CONTENT

S.N CHAPTERS PAGE

.
NO.
1 ABSTRACT
6

2 INTRODUCTION 7

3 Type of validation 9

4 12
Stages of Process Validation

5 Equipment validation 14

6 Validation life cycle 15

7 ADVANTAGES & 16
DISADVANTAGES
8 CONCLUSION 17

9 REFERENCES 18
ABSTRACT:

Validation is the procedure which authorizing documentary evidence that

proves the following process will consistently produce the product which leads
to the expected result. According to GMP validation studies are important part
of GMP these are required to be done as per predefined protocols, the
minimum that should be validated include process, testing and cleaning as a
result such control procedure stablish to monitor the output and validation of
manufacturing processes that may be responsible for variability of drug
product. Validation is the one of the important part in achieving and
maintaining the quality of the final product. The validation study provides the
accuracy, sensitivity, specificity and reproducibility of the test methods
employed by the firms, shall be established and documented. Process
validation is the process for improving the safety and quality of the dosage
form which is manufactured in the pharmaceutical industry. Process validation
is an integral part of quality assurance as per cGMP. Validation and quality
assurance will go hand in hand, ensuring the thorough quality for product.
Process validation plays a key role in the pharmaceutical manufacturing
process as it delivers a high degree of assurance and evidence that the process,
which is being carried out gives out the uniform results, that is, it means the
required specifications, which has been performed accurately. The purpose of
this review is to present an introduction and general review on validation in
pharmaceutical industry.

6
 INTRODUCTION:

The concept of validation was first proposed by two Food and Drug Administration
(FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the
quality of pharmaceuticals. The prime focus of validation is on ensuring if the quality is
built into the system at every step, and not just tested for at the end.1 Validation is a
concept that has evolved in united states in 1978.

The concept of validation has expanded through the years to embrace a wide range of
activities from analytical methods used for the quality control of drug substances and
drug products to computerized systems for clinical trials, labelling or process control.
Validation is founded on, but not prescribed by regulatory requirements and is best
viewed as an important and integral part of cGMP. 2,3

The key purpose of all pharmaceutical industries is to discover quality products

consistently, at the lowest possible cost. Validation plays a very significant role in
quality assurance and productivity improvement. Process validation establishes the
flexibility and constraints in the manufacturing process controls in the attainment of
desirable attributes in the drug product while preventing undesirable properties.4,5
Validation mainly based on, FDA regulations describing current good manufacturing
practice (cGMP) for finished pharmaceuticals are provided in 21 CFR parts
210 and 211. The cGMP regulations require that manufacturing processes be designed
and controlled to assure that in-process materials and the finished product meet
predetermined quality requirements and do so consistently and reliably. Process
validation is required, in both general and specific terms, by the cGMP regulations in
parts 210 and 211.6,7
Validation has become one of the Pharmaceutical industry’s most familiar and discussed
subjects. Its critical success factor in product support and ongoing commercialization.
Quality is always an authoritative requirement when we consider any product.
Therefore, the drugs must be manufactured to the highest quality levels. Finished
product testing by itself does not assurance the quality of the product. A process
validation procedure is required as specified by the current good manufacturing
practices Regulations for Finished pharmaceuticals and is therefore applicable to
manufacturing of drugs.8

7
 Why Valida on Is Required:
The pharmaceutical industry uses expensive material, sophisticated facilities and
equipment and highly qualified personals. It would not be feasible to use equipment
not knowing if it will produce the product we want, not to employ the people with no
assurance that they can do or fail to implement process checks or examination to
assure that product meet specification. Detailed study and control of the
manufacturing process batch validation is necessary if failure cost is to be reduced
and productivity is improved. Validation is helps in assurance of quality and
reduction of cost. The validation helps in reducing the reject, reworks, recalls and
complaints about the product.9

For existence of Safety, Quality, Efficacy1 in product. A validated process gives High
degree of pledge for uniformity. Process validation does not improve anything related
to quality of the product, but control and maintain the measures to fulfil requirements
consistently through adequate validations.10

8
Type of validation:

Process validation:
USFDA defined process validation as “establishing documented evidence
which provides high degree of assurance that a specific process will
consistently produce a product meeting its pre-determined specifications
and quality characteristics.” Process validation provides the flexibility and
constraints in the production process controls in the achievement of
desirable qualities in the drug product while preventing undesirable
attributes.

