Supplementary Training modules on Good Manufacturing Practices Validations –part 2 Workshop on GMP and Quality Assurance of TB products Kuala Lumpur Malaysia, 21 – 25 February 2005 Maija Hietava M.Sci.Pharm Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster Tel: +41.22.791.3598 Fax: +41.22.791.4730 World Health Organization E-mail: hietavam@who.int

Validation principles Objectives To review: WHO validation definition Philosophy of validation Personnel requirements Protocol requirements DQ IQ OQ and PQ summary Checklist for validation Objectives: To review: WHO validation definition Philosophy of validation Personnel requirements – who should be in a competent validation team? Protocol requirements – a list of items that should form a good index for a validation protocol DQ IQ OQ and PQ summary: the heart and soul of validation. Checklist for validation: something for you to take on your GMP inspections

Validation WHO validation definition The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results. As indicated in Part 1 of this module, the WHO validation definition is: “The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.” From: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992. (WHO Technical Report Series, No 823). Annex 1.

Validation The VMP The VMP provides a summary of the company’s philosophy, policy, intentions and approach to validation. The Validation Master Plan is an important prerequisite to a validation programme, as it provides a summary of the company’s philosophy, policy, intentions and approach to validation. The content of a VMP was covered in Part 1 of this module.

Validation The WHO GMP Guidelines state: Validation studies are an essential part of good manufacturing practice and should be conducted in accordance with predefined protocols. written report and conclusion process and procedures processing testing cleaning procedures The WHO GMP Guidelines state (Section 5.1): “Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

validation Validation Quality is designed and built into the process/method/premises Functionality, consistency and repeatability is confirmed by validation The WHO GMP Guidelines state (Section 5.1): “Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

Validation Validation as such does not improve the process but it Confirms and assures that the process Has been well developed It is well maintained It operates as it should The WHO GMP Guidelines state (Section 5.1): “Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

Advantages of validation: During the process the knowledge of process increases Assures the repeatability of the process Assures the fluency of production Assures that the product is continuously according to the marketing authorisation Decreases the risk of the manufacturing problems Decreases the expenses caused by the failures in production Decreases the risks of failing in GMP Decreases the expenses of the every day production even though the validation itself will create expenses The WHO GMP Guidelines state (Section 5.1): “Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

Validation Personnel - Validation team members Quality Assurance Engineering Manufacturing Other disciplines may be involved depending on the product and process: laboratory, technical services research and development, regulatory affairs clinical chemical engineering purchasing/planning Personnel - Validation team members: A competent validation team is a multi-disciplinary team comprising: Quality Assurance Mechanical engineering Manufacturing Other disciplines may be involved depending on the product and process, eg: - Laboratory - Technical services (calibration, electrical, plumbing) - Research and development - Regulatory affairs - Clinical - Chemical engineering - Purchasing/planning

Validation Protocol development (1) Identification of process Objective and measurable criteria Length and duration of the validation Shifts, equipment Identification and quality of utilities Identification of operators and operator training and qualification Protocol development: Detailed protocols for performing validations are essential to ensure that the process, whether solid dose, liquid or sterile, is adequately validated. Process validation protocols should include: Identification of process: Objective and measurable criteria for a successful validation - Determine WHAT to verify and measure - Determine HOW to verify and measure - Determine HOW MANY to verify and measure, i.e. what statistical test of significance will be applied and what will be the confidence in the result? - Determine WHEN to verify and measure - Define acceptance AND rejection criteria - Define the required level of documentation Length and duration of the validation: Challenges to the process should simulate conditions encountered during actual manufacturing. Challenges should include the range of conditions as defined by the various action levels. Shifts, equipment to be used in the process: This is most important for sterile manufacturing especially aseptic filling and lyophilization. Identification of utilities (air, water, gas, nitrogen, vacuum, etc.) for the process equipment and quality of the utilities Identification of operators and required operator training and qualification

