VALIDATION

AN OVERVIEW

Fiona OSullivan
1

What is Validation?
The documented act of proving that any procedure, process,
equipment, material, activity or system actually leads to the expected results W.H.O

Content
Evolution of Validation Regulations, Guidelines Definitions Why Validate? Commissioning, Qualification, Validation Lifecycle Approach to Validation Validation Documentation Validation Related Programmes Effective Validation, how much validation and benefits of validation

Evolution of Validation
In 1971 the first edition of the British Guide to Good Pharmaceutical Manufacturing Practice stated: Procedures should undergo a regular critical appraisal to ensure that they are, and remain, capable of achieving the results they are intended to achieve

Evolution of Validation
The 1983 edition of the UK GMP Guide defined validation as; The action of proving that any material, process, procedure, activity, equipment or mechanism used in the manufacture or control, can, will and does achieve the desired and intended result

Evolution of Validation
Prior mid 1970s validation only applied to analytical testing methods Mid 1970 with introduction of GMP rules in US and Europe wide spread validation began 1977: Sterilisation Validation 1979: Aseptic Processing Validation

Evolution of Validation
1981: Water Treatment Validation 1983: Nonaseptic Processing- FDA issued draft guidelines on General Principles of Process Validation - finalised in May 1987 Late 80s/early 90s - Cleaning Validation - Equipment Qualification - FAT, commissioning and qualification

Regulations
Code of Federal Regulation
www.fda.gov/cder/dmpq/cgmpregs.htm

EU Guide to GMP Vol 4.

-Annex 15 Qualification and Validation, July 2001
http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm

Guideline Documents
Recommendations on Validation Master Plan, Installation and Operational Qualification, Non Sterile Process Validation and Cleaning Validation, PIC/S, July 2004 Recommendation on the Validation of Aseptic Processes, PIC/S, July 2001 Guideline on the General Principles of Process Validation, FDA, May 1987 Guide to Inspection Validation of Cleaning Processes, FDA, July 1993

Regulations versus Guidelines

Regulations state what must be done and do not stipulate how to do it Guides and guidelines are written and made effective at any time without public notices or hearings and are not legally binding Many group have come together to write guidelines for Validation in the past 20 years Industry standards and practices

10

European definition
Documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes EU Guide to GMP, Annex 15, July 2001

11

US definition
Process Validation is establishing documented evidence
which provides a high degree of assurance that a specified process will consistently produce a product meeting its pre-determined specifications and quality characteristics US Food and Drug Administration, 1987

12

Why Validate?
Essential element of Quality Assurance. QC testing has too many limitations Regulatory requirement Improves equipment & process knowledge Enables continuous improvement Should reduce the risk of complaints and recalls

13

Why Validate?
A regulatory exercise & good business practice Products must be safe and effective. The validation process from research laboratory to commercial manufacturing is critical in assuring this claim A basic premise in the pharmaceutical industry - quality cannot be tested into the product. It must be built into the product and any method, device or system associated with its production

Validation - logical avenue to achieve this

14

What does Validation apply to?

VALIDATION

EQUIPMENT

FACILITIES

UTILITIES

CONTROL SYSTEMS

PROCESS & CLEANING

15

Terminology
Commissioning Qualification Validation

16

Purpose of Qualification
to provide assurance that they (systems) have been properly designed, installed and tested according to predetermined acceptance criteria, based on assessment of those installation and operational characteristics, and parameters with potential product quality impact ISPE Baseline Pharmaceutical Engineering Guide

17

Commissioning defined as.

A well planned, documented and managed engineering
approach to the start-up and turn over of facilities, systems and equipment to the end-user that results in a safe and functional environment that meets established design requirements ISPE Baseline Pharmaceutical Engineering Guide

18

Terminology
FAT Factory Acceptance Testing SAT Site Acceptance Testing Commissioning IQ - Installation Qualification OQ - Operational Qualification PQ - Performance Qualification

19

Definitions
Factory Acceptance Testing (FAT)
Testing performed at the vendor site to demonstrate that the system functions in accordance with the user requirements

Site Acceptance Testing (SAT)

Testing performed at the production site to demonstrate that the system functions in accordance with the user requirements

20

Definitions
Installation Qualification (IQ)
Documented verification that all aspects of a facility utility or equipment that can affect product quality adhere to approved specifications and are installed correctly

