PHARMACEUTICAL
VALIDATION

Presented By:

M. Gayathri,
M. Pharm, I-yr,
Dept of Pharmaceutics,
College of Pharmacy,
Madras Medical College.

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CONTENTS

1. VALIDATION DEFINITION

2. NEEDS & PURPOSE OF VALIDATION

3. MAJOR PHASES OF VALIDATION

4. TYPES OF VALIDATION

A) Analytical validation

B) Equipment validation

C) Process validation

D) Cleaning validation

E) Computer system validation

5. GOVERNMENT REGULATION

6. URS, DQ, IQ, QQ AND PQ OF FACILITIES

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VALIDATION

❑ Validation is the documented act of proving that any procedure,
process, equipment, material, activity or system actually leads to
the expected result.

❑ As per ISO definition,

➢ Validation is the confirmation by examination and the provision of
objective evidence that the particular requirements for a specific intended
use are fulfilled.

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According to Food and Drug Administration (FDA), the goal
of validation is:

➢To establish documented evidence which provides a high
degree of assurance that a specific process will consistently
produce a product meeting its predetermined specifications
and quality attributes.

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NEEDS OF VALIDATION

a) Before introduction of a new method into routine use.

b) Whenever the conditions change for which a method has been validated.
Eg., Instrument with different characteristics.

c) Whenever the method is changed, and the change is outside the original
scope of the method.

d) For compliance to current GMPs, validation is essential.

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PURPOSE OF VALIDATION

❑ To accept an individual sample as a member of a population under study.

❑ To admit samples to the measurement process.

❑ To minimize later questions on sample authenticity.

❑ To provide an opportunity for resampling when needed.

❑ Due to successful validation, there is a decrease in sampling and testing procedures
and there are less no. of product rejections and retesting. This leads to cost-saving
benefits.

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PHASES OF VALIDATION:

1. PREVALIDATION QUALIFICATION PHASE

2. PROCESS VALIDATION

3. VALIDATION MAINTAINANCE

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1. PREVALIDATION QUALIFICATION PHASE:

This includes all activities relating to product Research and Development
(R&D), pilot batch studies, scale up studies, establishing stability conditions and
storage & analysis of in- process and finished dosage forms, equipment qualification,
installation qualification, master production document, operational qualification and
process capacity.

2. PROCESS VALIDATION PHASE:

In this phase the limits of all critical process parameters are established,
verified and validated to ensure that the desired quality of product can be achieved
even under the worst condition.

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3. VALIDATION MAINTAINANCE PHASE:

This includes review of all documents related to process validation
of audit reports, to make sure that no changes and deviations in standard
operating procedures (SOP) that have been followed. Hence there is no
need for requalification and revalidation.

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TYPES OF VALIDATION

❑ ANALYTICAL VALIDATION

❑ EQUIPMENT VALIDATION

❑ PROCESS VALIDATION
1. Prospective validation
2. Retrospective validation
3. Concurrent validation
4. Revalidation

❑ CLEANING VALIDATION

❑ COMPUTER SYSTEM VALIDATION

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ANALYTICAL VALIDATION

Validation of analytical methods can be defined as “ The process by which it
is established that the selected analytical procedure will give reliable results that
are adequate for the intended purpose”. The typical analytical characteristics can
be listed as follows.

1. ACCURACY
2. PRECISION
3. SPECIFICITY
4. LIMIT OF DETECTION
5. LIMIT OF QUANTITATION
6. LINEARITY
7. RANGE
8. RUGGEDNESS
9. ROBUSTNESS

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1. ACCURACY :
Accuracy of an analytical method may be defined as “The closeness of

test results obtained by some specific method to the true value”. It is the
ability of a method measure the true value of a sample.

2. PRECISION:
Precision of analytical method may be defined as “The degree of

agreement among individual test results when the method is applied
repeatedly to multiple sampling of a homogenous sample”. It is the ability of
a method to estimate reproducibility of any given value.

