Process Validation
Bijoylakshmi Shaw
Student
Bengal School of Technology
(A college of Pharmacy)
Process Validation
Student
Bengal School of Technology
(A college of Pharmacy)
Process Validation
1.
Introduction:
Validation is the most recognized and
important parameter of GMPs. Process Validation of a process will ensure
production of drug of reproducible quality. In pharmaceutical industry, process
validation performs to build the quality into the product; it’s proven to be an
important tool for quality management of pharmaceuticals. It involves the
systemic study of systems, facilities and processes aimed at determining
whether they perform their intended functions adequately and consistently as
specified. A validated process is one which has been demonstrated to provide a
high degree of assurance that uniform batches will be produced that meet the
required specifications and has therefore been formally approved. The
requirement of process validation appears of the quality system regulation. The
goal of a quality system is to consistently produce products that are fit for
their intended use. Process validation is a key element in assuring that these principles
and goal are met. The process validation is standardization of the validation
documents that must be submitted with the submission file for marketing
authorization. It is intended to assist manufactures in understanding
management system requirements concerning process validation and has general
applicability to manufacturing process. So, the word validation simply means assessment
of validity or action of proving effectiveness. Validation is a team effort
where it involves people from various disciplines of the plant.
2. History of validation:
The concept of validation was first proposed by two FDA
officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the
quality of pharmaceutical. It was proposed in direct response to several
problems in the sterility of large volume parenteral market. The first
validation activities were focused on the processes involved in making these
products, but quickly spread to associated process of pharmaceutical.
U.S.F.D.A. was the pioneer in advocating the concept of process
validation, but till 29th September 1978 the definition of process
validation did not appear in any part of literature of U.S.F.D.A. no cGMP
regulations talked anything about process validation.
3. Process
Validation Definition:
Validation can be defined as a procedure that demonstrates
that a process under standard conditions in capable of consistently producing a
product that meets the established product specification. K.G Chapman calls
process validation as “organized documented common sense ’’. Validation means
demonstration, by provision of objective evidence that consistently meets its
predetermined requirements. It is, therefore, an element of the quality assurance
program associated with a particular product or process.
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
provide a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage form) will consistently produce
a product meeting its pre-determined
specifications and quality characteristics’’.
4. Stages of Process
Validation:
Process validation is defined as 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. Process validation involves a series
of activities taking place over the cycle of the product and process. The
activities relating to validation studies may be classified into three stages:-
Stage 1: process Design
Stage 2: process Qualification
Stage 3: Continued Process Verification
Fig.
1: Approaches to process validation
4.1 Stage 1:-
Process Design: The
commercial manufacturing process is defined during this stage based on
knowledge gained through development and scale up activities.
Focusing exclusively on qualification efforts without also understanding
the manufacturing process is defined during this stage based on knowledge
gained through development and scale up activities. It covers all activities
relating to product research and development, commercial scale batches, establishing
stability conditions, storage and handling of in-process and finished dosage
forms, equipment qualification, installation qualification, master production
documents, operational qualification, process capability. Also this is the
stage in which the establishment of a strategy for process control is taking
place using accumulation knowledge and understanding of the process.
4.2 4.2
Stage 2:-
Pro process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing.
It confirms that all established limits of the critical process parameters are
valid and that satisfactory products can be produced even under “worst case ’’
conditions. GMP complaint procedures must be followed in this stage and
successful completion of this stage is necessary before commercial distribution
of a product. There are two aspects of process
qualification:
a) Design of facilities and Qualification of Equipment and
Utilities.
Ø Proper design of manufacturing facility is desired under than
21 CFR parts 211, subpart C, of the cGMP regulation on buildings and
facilities.
Ø Activities performed to assure proper facility
design and that the equipment and utilities are suitable for their intended use and perform properly.
b) Process Performance Qualification Criteria and process
performance indicators that allow for a science and risk based decision about
the ability Of the process to consistently produce quality product.
Ø Part of the planning for stage 2
involves defining performance criteria and deciding what data to collect when,
how much data, and appropriate analysis of the data.
Ø Likely consist of planned comparisons
and evaluations of some combination of process measures as well as in-process
and trial product attributes.
