1. Supplementary Training modules on Good Manufacturing Practices
Validations –part 2
Workshop on
GMP and Quality Assurance of TB products
Kuala Lumpur
Malaysia, 21 – 25 February 2005
Maija Hietava
M.Sci.Pharm
Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster
Tel: Fax:
World Health Organization

2. Validation principles
Objectives
To review:
WHO validation definition
Philosophy of validation
Personnel requirements
Protocol requirements
DQ IQ OQ and PQ summary
Checklist for validation
Objectives:
To review:
WHO validation definition
Philosophy of validation
Personnel requirements – who should be in a competent validation team?
Protocol requirements – a list of items that should form a good index for a validation protocol
DQ IQ OQ and PQ summary: the heart and soul of validation.
Checklist for validation: something for you to take on your GMP inspections

3. Validation WHO validation definition
The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.
As indicated in Part 1 of this module, the WHO validation definition is:
“The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results.”
From: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, (WHO Technical Report Series, No 823). Annex 1.

4. Validation
The VMP
The VMP provides a summary of the company’s philosophy, policy, intentions and approach to validation.
The Validation Master Plan is an important prerequisite to a validation programme, as it provides a summary of the company’s philosophy, policy, intentions and approach to validation.
The content of a VMP was covered in Part 1 of this module.

5. Validation The WHO GMP Guidelines state:
Validation studies are an essential part of good manufacturing practice and should be conducted in accordance with predefined protocols.
written report and conclusion
process and procedures
processing
testing
cleaning procedures
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

6. validation Validation Quality is designed and built into the
process/method/premises
Functionality, consistency and repeatability
is confirmed by
validation
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

7. Validation Validation as such does not improve the process but it
Confirms and assures that the process
Has been well developed
It is well maintained
It operates as it should
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

8. Advantages of validation:
During the process the knowledge of process increases
Assures the repeatability of the process
Assures the fluency of production
Assures that the product is continuously according to the marketing authorisation
Decreases the risk of the manufacturing problems
Decreases the expenses caused by the failures in production
Decreases the risks of failing in GMP
Decreases the expenses of the every day production even though the validation itself will create expenses
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

9. Validation Personnel - Validation team members Quality Assurance
Engineering
Manufacturing
Other disciplines may be involved depending on the product and process:
laboratory, technical services
research and development, regulatory affairs
clinical
chemical engineering
purchasing/planning
Personnel - Validation team members:
A competent validation team is a multi-disciplinary team comprising:
Quality Assurance
Mechanical engineering
Manufacturing
Other disciplines may be involved depending on the product and process, eg:
- Laboratory
- Technical services (calibration, electrical, plumbing)
- Research and development
- Regulatory affairs
- Clinical
- Chemical engineering
- Purchasing/planning

10. Validation Protocol development (1) Identification of process
Objective and measurable criteria
Length and duration of the validation
Shifts, equipment
Identification and quality of utilities
Identification of operators and operator training and qualification
Protocol development:
Detailed protocols for performing validations are essential to ensure that the process, whether solid dose, liquid or sterile, is adequately validated. Process validation protocols should include:
Identification of process: Objective and measurable criteria for a successful validation - Determine WHAT to verify and measure - Determine HOW to verify and measure - Determine HOW MANY to verify and measure, i.e. what statistical test of significance will be applied and what will be the confidence in the result? - Determine WHEN to verify and measure - Define acceptance AND rejection criteria - Define the required level of documentation
Length and duration of the validation: Challenges to the process should simulate conditions encountered during actual manufacturing. Challenges should include the range of conditions as defined by the various action levels.
Shifts, equipment to be used in the process: This is most important for sterile manufacturing especially aseptic filling and lyophilization.
Identification of utilities (air, water, gas, nitrogen, vacuum, etc.) for the process equipment and quality of the utilities
Identification of operators and required operator training and qualification

11. WBS/Validation of new premises
Clean area
Premises
Utility
Systems
Manufacturing
Support Syst.
Equipment
Manufacturing
Processes
HVAC System
LAF Units
Cold Storage
Env. Monitoring
Facility Cleaning
Transfer hatches
Verifi. of classific.
Water systems
Plant Steam
Pure/Clean Steam
Process Gases
Sterilizers
Depyrogenators
SIP Systems
CIP Systems
Washing
Waste Systems
Fermentors
Scales
Incubators
Filtration Units
Filling Equipment
Computerised
systems
Fermentation
Separation
Purification
Filtration
Filling
Aseptic
Processing
Packaging &
Labeling
In-Process
Control
Personnel
Training
Analytical
Methods
Media Fills
Packaging
Labeling
Process Measurem.
Visual Inspection
Label Control
Sampling
GMP
Gpwning valid..
SOPs
Equipment
Processes
Chemical - Cleaning valid
Physical - Sterility tests
Biological - Stability