3. LIMIT OF DETECTION:
The limit of detection may be defined as “The lowest amount of analyte

in a sample that can be detected, but not necessarily quantitated, under the
stated experimental condition”.

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4. LIMIT OF QUANTITATION:
It can be defined as “ A characteristic of quantitative assay for low levels of

compounds in a sample matrixes such as impurities in a bulk substances and
degradation products in finished pharmaceuticals.

It is the lowest amount of analyte at which the instrument is able to detect and
quantify.

5. LINEARITY:
The linearity of an analytical method may be defined as “Its ability to elicit

tests that are directly, or by a well defined mathematical transformations
proportional to the concentration of analyte in samples within a given range”.

6. RANGE:
The range may be defined as the “Interval between the upper and the lower

levels of analyte that have been demonstrated to be determinable with a suitable
level of precision, accuracy and linearity”.

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7. RUGGEDNESS:
The ruggedness of an analytical method may be defined as “The degree of

reproducibility of test results obtained by the analysis of the same sample under a
variety of conditions such as different laboratories, different analysts, different
instruments, different lots of reagents, different elapsed assay times, different
assay temperatures, different days, etc.”

8. ROBUSTNESS:
The robustness of an analytical method may be defined as “A measure of its

capacity to remain unaffected by small but deliberate variations in method
parameters such as mobile phase composition, column age, column temperature
and provides an indication of its reliability during normal usage”.

9. SPECIFICITY:
It is the ability of an analytical method, to measure accurately an analyte in the

presence of interferences that may be expected to be present in the sample matrix.
Eg. Impurities, degradation products and matrix components.

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EQUIPMENT VALIDATION

❑ Equipment validation is established
documented set up that proves any equipment
works correctly and leads to accepted and
accurate (predetermined) result. 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.

❑ Process equipment used in the development
phase is assessed relative to its suitability for
large scale manufacture.

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This protocol can be divided into,

▪ USER REQUIREMENT SPECIFICATION

▪ DESIGN QUALIFICATION

▪ INSTALLATION QUALIFICATION

▪ OPERATIONAL QUALIFICATION

▪ PERFORMANCE QUALIFICATION

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USER REQUIREMENT SPECIFICATION (URS):

▪ The user requirements document (URD) or user requirements specification (URS)
is a document that specifies what the user expects the software to be able to do.

▪ Once the required information is completely gathered, it is documented in a URD,
which is meant to spell out exactly what the software must do and becomes a part
of the contractual agreement.

▪ A customer cannot demand features not in the URD, while the developer cannot
claim the product is ready if it does not meet an item of the URD.

▪ The URD can be used as a guide for planning cost, timetables, milestones, testing,
etc.

▪ Customer or the user of the equipment has certain expectations about the
equipment which he wants to use.

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▪ This expectations are generally put in the form of his requirements.

▪ Some of the general requirements may be stated in the form of certain
parameters like;

1. Size of the equipment
2. Speed of the equipment
3. Effectiveness of equipment e.g. Mixers, etc.
4. Availability of spares, change parts, prompt services at reasonable cost.
5. Ease of operation, cleaning and maintenance.
6. Low dust and sound generation
7. Lesser breakdowns
8. Materials of construction
9. Auto control systems
10.Easy change over
11. Overall good construction and workmanship etc.

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DESIGN QUALIFICATION:

• It is the documented verification of the design of equipment and manufacturing
facilities.

• If a particular equipment is to be fabricated as per User Requirements then the
detailed design qualification document become very important and essential. It
should be agreeable to both the parties(purchaser and manufacturer).

• Design qualification provides documented verification that the design of new
equipment will result in a system that is suitable for the intended purpose.

• It is prepared by departments like,

o Engineering
o R & D
o User
o QA
o QC
o Maintenance department
o Production department 20

▪ 3 Steps are involved in DQ.

STEP 1:

▪ First is to cross check URS with the PO(Purchase Order).

