Validation

1. Validation

2. Validation in the pharmaceutical and medical device industry is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a requirement for Good Manufacturing Practices and other regulatory requirements. Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following

3. Cleaning Validation • Process Validation • Analytical Method Validation • Computer System Validation Similarly, the activity of qualifying systems and equipment is divided into a number of subsections including the following:

4. Design qualification (DQ) • Component qualification (CQ) • Installation qualification (IQ) • Operational qualification (OQ) • Performance qualification (PQ)

5. Process validation is important to a wide range of industries, particularly that of pharmaceutical production. Without process validation, manufactured products would be both inconsistent and substandard

6. The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production.

7. In a guideline, validation is act of demonstrating and documenting that any procedure, process, and activity will consistently lead to the expected results. It includes the qualification of systems and equipment. • The goal of the validation is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. • In general, an entire process is validated and a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.

8. Why Is Validation Required? • It would not be feasible to use the equipments without knowing whether it will produce the product we wanted or not. • The pharmaceutical industry uses expensive materials, sophisticated facilities & equipments and highly qualified personnel. • The efficient use of these resources is necessary for the continued success of the industry. The cost of product failures, rejects, reworks, and recalls, complaints are the significant parts of the total production cost. • Detailed study and control of the manufacturing process- validation is necessary if failure to be reduced and productivity improved.

9. The pharmaceutical industries are concerned about validation because of the following reasons. • Assurance of quality • Cost reduction • Government regulation

10. Department Responsible • Site validation committee (SVC): Develop Site master Validation plan, Prepare/execute/approve validation Studies • Manufacturing department: Prepares the batches as a routine Production batch • Quality assurance: Ensure compliance, see that documentations/procedures are in place, approves protocols and reports • Quality control: Perform testing and reviews protocol and report as needed.

11. Responsible Authorities For Validation • The validation working party is convened to define progress, coordinate and ultimately, approve the entire effort, including all of the documentation generated. The working party would usually include the following staff members, preferably those with a good insight into the company's operation. • Head of quality assurance • Head of engineering • Validation manager • Production manager • Specialist validation discipline: all areas

12. Manager Production : • Responsible for manufacturing of batches and review of protocol and report. • Manager QC : • Responsible   for   analysis   of   samples collected • Executive QC: • Responsible for samples collection and submission to QC • Manager Maintenance: • Providing     utilities     and     engineering support • Executive Production : • Responsible for preparation of protocol and manufacturing of validation batches • Manager QA: • Responsible   for   protocol   authorization and preparation of summary report.

13. 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

14. 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: • Ø Installation conditions (wiring, utilities, and functionality) • Ø Calibration, preventative maintenance, cleaning schedules • Ø Safety features • Ø Supplier documentation, prints, drawings and manuals • Ø Software documentation • Ø Spare parts list • Ø Environmental conditions (such as clean room requirements, temperature and humidity) • Ø Equipment design features (i.e. materials of construction clean-ability)

15. 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: • Ø Process control limits (time, temperature, pressure, line speed and setup conditions) • Ø Software parameters • Ø Raw material specifications • Ø Process operating procedures • Ø Material handling requirements • Ø Process change control • Ø Training • Ø Short term stability and capability of the process, (latitude studies or control charts) • Ø Potential failure modes, action levels and worst-case conditions (Failure Mode and effects • Ø Fault tree analysis

16. 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: • Ø Actual product and process parameters and procedures established in OQ • Ø Acceptability of the product • Ø Assurance of process capability as established in OQ • Ø Process repeatability, long term process stability

17. Process 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. Process validation is a requirement of current Good Manufacturing Practices (GMPs) for finished pharmaceuticals and of the GMP regulations for medical devices and therefore applies to the manufacture of both drug products and medical devices. Process validation involves a series of activities taking place over the lifecycle of the product and process.

18. The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation: - “PROCESS VALIDATION” is establishing documented evidence which provides a high degree of assurance that a specific process consistently produces a product meeting its predetermined specifications and quality attributes”

21. The Process validation activities can be described in three stages. • 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.

22. Types Of Process Validation : - • The guidelines on general principles of process validation mentions four types of validation: • A) Prospective validation (or premarket validation) • B) Retrospective validation • C) Concurrent validation • D) Revalidation

23. A) Prospective validation: • Establishing documented evidence prior to process implementation that a system does what it proposed to do based on preplanned protocols. 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.