9
Types of Process Validation:
A) Prospective process validation:
It is defined as the established documented evidence that a system does what it implica ons
to do based on a pre- planned protocol. This valida on usually carried out prior to
distribu on either of a new product or a product made under a revised manufacturing
process performed on at least three successive produc on batches
The objec ve of the prospec ve valida on is to prove or demonstrate that the process will
work in accordance with valida on protocol prepared for the pilot produc on trials.
Prospec ve valida on should normally be completed prior to the distribu on and sale of the
medicinal product. In Prospec ve Valida on, the valida on protocol is executed before the
process is put into commercial use. During the product development phase the produc on
process should be broken down into individual steps. Each step should be evaluated on the
basis of experience or theore cal considera ons to determine the cri cal parameters that
may affect the quality of the finished product. A series of experiments should be designed to
determine the cri cality of these factors. Each experiment should be planned and
documented fully in an authorized protocol

Prospective process validation is executed after the completion of the R and D trial in order to produce
the product for the commercial purpose. This is one of the crucial part of the process validation as most
validation efforts depends on the prospective experimentation so that data that support the validation
could be generated. This type of validation is generally connected with the introduction of new drug
product into the market and involves the studies of all their manufacturing processes.16

Prospective validation should include the following

1. Short description of the process
2. summary of the critical processing steps to be investigated
3. List of the equipment’s to be used along with their calibration status
4. Finished product specifications for release
5. List of analytical methods
6. Proposed in-process controls with acceptance criteria
7. Additional testing to be carried out
8. Sampling plan
9. Methods for recording and evaluating results
10. Functions and responsibilities.

B) Concurrent Process Validation:

The concurrent process validation establishes documented evidence that the process is in a state of
control during the actual execution of the process. The in-process testing and/or monitoring of critical
operations during the manufacture of each production batch is done for concurrent process validation. 18

It is a process where current production batches are used to monitor processing parameters. It gives of
the present batch being studied, and offers limited assurance regarding consistency of quality from batch
to batch. After three initial commercial batches are taken and the process is handed over to the
manufacturing facilities, batch after batch and studied if any deviation is observed or required. This time
the in-process quality control parameter are also decided and monitored which finally becomes the
I.P.Q.C. test for regular production.17

Concurrent Validation may be the practical approach under certain circumstances. Examples of these
may be when:
10
 C) Retrospec ve Process validation:
It is defined as established documented evidence that a system does what it purports to do on the review and analysis
of historical information. This is achieved through the review of the historical manufacturing testing data to prove
that the process has always remained in control. (20) It is conducted for a product already being marketed, and is
based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older
products which were not validated by the fabricator at the time that they were first marketed, and which is now to
be validated to confirm to the requirements of division 2, Part C of the Regulation to be Food and Drugs Act.
Retrospective Validation is only acceptable for well- established detailed processes and will be Inappropriate where
there have recent changes in the formulation of the products, operating procedures, equipment and facility.21,22

The retrospective process validation should contain the following

Batches manufactured for a defined period (minimum of 10 last consecutive batches)
Number of lots released per year
Batch size/strength/manufacturer/year/period
Master manufacturing/packaging documents
Current specifications for active materials/finished products
List of process deviations, corrective actions and changes to manufacturing documents
Data for stability testing for several batches
 Trend analyses including those for quality related complaint

A) Revalidation:
Required when there is a change in any of the critical process parameters, formulation, primary packaging
components, raw material fabricator, major equipment or premises. Failure to meet product and process
specifications in batches would also require process re- validation. Re-validation provides the evidence that changes
in a process and/or 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. 24,25

Revalidation becomes necessary in certain situations. Some of the changes that require validation are as follows:
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)

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Stages of Process Validation:

Process Validation is explained as the group and assessment of data, from the
process
design stage and between commercial production, which gives scientific
confirmation that a process is capable of continually delivering quality product.
Process Validation require a sequence of activities taking place over the lifecycle
of the product and process. The venture relating to validation studies may be
categorized into three stages

Stage 1 – Process Design:

This stage is to design a process suitable for routine commercial manufacturing based on
knowledge gained through development and scale-up activities that can consistently deliver a
product that meets its quality attributes. This stage provides a key input to the studies that are
carried without the application of good manufacturing practices, during the product
development studies which ultimately helps in the various design stages such as anticipated
dosage form, manufacturing route.27

Stage 2 – Process Qualification:

During this stage, the process design is confirmed as being capable of reproducible commercial
manufacturing. It confirm that all established limits of the Critical Process Parameters are valid
and that satisfactory products can be produced even under “worst case” conditions.

Process qualifica on has two stages. They are:

1. Design of the facility and qualification of the equipment and utilities

Process performance qualification (PPQ), in this stage CGMP-compliant

procedures must be followed.

3) Stage 3 – Con nued process validation:

All the continual data assembled to sustain the quality of product are evaluated in the third
stage. The goal of the third validation stage is ongoing assurance is gained that the process
remains in a state of control during routine commercial manufacturing.21

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 Phases of process validation:
1 Phase 1:

Phase 1 is also called as Pre-validation Qualification Phase. It covers all activities

relating to product research and development, formulation pilot batch studies, scale-
up studies, transfer of technology to commercial scale batches, establishing stability
conditions and storage and handling of in-process and finished dosage forms,
equipment qualification, installation qualification, master production document,
operational qualification and process capacity.29

1) Phase 2:
Phase 2 is also called as process validation phase. It is designed to verify that all
established limits of the critical process parameter are valid and that satisfactory
products can be produced even under the worst conditions.30

2) Phase 3:
Phase 3 is also called as validation maintenance phase. It requires frequent review
of all process related documents, including validation of audit reports, to assure that
there have been no changes, deviations failures and modifications to the production
process and that all standard operating procedures (SOPs), including change control
procedures, have been followed.31