▪ Purchase order can also be said as Request For Purchase(RFP).

▪ RFP can be made by a vendor who is finalized to supply you such material
meeting all the technical and financial terms.

STEP 2:

▪ In the second step you have to verify all the Detailed Design Specifications that
are submitted in the RFP by the vendor with your URS.

▪ In this phase if any deviations are there you must make DEVIATION REPORTS
and resubmit to your vendor and document the same at your company.

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▪ When a new RFP with revised technical specs and drawings are received you
have to look those deviation reports and make necessary corrective actions by
verifying them with the new document you receive from vendor.

STEP 3:

▪ The last step is to cross check between the Detailed Design specifications with
Final Technical Annexures (FTA) results.

▪ This is based on the deviation reports that has been created earlier and you
have to summarize all results.

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INSTALLATION QUALIFICATION:

❑ Installation qualification is a documented verification process that the
instrument or piece of equipment has been properly delivered, installed
and configured according to standards set by the manufacturer or by an
approved installation checklist.

❑ The performance of tests to ensure that the installations(such as machines,
measuring devices) used in manufacturing process are appropriately
selected and correctly installed and operated in accordance with
established specifications and drawings.

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❑ Important IQ considerations:

✓ CALIBRATION,
✓ PREVENTIVE MAINTENANCE
✓ SAFETY FEATURES
✓ SOFTWARE DOCUMENTATION
✓ EQUIPMENT DESIGN FEATURES

❑ This protocol has two unique components:

1. INSPECTION CHECKLIST
2. INSTALLATION CHECKLIST

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INSPECTION CHECKLIST:

❑ An “Instruction sheet” explains how this section is physically executed.

❑ A Table of Contents list all the major components of a piece of equipment
or system.

❑ Each component is looked at individually, the manufacturer’s
specifications are listed in the “Specified column” and what is actually
observed is recorded in the “Actual column”.

❑ Done before installation .

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INSTALLATION CHECKLIST:

❑ This section of the protocol determines whether or not the piece of equipment or
system as a whole meets the manufacturer’s design specifications.

❑ A “Yes or No” answer is required.

❑ All “No” responses will be recorded in the Deficiencies and Deviations section
of the protocol.

ENVIRONMENTAL REQUIREMENT:

❑ This section specifically addresses any temperature, humidity, etc. requirements
of a particular piece of equipment or system.

❑ It may be added to the Inspection checklist of each component and will be used
only if applicable .

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OPERATION QUALIFICATION:

➢After Installation Qualification is completed, a verification of equipment or system
capability is performed.

➢ It is the documented verification of equipment or system performance in the target
operating range.

➢Testing may involve simulated runs using components that will be used with the
marketing product.

➢ It is conducted in 2 stages : Component operational qualification and
System operational qualification.

➢ Important OQ considerations:

1. Software procedures
2. Raw material specification
3. Process operation procedures
4. Material handling requirements

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PERFORMANCE QUALIFICATION:

▪ Performance Qualification is the FINAL PHASE of equipment validation process.
▪ It is the documented verification that equipment system operates as expected under

routine production conditions. The performance must be reproducible, reliable and in a
state of control.

▪ Before this Validation Testing is implemented in all process and/or product
specifications must be established and judged acceptable.

▪ This test will validate the effectiveness and reproducibility of the process or product.
▪ Important PQ considerations:

➢ Actual product and process parameter

➢ Acceptability of the product

➢ Process repeatability

➢ Long term process stability

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CONTENTS

▪ INTRODUCTION
▪ TYPES OF PROCESS VALIDATION

1) Prospective validation
2) Retrospective validation
3) Concurrent validation
4) Revalidation

▪ PREREQUISITE FOR PROCESS VALIDATION
▪ APPROACHES FOR PROCESS VALIDATION
▪ ACTIVITIES OF PROCESS VALIDATION

1) Process design
a)QTTP
b)CQAs
c)CPPs
d)Risk Assessments

2) Process qualification
3) Continued process verification

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PROCESS VALIDATION

❑ The U.S. Food and Drug Administration (FDA) in its most recently proposed guidelines
has offered the following definition for process validation: “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 pre-determined specifications and quality
characteristics.”

