2005.06.28. dr. pogány - who, pretoria 1/26 supplementary training workshop on good manufacturing...

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

Supplementary Training Workshop on Good Manufacturing Practices (GMP)

VALIDATION MASTER PLAN (VMP)

János Pogány, pharmacist, PhD, consultant to WHO

Pretoria, South Africa, 28 June 2005E-mail: pogany@t-online.hu

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Incidents/accidents leading to regulatory actions

1937 Sulfanilamide elixir1962 Thalidomide1982 Tylenol cyanide tampering1989 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 inspections by teams (engineers and microbiologists)

validation as a requirement in the 1978 US-GMP terms protocol, qualification, and validation first used

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

configuration) terminal sterilization of product compressed air (generation and distribution) premises QC laboratories (analytical and microbiological) production and control operations involved in the

manufacture of LVPs

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

principles for pharmaceutical products – Section 4. Qualification and validation (see notes page below)

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

Supplementary guidelines on good manufacturing practices (GMP): Validation Rev.1 (2003) – Draft

http://www.who.int/medicines/organization/qsm/expert_committee/Guidelines/QAS_055_Rev1_validation.doc

No specific guideline on the VMP.

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Why do we validate? Interchangeability of generic FPPs =

Pharmaceutical equivalence + bioequivalence Pharmaceutical equivalence

Product and manufacturing process equivalence (prospective and concurrent validation)

GMP equivalence (concurrent validation) Maintenance and continuous improvement of the

validated status [concurrent and retrospective validation, Process Analytical Technology (PAT)]

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Why do we validate processes? Small quantity of waste creates serious danger to

health (1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972)

Low chance that 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 PROBLEM

The whole batch is released to the patient

But only the sample is tested

BATCH

Sample

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4.4 What should be validated?

„Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.”

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GMP, QUALIFICATION and

VALIDATION STARTS WITH

DESIGN + CONSTRUCTION

OF FACILITIES AND

PURCHASING EQUIPMENT

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Qualification Stage Validation Stage

Key elements Design Installation Operation Prospective Concurrent

Premises and Engineering phase Manufacturing Start-Up

Equipment

VMP Validation Protocols Validation Reports

Product and Process Laboratory Phase Scale-Up Phase Manufacturing Phase

Validation of 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 pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.

2. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan (VMP).”

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WHO draft guide „The Validation Master Plan (VMP) complements the

manufacturer’s site master file and should be the first document to be reviewed during inspection by a regulatory authority.”

„The VMP reinforces the commitment of the company to GMP. It is a formal policy document which describes the overall philosophy of the company towards validation and which also describes the key elements of the validation programme, organizational structure of validation, schedules and responsibilities.”

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4.5-4.7 Validation policy5. Qualification and validation should not be considered

as one-off exercises. An on-going programme should follow their first implementation (continuous improvement within the design space … speaker’s remark) and should be based on an annual review.

6. The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan.

7. The responsibility of performing validation should be clearly defined.

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Validation master plan

The VMP is a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such 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

manual that includes

a) 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 processes of the quality management system.

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Types of VMP Construction of new premises Introduction of a group of new FPPs (individual

validation protocols may suffice for single new FPPs) Major renovation or additions to existing

premises First time validation of previously unvalidated

processes or unit operations Automation or computerized implementations

that span a number of applications

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Functions of VMP

Education of management

Project monitoring and management

Project training

Audit of the validation program

Update of regulatory agency requirements

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Basic questions to be answered What will be validated? Who is responsible for the validation tasks? How will the equipment be qualified and the

processes validated? How will the validation be documented? What are the criteria by which a successful

validation will be judged?

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Content of VMP Title, approval (top management and members

of the validation team) and table of contents

Glossary of terms Introduction (policy and objectives) Scope [separate VMPs for manufacturing

processes, pharmaceutical utility systems (e.g. HVAC, water)].

Responsibilities

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Content of VMP Production and QC premises, including controlled

environments

Process and QC equipment, including location

Pharmaceutical air (HVAC) and water systems All potentially critical 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 Manufacturing processes List of validation protocols, including format

List of relevant SOPs

Product specifications including prospective (and tentative) IPC acceptance criteria

QC and IPC methods, validation, if applicable

Reasonable unexpected events

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Content of VMP Equipment cleaning Planning and scheduling (Gant chart) Preventative maintenance program Worker and environment safety Change Control/including Revalidation Training requirements Documentation requirements

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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 personnel involved in the validation when

creating 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 the project.

The life cycle mandates that the validation process becomes an ongoing project, which requires constant attention.

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Literature Qualification and validation, Annex 15 to the EU

Guide to Good Manufacturing Practicehttp://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-en/v4an15.pdf

Validation Master Plan, Installation And Operational Qualification, Non-sterile Process Validation, Cleaning Validation (PIC/S, August 2001)

Model VMP for Tableting Plants (distributed among participants of the training course)