3. Background
• Validation is a concept that has been
evolving continuously since its first formal
appearance in the United States in 1978.
• Validation guideline - FDA's 1987
4. Reference
• ICH: GMP - Q7 (12.4, 12.5 &12.6)
• USFDA: Process Validation- General principles and
Practices Jan-2011
• WHO: TRS # 937-2006- Annex-4
• PIC/s : VMP… Non-sterile process validation- Aug
2001
• EMEA: Note for Guidance on process validation
5. Definitions: (USFDA)
“Establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product meeting its predetermined
specifications and quality attributes”
6. Definition
Validation means confirmation by examination and provision of
objective evidence that the particular requirements for a specific
intended use can be consistently fulfilled. [CFR 21 Part 820.3(z)]
Verification means confirmation by examination and provision
of objective evidence that specified requirements have been
fulfilled. [CFR 21 Part 820.3(aa)]
Validation Examples:
•Process Validation, cleaning validation, Sterilization Validation, Test Method
Validation, Software Validation, and (dynamic)
Verification Examples:
•Design Verification and Process Verification. (static)
7. Definition
• Process performance qualification - Establishing
confidence that the process is effective and reproducible.
• Product performance qualification - Establishing
confidence through appropriate testing that the finished
product produced by a specified process meets all release
requirements for functionality and safety.
• Prospective validation - Validation conducted prior to the
distribution of either a new product, or product made
under a revised manufacturing process, where the
revisions may affect the product's characteristics.
8. Definition
Predetermined Specification:
Validation activities start with the definition of
specifications. The performance of equipment is
then verified against these specifications.
Acceptance Criteria must be defined prior to
testing.
Documented Evidence:
Validation requires a through documentation
everything that is not documented is considered
incomplete.
9. Advantages of validation
• Reduction in rejection and reworking
• Reduction in utility cost avoidance of capital
expenditure
• Reduce down time
• improving efficiency and productivity by optimisation
• Easier scale up from development work
• Improved employee awareness of processes
• Reduced testing in process and in finished goods.
• Compliance to meet regulatory requirement
10. Validation approach
FDA guidance describes process validation activities as below;
• Stage 1 – Process Design: The commercial manufacturing
process is defined during this stage based on knowledge
gained through development and scale-up activities.
• Stage 2 – 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: Ongoing assurance
is gained during routine production that the process remains
in a state of control.
11. Purpose
• To gain high degree of assurance in the performance of the
manufacturing process such that it will consistently produce
APIs and drug products meeting those attributes relating to
identity, strength, quality, purity, and potency.
• To confirm the process, manufacturers must maintain the
process in a state of control over the life of the process, even
as materials, equipment, production environment, personnel,
and manufacturing procedures change
• Manufacturers should use ongoing programs to collect and
analyze product and process data to evaluate the state of
control of the process.
12. Sequence to Validation
Process Development / (Lab scale)
Optimized Laboratory Process
Validation of Sub-Processes
(Analytical Methods, Lab instruments; Equipment and
Utility Qualification; Cleaning process &methods etc.)
Optimized Plant Batch (Plant scale)
Process Validation (Plant Scale)
Ongoing Process Validation
13. Sequencing Validation Activities
Process Validation
Equipment Method Cleaning Water System AHU
Qualification validation validation validation Qualfn
(IQ, OQ, PQ) (In-process
(Reactor Impurities
Drier & Intermediate)
Blender) Sampling Qualifn Qualification
( DQ,IQ, OQ) (DQ, IQ,OQ &PQ)
Instrument method Validation
Qualification of detection
(DQ,IQ,OQ) method
14. Validation Approach
Multi Functional activity
Team approach
QA co-ordination
Protocol Driven (Planning)
15. Types of process validation
• Prospective Process Validation
• Concurrent Validation
• Retrospective Validation
• Revalidation
16. Types of Process Validation
• Prospective Validation: It would normally be
expected that Process Validation be
completed prior to the manufacture of
finished product that is intended for sale.
• Concurrent Validation: Where this is not
possible, it may be necessary to validate
processes during routine production .
• Retrospective Validation: Processes which
have been in use for some time should also be
validated .
17. Prospective Validation
• Prospective validation involves manufacturing,
sampling, and testing of validation batches according
to a pre-approved validation protocol.