❑ The collection and evaluation of data, throughout the product life cycle, which provides
documented scientific evidence that a process is capable of consistently delivering quality
products.

❑ Validation of the individual steps of the processes is called process validation.

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❑ Process validation involves a series of activities taking place over the
lifecycle of the product and process.

❑ This guidance describes process validation activities in 3 stages.

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TYPES OF PROCESS VALIDATION:

❖ Prospective Validation

❖ Concurrent Validation

❖ Retrospective Validation

❖ Revalidation

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PROSPECTIVE VALIDATION:

▪ Prospective validation is carried out during the development stage. It includes,
those considerations that should be made before an entirely new product is
introduced by a firm or when there is a change in the manufacturing process which
may affect the product’s characteristics such as uniformity and identity.

▪ A risk analysis is performed as individual steps and then evaluated on the basis of
past experience to determine whether they might lead to critical situations.

▪ Where possible critical situations are identified, the risk is evaluated, the potential
causes are investigated and assessed for probability and extent, the teal plans are
drawn up and the priorities set.

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▪ The trial are then performed and evaluated and an overall assessment is made.

▪ It must include the following,

1. Short description of the process
2. Summary of the critical processing steps to be investigated
3. List of equipments to be used with their calibration status
4. List of analytical methods
5. Sampling plan
6. Additional testing to be carried out
7. Finished product specifications for release

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CONCURRENT VALIDATION:

▪ Concurrent validation is carried out during normal production.

▪ It is used for establishing documented evidence that a facility and processes do
what they purport to do, based on information generated during actual imputation
of the process.

▪ This approach involves in-process monitoring of critical processing steps and
end product testing of current production, to show that the manufacturing process
is in a state of control.

▪ Such validation document can be provided from the test parameter and data
sources disclosed in the section on retrospective validation

▪ This method is effective only when the development stage has resulted in a
proper understanding of the fundamentals of the process.

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RETROSPECTIVE VALIDATION:

▪ As the prefix “retro” implies, this type of validation is carried out through the use of
information already exists ( Retrospective- Recollective ).

▪ Retrospective validation involves the examination of past experience of production on
the assumption that composition, procedures and equipment remains unchanged; such
experience and the results of in-process and final control test are then evaluated.

▪ This type of validation is only acceptable for well established process only and will be
inappropriate where there have been recent changes in the composition of product,
operating process or equipment.

▪ Recorded difficulties and failures in production are analysed to determine the limits of
process parameters.

▪ Retrospective validation is not a quality assurance measure in itself and should never
be applied to new processes or products.

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REVALIDATION:

▪ Revalidation is needed to ensure that changes in the
process and/or in the process environment, whether
intentional or unintentional, do not adversely affect
process characteristics and product quality.

▪ Revalidation may be divided into two broad categories

1. Revalidation after any change having bearing on
product quality

2. Periodic Revalidation carried out at scheduled
intervals.

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1. REVALIDATION AFTER CHANGES:

▪ Revalidation must be performed on introduction of any changes affecting a
manufacturing and/or standard procedure having a bearing on the established
product performance characteristics.

▪ Such changes may include those in

1. Starting material
2. Packaging material
3. Manufacturing processes
4. Equipment
5. In-process controls
6. Manufacturing areas
7. Support systems(water, steam, etc.)

▪ Revalidation after changes may be based on performance of the same tests and
activities as those used during the original validation, including tests on sub
processes and on the equipment concerned

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2. PERIODIC REVALIDATION:

▪ Revalidation indicated that the process must be validated once again.

▪ Revalidation at scheduled time is advisable even if no changes have been
deliberately made.