13
 Equipment validation:

Equipment validation is established documented set up that proves any equipment works correctly
and leads to accepted and accurate results. The process of equipment validation is based on the
principle that equipment must be designed, constructed, maintained, and adapted to perform the
operations which are to be carried out.32

Types of Equipment Validation:

A) Design Qualification:
“It is a documented verification that the proposed design is suitable for intended purpose.” The
design qualification outline the key features of the system designed to address the user requirements,
regulatory compliance and selection rationale of a particular supplier.33

Important DQ consideration include:

1. GMP‟s and regulatory requirements.
2. Performance criteria.
3. Facility air flow, movement flow and pressure regimens.
4. Reliability and efficiency.
5. Commissioning requirements
6. Construct ability and installation of equipment.34

B) Installa on Qualification:
It is a documented verification that all the aspects of a facility, utility or equipment that can affect product
quality adhere to approved specifications and are correctly installed. Establishing confidence that
process equipment and ancillary systems are capable of consistently operating within established limits
and tolerances food and drug administration (FDA).35

Important IQ considera on include:

1. Installation conditions (wiring, utilities, and functionality)
2. Calibration, Preventive maintenance, cleaning schedules.
3. Safety features.
4. Supplier documentation, prints, drawings and manuals.
5. Software documentation
6. Spare parts list.34

C) Opera onal Qualification:

It is a documented verification that all aspects of a facility, utility or equipment that can affect product
quality operate to intend throughout all anticipated ranges. During OQ, critical operating parameters for
the equipment and systems should be identified and studies are carried out for critical variables. Studies
includes condition or a set of conditions including both upper and lower operating limits referred to as
“worst case” conditions.36

OQ considera ons include:

1. Process control limits (time, temperature, pressure, line speed, and setup conditions).
2. Software parameters.
3. Raw material specification.
4. Process operating procedures
5. Material handling requirements.
6. Process change control
7. Training
8. Short term stability and capability of the process34

D) Performance Qualification:

It is a documented verification that all aspects of a facility, utility or equipment perform as intended in meeting
predetermined acceptance criteria. PQ is establishing confidence that the process is effective and reproducible,
establishing confidence that a process in accordance with the design qualifications.37

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Valida on life cycle
Validation is a continuing and evolving process. The validation process which extends from very
basic to very broad theoretical and methodical investigation of how the system and processes
perform. Its scope encompasses documentation revision control, training and maintenance of the
system and process. Evidence of validation should be seen at the corporate level and be reflected in
the 15management structure. Validation is a method for building and maintaining quality.

15
Advantages of validation:
1. Consistent through output.
2. Reduction in rejections and reworks.
3. Reduction in utility cost.
4. Avoidance of capital expenditures.
5. Fewer complaints about process related failure.
6. Reduced testing process and finished goods.
7. More rapid and accurate investigations into process deviation.
8. More rapid and reliable start-up of new equipment.
9. Easier scale-up from development work.
10. Easier maintenance of equipment.
11. Improve employee awareness of processes.
12. More rapid automation.40

Disadvantages of validation:
1. Validation is time consuming process.
2. The process for manufacture is often complex and costly.
3. Validation also has practical limit and related cost.

Application of validation41 Reduction of quality cost:

Through correct validation, cost of the following procedures can be improved.
a) Preventive costs can incurred in order to prevent failure and reduce appraisal costs.
b) Appraisal costs of inspection, testing and quality evaluation.
c) Internal failure costs

Process Optimization:
The development of the facility, equipment system, closures etc. results in a product that encounter
quality necessities at the lesser costs. Trained and qualified personnel’s are the key elements in the
process optimization that results in upgrading efficiency and productivity.

Assurance of quality:
Validation and the process control are one of the important protocols of GMPs. Without validation and
controlled process, it is impossible to attain quality products. Hence validation is a key element in
assuring the quality of the product.

Safety:
Validation can also result in increased worker safety. Properly standardized, validated instruments and
devices are used to reduce accidents and results in safety. Validation can also result in the increase in
operation safety. e.g. instruments used on equipment that intended to operate at certain temperature and
pressures must be dependable i.e. They need to be calibrated.

Better consumer quality:

Through proper validation, market recall is evaded which results in better consumer care and quality
of the product. Quality costs are divided in to four categories.

They are:
Preven ve costs.

1. Appraisal costs.
2. Internal failure costs.
3. External failure costs

16
 CONCLUSION:
This review gives an idea about the validation in pharmaceutical industry. Validation is an
essential component of GMP. Validation helps assure product will meet standard quality,
safety, efficacy, purity, effectiveness according to GMP. Validation is commonly used in
drug development, manufacturing and specification of final product. Validation is helps in
eliminating the chances of batch failure as the product are manufactured under optimizing
each manufacturing stage. Validation helps in reduce the cost of quality which gives the
best quality of product. Validation includes a sequence of activities taking place in the
lifecycle of product and process. Finely the pharmaceutical validation helps to provide a
positive assurance of batch consistency and integrity of final product which is
manufactured under rules and regulations of GMP.

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