PHARMACEUTICAL CALIBRATION & VALIDATION. What is Validation? What is calibration? What are the types of Validation ? Validation and calibration Basic Difference

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VALIDATION
&
CALIBRATION
M.Mitra
CDSCO(NZ)
www.pharmanotes.org

2. History
– Drug product quality was seen as the
function of the status of the product itself.
– Flawed approach- destructive tests-
individual products can not be tested.
– No statistical method was available to
ensure quality of a batch of drug.

3. History
– US FDA included some form of validation
around mid 1970s
(Process validation 21 CFR parts 210 and 211)
– Initially limited to sterile products and later
extended to other dosage forms
– This was out of a concern to develop a
verification mechanism that would need to be
applied to the process to be meaningfully
extrapolated to an entire batch

4. History
– In the Indian scene this emerged as a requirement
for those firms who wished to register with
foreign agencies.
– Followed by those requiring WHO GMP
Certification for COPP.
– Now included in the revised schedule M

5. Calibration---what is it?
– A set of operations that establish, under specified
conditions, the relationship between values
indicated by an instrument or system for
measuring, recording, and controlling, or the
values represented by a material measure, and
the corresponding known values of a reference
standard. limits of acceptance of the results of
measuring should be established.

6. Calibration
The key requirements for critical instruments are
as follows:
each instrument should have a record in a
permanent file
all instruments should be assigned a unique
number and tagged with that number
the calibration method should be defined and
approved
calibration frequency and process limits should be
be defined for each instrument

7. Calibration
– all records shall be maintained
– each standard should be traceable to a recognized
standard
– The calibration standards must be more accurate
to a closer tolerance that the instrument being
tested
– calibration status should be identified on each
instrument

8. Calibration
all instruments shall be fit for the purpose
training records for all personnel involved in the
calibration must be maintained
a change control system must be in place
the instruments must meet all GMP
requirements

9. Calibration
– Frequency of calibration shall be determined by the
following:
– manufactures recommendations
– duty of the instrument
– relevant standards and regulations
– historical information
– consequence of calibration failure
– experience

10. Calibration
– Documentation
– Key documents:
 Schedule date for calibration and frequency
 Instrument ID
 Calibration range
– others
• all records must be clear and unambiguous
• unique number must identify the instrument
• any instrument removal must be documented
• replacement instrument must have documented history
• removed instrument should be calibrated immediately to ascertain the cause or
impact of failure

11. Validation And Process Validation
- Validation studies shall be an essential part of
Good manufacturing Practices and shall be
conducted as per the pre-defines protocols.
These shall include validation of processing
testing and cleaning procedures.
- A written report summarizing recorded results
and conclusions shall be prepared, documented
and maintained.

12. Validation And Process Validation.
– Processes and procedures shall be established on he basis
of validation study and undergo periodic revalidation to
ensure that they remain capable of achieving the intended
results. Critical processes shall be validated, prospectively
or retrospectively.
– When any new master formula or method of preparation is
adopted, steps shall be taken to demonstrate its suitability
for routine processing. The defined process, using the
materials and equipment specified shall be demonstrated
to yield a product consistently of the required quality.

13. Significant changes to the manufacturing
process, including any change in equipment
or material that may affect product quality
and / or the reproducibility of the process,
shall be validated.

14. What is Validation ?
– Documented proof that everything, within
reasonable certainty, that is involved in the
manufacture of a product is under control.
– This includes the facility, the environment, the materials,
the equipment and the processes including manufacture
and cleaning procedures.

15. WHY VALIDATION
–To Establish by documented
Evidence to provide a high
degree of assurance that a
planned process will consistently
perform according to the
intended specified outcomes

16. MASTER VALIDATION PLAN
–It is a document pertaining to the “whole
facility” that describes which Equipment.
Systems. Methods and Processes will be
validated and when they will be validated.
–It also includes Re-Validation- why and
when

17. VALIDATION CONSISTS OF
–Design Qualification - DQ
–Installation Qualification - IQ
–Operational Qualification - OQ
–Performance Qualification - PQ

18. DESIGN QUALIFICATION
– Necessary when planning and choosing equipment or
systems to ensure that components selected will have
adequate capacity to function for the intended purpose.
– Example- selection of steam generator.
– Master Validation Plan must address sequence of DQ.