▪ Possible reason for starting the revalidation process include:

➢ The transfer of product from one plant to another

➢ Changes to the product, the plant, the manufacturing process, the cleaning
process, or other changes that could affect product quality.

➢ The necessity of periodic checking of the validation results.

➢ Significant increase or decrease in batch size.

➢ Sequential batches that fail to meet product and process specifications.
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PREREQUISITE FOR PROCESS VALIDATION:

❖Manufacturing Equipment Qualification

❖ Control instruments Qualification

❖ Formulation Qualification

❖ Services validation(water, air, nitrogen, power supply, etc.)

❖ Equipment Cleaning

❖ Sanitation of premises

❖ Proper training and motivation of personnel

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APPROACHES:

❑ Two basic approaches,

1. Experimental approach
2. Approach based on the analysis of historical data.

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1. EXPERIMENTAL APPROACH:

❑ Applicable to both prospective and concurrent validation. It may include:

a. Extensive product testing.

b. Simulation process trial.

c. Challenge/worst case trials.

d. Controls of process parameters.

2. APPROACHES BASED ON ANALYSIS:

❑ Applicable to Retrospective validation.

❑ All available historical data concerning a number of batches are combined and
jointly analyzed.

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PROCESS VALIDATION ACTIVITIES:

STAGE 1: Process Design
STAGE 2: Process Qualification
STAGE 3: Continued Process Verification

STAGE 1: Process Design:
The commercial process is defined during this stage based on knowledge gained through
development and scale-up activities.

STAGE 2: Process Qualification:
During this stage, the process design is confirmed as being capable of reproducible
commercial manufacturing.

STAGE 3: Continued Process Verification:
Ongoing assurance is gained during routine production that the process remains in a
state of control.

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STAGE 1: Process Design

❖ This is the Research and Development phase and involves defining a process for
manufacturing the product. It usually includes the following:

✓ Creation of Quality Target Product Profile (QTPP).

✓ Identifying Critical Quality Attributes(CQAs).

✓ Defining Critical Process Parameters(CPPs).

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❖ Design of experiments(DoE) study can help develop process knowledge by revealing

• Relationship of variables to quality attributes.

• Multivariable impact on quality attributes.

• In-process tests and limits.

• Requirement of isolation of intermediates or in situ route

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QUALITY TARGET PRODUCT PROFILE (QTTP):

▪ QTTP is defined as the “ A prospective summary of the quality
characteristics of a drug product that ideally will be achieved to ensure the
desired quality, taking into account safety and efficacy of the drug
product”.

▪ These quality characteristics are essential to ensure the finished product
meets the requirements of standard of quality.

▪ Things that are considered when creating a QTTP include the,

o Dosage strength
o Dosage form
o Delivery system
o Container system
o Purity
o Stability
o Sterility

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▪ QTPP is an essential element of a QbD (Quality by Design) approach and forms
the basis of design for the development of the product.

▪ It describes the design criteria for the product and should therefore forms the
basis for the development of

1. CQAs
2. CPPs
3. Control Strategy

▪ The USFDA says the QTPP should also consider the “safety and efficacy” of the
product

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QbD – Quality by Design:

➢ In a QbD approach, to manufacture a pharmaceutical product, we
consider the quality of the product at the earliest possible stage rather
than simply testing the product for quality towards the end.

➢ In practice, this means identifying the sources of variability that could
possibly affect a process. Then we should document these sources of
variability as well as determining how to manage them. This should be
documented too.

➢ This approach ensures the proper identification of the root causes of
quality issues. The end result is a pharmaceutical product that meets
predefined quality standards from the start.

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CRITICAL QUALITY ATTRIBUTE:

❖ FDA says CQA apply to any physical, chemical, biological or microbiological
property or characteristic that should be within an appropriate limit, range or
distribution to ensure the desired product quality.

❖ CQAs are generally associated with the

• Drug substance

• Excipients

• Intermediates(in-process materials)

• Drug product.

