The document outlines pharmaceutical process validation, which ensures that procedures and equipment consistently produce quality products through defined protocols and scientific study. It covers the need for validation, associated documentation, stages of validation, and types like prospective and retrospective validation. Additionally, it addresses the importance of qualification and requalification, emphasizing that validation is essential for meeting regulatory requirements and optimizing production processes.

1. Pharmaceutical
Process Validation

2. Validation
Definition:
• Validation is the action of
proving that any procedure,
process, equipment,, method,
material or activities actually
leads to the expected results
and produce a quality
products.

3. Why Validation?
Need of Validation:
• To obtain consistent, reliable
and accurate data
• Act as a proof in decision
making
• To get assurance of Quality
product

5. Validation is the scientific study of a process:
• To prove that the process is consistently doing what it is
supposed to do (i.e., that the process is under control)
• To determine the process variables and acceptable limits
for these variables, and to set up appropriate in- process
controls.
Validation in Pharmaceutical Industry:
• Assurance of Quality
• Cost Reduction
• Government Regulation

6. Documentation associated with validation includes:
• Standard Operating Procedures (SOPs):
• Specifications
• Validation Master Plan (VMP)
• Qualification Protocols and Reports
• Validation Protocols and Reports.
Standard Operating Procedures (SOPs):
• An authorized written procedure giving instructions for
performing operations not necessarily specific to a given
product or material but of a more general nature (e.g.
equipment operation, maintenance and cleaning;
validation; cleaning of premises and environmental
control; sampling and inspection)

7. Validation protocol (or plan) (VP):
• A document describing the activities to be performed in a
validation, including the acceptance criteria for the
approval of a manufacturing process or a part thereof for
routine use.
Validation report (VR):
• A document in which the records, results and evaluation
of a completed validation programme are assembled and
summarized.
• It may also contain proposals for the improvement of
processes and/or equipment.

8. Resources required to implement validation:
• Time:
• rigorous time schedules.
• Financial:
• time of specialized personnel and
• expensive technology.
• Human:
• collaboration of experts from various disciplines
• e.g. a multidisciplinary team, comprising quality
assurance, engineering, manufacturing and other
disciplines, depending on the product and process to be
validated.

9. Scope of Validation
• Appropriate and sufficient system – to perform validation
tasks in a timely manner.
• organizational structure and
• documentation
• infrastructure,
• sufficient personnel – with specific qualification and
• financial resources
• Proper preparation and planning before performing
validation activities
• Validation performed in a structured way according to
protocols and documented procedures.

10. Scope of Validation
• A written report on outcome of validation should be
produced for documentation.
• Validation should be performed:
• for new premises, equipment, utilities and systems, and processes
and procedures;
• at periodic intervals; and
• when major changes have been made.
• Validation should be done over a period of time.
• e.g. at least three consecutive batches should be validated, to
demonstrate consistency.

11. Scope of Validation
• In-process controls and validation:
• In-process tests are performed during the manufacture of each
batch according to specifications and methods devised during the
development phase.
• Objective of in-process controls - to monitor the process
continuously.
• Significant changes to the facilities or the equipment,
and processes that may affect the quality of the
product should be validated.
• A risk assessment approach should be used to
determine the scope and extent of validation
required.

12. Validation Master Plan (VMP)
• Definition: It is a high-level document that establishes an
umbrella validation plan for the entire project and
summarizes the manufacturer’s overall philosophy and
approach, to be used for establishing performance
adequacy.
• It provides information
• on the manufacturer’s validation work programme and
• defines details of and timescales for the validation
work to be performed
• It should reflect the key elements of the validation
programme.

13. Validation Master Plan
• It should be concise and clear and contain at least the
following:
• a validation policy
• organizational structure of validation activities
• summary of facilities, systems, equipment and
processes validated and to be validated
• documentation format (e.g. protocol and report format)
• planning and scheduling
• change control
• references to existing documents.

14. Validation Protocol
• Definition: A document describing the activities to be
performed in a validation, including the acceptance
criteria for the approval of a manufacturing process or a
part thereof for routine use.
• A protocols should include
• the objectives of the study
• the site of the study
• the responsible personnel
• description of SOPs to be followed
• equipment to be used; standards and criteria for the relevant
products and processes
• the type of validation
• the processes and/or parameters
• sampling, testing and monitoring requirements
• predetermined acceptance criteria for drawing conclusions

15. Validation and Qualification
• Validation: Action of proving and documenting that any
process, procedure or method actually and consistently
leads to the expected results.
• Qualification: Action of proving and documenting that
any equipment, utilities and systems actually and
consistently leads to the expected results
• Validation and qualification are essential components of
the same concept.
• Qualification is part of validation

16. Qualification
• Qualification: Action of proving and documenting that
any equipment, utilities and systems actually and
consistently leads to the expected results
• Qualification should be completed before process
validation is performed.
• The process of qualification –
• logical,
• systematic process
• should start from the design phase of the premises,
equipment, utilities and equipment.

17. Qualification
• There are four stages of qualification:
• design qualification (DQ)
• installation qualification (IQ)
• operational qualification (OQ)
• performance qualification (PQ).
• All SOPs for operation, maintenance and calibration
should be prepared during qualification.
• Training should be provided to operators and training
records should be maintained.

18. Design Qualification:
• Documented evidence that the premises, supporting
systems, utilities, equipment and processes have been
designed in accordance with the requirements of GMP
Installation qualification (IQ):
• Installation qualification should provide documented
evidence that the installation was complete, satisfactory
and operate in accordance with established specifications.
• Installation qualification verified –
• The purchase specifications,
• drawings, manuals,
• spare parts lists and
• vendor details

19. Operational qualification (OQ):
• Operational qualification should provide documented
evidence that utilities, systems or equipment and all its
components operate in accordance with operational
specifications.
• Operation controls, alarms, switches, displays and other
operational components should be tested.
Performance qualification (PQ):
• Performance qualification should provide documented
evidence that utilities, systems or equipment and all its
components can consistently perform in accordance with
the specifications under routine use.
• Test results should be collected over a suitable period of
time to prove consistency.

