Introduction to Validation

Jin Myung Tech.

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FDA-Food and Drug Administration (USA)

■Belongs to the ministry of health■ Responsibilities ;

• Regulations for food and pharmaceutical industry

• Inspections• Positive list of materials(eg. EPDM, PVDF)• Issues the Code of Federal Regulations(CFR)• FDA dose not certify any instrument

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FDA certification terms■ FDA Approved ; for drug which passed

authorization■ FDA validated ; for processes which passed

validation■ FDA registered ; tracking number for

documents■ FDA certified ; dose not exist■ FDA conform ; possible term for equipment

regarding CGMP

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Regulations 1.

■ Regulations are those rules that are enforceable by law

■FDA expects compliance with these regulations■ Current Good Manufacturing Practice(CGMP)

• In manufacturing, processing, packing or holding drugs(CFR 210)

• For finished pharmaceuticals(CFR 211)• For biological products(CFR600-680)

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Regulations 2.

■Contains• General regulations to ensure repeatability of

drug production• Quality

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Guide/Guideline/Guidance

■ Guidelines are documents developed by the FDA which spell out the way a manufacturer should operate his facility to comply with CGMP

■ Guidelines cannot be enforced by law; they are merely “suggestion”

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Points to Consider(PTC)

■ In 1982 and 1984, the FDA issued a document called “Points to Consider” through the NIH

■ When working in the areas of DNA, tissue and cell culture etc. PTC must be considered

■ The FDA is treating PTC as a guideline

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FDA Story

■ 1976 : Proposed LVP-CGMP

■ 1976 : Sterilization Validation

■ 1978 : CGMP

■ 1983 : Software Validation

■ 1987 : Process Validation■ 1996 : Proposed amendments of certain

requirements

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Why Validation?

■ To guarantee health care products of consistent potency, purity, safety and efficacy

■ To understand equipment and process and to facilitate troubleshooting

■ To satisfy the requirements of GMP regulations

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Why Validation?

■ In 1986, two died and one was seriously injured as a result of a malfunction in the software of a radiation therapy device.⇒ Software Validation

■ In 1955, inactivation viral inactivation processes of polio vaccine resulted in the paralysis of 51 children(10 died ).⇒ Equipment Validation

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Validation

“ … control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variabilityin the characteristics of in-process material and the drug product. ”

21 CFR, Part 211.110

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Definition of Validation

“ Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes ”

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Validation

■ Prospective

■ Concurrent

■ Retrospective

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Prospective Validation

“ Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product’s characteristics.”

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Prospective Validation

■ Design Qualification (DQ)

■ Installation Qualification (IQ)

■ Operational Qualification (OQ)

■ Performance Qualification (PQ)

■ Product Performance Qualification

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Design Qualification

■ Definition“Documentation confirms that chosen equipment is suitable for application”

■ Documents• PFD • P&ID• Requirements and specifications of materials

and product• Requirements and specifications of equipment• Detailed equipment design drawing

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Installation Qualification 1.

■ Definition

“ Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.”

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Installation Qualification 2.

■ Documents• As built drawings vs. design drawings• Equipment and instrument lists• Material certifications • Installation and lubricant check sheet• Calibration checks• IQ policies and SOPs• IQ personnel training records

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Operational Qualification 1.

■ Definition“ Documented verification that the equipment, when assembled and used according to the standard operating procedures, performs its intended function.”

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Operational Qualification 2.

■ Documents• P&IDs• Functional requirements specifications(based on URS)• Operations manuals and SOPs• Calibration reports• Vendor drawings and specifications• Equipment and instrument lists• Alarm/interlock schedule• Control system operation manuals

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Performance Qualification

■ Definition“ Establishing confidence that the process is effective and reproducible.”

■ Documents• Requirements and specifications of equipment andproduct

• Execution of monitoring protocols • Cleaning SOP• Challenge plan

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Definition :Worst Case

“ A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operation procedures, which pose the greatest change of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.”

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Retrospective Validation

■ Definition“ Validation of a process for a product already in distribution based upon accumulated production, testing and control data.”

■ Documents• Batch records• Data sheet

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Definition :Concurrent Validation

“ Prospective validation in slow motion ”- Jim Agallaco

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Benefits of Validation

■ Questioning approach to equipment■ Understanding how process works■ Highlights potential weakness■ Allows corrective action to be taken■ Foundation for monitoring and in-process

control■ Reliable and consistent performance■ Easy measurement and control of quality■ Encourages communication between people

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Validation Related Programs

■ Equipment calibration■ Change control■ Documentation■ Process development■ Equipment qualification ■ Performance qualification

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Documentation

■ Validation master plan■ Validation protocol and reports■ Standard operating procedures■ Master batch records■ Production batch records■ Product specification■ Log books■ Calibration certificates■ Development reports

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Validation Master Plan

■ Introduction■ Facility description and design■ Process description■ Process control■ Services and utilities■ Systems/equipment to be validated■ Validation schedule■ Support programs■ Management structure■ Attachment

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Validation Protocol

■ Provide an outline of the validation effort■ Include a clear definition of what is to be

validated■ Each is uniquely identified, dated, and

approved by competent individuals■ Are suitable for review by regulatory

authorities

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Validation Time Diagram

Design Install Prepare Start-up Operate

ProcessPQ

RetrospectivevalidationIQ & OQ

Prospective Validation

Market Approval

Clinical Trials