12. Validation Protocol development (2)
Complete description of the process
Relevant specifications and tests
Samples and sampling methods
Special controls or conditions
Process parameters to be monitored
Methods for controlling and monitoring
Protocol development: (Contd.)
This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat:
Complete description of the process
Relevant specifications that relate to the product, ingredients, manufacturing methods, etc. Utilization of standard test methods such as those contained in international or national standards will provide guidance on how to measure specific parameters.
Samples and sampling methods
Any special controls or conditions to be placed on preceding processes during the validation
Process parameters to be monitored, and methods for controlling and monitoring

13. Validation Protocol development (3)
Objective and subjective criteria used to evaluate the product
Definition of non-conformance
Statistical methods
Maintenance and repairs
Criteria for revalidation
Criteria for change control
Protocol development: (Contd.)
This continues the protocol development which is common for liquids, solid dosage forms such as tablets and capsules, and sterile products being manufactured using moist or dry heat:
Any objective or subjective criteria used to evaluate the product
Definition of what constitutes non-conformance for both measurable and subjective criteria (such as odour, appearance, taste)
Statistical methods for data collection and analysis
Consideration of maintenance and repairs of manufacturing equipment
Criteria for revalidation
Criteria for change control

14. Validation DQ IQ OQ PQ relationships and considerations:
DQ (Design Qualification) should relate to Process: what needs to be done? DQ can be user requirements.
IQ (Installation Qualification) considerations include:
Equipment design features (i.e. materials of construction cleanability, etc.)
Installation conditions (functionality, utilities, wiring, etc.)
Calibration, preventative maintenance, cleaning schedules; safety features
Supplier documentation, prints, drawings and manuals, software documentation
Environmental conditions (such as clean room requirements, temperature, humidity)
Spare parts list
OQ (Operational Qualification) considerations include:
Process control limits (e.g. time, temperature, pressure, line speed, setup conditions)
Software parameters; starting material specifications
Process operating procedures; material handling requirements
Process change control; training; short term stability and capability of the process, (latitude studies or control charts)
Risk analysis and potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis)
PQ (Performance Qualification) includes:
Actual product and process parameters and procedures established in OQ
Assurance of process capability as established in OQ
Acceptability of the product
Process repeatability, long term process stability

15. Validation GMP Inspector’s check list for validation (1)
Check that the manufacturer has:
A VMP and multi-functional team for validation
Planned approach , defined requirements
Identified and described processes
Analyse the amount of validation work to perform
Check list for validation:
This is a list of activities which may be used as a checklist to review validation activity. The manufacturer should:
Create a master validation plan: as described in Part 1.
Form a multi-functional team for validation: as described in Part 1.
Plan the approach, and define the validation requirements.
Identify and then describe the processes.
Specify the process parameters and desired output.
Analyse the amount of validation work to perform. It is most important that the inspectorate and the manufacturer agree on the risk involved and the extent of validation. High risk products, such as biologicals derived from human blood must be at one end of the scale (requiring considerable validation effort), while at the other end may be very simple, low risk, over- the-counter medicines requiring less validation.

16. Validation GMP Inspector’s check list for validation (2)
Check that the manufacturer has:
Selected methods and tools for validation
Created protocols
Performed DQ, IQ, OQ, PQ and documented results
Exerted change control, set revalidation time
Check list for validation: (Contd.)
This is a continuation of the list of activities which may be used as a checklist to review validation activity. The manufacturer should:
Select methods and tools for validation
Create validation protocols
Perform DQ, IQ, OQ, PQ and document results
Exert change control and set revalidation time or frequencies

17. Validation Summary Logical entity: protocol + procedure + report
A quality tool that makes lot of sense
A prevention-based activity= important part of quality building process
Expensive in the beginning later will "save the money back"
In danger of becoming overwhelming
Risk-based assessment of what needs to be validated or verified
The process must be under control/validation as such does not improve the process
Logical entity: protocol + procedure + report
Summary
Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective.
Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life.
Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be.
A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits.
Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.

18. Validation
Question no 29-31
What are the three important parameters confirmed by validation?
Summary
Validation is a quality tool to ensure that quality is designed into a process. Validation is a requirement that has always made sense from both a regulatory and quality perspective.
Validation is regarded as a prevention-based activity: if more effort is placed on development and validation at the beginning, then there will be less chance of failure during the product’s life.
Validation is expensive, a growth industry and in danger of becoming overwhelming for many pharmaceutical manufacturers, particularly those in developing nations. The result may be not to complete any validation work at all. However, the risk-based assessment and determination of critical steps of manufacture should be used to identify what needs to be validated, and what can be simply verified, by testing if needs be.
A key statement is: “The process must be under control”; that is, by quality terms, it must be a capable process. Juran defines process capability as "the measured, inherent reproducibility of the product turned out by a process.” In validation the manufacturer is trying to measure reproducibility and establish that the variability falls within pre-established confidence limits.
Suggested Reading: J. M. Juran and Frank M. Gryna, eds., Juran's Quality Control Handbook, 4th Edition, McGraw-Hill, Inc, 1988.