Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation: – “PROCESS VALIDATION” is establishing documented evidence which provides a high degree of assurance that a specific process consistently produces a product meeting its predetermined specifications and quality attributes.

1. TRAINING
ON
PROCESS VALIDATION
Presented by:
MD ZAKARIA FARUKI
Manager, Quality Assurance
Silva Pharmaceuticals Limited
Date of Training January 25, 2023
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2. Process Validation in Brief…
• 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.
• According to the FDA, assurance of product
quality is derived from careful and systemic
attention to a number of important factors,
including: selection of quality components and
materials, adequate product and process
design, and (statistical) control of the process
through in-process and end-product testing.
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3. Process Validation in Brief…
• Thus, it is through careful design (qualification) and
validation of both the process and its control
systems that a high degree of confidence can be
established that all individual manufactured units of
a given batch or succession of batches that meet
specifications will be acceptable.
• According to the FDA’s Current Good Manufacturing
Practices (CGMPs) 21CFR 211.110 a:
 Control procedures shall be established to monitor
output and to validate performance of the
manufacturing processes that may be responsible
for causing variability in the characteristics of
in-process material and the drug product.
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4. Types of Process Validation
 There are 4 types of Process Validation which are as follows-
1. Prospective Process Validation: This approach to validation is
normally undertaken whenever the process for a new formula (or within
a new facility) must be validated before routine pharmaceutical
production commences. In fact, validation of a process by this approach
often leads to transfer of the manufacturing process from the
development function to production.
2. Concurrent Process Validation: Establishing documented evidence
that the process is in a state of control during the actual implementation
of the process. This is normally performed by conducting in-process
testing and/or monitoring of critical operations during the manufacture of
each production batch.
3. Retrospective Process Validation: Where historic data taken from the
records of the completed production batches are used to provide
documented evidence that the process has been in a state of control
prior to the request for such evidence.
4. Re-validation: Revalidation is required based on the assessment in the
change request whenever there are changes in the process,
components, equipment/ facilities or the stating materials, which could
impact on product effectiveness or product characteristics and whenever
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5. Process Validation Stages
• Stage 1 – Process Design: The process is defined during
this stage based on knowledge gained through
development and scale-up activities.
Identify sources of Variability
• Stage 2 – Process Qualification: During this stage, the
process design is evaluated to determine if the process is
capable of reproducible commercial manufacturing.
Control of Variability
• Stage 3 – Continued Process Verification: On going
assurance is gained during routine production that the
process remains in a state of control.
Monitoring Variability - remains “in control”
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6. EMA Approach to Process Validation
 “A quality risk management approach should be applied
throughout the lifecycle of a medicinal product. As part of a
quality risk management system, decisions on the scope and
extent of qualification and validation should be based on a
justified and documented risk assessment of the facilities,
equipment, utilities and processes.”
 A robust product development process is required to enable
successful process validation.
 Before product is released to the market, the process must
be shown to be robust and ensure consistent product quality
irrespective of the approach used.
 Retrospective validation no longer acceptable by EMA.
 Concurrent validation only acceptable where there is a
strong benefit-risk ration for the patient.
 Appropriate quality oversight over the whole validation life
cycle is essential.
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7. FDA Approach to Process Validation
 Process Validation is “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.”
 Objective of PV
To understand and control input variability impact and
manufacturing process to assure consistent product quality and
reliable supply.
 Science and Risk based PV / PPQ – product and process
understanding, good science, statistical confidence.
- Statistically based sampling plans and acceptance criteria
for PPQ / PV and release.
 Understanding the impact of variability and demonstrating
control strategy is robust beyond the variability
– Variability in raw materials / excipients, parameter control,
operators, shifts, equipment sets, etc.
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8. FDA Approach to Process Validation
 PV Stage 3a (Establishing initial process variability)
• “We recommend continued monitoring and sampling
of process parameters and quality attributes at the
level established during the process qualification
stage until sufficient data are available to generate
significant variability estimates.”
 PV Stage 3b (After variability established)
• “Monitoring can then be adjusted to a statistically
appropriate and representative level.”
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13. Process Validation Demonstrates-
The validity of the process design and the
suitability of the process control strategy
 At full-scale (commercial manufacture)
Provides confidence (documented evidence)
that systems of monitoring, control and SOPs
in production are capable of detecting and
compensating for potential sources of process
variability over the product lifecycle
The number of PV batches to be produced
should be justified
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14. SOP/PD/001/01: Process Validation
1. Purpose :
To provide documents evidence and
procedure of process validation which
confirm that a process is capable of
reliably and repeatedly rendering a
product of the required quality.
