3. 3
Safety Review
by NRA
Preclinical R&D
(GMP/GLP)
Clinical Trial
(GCP)
NDA or
Licensure
Post-market
surveillance
Phase 1 Phase 2 Phase 3
STAGES INVOLVED in REGULATING DRUGS
4. 4
The minimal necessary level
of operation and administration
of facilities, methods and controls
To manufacture drug products
of consistently high quality
(to assure that the products meets the requirements of the act
as to safety and effectiveness which the product purports)
GMP(Good Manufacturing Practice)
5. 5
Designation of a Responsible Person
And Independent Quality Assurance Unit
Maintenance of Suitable Facilities
Definition of Scientifically Sound
(Validated) Analytical Methods)
The issuance of a Final Report
Fully Retrievable and Available Raw Data
Use of Calibrated Equipment
Accuracy and precision
Use of well Maintained Equipment
Conducted by Standard Operating Procedures (SOP’s)
Conducted by Qualified Personnel
cGMP Laboratory 21 CFR Ch. 1, Part 211
6. 6
FOUR BASIC ELEMENTS of GMP: “4Ms”FOUR BASIC ELEMENTS of GMP: “4Ms”
Men: adequate training
Materials: raw materials, products, reagents,
labels, containers
Machinery: facilities, systems, equipment
Methods: manufacturing, control, validation,
documentation
7. 7
VALIDATIONVALIDATION
Establishing documented evidence which provides
a high degree of assurance that a specific process
will consistently produce a product meeting its
pre-determined specifications and quality attributes
8. 8
REFERENCESREFERENCES
US FDA
Guideline for general principles of process validation
May, 1987
Guideline on sterile drug products produced by
aseptic processing, June, 1987
WHO
A WHO Guide to GMP, Requirements, Part 2:
Validation, January, 1997
European Commission
Final Version of Annex 15 to the EU Guide to GMP
Title: Qualificaiton and Validation, September, 2001
11. 11
ELEMENTS of VALIDATIONELEMENTS of VALIDATION
Equipment validation: Installation Qualification(IQ)
Operational Qualification(OQ)
Process validation: Performance Qualification(PQ)
12. 12
STEPS INVOLVED in VALIDATIONSTEPS INVOLVED in VALIDATION
Validation master plan
Validation protocol
Execution of validation
Validation report
Preparation of SOPs
13. 13
MAJOR VALIDATION ITEMSMAJOR VALIDATION ITEMS
Steam-sterilization
Depyrogenation
Freeze-drying
Clean in place
Sterilization in place
Purification
Filling
Inactivation
Decontamination
Sterile Filtration(Liquid)
Water for Injection system
Air Handling system
Clean Steam system
14. 14
FDA Guideline Definition…
“PROCESS VALIDATION” is establishing documented evidence
which provides a high degree of assurance that a specific
process consistently produce a product meeting it’s
predetermined specifications and quality attributes”
From….
Guidelines on General Principles of Process Validation
May, 1987. US FDA
PROCESS VALIDATIONPROCESS VALIDATION
16. 16
Validation versus Qualification
VALIDATION:
Refers to the total life cycle of a product from development
through use and maintenance.
Customers(Owners) are responsible for Validating Their
Processes(personnel, equipment, methods, SOPs) to ensure
compliance to CGMP/GLP regulations.
QUALIFICATION: (Inspection, functional testing and documentation review)
Is a part of the validation process which verifies module and
system functional performance prior to being placed on-line
and thereafter according to a standard operating procedure.
VALIDATION vs. QUALIFICATIONVALIDATION vs. QUALIFICATION
17. 17
QUALIFICATION vs. CALIBRATIONQUALIFICATION vs. CALIBRATION
QUALIFICATION CALIBRATION
Qualification Workbooks(IQ, OQ,
PQ) & Project Diskettes
Accuracy, Linearity and
Precision Tests
Appropriate for companies
without approved
qualification procedures
Meets or exceeds US FDA
qualification requirements.
