Sei sulla pagina 1di 26
Supplementary Training Workshop on Good Manufacturing Practices (GMP) VALIDATION MASTER PLAN (VMP) János Pogány, pharmacist, PhD,
Supplementary Training Workshop on Good
Manufacturing Practices (GMP)
VALIDATION MASTER
PLAN (VMP)
János Pogány, pharmacist, PhD,
consultant to WHO
Pretoria, South Africa, 28 June 2005
E-mail: pogany@t-online.hu
Supplementary Training Workshop on Good Manufacturing Practices (GMP) VALIDATION MASTER PLAN (VMP) János Pogány, pharmacist, PhD,
Incidents/accidents leading to regulatory actions 1937 Sulfanilamide elixir 1962 Thalidomide 1982 Tylenol cyanide tampering 1989 Generic
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

2/26

Systems approach  water (generation, receipt, and distribution)  heating, ventilation, and air conditioning (HVAC) 
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

3/26

WHO GMP and Guidelines  WHO good manufacturing practices (GMP): main principles for pharmaceutical products –
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.
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

4/26

Why do we validate?  Interchangeability of generic FPPs = Pharmaceutical equivalence + bioequivalence  Pharmaceutical
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)]
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

5/26

Why do we validate processes?  Small quantity of waste creates serious danger to health (1/3
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
2005.06.28.
Dr. Pogány - WHO, Pretoria
6/26
SAMPLING PROBLEM The whole batch is released to the BATCH patient But only the Sample sample
SAMPLING PROBLEM
The whole
batch is
released to the
BATCH
patient
But only the
Sample
sample is tested
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

7/26

4.4 What should be validated? „Any aspect of operation, including significant changes to the premises, facilities,
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.”
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

8/26

GMP, QUALIFICATION and VALIDATION STARTS WITH DESIGN + CONSTRUCTION OF FACILITIES AND PURCHASING EQUIPMENT
GMP, QUALIFICATION and
VALIDATION STARTS WITH
DESIGN + CONSTRUCTION
OF FACILITIES AND
PURCHASING EQUIPMENT
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

9/26

Qualification Stage Validation Stage Key elements Design Installation Operation Prospective Concurrent Premises and Engineering phase Manufacturing
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
2005.06.28.
Dr. Pogány - WHO, Pretoria
10/26
4.1-4.2 Validation master plan 1. „In accordance with GMP, each pharmaceutical company should identify what qualification
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).”
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

11/26

WHO draft guide  „The Validation Master Plan (VMP) complements the manufacturer’s site master file and
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.”
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

12/26

4.5-4.7 Validation policy 5. Qualification and validation should not be considered as one-off exercises. An on-going
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 … 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.
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

13/26

Validation master plan The VMP is a summary document and should therefore be brief, concise and
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.
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

14/26

ISO9001 :2001 - 4.2.2 Quality manual The organization shall establish and maintain a quality manual that
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.
2005.06.28.
Dr. Pogány - WHO, Pretoria
15/26
Types of VMP  Construction of new premises  Introduction of a group of new FPPs
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

16/26

Functions of VMP  Education of management  Project monitoring and management  Project training 
Functions of VMP
Education of management
Project monitoring and management
Project training
Audit of the validation program
Update of regulatory agency requirements
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

17/26

Basic questions to be answered  What will be validated?  Who is responsible for the
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?
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

18/26

Content of VMP  Title, approval (top management and members of the validation team) and table
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

19/26

Content of VMP  Production and QC premises, including controlled environments  Process and QC equipment,
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

20/26

Matrix for qualification of equipment Equipment No. Description IQ OQ PQ Unidirectional air flow hood High-speed
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
2005.06.28.
Dr. Pogány - WHO, Pretoria
21/26
Content of VMP  Manufacturing processes  List of validation protocols, including format  List of
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

22/26

Content of VMP  Equipment cleaning  Planning and scheduling (Gant chart)  Preventative maintenance program
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

23/26

EU-VMP should contain at least the following data a) validation policy b) organisational structure of validation
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
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

24/26

Main Points Again  Target all personnel involved in the validation when creating the master plan.
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.
  • 2005.06.28. Dr. Pogány - WHO, Pretoria

25/26

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