Supplementary Training Workshop on Good Manufacturing Practices (GMP)

VALIDATION MASTER PLAN (VMP)

Jnos Pogny, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hu
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Incidents/accidents leading to regulatory actions

1937 Sulfanilamide elixir 1962 Thalidomide 1982 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 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 nonconformance to specification in time (1996 Haiti) Limitations of sampling

Percent of nonconformance: 0,1 1,0 5,0 Percent probability of release: 98 82 36

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SAMPLING PROBLEM
The whole batch is released to the patient But only the sample is tested
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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 Key elements Design Installation Operation

Validation Stage Prospective Concurrent

Premises and Equipment

Engineering phase

Manufacturing Start-Up

VMP

Validation Protocols

Validation Reports

Product and Process Validation of analytical methods

Laboratory Phase Critical variables and Process selection

Scale-Up Phase Process optimization

Manufacturing Phase Process & cleaning validation 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 manufacturers 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 policy

5. 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 speakers 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
Unidirectional air flow hood High-speed mill High-speed, high shear granulator Sizer (re-granulator) Jacketed tank with stirrer Blender

IQ

OQ

PQ

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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 Practice
http://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)

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