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2005.06.28. Dr. Pogny - WHO, Pretoria 1/26

Supplementary Training Workshop on GoodManufacturing Practices (GMP)

VALIDATION MASTER

PLAN (VMP)

Jnos Pogny, pharmacist, PhD,

consultant to WHO

Pretoria, South Africa, 28 June 2005

E-mail:[email protected]
mailto:[email protected]:[email protected]:[email protected]:[email protected]

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Incidents/accidents leading to

regulatory actions1937 Sulfanilamideelixir1962 Thalidomide1982 Tylenol cyanide tampering

1989 Generic drug scandal(there is no new thing under the sun)1970- Sterility problems found by FDA employees in

the large-volume parenteral (LVP) industry systems inspectionsbyteams (engineers and

microbiologists) validation as arequirementin the 1978 US-GMP termsprotocol, qualification, and validationfirst used

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Systems approach water(generation, receipt, and distribution) heating, ventilation, and air conditioning (HVAC) sterilizers(operations, engineering, and

configuration) terminal sterilizationof product compressed air(generation and distribution) premises

QC laboratories(analytical and microbiological) production and control operationsinvolved in the

manufacture of LVPs

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WHO GMP and Guidelines WHOgood manufacturing practices (GMP): main

principlesfor pharmaceutical productsSection 4.Qualificationandvalidation(see notes page below)

http://www.who.int/medicines/library/TRS/trs908/trs908-4.pdf

Supplementary guidelines on good manufacturing

practices(GMP):ValidationRev.1 (2003)Draft

http://www.who.int/medicines/organization/qsm/expert_committee/Guidelines/QAS_055_Rev1_validation.doc No specific guideline on the VMP.
http://www.who.int/medicines/library/TRS/trs908/trs908-4.pdfhttp://www.who.int/medicines/organization/qsm/expert_committee/Guidelines/QAS_055_Rev1_validation.dochttp://www.who.int/medicines/organization/qsm/expert_committee/Guidelines/QAS_055_Rev1_validation.dochttp://www.who.int/medicines/library/TRS/trs908/trs908-4.pdfhttp://www.who.int/medicines/library/TRS/trs908/trs908-4.pdfhttp://www.who.int/medicines/library/TRS/trs908/trs908-4.pdf

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Why do we validate? Interchangeabilityof generic FPPs =

Pharmaceutical equivalence+bioequivalence

Pharmaceutical equivalence Productand manufacturingprocess equivalence

(prospective and concurrent validation)

GMP equivalence(concurrent validation)

Maintenance and continuous improvement of thevalidated status[concurrent and retrospective

validation, Process Analytical Technology (PAT)]

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Why do we validate processes?

Small quantityof waste creates serious dangertohealth(1/3 of 5% dextrose infusionwas notsterile, Evans Medical, 1972)

Low chancethat patient or doctor recognizes non-conformance to specification in time(1996 -Haiti)

Limitations of sampling

Percent of nonconformance:0,1 1,0 5,0 10,0

Percent probability of release:

98 82 36 12

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SAMPLING PROBLEMThe whole

batch is

released to thepatient

But only thesample is tested

BATCH

Sample

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4.4 What should be validated?Any aspect of operation, including significantchanges to the premises, facilities, equipment or

processes, which may affect the quality of theproduct, directly or indirectly, should be qualified

and validated.

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QualificationStage ValidationStage

Key elements Design Installation Operation Prospective Concurrent

Premisesand Engineering phase Manufacturing Start-UpEquipment

VMP ValidationProtocols ValidationReports

Productand Process Laboratory Phase Scale-Up Phase Manufacturing Phase

Validationof Critical variables Process Process& cleaning

analytical and Process optimization validation

methods selection Revalidation

Quality Development

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4.1-4.2 Validation master plan

1. In accordance with GMP, each pharmaceuticalcompany should identify what qualification and

validation work is required to prove that the

critical aspects oftheir particular operationare

controlled.

2. The key elements of a qualification and

validation programme of a company should beclearly definedand documented in avalidation

master plan (VMP).

