Process Validation in Pharma

The purpose of this SOP is to define the approach to be followed to establish documented
evidence that a specific process will consistently produce a result meeting its
predetermined specification and quality attributes.

Approaches to Process Validation: Process Validation (PV) is the documented

evidence that the process, operated within established parameters, can perform effectively
and reproducibly to produce an intermediate or API meeting its predetermined
specifications and quality attributes.

There are three approaches to process validation.

Prospective Validation
Concurrent validation
Retrospective validation

Prospective Validation (PV): Prospective validation shall be performed on processes of

API for new drug substance, new manufacturing process, new route of synthesis, change
in manufacturing location, change of equipments (unlike equipments with respect to
existing equipments), change in utilities, change in critical process parameters and
change in final specification. Prospective validation should extend to those operations
determined to be critical to the quality of the drug substance.

For prospective process validation, following criterion shall be considered:

Three consecutive successful production batches shall be considered.
Minimum three consecutive batches shall be kept for stability study at
- Long Term Stability (25°C ± 2°C / 60% ± 5% RH) and
- Accelerated condition (40°C ± 2°C / 75% ± 5% RH).
Batches can be released, after the completion of prospective validation with consecutive
three batches and the satisfactory compliance of minimum three months Accelerated
stability data.

Concurrent Validation (CV): Concurrent validation shall be performed on processes of

API for:
When data from replicate production runs are unavailable because only limited number of
API batches have been produced, API batches are produced infrequently, API batches are
produced by a validated process that has been modified for following changes e.g.
Vendor change for key starting material, Process changes that shall have no impact on the
API quality, Change in in-put qty. of intermediates or raw materials proportionally with
respect to validated process of API, Solvent qty. to be increased or decreased for
purification of API, Modification in existing equipments.

For concurrent process validation, following criterion shall be considered

Three consecutive successful production batches shall be selected.
Minimum one batch among of the selected batches for concurrent validation, shall be
kept for stability study at Long Term Stability (25°C ± 2°C / 60% ± 5% RH).
 Prior to completion of concurrent validation, batches can be released and used in final
drug product for commercial distribution based on thorough monitoring and testing of the
API batches.

Retrospective Validation (RV): Retrospective validation can be conducted based on the

historical data of batches, for well established processes that have been used without
significant changes to API quality due to:
Equipment changes
Changes in raw materials,
Systems changes
Facilities changes
For retrospective validation, generally data from ten to thirty consecutive batches should
be examined to assess process consistency, but fewer batches should be taken if the
number of process run are less than the ten and it should be justified and documented.
Selected batches for retrospective validation should be representative of all batches made
during the review period, including any batches that failed to meet specifications, and
should be sufficient number to demonstrate process consistency.

For retrospective process validation, following criterion shall be considered for the
existing process:
Critical quality attributes and critical process parameters have been identified.
Appropriate in-process acceptance criteria and controls have been established.
There have not been significant process / product failures attributable to causes other than
operator error or equipment failures unrelated to equipment suitability.
Impurity profiles have been established for the existing API.
Retain samples can be tested to obtain data to retrospectively validate the process.

Validation Documentation: A written validation protocol should be established that

specifies how validation of a particular process will be conducted. The protocol should be
reviewed and approved by the quality unit (s) and other designated units. The validation
protocol should specify critical process steps and acceptance criteria as well as the type of
validation to be conducted (e.g. prospective, retrospective, concurrent) and the number of
process runs. A validation report that cross-references the validation protocol should be
prepared, summarising the results obtained, commenting on any deviations observed and
appropriate conclusion. Any variations from the validation protocol should be
documented with appropriate justification.

Process Validation Protocol: Process Validation Protocol shall consist of the following
points:

a. Protocol Approval
b. Overview

1. Objective
2. Purpose and Scope
3. Role and Responsibility
4. Validation Team
c. Process details of API.
1. Process flow diagram of API and Intermediates stages
2. Batch Production and Control Records (BPCR) of API and Intermediates.
3. Sampling Plan for process validation.
4. Critical in-process parameters and specification of API and Intermediates.
5. Critical process parameters in-process of API and Intermediates stages.
6. Solvent usage details in process of API and Intermediates stages.
7. Water quality used in process of API and Intermediates stages.
8. Specification of API and Intermediates.
9. Packing and Storage details of API.
d. Equipment Details.
e. Validation Procedure
f. Acceptance Criteria
g. Stability plan for selected validation batches
h. Revalidation Criteria
i. Documentation
1. Compilation (Format designs for the In-process, Intermediate and the API for exhibit
batches)
2. Summary Report (Summarising validation data)
3. Conclusion and Approval (for observations, justification, action and approval /
rejection of the Validation.)

Validation report shall be generated based on the activities performed according to the
protocol, Recorded observations
Summary ( summarising the stability samples details, validation activity etc., Justification
/ Recommendation (for any deviation and / or for process improvement), Conclusion (for
comment on approval or rejection of the process validation)

Periodic Review of Validation Systems: Process and system shall be periodically

evaluated to verify that they are still operating in a valid manner and where no significant
changes have been made to the system or process. The quality shall be evaluated based
on the PQR (Product Quality Review) for API. The quality review should confirm that
the process or system is consistently producing material, meeting its specifications. The
quality review can conclude and recommend the need for revalidation.