Process validation

2. Process validation is establishing documented evidence which
provides a high degree of assurance that a specific process (such as
the manufacture of pharmaceutical dosage forms) will consistently
produce a product meeting its predetermined specifications and
quality characteristics.

3.  According to the FDA, assurance of product quality
is derived from careful and systematic attention to a
number of important factors, including selection of
quality components and materials, adequate product
and process design and control of the process
through in-process and end product testing.

4. Conventional quality control procedures for
finished product testing includes 3 basic steps:
• Establishment of specifications and performance
characteristics.
• Selection of appropriate methodology, equipment
and instrumentation.
• Testing of the final product, using validated
analytical and testing methods to ensure that
finished product meets specifications

5.  Qualification of the processing facility and its
equipment.
 Qualification and validation of the manufacturing
process through appropriate means
 Auditing, monitoring, sampling or challenging the
key steps in the process for conformance to in-
process and final product specifications.
 Revalidation when there is a significant change in
either the product or its manufacturing process.

6. 
Process capability is defined as the studies used to determine
the critical process parameters or operating variables that
influence process output and the range of numerical data for
critical process parameters that result in acceptable process
output.
Process qualification represents the actual studies or trials
conducted to show that all systems or unit operations of a
manufacturing process is intended, that all critical process
parameters operate within their assigned control limits.

7. The strategy selected for process validation should be
simple and straight forward.
1.The use of different lots of raw materials should be
included.
2. Batches should be run in succession and on different
days and shifts.
3.Batches should be manufactured in the equipment and
facilities designed for eventual commercial
production.

8. 4.Critical process variables should be set within
their operating ranges and should not exceed
their upper and lower control limits during process
operation.
5. Failure to meet the requirements of the validation
protocol with respect to process input and output
control should be subjected to process
requalification and subsequent revalidation
following an thorough analysis of process data
and formal discussion by the validation team.

9.  Phase I (Process capability Design)
 Phase II (Process qualification phase)
 Phase III (Validation Maintainace Phase)

10. A. Prospective Process(Pre market) Validation
An experimental plan called validation protocol is
executed before the process is put into commercial use.
This particular type of process validation is normally
carried out in connection with the introduction of new
drug products and their manufacturing processes.

11. The formalized process validation program should never be
undertaken unless and until the following operations
and procedures have been completed satisfactorily.
1. The facilities and equipment in which the process
validation is to be conducted meet CGMP
requirements(completion of installation qualification).
2. The supervising personnel should have understanding of
the process and its requirements
3. The design, selection and optimization of the formula have
been completed.
4. The qualification trials using pilot laboratory batches have
been completed in which the critical processing steps
and process variables have been identified.

12. 5. Detailed technical information on the product and
manufacturing process have been provided.
6. At least one qualification trial of a pilot production batch
has been made and shows there were no significant
deviations from expected performance of the process.
Validation of the process by this approach often leads to
transfer of the manufacturing process from the
development function to production

13. The retrospective validation option is chosen for established
products whose manufacturing processes are considered
stable.
Prior to undertaking retrospective validation 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 and validated in
conformance with CGMP requirements

14. Retrospective validation is achieving validation by
documenting all the historical information (e.g.
release data) for existing products and using that
data to support the position that the process is
under control.

15. 1. Gather the numerical values from the completed batch
record and includes assay values, end product test
results and in process data.
2. Organize these data in a chronological sequence,
according to batch manufacturing data.
3. Include data from at least 20-30 manufacturing
batches for analysis. If number of manufactured
batches is less than 20 then include all manufactured
batches in analysis.
4. Trim the data by eliminating test results from non
critical processing steps and delete all numerical
information.

16. 5.Subject the resultant data to statistical analysis
and evaluation.
6. Draw a conclusion as to the state of control of the
manufacturing process based upon the analysis of
retrospective analysis validation data.
7.Issue a report of your findings (documented
evidence)

17. 1. Individual assay results from content uniformity test.
2. Individual tablet hardness values
3. Dissolution time.
The statistical methods like Basic statistics (mean, S.D.)
,regression analysis etc. may be employed to
analyze above data.

18. In process monitoring of critical processing steps and
end product testing of current production can provide
documented evidence to show that the manufacturing
process is in a state of control.
Such validation documentation can be provided from
the
test parameter and data sources

19. Test parameter Data source
Content uniformity End product testing
Dissolution time End product testing
Particle size distribution In-process testing
Weight variation In-process testing
Tablet Hardness In-process testing
Disintegration Time In-process testing

20. Not all of the in-process tests enumerated above are required
to demonstrate that the process is in state of control.
Selection should be made on the basis of the critical
Processing variables to be evaluated
The critical in process test parameters would be particle or
granule size distribution, Tablet hardness etc.

21. Conditions requiring revalidation study and
documentation are listed
 Change in a critical component(usually refers to raw
materials)
 change or replacement in a critical piece of modular
equipment
 Change in facility and or plant(usually location or site)
 Significant increase or decrease in batch size
 Sequential batches that fail to meet product and
process specifications

22. Documentation associated with validation includes:
— standard operating procedures (SOPs)
— specifications
— validation master plan (VMP)
— qualification protocols and reports
— validation protocols and reports.

23. Validation master plan (VMP)
The VMP 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, including a statement of the responsibilities of those
implementing the plan.
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

24. The validation master plan (VMP) should reflect the key elements of the
validation programme.
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.

25. Validation protocols should include the following significant background information:
— 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 & processes
— the type of validation
— the processes and/or parameters
— sampling, testing and monitoring requirements
— predetermined acceptance criteria for drawing conclusions.

26. Validation reports
•There should be written reports on the qualification and validation performed.
•Reports should reflect the protocols followed and include at least the title
and objective of the study; reference to the protocol; details of material, equipment,
programmes and cycles used; procedures and test methods.
• The results should be evaluated, analysed and compared against the predetermined
acceptance criteria.
•The departments responsible for the qualification and validation work should approve
the completed report.
•The conclusion of the report should state whether or not the outcome of the
qualification and/or validation was considered successful.
•The quality assurance department should approve the report after the final review.

27. Process validation result in fewer product recalls
and troubleshooting assignments in manufacturing
operations and more technically and economically
sound batches and their manufacturing processes.
Thus through careful design and validation of both
the process and its control system can establish a
high degree of confidence that all individual
manufactured units of a given batch or succession
of batches that meet specifications will be
acceptable.

28.  Nash RA ,Wachter AH , Pharmacutical Process
Validation,An International 3rd
Edition ,Revised
&Expanded,Indian special edition,Informa
Healthcare, 2011 ,volume 129. p 607-609
 Potdar MA, Pharmaceutical Quality Assurance, 2nd
ed., Pune:
Nirali Prakashan , 2007
 ICH OFFICIAL WEB http://www.ich.org