Calibration Protocols
Accuracy Tests Only
Appropriate for companies
that have approved validation
procedures
Basic documentation for
maintenance and calibration
18. 18
The Validation Time Line
Vendor’s
Site
Owner’s site
Before
Purchase
Before Use After Use
Structurally
Validated
Products
DQ
Functional Validation
Installation Operational
Performance
Qualification Qualification
Qualification
Maintenance
OQ
PQIQ OQ PQ
System Suitability During Use
VALIDATION TIME LINEVALIDATION TIME LINE
19. 19
DESIGN QUALIFICATION (DQ)
“A documented review of the design, at an appropriate stage of stages
in the project, for conformance to operational and regulatory
expectations.”
Applies to the Critical Equipment/systems
DQ Check Items
- GMPs and Regulatory Requirements
- Performance Criteria (URS & FS)
- Facility Air Flow, Movement Flow & Pressure Regimes
- Reliability & Efficiency
- Commissioning Requirements
- Construct ability & Installation of Equipment
- Maintenance & Access to Critical Equipment & Instrumentation
- Safety & Environment Impact
20. 20
DQ REVIEW DOCUMENTS
User Requirement Specification (URS)
Functional Specification (FS)
System impact Assessments
Tender Specifications, P&ID’s and Drawings
Vendor Quality procedures and documents
Purchase Specification
21. 21
INSTALLATION QUALIFICATION (IQ)
“Documented verification that all aspects of a facility, utility or
equipment that can affect product quality adhere to approved
specifications and are correctly installed.”
Applies to the Critical Equipment/Systems
Protocols
Purpose
Description
References
Responsibilities
Installation Qualification (Test Plan)
IQ Acceptance Criteria
Modification/ Change Control and Revalidation
Comments/ Action Items
IQ Attachments
22. 22
TEST PLAN (CHECK LISTS)
Identification : Sanitary Vessel Data Sheet
Identification : Agitator Data Sheet
Equipment List
Filters
Materials in Product Contact
Recommended Spare Parts List
Instrument Calibration : Critical Instrument
Instrument Calibration : Reference Instrument
Documentation
Drawings
Piping IQ Check List
Utility Requirement : Electrical
Utility Requirement : Other Utilities
Grounding Checkout
Validation Test Instruments and calibrations
Installation Qualification Summary
Comments/Action Items
23. 23
OPERATIONAL QUALIFICATION (OQ)
“Documented verification that all aspects of a facility, utility or
equipment that can affect product quality operate to Intended
throughout all anticipated ranges.”
Applies to the Critical Equipment/Systems
Protocols
Purpose
Description
References
Responsibilities
Installation Qualification (Test Plan)
OQ Acceptance Criteria
Modification/ Change Control and Revalidation
Comments/ Action Items
OQ Attachments
24. 24
TEST PLAN (CHECK LISTS)
Validation Test Instruments and Calibrations
Alarm checkout
Control Panel Checkout
Pressure Hold Test
Water Batch Test-Agitator System checkout
Water Batch Test-Heating / Cooling System Checkout
Transfer System Check Out
CIP Qualification Check Out
SIP Sterilization Temperature Mapping
SIP Sterilization Filter Integrity Test Results
Filter Adsorption / Component Removal / Release of Extractable
PLC Screen Verification
SOP & Personnel Training
Operational Qualification Summary
Acceptance of New Equipment Form
Comments/Action Items
25. 25
PERFORMANCE QUALIFICATION (PQ)
“Documented verification that all aspects of a facility, utility or equipment
Perform as intended in meeting predetermined acceptance criteria.”
Applies to the Critical Systems (i.e.: HVAC Systems, Pharmaceutical
Grade Water Systems, Clean Compressed Gases, Clean Steam
System,
Process Package Systems)
Protocols
Purpose
Description
References
Responsibilities
Performance Qualification (Test Plan)
PQ Acceptance Criteria
Modification/ Change Control and Revalidation
Comments/ Action Items
PQ Attachments
-Test Data Sheet
-Test Instrument Calibration and Analytical Instrument Validation
26. 26
PERFORMANCE QUALIFICATION (PQ)
PQ Protocol should include the following:
Acceptance criteria
Number of samples for analytical testing
Location of sampling points
Duration of testing
Processing steps for testing
Batch records
Number of runs