2005.06.28. dr. pogány - who, pretoria 1/26 supplementary training workshop on good manufacturing...
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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: [email protected]
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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)