Introduction to Validation and Pharmaceutical Process Validation

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