2. Scope:
This SOP is applicable for process
validation of all products of Silva
Pharmaceuticals Limited.
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15. 3.0 Responsibility
3.1 Product Development department will form a validation team
with the help of Production, QA, QC and Engineering Department.
3.2 Product Development Department shall be responsible to
prepare the process validation protocol for the batches to be
validated, co-ordinate the entire process validation activity related
to the protocol, preparation of Report & summary.
3.3 Engineering department shall be responsible to provide the
utilities, status of calibration & preventive maintenance.
3.4 Quality Assurance department shall be responsible to review &
appropriate the process validation protocol, co-ordinate the entire
process validation activity related to the protocol.
3.5 IPQA shall be responsible to arrange the sample for analysis
as per protocol.
3.6 Quality Control department shall be responsible for analysis of
the finished product as per protocol.
3.7 Head of QA and Head of Product Development are
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16. 4.0 Abbreviations & Definitions
4.1 Abbreviations
PD= Product Development
PV= Process Validation
IPQA= In-Process Quality Assurance
SOP= Standard Operating Procedure
STP= Standard Testing Procedure
PIC/S= Pharmaceuticals Inspection Co-operation
Scheme
4.2 Definition of PV
Process Validation is the process of ensuring and
providing documentary evidence that process
(within their specified design parameters) is
capable of repeatedly and reliably producing a
finished product of the required quality.
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17. 5.0 Materials and Equipment
5.1 None
6.0 Precaution / Health and Safety
Considerations
6.1 Approved validation protocol before starting the
process validation activity.
6.2 Identify critical steps before process validation
activity.
6.3 Follow validation protocol strictly during process
validation activity.
6.4 Collect data and review against predetermined
acceptance criteria, while should be reflected in
process validation reports.
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18. 7.0 Procedure
7.1 Validation Procedure
7.1.1 Product Development department will prepare a validation protocol
for three consecutive batches to validate the whole process and get
approval from QA.
7.1.2 Product Development department will arrange the necessary
materials, manpower, equipment and are to execute the batch
manufacturing record and batch packaging record as per protocol.
7.1.3 Product Development department will follow up critical process
parameter as per protocol in every stage of process validation activity.
7.1.4 IPQA department will arrange the sample for analysis as per
protocol.
7.1.5 Product Development department will analyze bulk and
intermediate product as per protocol.
7.1.6 Quality Control department will analyze the finished product as per
approved STP.
7.1.7 Quality Assurance will collect and review all analytical reports to
release the product.
7.1.8 Product Development department will prepare the validation report
on the basis of batch document and process validation report.
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19. 7.2 Validation Protocol
A validation protocol should be prepared before starting the process
and the following steps/parameter should be included in the protocol
(Annexure-I) as draft/sample.
 Process description, Master Formula & Flow Chart
 Details of the equipment/facilities with its calibration status
 Personnel responsibilities
 Sampling plan
 Product Specification & Acceptance limit.
 Critically assessment for process stages, control variables &
measuring response justification
7.3 Critical Process and Testing Parameters
The purpose of the critical process parameter is to identify, evaluate and
document the critical process parameters, which have a significant
effect on the process or the quality of the product and to describe the
ranges of the operational parameters that lead to a compliant product
(design space), based on actual data generated at lab, pilot and full
scale. The process must be validated within a specified range of
operational for the identified critical process parameters.
7.0 Procedure (Continued…)
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20. Example of potentially critical parameters Example of quality characteristics to be monitored
- Drug substances specification - Disintegration time
- Excipients specification - Dissolution rate
- Mixing & choppering speeds times - Content uniformity
- Quantity of granulation liquid - Weight uniformity
- Sequences and speed of adding components - Friability
- Compression/ ejection force during tabletting - Hardness
- Spray rate, inlet/out air temperature of the
coater
- Thickness
- Drum rotation speed - Homogeneity (blend uniformity)
- Process time - Yield
- Amount of used film coating
suspension/solution
- Loss on drying/ Moisture content
Table 1: Example of potentially critical parameters for oral solid dosage form
Example of potentially critical parameters Example of quality characteristics to be monitored
- Drug substances specification - Homogeneity
- Excipients specification - Yield
- Packaging material specification - pH
- Temperature of solvent - Filling volume weight & sealing
- Sequences and speed of adding components - Microbial status
- Dissolving time - Viscosity
- Stirrer speed time stirring - Particle size dispersed drug
- Drum rotation speed - Biological activity
- Process time - Stability immediate
- Amount of used film coating
suspension/solution
Table 2: Example of potentially critical parameters for oral liquid dosage form
7.0 Procedure (Continued…)
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21. 7.4 Process optimization
If required, one or more optimization batches (smaller than the standard
batch size) can be produced using the production facilities for detailed
assessment of process parameters. Protocol and Report for optimization
batches have to be maintained.
