Quality Assurance & Quality Control

Lecture-9

Dr Shaouki Munir
MBBS (DU), MGMP (UTS), MPH (UNSW)
 Module Contents

This module covers the following topics:

a) Process validation & activities
b) Stages of process validation
c) WHEN SHOULD PROCESSES BE VALIDATED?
d) Types & general requirements of process validation
e) Validation protocols – contents
f) Validation reports – contents
Validation Life-Cycle
Process Validation

“Establishing documented evidence provides a high degree of

assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality
attributes. ’’

(Validation of the individual steps of the processes is called

process validation)
Process Validation Activities

Process validation involves a series of activities taking place

over the lifecycle of the product and process.

These process validation activities are divided into three

following stages.
• Stage 1 – Process Design
• Stage 2 – Process Qualification
• Stage 3 – Continued Process Verification
Stage 1 - Process Design

Process Design:
During this stage, the commercial manufacturing
process is defined based on knowledge gained through
development and scale-up activities.
Stage 2 – Process Qualification

Process Qualification:
During this stage, the process design is evaluated to
determine if the process is capable of reproducible
commercial manufacturing.
Stage 3 – Continued Process Verification

Continued Process Verification:

Ongoing assurance is gained during routine production
that the process remains in a state of control.
 GENERAL CONSIDERATIONS FOR PROCESS VALIDATION

• An integrated team approach to process validation that includes

expertise from various disciplines. Project plans, along with the full
support of senior management, are essential elements for success

• All studies should be planned and conducted according to sound

scientific principles, appropriately documented, and approved by the
established procedure

• Homogeneity within a batch and consistency between batches should

be the goals of process validation activities
Objectives of Process Validation

• To establish a record-keeping system that considers all concepts of

manufacturing process which includes controlled testing
• To evaluate all possible sources of variation in the process
• To identify all sources of variation that are possible from the materials,
machines, methods and men
• To evaluate the requirement for in-process testing and evaluation
• To document everything that is done to follow established procedures
and protocols as closely as possible
• Quality, safety and effectiveness must be designed and built into the
product
• Quality must be assured
WHEN IS PROCESS VALIDATION NEEDED?

• Before the introduction of a new method into routine use

• Whenever the conditions change for which a method has

been validated, e.g. instrument with different characteristics

• Whenever the method is changed, and the change is outside

the original scope of the method
 WHEN SHOULD PROCESSES BE VALIDATED?
The following model may be useful in determining whether or not a process should validated:
PROCESS VALIDATION: ORDER OF PRIORITY

A) Sterile product and their processes

1. large volume parenteral

2. Small volume parenteral
3. Ophthalmic, other sterile products, and medical devices
PROCESS VALIDATION: ORDER OF PRIORITY (contd.)

B) Non-sterile products and their processes

1. low dose/high-potency tablets and capsules

2. drugs with stability problems
3. other tablets and capsules
4. oral liquids, topical, and diagnostics aids
Process validation examples
▪ Cleaning
▪ Sanitization
▪ Fumigation
▪ Dehydrogenation
▪ Sterilization
▪ Sterile filling
▪ Fermentation
▪ Bulk production
▪ Purification
▪ Inactivation
▪ Filling, capping, sealing
▪ Lyophilisation
TYPES OF PROCESS VALIDATION
Prospective Process Validation

• An experimental plan called the validation protocols executed before

the process is put into commercial use

• Most validation efforts require some degree of prospective

experimentation to generate validation support data

• It is normally carried out in connection with the introduction of new

drug products and their manufacturing processes
Requirements

• Equipment/facilities should meet cGMP requirements

• Personnel have an awareness of the requirements

• Critical processing stages and process variables are identified

• At least one qualification trial (size x 100) made, which shows that there is
no significant deviation from the expected performance of the process

• Batches should be run on different days, shifts and different quantities

Retrospective Process Validation

• It is chosen for established products whose manufacturing processes

are considered stable, and when on the basis of economic
considerations alone and resource limitations, prospective validation
programs cannot be justified

• Wherein the numerical in-process and/or end-product test data of

historic production batches are subjected to statistical analysis

• The equipment, facilities and subsystems used in connection with the

manufacturing process must be qualified in conformance with CGMP
requirements
Requirements

• Gather all historical data of process/ product in chronological sequence

according to batch manufactured

• Data should consist of at least the last 20-30 manufactured batches for
analysis