• Validation conducted prior to distribution either of
– new product,
– process,
– Products transferred between plants,
– Changes to existing processes
18. Prospective Validation
• It is establishing documented evidence prior to
process implementation that a system what it
purports to do based on a preplanned protocol.
• It is conducted prior to distribution of either a new
product or a product made under a modified
Production process, where modifications are
significant and may affect product characteristics.
• This is a preplanned scientific approach and includes
initial stages of equipment validation.
19. Concurrent Validation
• It is establishing documented evidence that a
process does what it purports to do, based on
information generated during actual
implementation of the process.
• It may be practical approach under certain
circumstances.
– When a previously validated process is being
transferred to a third party contract manufacturer or
to another manufacturing site
– When number of batches produced are limited.
20. Retrospective Validation
• It is establishing documented evidence that a
system does what it purports to do, based on
review and analysis of historical information.
• It has become synonymous with achieving
validation by documenting all historical
information,
– e.g. release data for existing products and using
that data to support position that process is under
control.
– 20 to 30 batches
21. Revalidation
This is nothing but the repetition of the whole validation process
or a specific portion of it. It becomes necessary in certain
situations. Some of the changes are as follows.
• Changes in source of active Raw material manufacturers
• Changes in Raw Materials
• Changes in Packaging Materials
• Changes in process parameter e.g. Mixing, Time, Drying
Temperature, and Batch Size etc.
• Changes in Equipment
• Changes in Plant Facility
• Monitoring of equipment capabilities over a period of time.
• Changes in the Specification of API
23. Plan of work
• Literature Review
• Review of Product Development Report
• Identification of Critical Process Parameters
• Preparation of Process Validation Protocol
• Monitoring of Manufacturing Process
• Review of Process Validation Batches
• Data collection
• Data evaluation
• Documentation of Process Validation Report
24. Validation Protocol
1. Purpose & Scope
2. Type of Validation & Justification
3. Responsibilities
4. Batch Selection Criteria & Time schedules,
(cover 2nd
crop, ratio of intermediate, varying batch size)
5. Process description & flow chart including
sub process
6. Batch Manufacturing Instructions
7. Key equipments, Reference to qualification,
calibration
8. Quality of raw materials
25. Validation Protocol
9. Critical Process parameters & operations
10. Critical Quality Attributes & additional
analysis.
11. Sampling plan: where, when, how and how many,
12. Acceptance Criteria
13. Deviation
13. Format for validation report: (Details of methods for
recording and evaluating results, including statistical analysis)
14. Approval by concerned authority & QA
(May be in first page)
26. Responsibilities
Validation team responsibilities :
• Head - Quality Assurance: Responsible for protocol authorization
and preparation of summary report
• Head - Quality Control: Responsible for analysis of samples
collected
• Head - Production: Responsible for manufacturing of batches and
review of protocol and report.
• Team - Quality Assurance: Sampling and monitoring of process as
per process validation protocol
• Team - Quality Control: Sample analysis as per standard test
procedures.
• Team – Production: Execution of the process, data collection
27. Methodology
Purpose & Scope
• Background
• Purpose
• Scope
Define Process:
• Description of process
• Flow chart
• Batch production instructions
• Key equipments
• Batch size
28. Define RM quality
KSM & other material quality
• Specification
• Fresh solvents / Recovered
• Test methods (validated as required)
29. Equipment Qualification
• Demonstrate that utilities and equipment are suitable for
their intended use and perform properly.
– Utilities are appropriate for their specific uses
– Equipment- MOC, operating principles, and performance
characteristics
• Verifying that utility systems and equipment are built and
installed in compliance with the design specifications (e.g.,
built as designed with proper materials, capacity, and
functions, and properly connected and calibrated).
• Eg. Water, HVAC, compressed air, etc…
30. Equipment Qualification
• Verifying that utility systems and equipment operate in
accordance with the process requirements in all anticipated
operating ranges.
• This should include challenging the equipment or system
functions while under load comparable to that expected
during routine production.
• It should also include the performance of interventions,
stoppage, and start-up as is expected during routine
production.
• Operating ranges should be shown capable of being held as
long as would be necessary during routine production
31. Calibration of critical
Instruments
List of critical measuring instruments
(Temp & Pressure gauge, Balances, Flow
meters etc.)
Measuring range – Operating range
Accuracy and Process tolerance
(Fitness for the purpose)
32. In-process Controls
To assure that the final drug product will meet
its quality requirements and control batch-to-
batch variability.