24. B) Retrospective validation: • Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process. Validation of these facilities, processes, and process controls is possible using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. Therefore, this type of validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of product, operating processes, or equipment. • This approach is rarely been used today because it’s very unlikely that any existing product hasn’t been subjected to the Prospective validation process. It is used only for the audit of a validated process.

25. C) Concurrent validation: • Concurrent validation is used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual imputation of the process. This approach involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control.

26. D) Revalidation: • Revalidation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data. This approach is essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems. Possible reasons for starting the revalidation process include: • Ø The transfer of a product from one plant to another • Ø Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality • Ø The necessity of periodic checking of the validation results • Ø Significant (usually order of magnitude) increase or decrease in batch size. • Ø Sequential batches that fail to meet product and process specifications. • Ø The scope of revalidation procedures depends on the extent of the changes and the effect upon the product.

27. Change Control • Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations. • All changes must be formally requested, documented and accepted by the validation team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined.

28. Commitment of the company to control all changes to premises, supporting utilities, systems, materials, equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned. • The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the validation team. The team should decide if a re-validation must be conducted prior to implementing the proposed change.

29. Phases Of Process Validation8, 10, 11: - • 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.

30. 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.

31. 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

32. Validation Protocol3: - • A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested.

33. 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. • In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented.

34. The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: • 1. Title  • Process Validation : An Essential Process In Pharmaceutical Industry • Submitted by phviral on Fri, 10/01/2010 - 16:21 • ...Average: • 4.Your rating: None Average: 4 (3 votes) • Author(s): phviral

35. Standard operation procedure (SOP) • The term or abbreviation SOP (Standard Operation / Operating Procedure) is widely used but specifically in the manufacture of drug products, APIs (Active Pharmaceutical Ingredients), biologics, devices and the food and cosmetic industry. A SOP (Standard Operation / Operating Procedure) contains instructions having the force of a directive, covering those features of operations that lend themselves to a definite or standardized procedure without loss of effectiveness. Standard Operating/Operation Policies and Procedures can be effective catalysts to drive performance improvement and improving organizational and operational results. They assure that processes and manufacture will be done in a similar way and lead always to the expected quality of product. SOPs must be followed by operators performing the manufacture and the testing of drugs.

36. Each efficient quality management system is based on its standard operation procedures (SOPs). In clinical research, standard operating / operation procedures (SOPs) are defined by the International Conference on Harmonization (ICH) as \"detailed, written instructions to achieve uniformity of the performance of a specific function\". SOPs are necessary for a clinical research organization whether it concerns a pharmaceutical company, a sponsor, a contract research organization, an investigator site, an Ethics Committee or any other party involved in clinical research to achieve maximum safety and efficiency of the performed clinical research operations.

37. It is therefore a must that all people and sites involved in clinical studies (both at the sponsor and at the investigative sites) have appropriate SOPs in place in order to conduct clinical research and to ensure compliance with the current regulations. The ICH GCP (good clinical practice) Step 5 Guideline (Section 3.2.2) also suggests that an Institutional Review Board (IRB) have its own SOPs or written standard procedures. This it self proves that presence of SOPs are an integral part of the clinical trial at all levels.

38. The presence of these quality documents is essential when regulatory inspections (FDA, EMEA) take place since the most frequent reported deficiencies during inspections are the lack of written SOPs and/or the failure to adhere to them. The risk of GMP non-compliance is high at organizations with a poor availability of specific SOPs and also if at all they are available the staff or the people for whom they were written are not either following them. It therefore becomes very important for the personnel to be trained on these SOPs so that they are actually aware of why and how SOPs can play important role in fulfilling the specific regulatory requirements from WHO, FDA, EMEA or other national health authorities.

39. Health authorities world wide like the FDA or EMEA expect pharmaceutical, cosmetic and food producers to describe their manufacturing processes in written SOPs. A minimum set of Standard Operation / Operating Procedure should be available in GMP manufacturing areas for the following systems: SOP for quality management SOP for deviation and change control SOP for training and organization SOP for complaints SOP for Recalls SOP for preventive maintenance SOP for the release of raw materials and finished goods SOP for out of specification results SOP for environmental monitoring SOP for material management and goods receipt SOP for pest control

40. SOP for QC testing SOP for in process control IPC testing SOP for document management SOP for the creation of SOPs SOP for corrective and preventive actions SOP for format and content of batch records SOP for qualification and validation SOP for setting up product specifications SOP for supplier qualification SOP for internal audit or the self inspection program SOP for lot numbering process