• Trim data by eliminating results of non-critical steps

• Subject the resultant data to statistical analysis and evaluation

• Draw the control charting & go for conclusion

Advantages

• No additional samples necessary; only need history data

• No additional testing is required
• Cost saving compared with prospective
• No additional risk
• No longer time need
• Trained persons are easily available to perform the work
• It can be adapted to various types of processes/ products
• Well suited for an existing product which is not validated previously
Concurrent Process Validation

• It is in-process monitoring of critical processing steps and

end-product testing of current production

• It can provide documented evidence to show that the

manufacturing process is in a state of control

• It provides validation documentation from the test

parameter and data sources disclosed in the section on
retrospective validation
Process Re-Validation:

Required when there is a change in

• any of the critical process parameters

• formulations
• primary packaging components
• raw material
• major equipment or premises

Failure to meet product and process specifications in batches

would also require re-validation.
IMPORTANCE OF PROCESS VALIDATION

• Improve the use of technology

• Improve the business benefits
• Improve operational efficiency
• Improve compliance with regulations
• Reduce the risk of failure
• Reduce the cost
• Process optimisation
• Increased customer satisfaction
REVALIDATION

• Revalidation means repeating the original validation effort or any

part of it and includes an investigative review of existing
performance data

• It is done annually in the form of reviewing and analysing annual

records in the form of existing data, such as those from
manufacturing batch records, in Process control testing and stability
testing

• It reconfirms formally that control parameter ranges are appropriate

CONDITIONS FOR REVALIDATION

1. Change in critical components (raw materials)

2. Change or replacement in equipment
3. Changes in location or site
4. Significant increase or decrease in batch size
5. Sequential batches that fail to meet product and process
qualification
Validation Protocols
IQ Protocol (Contents)

• Approval Page
• Objectives
• System Description
• Responsibilities
• Acceptance Criteria
• Engineering Documentation Requirement
• Records of Signatures
• Qualification Test Equipment/Instrument List
• Product Contact Materials Review
• Utility Verification
• Control System Verification
IQ Protocol (Contents)

• Instrument/Control Devices Verification

• Equipment Verification
• Piping Installation Verification
• Discrepancy/Justification and corrective Action
• As built P&I Diagrams
• Specifications
• Conclusions
• References
• Modification/ Change Control
• Attachments / Appendices
IQ Protocol Approval

• After protocol execution is complete and deviations evaluated, post-

execution approval is required

• Requires sign-off by original signatories

• IQ execution should be complete and approved prior to the start of

OQ
OQ Protocol (Contents)

• Approval page
• Pre-requisites
• Objectives
• System Description
• Responsibilities
• Acceptance Criteria
• Records of signatures
• Qualification test Equipment/Instruments list
• Alarm and Interlocks test
• Operation testing
• Capacity testing
• Power failure testing
OQ Protocol (Contents)

• Sequence testing
• Test data sheets
• SOP’s
• Conclusions
• Modification/change control
• Discrepancy/Justification and corrective action
• Operational Qualification Summary
• References
• Attachments/Appendices
• Verification of test instruments
• Chart recordings
• P&I diagrams
• Printouts
PQ Protocol (Contents)
• Approval page
• Pre-requisites
• Objectives
• System Description
• Responsibilities
• Acceptance Criteria
• PQ test plan
• Challenge test plan
• Records of signatures
• Test equipment/Instrument list
• Test data sheets
• SOP’s
• References
• Conclusions
• Attachments
Validation Report – Contents

• Title
• objective of the study
• Refer to the protocol
• Details of material
• Equipment
• Programmes and cycles use
• Details of procedures and test methods
References
• Who.int. 2016. [online] Available at:
<https://www.who.int/medicines/areas/quality_safety/quality_assurance/validation-
without_appendices_2016_05_17.pdf> [Accessed 27 November 2021].

• En.wikipedia.org. 2021. Validation (drug manufacture) - Wikipedia. [online] Available at:

<https://en.wikipedia.org/wiki/Validation_(drug_manufacture)> [Accessed 27 November
2021].

• Ikev.org. 2021. ICH Q2B Guideline Validation of Analytical Procedures Methodology. [online]
Available at:
<https://www.ikev.org/haber/stabilite/kitap/36%201.8%20%20Stability%20Workshop%20IC
H%20Q2B%20C%20.pdf> [Accessed 27 November 2021].
Thank you