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WHO draft guide

The Validation Master Plan (VMP) complements themanufacturers site master file and should be the firstdocument to be reviewed during inspectionby a

regulatory authority. The VMP reinforces the commitment of the company to

GMP. It is a formal policy documentwhich describes the

overall philosophy of the company towards validation and

which also describes the key elements of the validationprogramme, organizational structure of validation,

schedules and responsibilities.

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4.5-4.7 Validation policy5. Qualification and validation should notbe considered

as one-off exercises. An on-going programme shouldfollow their first implementation (continuous

improvement within thedesign space speakers remark)and should be based on an annual review.6. The commitment to maintain continued validation

statusshould be stated in the relevant company

documentation, such as the quality manual orvalidation master plan.

7. The responsibilityof performing validation should beclearly defined.

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Validation master plan

The VMP is a summary documentand should

therefore be brief, concise and clear. It should not

repeat information documented elsewhere but refer

to existing documentssuch as

Policy documents,

SOP's and

Validation Protocols/Reports.

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ISO9001 :2001 - 4.2.2 Quality manual

The organization shall establish and maintain a quality

manualthat includesa) the quality policy

b) the scope of the quality management system, including

details of and justification for any exclusions (see 1.2),

c) the documented procedures established for the quality

management system, or reference to them, and

d) a description of the interaction between the processesof

the quality management system.

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Types of VMP

Construction ofnew premises

Introduction of a group ofnew FPPs (individualvalidation protocolsmay suffice for single new FPPs)

Major renovationor additions to existingpremises

First time validationof previously unvalidated

processesor unit operations Automationor computerized implementations

that span a number of applications

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Functions of VMP

Education of management

Project monitoringand management

Project training

Auditof the validation program

Update of regulatory agency requirements

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Basic questions to be answered

Whatwill be validated?

Whois responsible for the validation tasks?

Howwill the equipment be qualified and theprocesses validated?

Howwill the validation be documented?

Whatare the criteria by which a successful

validation will be judged?

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Content of VMP

Title, approval(top managementand membersof thevalidation team) and table of contents

Glossaryof terms

Introduction (policyandobjectives)

Scope[separate VMPsfor manufacturingprocesses, pharmaceutical utility systems(e.g.

HVAC, water)]. Responsibilities

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Content of VMP

Production and QCpremises, including controlledenvironments

Process and QCequipment, including location

Pharmaceutical air (HVAC) andwater systems

Allpotentiallycritical utilities (such as compressed

air, steam and cooling liquids, and so on)

Computer control systems

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Matrix for qualification of equipment

Equipment No. Description IQ OQ PQ

Unidirectional air flow hood

High-speed mill

High-speed, high shear granulator

Sizer (re-granulator)

Jacketed tank with stirrer

Blender

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Content of VMP

Manufacturingprocesses

List ofvalidation protocols, including format

List ofrelevant SOPs

Product specifications includingprospective (and

tentative)IPC acceptance criteria

QCand IPC methods,

validation, if applicable

Reasonableunexpected events

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Content of VMP

Equipmentcleaning

Planning andscheduling (Gant chart)

Preventative maintenance program Workerandenvironment safety

Change Control/including Revalidation

Trainingrequirements Documentationrequirements

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EU-VMP should contain at least the following data

a) validation policy

b) organisational structure of validation activities

c) summary of facilities, systems, equipment and processes

to be validated

d) documentation format: the format to be used for

protocols and reports

e) planning and scheduling

f) change control

g) reference to existing documents

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Main Points Again

Target all personnelinvolved in the validation whencreating the master plan.

Keep the VMP short, but provide enough information so

that the document is functional. Provide for flexibility to deal with changes, but do not

avoid making the required decisions early on in theproject.

The life cycle mandates that the validationprocessbecomes an ongoing project, which requires constantattention.

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Literature

Qualification and validation, Annex 15 to the EUGuide to Good Manufacturing Practice

http://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdf

Validation Master Plan, Installation AndOperational Qualification, Non-sterile ProcessValidation, Cleaning Validation(PIC/S, August2001)

Model VMP for Tableting Plants (distributed amongparticipants of the training course)
http://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdfhttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdfhttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdfhttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdfhttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdfhttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdf

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