• Establish levels and frequency of routine sampling and
monitoring
• Consider the extended sampling and monitoring based on
volume of production, process complexity, level of
process understanding
• In-process specifications
• Test methods (validated)
• Acceptance limits
33. Sampling Plan
• The sampling plan for each unit operation and attribute.
– sampling points,
– number of samples, and the frequency of sampling
• where, when, how, how many, and how much
• Selection can be based on risk analysis as it relates to the
particular attribute under examination.
• Additional tests: Sampling during this stage should be more
extensive than is typical during routine production.
Sampling Procedures
Use PAT
34. Critical Process Steps /
Parameters
Parameters having Impact on product quality
Temp, time, pH, agitation/speed, etc
Establish the manufacturing condition based on
scientific judgment and cumulative data from;
Design Of Experiment, Laboratory, Pilot and
commercial batches.
Define and monitor the critical process
parameters and critical operations.
Define the acceptance range :Specification Limit
and control limits where required.
36. Training:
All personnel involved in the validation:
• Production, QC, microbiology, QA Engineering
• Production staff must know critical steps / parameters,
execution, sampling, data collection
• Analyst/microbiologist should know the sampling plan,
technique, analysis, method, data etc
• Engineering to support, qualification & calibration
• Identify any special training needs
37. Acceptance Criteria
Criteria for Validation to be Successful:
Product Quality
Yield / efficiency
Critical process parameters
Quality attributes; In-process test
results
38. Carry out the Process
Monitor Closely
Record relevant data
Analyse the Data
Validation Report
39. Evaluation of Validation
Data
The data to be collected and when and how it will be
evaluated.
• Evaluate deviations; Assignable causes
• Statistical Tools:
Trend analysis - Critical process parameters,
In-process results & Yields
Control /Alert limits
Process Capability Analysis Cp & Cpk values
40. Deviation
• Provision for addressing deviations from expected conditions
and handling of nonconforming data.
• Data should not be excluded from further consideration in
terms of PPQ without a documented, science-based
justification
Examples:
Minor: Time delay due to power failure in non-critical operation,
minor equipment failure in short time etc .. and product
meets the quality attributes.
Major: Deviation in critical process parameter and resulting in
quality failure
41. Validation report:
• Background , Scope & responsibility
• A description of the process
• Batch/Packaging Document reference
• Equipment qualification & calibration status
• KSM quality
• Input and out put of RMs
• Details of critical process parameter and operation data,
• A detailed summary of the results obtained from in-process
and final testing, including data from failed tests.
• Additional tests : Different spec (USP/EP/IP) PSD, bulk
density(BD/TD), XRD etc
42. Validation report:
• Any work done in addition to that specified in the
protocol or any deviations from the protocol should be
recorded along with an explanation
• Summarize and discuss all manufacturing non-
conformances such as deviations, unexpected
observations, aberrant test results, or other information
that has bearing on the validity of the process.
• A review and comparison of the results with those
expected,
• Conclusion: Formal acceptance/rejection of the
validation work
43. Conclusion
• State a clear conclusion as to whether the data indicates the
process met the conditions established in the protocol and
whether the process is considered to be in a state of control.
• If not, the report should state what should be accomplished
before such a conclusion can be reached.
• This conclusion should be based on a documented
justification for the approval of the process, and release of
lots produced by it to the market in consideration of the
entire compilation of knowledge and information gained from
the design stage through the process qualification stage.
44. Stage 3-Continued Process Verification
• The goal is continual assurance that the process remains in a
state of control (the validated state) during commercial
manufacture.
• Evaluating the performance of the process identifies
problems
• CAPA to ensure the process remains in control (§ 211.180(e)).
• An ongoing program to collect and analyze product and
process data that relate to product quality must be
established (§ 211.180(e)).
• The data collected should include relevant process trends and
quality of incoming materials or components, in-process
material, and finished products.
• Review of facility, utilities, and equipment and maintenance
45. Revalidation
• Re-validation provides the evidence that changes in a
process and/or the process environment, introduced
either intentionally or unintentionally, do not
adversely affect process characteristics and product
quality.
• There are two basic categories of Re-validation:
• (a) Re-validation in cases of known change
• (b) Periodic Re-validation carried out at scheduled
intervals.
• Documentation requirements will be the same as for
the initial validation of the process, and in many cases
similar protocols can be employed.
• Change to a process or process environment
