing a strategy for process controls : The process controls are examined for each unit operation as well as the process as a whole. The strategies include reducing input variation and adjusting the process. Attention should be paid to critical steps and efforts must be continued, until the process failure is not noticed.

27. Process qualification : Qualification refers to activities for demonstrating suitability (meaning yes or no decision) for commercialization. This helps in easy transfer of the process to the manufacturing site, with minimal problems. It can be achieved in four steps. Design of a facility and qualification of utilities and equipment. Process performance qualifications (PPQ). PPQ protocol. PPQ protocol execution and report.

28. 1. Design of a facility and qualification of utilities and equipment : The facility, utilities and equipment are evaluated for qualifications (some of them are also described separately in CGMP ). Each is covered under individual plans of the overall project plan. The plan should identify the following. i ) studies or tests to use. ii) criteria appropriate to assess outcomes. iii) timing of qualification activities. iv) procedure for approval of qualifications and documentation. The relevant departments and quality unit are responsible to finalize the qualifications.

29. 2. Process performance qualifications (PPQ): combines the actual facility, utilities, equipment and trained personnel. The focus is on measurements, systems and attributes, to support the data for commercial production. During PPQ, higher levels of sampling, additional testing and greater scrutiny are attempted compared to commercial samples for obtaining greater quality assurance. Such data support the production batch. The cumulative data from all relevant studies (e.g. design studies, pilot and commercial batches) should establish manufacturing conditions, at this stage (PPQ). Based on these observations, a protocol is prepared.

30. 3. PPQ protocol : PPQ protocol is an outline of the sequence of process steps. A protocol has several details (e.g. sample plan, sampling points, number of samples, sample size, statistical analysis, etc.) related to process validation. The protocol is reviewed and approved by appropriate departments and the quality unit.

31. 4. PPQ protocol execution and report : Once a protocol is prepared, it is made available for execution, when commercial production begins. A report is then, prepared with the following details. * Summary of data collected and analysis of the data. * Evaluation of unexpected deviations and additional data, if required. * Summary of deviations and aberrations in test results that impact the validity of the process. Detailed description of corrective actions or changes Statement of conclusions in clear terms, to demonstrate that the process is in a state of control.

32. 3. Continued process verification : Continued process verification is an ongoing assurance that the process remains in a state of control, as indicated by the initial two stages (1 & 2), as observed during routine production. The process is continuously monitored At this stage, testing requirements are same or more stringent than those proposed for testing during process validation runs, due to simultaneous evaluation of validation and production.

33. Concurrent Release Concurrent release process validation means that the studies of PPQs and commercial production (of products) are conducted simultaneously. The concurrent release is rarely applied but encouraged for reasons below. Drugs with limited demand (e.g. orphan drugs, minor use, minor species, veterinary, etc.). Drugs having short half lifes (e.g. radiopharmaceuticals and those used in positron emission tomography).

34. Documentation   At each stage, documentation is made throughout the stages of the process validation lifecycle . The information should be transparent, accessible and communicated effectively.