Ø Manufacturer must scientifically
determine suitable criteria and justify it.
Ø Objective measures, where possible.
Ø May be possible to leverage earlier
study data if relevant to the commercial scale.
4.3 Stage 3:-
Continued Process Verification: ongoing
assurance is gained during routine production that the process remains in a
state of control. The validation maintenance stage requires frequent review of
all process related documents, including validation audit reports to assure
that there have been no changes and deviation, failures, modification to
the production process, and that all SOPs have been followed, including change
control procedures.
A successful validation program
depends on the knowledge and understanding and the approach to control
manufacturing processes. These include the source of variation, the limitation
of the detection of the variation, and the attributes
susceptible of the
variation.
Fig. 2: Three model of process validation
according to FDA Guidance for Industry- Process validation
5. Need of Validation:
Quality is always an imperative prerequisite when we consider
any product. Validation is an integral part of quality assurance. It involves
the systematic study of systems, facilities and processes aimed at determining
whether they perform their intended functions adequately and consistently as
specified. It becomes primes when it relates to life saving products like
pharmaceuticals. Although it is mandatory from the government and regulatory
bodies but it is also a fact that quality of a pharmaceutical product cannot be
adequately controlled solely by pharmacopoeia analysis of the final product.
·
Validation
gives confident over the product manufacturing process.
· It’s
give assurance to the product quality as per customer requirements.
·
To
obtain consistent reliable and accurate data.
·
Act
as a proof in decision making.
· Validation
mandatory as per regulatory requirements. If we are not going for validation
then following problems can be occur.
6. Types of Process
Validation:
The guidelines on general principles of process validation mention
four types of validation:-
A.
Prospective Validation
B. Concurrent Validation
C.
Retrospective Validation
D.
Revalidation
Fig.
3: Types of Process Validation
6.1
6.1 Prospective Validation:
It is defined as the established documented evidence that a
system does what it purports to do based on a preplanned protocol. This
validation is conducted prior to the distribution of new product. This
validation usually carried out prior to distribution either of a new product or
product made under a revised manufacturing process. Performed on at three successive consecutive batches.
· A
description of the process / experiments
·
Details
of the equipment / facilities to be used
·
The
variables to be monitored
·
The
samples to be taken where, when, how and how many
·
The
product performance characteristics / attributes to be monitored, together with
the test
6.2 Concurrent Validation:
It is establishment of documented evidence of what a system
does or what it purports to do information generated during implemented of the
system.
·
This
validation involves in-process monitoring of critical processing steps and product
testing. This helps to generate and documented evidence to show that the
production process is in a state of control.
·
In
exceptional circumstances it may be acceptable not to complete a validation
programme before routine production starts.
· The
decision to carry out concurrent validation must be justified, documented and
approved by authorized personnel.
·
Documentation
requirements for concurrent validation are the same as specified for
prospective validation.
It is important in this case however, that the system and
equipment to be used have been fully validated previously. The justification
for conducting concurrent validation must be documented and the protocol must
be approved by the validation team.
6.1 6.3 Retrospective Validation:
It is defined as the established documented evidence that a
system does what it purports to do on the review and analysis of historical
information. This is achieved by the review of the historical manufacturing
testing data to prove that the process has always remained in control.
·
Batches
manufactured for a defined period
·
Number
of lots released per year.
·
Batch
Size/strength/manufacture/year/period.
·
Master
manufacturing/packaging documents.
· List
of process deviations, corrective actions and changes to manufacturing
documents.
6.4 Revalidation:
Revalidation provides the evidence that changes in a process
and the process environment that are introduced do not adversely affect process
characteristics and product quality. Documentation requirements will be the
same as for the initial validation of the process.
·
Changes
in raw materials (physical properties such as density, viscosity, particle size
distribution and moisture etc that may affect the process or product).
·
Changes
in the source of active raw material manufacturer.
·
Changes
in packaging material (primary container/closure system).
·
Changes
in the process (e.g. mixing time, drying temperatures and batch size).