WBS/Validation of new premises Clean area Premises Utility Systems Manufacturing Support Syst. Equipment Manufacturing Processes HVAC System LAF Units Cold Storage Env. Monitoring Facility Cleaning Transfer hatches Verifi. of classific. Water systems Plant Steam Pure/Clean Steam Process Gases Sterilizers Depyrogenators SIP Systems CIP Systems Washing Waste Systems Fermentors Scales Incubators Filtration Units Filling Equipment Computerised systems Fermentation Separation Purification Filtration Filling Aseptic Processing Packaging & Labeling In-Process Control Personnel Training Analytical Methods Media Fills Packaging Labeling Process Measurem. Visual Inspection Label Control Sampling GMP Gpwning valid.. SOPs Equipment Processes Chemical - Cleaning valid Physical - Sterility tests Biological - Stability

Validation Protocol development (2) Complete description of the process Relevant specifications and tests Samples and sampling methods Special controls or conditions Process parameters to be monitored Methods for controlling and monitoring Protocol development: (Contd.) This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat: Complete description of the process Relevant specifications that relate to the product, ingredients, manufacturing methods, etc. Utilization of standard test methods such as those contained in international or national standards will provide guidance on how to measure specific parameters. Samples and sampling methods Any special controls or conditions to be placed on preceding processes during the validation Process parameters to be monitored, and methods for controlling and monitoring

Validation Protocol development (3) Objective and subjective criteria used to evaluate the product Definition of non-conformance Statistical methods Maintenance and repairs Criteria for revalidation Criteria for change control Protocol development: (Contd.) This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat: Any objective or subjective criteria used to evaluate the product Definition of what constitutes non-conformance for both measurable and subjective criteria (such as odour, appearance, taste) Statistical methods for data collection and analysis Consideration of maintenance and repairs of manufacturing equipment Criteria for revalidation Criteria for change control

Validation DQ IQ OQ PQ relationships and considerations: DQ (Design Qualification) should relate to Process: what needs to be done? DQ can be user requirements. IQ (Installation Qualification) considerations include: Equipment design features (i.e. materials of construction cleanability, etc.) Installation conditions (functionality, utilities, wiring, etc.) Calibration, preventative maintenance, cleaning schedules; safety features Supplier documentation, prints, drawings and manuals, software documentation Environmental conditions (such as clean room requirements, temperature, humidity) Spare parts list OQ (Operational Qualification) considerations include: Process control limits (e.g. time, temperature, pressure, line speed, setup conditions) Software parameters; starting 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) Risk analysis and potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis) PQ (Performance Qualification) includes: Actual product and process parameters and procedures established in OQ Assurance of process capability as established in OQ Acceptability of the product Process repeatability, long term process stability

Validation GMP Inspector’s check list for validation (1) Check that the manufacturer has: A VMP and multi-functional team for validation Planned approach , defined requirements Identified and described processes Analyse the amount of validation work to perform Check list for validation: This is a list of activities which may be used as a checklist to review validation activity. The manufacturer should: Create a master validation plan: as described in Part 1. Form a multi-functional team for validation: as described in Part 1. Plan the approach, and define the validation requirements. Identify and then describe the processes. Specify the process parameters and desired output. Analyse the amount of validation work to perform. It is most important that the inspectorate and the manufacturer agree on the risk involved and the extent of validation. High risk products, such as biologicals derived from human blood must be at one end of the scale (requiring considerable validation effort), while at the other end may be very simple, low risk, over- the-counter medicines requiring less validation.

Validation GMP Inspector’s check list for validation (2) Check that the manufacturer has: Selected methods and tools for validation Created protocols Performed DQ, IQ, OQ, PQ and documented results Exerted change control, set revalidation time Check list for validation: (Contd.) This is a continuation of the list of activities which may be used as a checklist to review validation activity. The manufacturer should: Select methods and tools for validation Create validation protocols Perform DQ, IQ, OQ, PQ and document results Exert change control and set revalidation time or frequencies

Validation Summary Logical entity: protocol + procedure + report A quality tool that makes lot of sense A prevention-based activity= important part of quality building process Expensive in the beginning later will "save the money back" In danger of becoming overwhelming Risk-based assessment of what needs to be validated or verified The process must be under control/validation as such does not improve the process Logical entity: protocol + procedure + report Summary Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective. Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life. Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be. A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits. Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.

Validation Question no 29-31 What are the three important parameters confirmed by validation? Summary Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective. Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life. Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be. A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits. Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.