Operational Qualification (OQ)

Documented verification that all aspects of a facility utility or equipment that can affect product quality operate as intended throughout all anticipated ranges
21

Definitions continued
Performance Qualification

Documented verification that the system as a whole performs its intended functions reliably and reproducibly

22

Lifecycle Approach to Validation

PROCESS REQUIREMENTS & PRODUCT SPECIFICATIONS PROCESS & CLEANING VALIDATION

USER REQUIREMENTS & SPECIFICATIONS

PERFORMANCE QUALIFICATION

FUNCTIONAL SPECIFICATIONS

OPERATIONAL QUALIFICATION

DETAILED DESIGN DESIGN QUALIFICATION

INSTALLATION QUALIFICATION

CONSTRUCTION / FABRICATIONS

SAT / COMMISSIONING

FACTORY ACCEPTANCE TESTING

23

Project Plan

24

Validation
Process Validation Cleaning Validation Analytical Method Validation Control/Computer System Validation

25

Process Validation Terminology

Prospective Concurrent Retrospective

26

Validation Terminology
Prospective Validation
Validation conducted prior to the distribution of either a new product or a product made under revised manufacturing process where the revisions may affect the products characteristics

Concurrent Validation
Validation during routine production

Retrospective Validation
Validation of a process for a product already in distribution based upon accumulated production, testing and control data
27

An Example
Validation of a Sterile Product
Manufacturing operations mixing/blending heating/cooling.. Sterilisation operations aseptic process terminal sterile filtration steam, dry heat, ETO etc. Environmental control systems clean room LAFs

28

Validation of a Sterile Product

Personnel Monitoring Validation of aseptic process Process Simulation/Media Fill Market container/closure sterilisation Autoclave validation sterilisation tunnel Equipment sterilisation Disinfection etc..etc

29

Validation Documentation
Validation Master Plan (VMP) Validation protocol Equipment, systems & services files for qualification Validation SOPs & procedures Validation raw data Validation Summary Reports Validation approvals
30

Validation Master Plan

A validation master plan (VMP) should provide information on the way a company organises its validation work The purpose of a VMP is to: - briefly describe why, what, by whom, how and when the validation is to be carried out - provide up to date information about the state of affairs relating to the validation - demonstrate the company commitment to carry out adequate validation

31

Advantages of a VMP
A VMP ensures: -management know what the validation program involves with respect to time, people and money and understand the necessity for the programme - the prevention of wasting resources on ineffective or unnecessary validation -members of the validation team know their tasks and responsibilities

32

Suggested Content for VMP

Introduction including company business and structure Facility description and design including Plant Layout and area plans Process description Process control Services and utilities Systems/equipment/utilities/process to be validated Validation schedule Support programmes Management structure Approval by key personnel

33

When should Plan be written

Ideally prior to commencing any validation for existing facilities For new facilities during construction Revise as appropriate

34

VMP Inputs
Corporate or Company Policy GMP Regulatory Requirements Market Requirements

35

Validation protocols
Introduction Purpose/Objective Description of process, system or equipment Documentation prerequisites prior to validation Scope Procedure & evaluation Acceptance criteria Responsibility Approval & follow up required

36

Scope of Validation
How many consecutive runs? 3 consecutive runs Frequency of validation Extent of validation? For Process Validation - all products ? - all manufacturing operations? Sound scientific rationale for strategy used

37

Revalidation Policy
Regular review of systems, equipment and processes Revalidation policy of 3-5 years Change control review of requirement to revalidate following change

38

Validation Related Programmes

Equipment calibration Process development Equipment qualification Change control

39

Effective Validation requires..

Validation Master Plan Good Validation Team Training all relevant personnel in validation requirements Company commitment & resources Good protocols, reports, records and follow through Good communication

40

How much Validation?

How much validation is too much? Satisfy regulatory authorities Industry trends and guidelines Value of work

41

How much Validation?

Logic, common sense and sound scientific rationale Company has responsibility to define appropriate level of validation based on judgement, experience and regulatory requirements Risk assessment- investigate and evaluate risks

42

Benefits of Validation
Questioning approach to equipment/systems/utilities/process

Understanding how process works Highlights potential weaknesses Allows corrective action to be taken Foundation for monitoring and in-process control

43

Benefits of Validation
Reliable and consistent performance Easy measurement and control of quality

Encourages communication between people Reduce level of testing

44