PROCESS VALIDATION

Instructor: Prof. Dr. Didare Alam Muhsin; Preparer: Jhuma Sarker

Assignment: Elaborate 21 CFR 211 & 21 CFR 820

Definition of Validation Process Validation
Validation involves the systematic study of systems, facilities, and  As per FDA guidelines, Process Validation may be defined as the
processes to determine whether they perform their intended functions collection and evaluation of data, from the process design stage
adequately and consistently as specified. through commercial production, which establishes scientific evidence
that a process is capable of consistently delivering quality products.
 Process validation is a requirement of current Good Manufacturing
Where to consider validation? Practices (GMPs) for finished pharmaceuticals (21 CFR 211) and of the
Validation should be considered in t following situations: GMP regulations for medical devices (21 CFR 820) and therefore
applies to the manufacture of both drug products and medical
 Totally new process devices.
 New equipment
 Process and equipment which have been altered to suit changing
priorities Stages of Process Validation
 Process where the end-product test is poor and an unreliable  Process validation involves a series of activities taking place over the
indicator of product quality. lifecycle of the product and process.
 The Process validation activities can be described in 3 (three) stages:

Importance of Validation
Adequate validation can provide a number of important benefits to the
manufacturer:
 It deepens the understanding of processes; decreases the risk of
preventing problems and thus assures the smooth running of the
process.
 It decreases the risk of defect costs.
 It decreases the risk of regulatory noncompliance.
Fig.: Three stages of process validation according to 'FDA Guidance for Industry Process
 A fully validated process may require less in-process controls and end-
Validation'
product testing.
 Stage 1 - Process Design: There are two aspects of process qualification:
 Process design is the activity of defining the commercial 1) Design of a facility and qualification of equipment and utilities
manufacturing process based on the knowledge gained through
This include activities performed to assure proper facility design and that
development and scale-up activities.
the equipment and utilities are suitable for their intended use and
 The goal of this stage is to design a process suitable for routine
perform properly.
commercial manufacturing that can consistently deliver a product
that meets its quality attributes. 2) Process performance qualification
It covers all activities relating to: This involves assessment of the criteria and process performance
indicators that allow for a science and risk based decision about the
✓ Product research and development
ability of the process to consistently produce quality products.
✓ Formulation
✓ Pilot batch studies, Scale-up studies, Transfer of technologies to
commercial scale batches
Stage 3 Continued Process Verification (CPV)/ Validation Maintenance
✓ Establishing stability conditions and storage
Stage/Phase:
✓ Handling of in-process and finished dosage forms
✓ Equipment qualification, Installation qualification  Gaining ongoing assurance, during routine. production, that the
✓ Master production document, Operational qualification, Process process remains in a state of control (ie, validated state).
capacity  Frequent review of all process related documents, including
✓ Establishment of a strategy for process control. validation audit reports, is done to assure that there have been no
changes, deviations, failures and modifications to the production
process, and that all standard operating procedures (SOPs) have been
Stage 2 - Process Qualification: followed.
During this stage, the process design is evaluated to determine if the
process is capable of reproducible commercial manufacturing.
Types of Process Validation
 It confirms that all established limits of the Critical Process
1) Prospective Validation
Parameters are valid and that satisfactory products can be produced
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even under "worst case" conditions. 2) Concurrent Validation

 GMP compliant procedures must be followed during this stage and
3) Retrospective Validation
successful completion of this stage is necessary before commercial
distribution of a product. 4) Process Re-Validation
Prospective Validation Retrospective Validation
 In Prospective Validation, the validation protocol is executed before  Conducted for a product already being marketed, and is based on
the process is put into commercial use. extensive data accumulated over several lots and over time.
 It is conducted prior to the distribution of either a new product or a  Retrospective validation may be used for older products which were
product made under a modified production process. not validated by the fabricator at the time that they were first
 It is a preplanned scientific approach and includes the initial stages of marketed, and which are now to be validated to conform to the
formulation development, process development, setting of process requirements of division 2, Part C of the Regulation of the Food and
sampling plans, designing of batch records, defining raw material Drugs Act.
specifications, completion of pilot runs, transfer of technology from  Retrospective Validation is only acceptable for well-established
scale-up batches to commercial size batches, listing major processes detailed processes and will be inappropriate where there have been
executed and environmental controls. recent changes in the formulation of the products, operating
procedures, equipment, and facility.

Concurrent Validation
Process Re-Validation
 A process where current production batches are used to monitor
processing parameters.  Required when there is a change in any of the critical process
 It gives assurance of the present batch being studied, and offers parameters, formulation, primary packaging components, raw
limited assurance regarding consistency of quality from batch to material fabricator, major equipment, or premises.
batch.  Failure to meet product and process specifications in batches would
 Concurrent validation may be the practical approach under certain also require process re-validation.
circumstances.
For example:
✓ When a previously validated process is being transferred to a
third- party contract manufacturer or to another site.
✓ When the product is a different strength of a previously validated
product with the same ratio of active/inactive ingredients.
✓ When the number of lots evaluated under the Retrospective
Validation were not sufficient to obtain a high degree of assurance

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demonstrating that the process is fully under control.
✓ When the number of batches produced are limited.
✓ Process with low production volume per batch and market
demand due to drug shortage or absence of supply.