7.5 Re-validation
Revalidation for non-sterile products has to be performed after two years
only for highly regulated market and five years for others market
depending on trend, modifications, deviations and/or changes assessed
in the annual product review/ product quality review.
The documentation for revalidation is to be established in the same way
as for the initial validation. A formal change control to initiate which
defines how changes are evaluated and managed.
In case of planned changes, it has to be considered whether and to what
extent a revalidation of the process has to be performed. In case of
deviations, resulting in e.g. failing analytical results, the process has to be
thoroughly investigated and the root cause determined. The affected
process steps have to be reviewed and optimizes process may have to
be validated, based on a risk assessment.
7.0 Procedure (Continued…)
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22. 7.5 Re-validation Contd…
Examples of changes:
 Manufacturing: changes of the manufacturing procedure, specifications,
analytical procedures
 Drug substances: Changes of the route of synthesis, of physical properties,
of specifications, of supplies
 Excipients: Changes of supplier, change of specifications
 Equipment: Changes of type or size, change in maintenance and/or
calibration, change of cleaning procedure
 Batch size
 Change in the facility and/ or plant (location or site)
 Production area support system
 Accumulation of a number of minor changes
7.0 Procedure (Continued…)
7.6 Validation Report
The process validation report documents the validation activities performed. It
presents all pertinent findings and conclusion, especially the validation status. It
has to contain at least the following (Annexure- II) as draft/sample.
 The study objective and a reference to be validation protocol.
 A summary of the performed activities with conclusions and validation status.
 Any deviations from the protocol, from the process or the acceptance criteria
set with short description, evaluation, assessment, corrective/ preventive
action as needed and conclusion
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23. 7.0 Procedure (Continued…)
8.6 Validation Report contd…
 The starting materials used including batch numbers or a reference to
attached batch documentation.
 Facilities, equipment and control instruments used or a reference to the
validation protocol or
 A detailed summary of all results, as required by the validation protocol from in
process controls,
 final testing and additional testing. The results have to be compared with their
acceptance criteria as defined or referenced in the validation protocol.
 Results of any supplementary studies as defined in the validation protocol.
 The decision to accept or not accept the validation study and as appropriate
the rationale.
 Anny corrective or follow-up actions needed.
 As appropriate recommendations with respect to the extent and frequency of
monitoring and in-process controls and their limits necessary routine
production based on the experience from the validation batches.
 Final process parameters and their corresponding ranges
 Actions to be taken in the event of the acceptance limit being exceeded
 Short assessment/ reference to transport studies and stability reports for bulk
holding times and final product as appropriate.
 The conclusion and recommendation should be incorporated in to the batch
manufacturing and the batch packaging documents. Action to be taken in the
events of limits being exceeded should be specified.
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24. 7.7 Release Procedure of Validation Batches
After completion of validation of one batch a preliminary release
notification documents will be approved by QA intended to be sold or
supplied when all raw data has been generated, reviewed and meets
the pre-determined acceptance criteria and when all deviations or OOS
results have been investigated, evaluated, assessed, resolved
documented and approved by QA.
On the basis commercial distribution of the drug product will be initiated
while the validation report is being completed.
8.0 Reference Document
8.1 As per WHO GMP guideline, Volume 2
8.2 PIC/s; PI 006-3, 25 September 2007
8.3 Book of Pharmaceuticals Process Validation by Robert A. Nash
9.0 Annexes
9.1 Annexure-I: Process Validation Protocol
9.2 Annexure-II: Process Validation Report
9.3 Annexure-III: Re-validation Schedule
7.0 Procedure (Continued…)
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25. 11.0 Training
11.1 Training is required for Officers to Above of all Departments trained
by Head of Product Development department
10.0 Revision History
Version
No.
Brief Reason for the Revision
Effective
Date
Remarks
01 New 04/01/2018 -
02 Revision for after validity of period 26/12/2020 -
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Conclusion:
Because of resource limitation, it is not always possible to validate an
entire company’s product line at once. With the obvious exception that
a company’s most profitable products should be given a higher priority,
it is advisable to draw up a list of product categories to be validated.
Process validation is done by individuals with the necessary training
and experience to carry out the assignment.

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