7. Pre-requisites of validation:
Qualification is pre-requisite of validation. Qualification
includes the following:-
Design
qualification
Installation
qualification
Operational
qualification
Performance qualification
Fig. 4:
Pre-requisites of validation
8. Validation Master
Plan (VMP):
The validation master plan should provide an overview of the
entire validation operation, its organizational structure, its content and
planning. The main elements of it being the list/inventory of the items to be
validated and the planning schedules.
All validation activities relating to critical technical operations,
relevant to product and process controls within a firm should be included in validation
master plan.
It should comprise prospective, concurrent and retrospective validation
as well as revalidation.
The validation master plan should be a summary document and should
therefore be brief, concise and clear.
SOP’s and validation
protocols and reports. The format and content should include:
·
Introduction:
validation policy, scope, location and schedule.
·
Organizational
structure: personnel responsibilities.
·
Plant/process/product
description: rational for inclusions or exclusions and extent of validation.
· Specific
process considerations that are critical and those requiring extra attention.
9. Validation protocol:
After performing VMP, the next step is to prepare validation
protocol. Detailed protocol for performing validations is essential to ensure
that the process is adequately validated. There are the following contents in a
validation protocol:-
·
Purpose
& scope of validation.
· Responsibilities
and functioning of persons/ organizational units involved in the validation.
·
Type
of validation to be conducted.
·
Number
of process validation runs.
·
Quality
of materials used in the process.
·
Description
of the process (e.g. unit operation, flow diagram).
· All
major equipment to be used, their types/ design and their installation and
operational qualification (IQ/OQ).
·
Critical
process parameters and operating ranges.
10. Importance of
process validation:
Effective process validation
contributes significantly to assuring drug quality, the basic principle of
quality assurance is that a drug should be produced that is fit for its
intended use. The most compelling reasons to optimize and validate
pharmaceutical productions and supporting processes are quality assurance and
cost reduction. The basic principles of quality assurance have as their goal
and the production of articles that are fit for their intended use.
·
Improve
the use of technology.
·
Improve
the business benefits.
·
Improve
operational efficiency.
·
Improve
compliance with regulations.
·
Reduce
the risk of failure.
·
Reduce
the cost.
·
Process
optimization.
·
Increased
customer satisfaction.
·
It
gives assurance of quality and safety.
·
It
assures the smooth running of the process.
11. Conclusion:
Validation is the most widely used
word in the areas of drug development, manufacturing and specification of
finished products. The consistency and reliability of a validated process to
produce a quality product is the very important for an industry. Pharmaceutical
process validation is the most important and recognized parameters of cGMP. The
process validation is intended to assist manufactures in understanding quality
management system (QMS) requirements concerning process validation and has
general applicability to manufacturing process. Validation has been proven
assurance for the process efficiency and sturdiness and it is the full-fledged
quality attributing tool for the pharmaceutical industries. It also renders
reduction in the cost linked with process monitoring, sampling and testing. Finally it can be concluded that process
validation is a key element in the quality assurance of pharmaceutical product.
12. References:
1. Kaur H, Singh G, Seth N;
Pharmaceutical Process Validation: A Review. 2013; 3 (4): 189-194.
2. Sharma A, Saini S; Process Validation of Solid
Dosage Form: A Review. International Journal of Research in Pharmacy and
Science, 2013; 3 (2): 12-30.
3. Kavita, khurana G, Chaudhary S; Process
Validation of Solid Dosage Form: A Review. Pharma Science Monitor, an
International Journal of Pharmaceutical Sciences, September 2013; 4 (4):
390-391.
4. Sharma PP; Validation in Pharmaceutical
Industry.6th Edition, Vandana Publication, New Delhi, 2008; 91-115.
5. Chapman K. G: A History of Validation in the
United States, Part I, Pharma Technology. November 1991; 39-98.
6. Potdar MA; Current Good Manufacturing
Practices for Pharmaceuticals. 2nd Edition, Pharma Med Press
Publication, Delhi, December 2007: 8.2-8.3.
7. Kumar NL, Moorthy DG, Kumar SR; An Overview of
Pharmaceutical Validation: Quality Assurance view point. 2011; 1 (4): 1003-1014.
8. Patel RC, Bhuva CK; Pharmaceutical Process
Validation: Pharmatutor, ART-1053 .
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