VALIDATION OFPHARMACEUTICAL INDUSTRIES PRIMA RAMADHANI 1111011003 GMP DESCRIPTION • As a process of establishing documented evidence that establishes a high degree of certainty that a particular process will consistently a product that provides the previously established specifications and quality attributes are available. Validation should thus be considered in the following situations: • Totally new process; • New equipment; • Process and equipment which have been altered to suit changing priorities; • Process where the end-product test is poor and an unreliable indicator of product quality. Elements Of Validation Design Qualification (DQ) It is documented review of the design, at an appropriate stage of stages in the project, for conformance to operational and regulatory expectations. DQ Check Items: • GMPs and regulatory requirements • Performance criteria • Facility air flow, movement flow & pressure regimes • Reliability & efficiency • Commissioning requirements • Construct ability & installation of equipment • Maintenance & access to critical equipment & instrumentation • Safety & environment impact Installation Qualification (IQ) It is documented verification that all aspects of a facility, utility or equipment that can affect product quality adhere to approved specifications and are correctly installed. Important IQ considerations are: • Installation conditions (wiring,utilities, and functionality) • Calibration, preventative maintenance, cleaning schedules • Safety features • Supplier documentation, prints, drawings and manuals • Software documentation • Spare parts list • Environmental conditions (such as clean room requirements, temperature and humidity) • Equipment design features (i.e. materials of construction cleanability) Operational Qualification (OQ) It is documented verification that all aspects of a facility, utility or equipment that can affect product quality operate to Intend throughout all anticipated ranges. OQ considerations include: • Process control limits (time, temperature, pressure, line speed and setup conditions) • Software parameters • Raw material specifications • Process operating procedures • Material handling requirements • Process change control • Training • Short term stability and capability of the process, (latitude studies or control charts) • Potential failure modes, action levels and worst-case conditions (Failure Mode and effects • Fault tree analysis Performance Qualification (PQ) It is documented verification that all aspects of a facility, utility or equipment perform as intended in meeting predetermined acceptance criteria. PQ considerations include: • Actual product and process parameters and procedures established in OQ • Acceptability of the product • Assurance of process capability as established in OQ • Process repeatability, long term process stability TYPE OF VALIDATION Prospective validation • Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps: these are then evaluated on the basis of past experience to determine whether they might lead to critical situations. • Where possible critical situations are identified, the risk is evaluated, the potential causes are investigated and assessed for probability and extent, the trial plans are drawn up, and the priorities set. • The trials are then performed and evaluated, and an overall assessment is made. • If, at the end, the results are acceptable, the process is satisfactory. • Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory. • This form of validation is essential in order to limit the risk of errors occurring on the production scale, e.g. in the preparation of injectable products. Concurrent validation • Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. • The first three production-scale batches must be monitored as comprehensively as possible. • 1The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring. • This careful monitoring of the first three production batches is sometimes regarded as prospective validation. 1 • Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product. Retrospective validation • Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated. • Recorded difficulties and failures in production are analysed to determine the limits of process parameters. • A trend analysis may be conducted to determine the extent to which the process parameters are within the permissible range. • Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. • Retrospective validation may then be useful in establishing the priorities for the validation programme. • If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be validated in accordance with the normal schedule. • For tablets which have been compressed under individual pressure-sensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. • On the other hand, it should not be applied in the manufacture of sterile products. Revalidation • Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality. • Revalidation may be divided into two broad categories: 1. Revalidation after any change having a bearing on product quality. 2. Periodic revalidation carried out at scheduled intervals. 1. Revalidation after any change having a bearing on product quality. • Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. • Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). • Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent. 2. Periodic revalidation carried out at scheduled intervals. • It is well known that process changes may occur gradually even if experienced operators work correctly according to established methods. • Similarly, equipment wear may also cause gradual changes. • Consequently, revalidation at scheduled times is advisable even if no changes have been deliberately made. • The decision to introduce periodic revalidation should be based essentially on a review of historical data, i.e. data generated during in-process and finished product testing after the latest validation, aimed at verifying that the process is under control. • During the review of such historical data, any trend in the data collected should be evaluated Process activities validation Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. • Stage 1 Process Design: The commercial process is defined during this stage based on 100 knowledge gained through development and scale-up activities. • Stage 2 - Process Qualification: During this stage, the process design is confirmed as 103 being capable of reproducible commercial manufacturing. • Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. PHASES OF VALIDATION PROCESS Phase 1 • Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production documents, operational qualification, process capability. Phase 2 • Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the critical process parameters are valid and that satisfactory products can be produced even under the "worst case" conditions. Phase 3 • Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures. • At this stage the validation team also assures that there have been no changes/ deviations that should have resulted in requalification and revalidation. • The validation protocol provides a synopsis of what is hoped to be accomplished. • The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. • The date of approval by the validation team should also be noted. The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: 1. 2. 3. 4. 5. 6. 7. 8. 9. Title Objective & Scope Responsibility Protocol Approval Validation Team Product Composition Process Flow Chart Manufacturing Process Review of Equipments / Utilities 10.Review of Raw Materials and Packing Materials 11. Review of Analytical and Batch Manufacturing Records 12. Review of Batch Quantities for Validation (Raw Materials) 13. Review of Batch Quantities for Validation (Packing Materials) 14. HSE Requirements 15. Review of Process Parameters 16. Validation Procedure 17. Sampling Location 18. Documentation 19. Acceptance Criteria 20. Summary 21. Conclusion • Validation Master Plan is a document that summarizes the company's overall philosophy, intentions and approaches to be used for establishing performance adequacy. The validation master plan should be agreed upon by management. • The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements include the list/inventory of the items to be validated and planning schedule. The format and content should include • Introduction: validation policy, scope, location and schedule • Organizational structure: personnel responsibilities • Plant/ process /product description: rational for inclusions or exclusions and extent of validation • Specific process considerations that are critical and those requiring extra attention • List of products/ processes/ systems to be validated, summarized in a matrix format, validation approach • Re-validation activities, actual status and future planning • Key acceptance criteria • Documentation format • Reference to the required sop's • Time plans of each validation project and sub-project. THANK YOU