20. Requalification
• Requalification should be done in accordance with a
defined schedule.
• The frequency of requalification may be determined on
the basis of factors such as the analysis of results relating
to calibration, verification and maintenance.
• There should be periodic requalification, as well as
requalification after changes (such as changes to utilities,
systems, equipment; maintenance work; and movement).
• Requalification should be considered as part of the
change control procedure.

21. Advantages of Validation
Main advantages of Validation:
Assurance of quality
• Validation is an extension of the concepts of quality
assurance since close control of the process is necessary
to assure product quality.
• It is not possible to control a process properly without
thorough knowledge of the capabilities of that process.
• Without validated and controlled processes, it is
impossible to produce quality products consistently

22. Process optimization
• Optimize – to make as effective, perfect or useful as
possible
• Validation helps to optimize the process for its maximum
efficiency with maintaining its quality standards.
• The optimization of the facility, equipment, systems, and
processes results in a product that meets quality
requirements at the lowest cost.
Reduction of quality costs
• Any validated and controlled process will result in fewer
internal failures like
• Fewer rejects
• Reworks
• Re-tests
• Re-inspection

23. Process Validation
Process Validation – Statutory and Regulatory
requirement
• Requirement of cGMPs for finished pharmaceuticals (21
CFR 211)
• Requirement of GMPs for medical devices (21 CFR 810)
• Apply to manufacturing of both drug product and medical
devices

24. Definition of Process Validation (as per US FDA):
• Process validation is 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 characteristics.
In short,
• Process validation is defined as the collection and
evaluation of data, from the process design stage through
commercial production, which establishes scientific
evidence that a process is capable of consistently
delivering quality product.

25. Process Validation Activities
• Process validation involves a series of activities taking
place over the lifecycle of the product and process.
• Process validation activities in three stages
• Stage I: Process Design
• Stage II: Process qualification
• Stage III: Continued process verification

26. 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:
• On-going assurance is gained during routine production
that the process remains in a state of control.

27. Types of Process Validation
The guidelines on general principles of Process Validation
mention four types of validation.
• Prospective Validation (Premarket validation)
• Retrospective Validation
• Concurrent Validation
• Revalidation

28. Prospective Validation
• Definition: It is establishing documented evidence prior
to process implementation that a system does what it
proposed to do based on pre-planned protocols.
• An experimental plan called the validation protocol is
executed before the process is put into commercial use.
• It is normally undertaken for a new drug product or new
facilities are introduced into a routine pharmaceutical
production.
• Objective: To prove that the process will work in
accordance with a validation protocol

29. • During Product development stage
• Production process broken down into individual steps
• Each steps evaluated on the basis of experience or theoretical
considerations
• Critical factors that may affect the quality of the finished product
are determined.
• Personnel involved in Prospective validation are
• Representatives from Production
• QC/QA, Engineering
• Research and Development
• It is a challenge element to determine the robustness of
the process. Such a challenge is generally referred to as a
"worst case" exercise.

30. Everything should be planned and documented fully in an
authorized protocol. It contains…
a) Objective, scope, responsibilities
b) Process Flow
c) A description of the process,
d) A description of the experiment,
e) Details of the equipment/facilities to be used together
with its calibration status,
f) The variables to be monitored,
g) The samples to be taken - where, when, how and how
many,
h) The product performance characteristics/attributes to
be monitored, together with the test methods,
i) The acceptable limits,
j) Time schedules,
k) Details of methods for recording and evaluating
results, including statistical analysis.
l) Summary / Conclusion

31. Pre-Requisite of process validation
• All equipment to be used should have been qualified
(Installation/Operational Qualification),
• The production Facility and area should be validated.
• Analytical testing methods to be used should have been
fully validated,.
• Critical support systems like water system, compressed
air system etc, should be validated.
• Raw and packaging material specifications are approved.
• Staff taking part in the validation work should have been
appropriately trained.

32. Retrospective Validation
• Definition: It is an establishing documented evidence that
a process does what it is supposed to do based on review
and analysis of historic data.
• Many process – routine use – not validated
• Validation of these processes - historical data to provide
the necessary documentary evidence that the process is
doing what it is supposed to do.
• Steps require for validation
• Protocol preparation
• Validation reports
• Data analysis
• Conclusion
• Recommendations

33. Concurrent Validation
• Definition: Concurrent Validation means establishing
documented evidence a process does what it is supposed
to do based on data generated during actual
implementation of the process.
• Validation – during routine production
• Validation involves –
• In-process monitoring
• End product testing
• Personnel – Authorized staff
• Documentation – as per Prospective Validation

35. Revalidation
• Definition: 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:
• Re-validation in cases of known change (including
transfer of processes from one company to another or
from one site to another),
• Periodic Re-validation carried out at scheduled
intervals

36. Changes that are likely to require Re-validation are as
follows:
• Changes of raw materials (physical properties such as
density, viscosity, particle size distribution may affect the
process or product),
• Change of starting material
• Changes of packaging material (e.g. substituting plastic
for glass),
• Changes in the process (e.g. mixing times, drying
temperatures),
• Changes in the equipment (e.g. addition of automatic
detection systems).
• Changes of equipment
• Production area and support system changes (e.g.
rearrangement of areas, new water treatment method),
• Transfer of processes to another site