19. INSTALLATION QUALIFICATION
– Qualification of a piece of equipment
should check for the requirements that
are mentioned in the DQ
– Compare with the purchasing information
and invoice data
– Requirements- Name, description, model,
identification numbers, location, utility
requirements, connections, safety
measures 0f the system

20. IQ - continued
– During Installation Qualification it should be verified that
the following matches the purchase specification:
Drawings,
manuals,
spare parts list,
vendor address and contact number,
Other pertinent documentation.

21. Simple Example of
Installation Qualification
1. Equipment: _________________
2. Model: _________________
3. Manufacturer: _______________
4. Date of Purchase: ____________

22. 1. Manual Provided/Not Provided Remarks
2. Physical Damage OK/Damage found
3. Dimensions Not / As per
requirement
4. Switches OK/Damage/Inadequate
5. Covers Working OK/Damage/Inadequate
6. Limit Switches OK/Damage/Inadequate
7. Electrical
Fittings
OK/Damage/Inadequate
8. All fastenings OK/Damage/Inadequate

23. The details of the equipment should be
critically tallied with the order placed
with the vendor. Needless to add the
order placed should be as per the
Design Qualification (DQ). All critical
components of the equipment should be
tabulated and only after successful
verification should the equipment
verified as conforming to IQ

24. OPERATIONAL
QUALIFICATIONS
– Outlines the information required to provide
evidence that all the components of a system
or equipment operate as specified.

25. OPERATIONAL
QUALIFICATIONS
– This involves testing of all:
 normal operation controls,
 all alarm points,
 all switches,
 all displays,
 interacting controls,
 any other indications of operation & functions

26. OQ - continued
Specifications and acceptance criteria must be
defined for all operation
Should provide a listing of SOPs, reference to
specific manual instructions for operation,
maintenance and calibration

27. Performance Qualification
– To be carried out after both IQ and OQ have
been successfully completed
– Describes the procedures for demonstrating
that a system or piece of equipment can
consistently perform and meet required
specifications under routine operation, and
where appropriate, under worst case
situations.

28. PQ - continued
– Describe the preliminary procedure required
– Detailed performance test
– acceptance criteria for each test
– all supporting systems and procedures should have been
validated (e.g.. Steam system should be validated before
autoclave validation)

29. Process Validation
Performance (How to do it)
- Process : Run the process according to SOP three
times and record all required data.
– Deviations to the procedures must be recorded
on the data record forms.
– Analytical tests : Perform the routine tests
associated with the process according to SOP,
Test results must be approved by the QC.

30. Evaluation
– Attach all data record forms and charts.
– Perform all calculations and analyses which are
predetermined and approved.
– Compare with the accepted criteria.

31. Prepare Deviation Report
– Deviation if any must be recorded and
justification for acceptance, if any, mentioned.

32. Prepare Process Validation
Report
– This must mention start date, completion date,
observations, problems encountered,
completeness of information, summary of the
deviation report, results of test, comparison with
the accepted criteria, other relevant data.
– Conclusion should take into account individual as
well as the results of three consecutive validation
runs.

33. Approval and Acceptance
– QA should review and approve the report.
– The Process must meet all specifications
– For three consecutive runs

34. Process validation
– Experimental
– Prospective validation
– Concurrent validation
– Analysis of historical data
– Retrospective validation
– Revalidation
– After change
– periodic

35. Process Validation Requirements
Type of process
Validation
Requirements
New •Every new process must be validated
before approval for routine production
Existing
1. Process designed to
render a product sterile
•All processes affecting sterility and
manufacturing environment must be
validated; the most important is the
sterilization stage.
2. Non- sterile production •Low-dose tablets and capsules
containing highly active substances:
validation of mixing and granulation in
relation to content uniformity.
•Other tablets and capsules: Validation
of tablet compressing and capsule
filling in relation to uniformity of
mass.
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36. Example of Process Validation
Manufacture of Paracetamol tablets
Procedure of receipt of RM to the plant
Procedure of storage and testing
Procedure of issue of material to Prod.
Actual manufacturing:
Weighing
Sieving
mixing
Granulation
Drying

37. Example of Process Validation Contd.
 Lubrication
 Compression
 Release & Packing
Each of the above operations have to be validated
against the requirements of the procedure and
documented!!!!

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Thank You