❖ This is the ideal time to establish acceptable limits and ranges as well as establishing
protocols for measurement, data collection, and data analysis.

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CRITICAL PROCESS PARAMETER:

❖ CPP is a variable that can impact the CQA. It include

• Temperature

• pH

• Cooling rate

• Rotation speed etc.

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STAGE 2: Process Qualification

❖ This stage evaluate/qualifies the process designed earlier to ensure it can reproduce
consistent and reliable levels of quality. It involves collecting and evaluating data on all
aspects and stages of the manufacturing process. It includes:

✓ The building and facilities ,i.e. Ensuring they adhere to local regulations as well as
pharmaceutical manufacturing regulations

✓ The transportation of raw materials

✓ Storage of raw materials

✓ The knowledge, training, working practices of production line employees

✓ Every step of process to turn raw material into finished product.

✓ Finished product packaging, storage, distribution.

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STAGE 3: Continued Process Verification

❖ Continued Process Verification involves ongoing validation during production of the
commercial product to ensure the process designed and qualified in the previous
stages continues to deliver consistent quality

❖Main aim: To detect and resolve process drift.

❖ This stage involves

✓ Product sampling

✓ Analysis

✓ verification

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CLEANING VALIDATION

❖ Documented evidence to establish that cleaning procedures are removing
residues to predetermined level of acceptability, taking into consideration factors
such as batch size, dosing, toxicology and equipment size.

❖ Cleaning directly related to the safety and purity of the pharmaceutical products.

❖ Equipment and utensils shall be cleaned, maintained and sanitized at appropriate
intervals to prevent malfunctions or contamination that would alter the safety,
identity, strength, quality or purity of the drug product beyond the official or
other established requirements.

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VALIDATION OF COMPUTER SYSTEM:

❖ Confirmation by examination and provision of objective documented evidence
that computerized system specifications conform to user needs and intended uses,
and that all requirements can be consistently fulfilled.

❖ Use of computer systems in pharmaceutical production, quality control, quality
assurance and R&D is increased and this raised certain types of issues of its
performance and security of information systems being handled by the computer
systems

❖ It is mandatory to confirm the performance of such systems with respect to its
consistency, repeatability and accuracy of the results and reports.

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Computer validation is required mainly for
following reason:

• Risk
• Business opportunity
• Information

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GOVERNMENT REGULATION

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REGULATORY BASIS:

❖ The regulatory basis validation program of process validation is embodied within the
regulations and guidelines provided by cGMP and FDA.

❖ The ultimate legal authority is Sec50(a)(2)(B)by the FD&C Act, which states “Drug is
deemed to be adulterated due to the method/facilities used for the manufacturing,
processing, packing/ holding fails to administer in conformity-cGMP.”

❖ Validation-Process validation is not just an FDA or U.S. requirement. Similar
requirements included in the World Health Organization(WHO), the Pharmaceutical
Inspection Co-operation Scheme(PIC/S) and the European Union(EU).

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REGULATION OF VALIDATION UNDER USFDA:

❖ Section 211.100(a): Written Procedures/deviations.

❖ “There shall be written procedures for production and process control
designed to assure that the drug products have the identity, strength, quality
and purity”.

❖ Section 211.110: Sampling and testing of in-process materials and drug
products

❖ “… control procedures shall be established to monitor the output and Validate
the performance of those manufacturing processes that may be responsible for
causing variability in the characteristics of in-process material and the drug
product.”

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❖ 21CFR211.133: Control of microbiological Contamination

❖ “Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established and
followed. Such procedures shall include Validation of any sterilization process.”

❖ FDA must inspect every drug manufacturing establishment at least once every 2
years.

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REGULATORY REQUIREMENT FOR VALIDATION IN cGMP:

❖ The first cGMP regulations, based largely on the Pharmaceutical Manufacturers
Association’s(PMA’s) manufacturing control guidelines,.

❖ The Medicines Act(1968) covers most aspects of cGMP in what is commonly
referred to as “The Orange Guide”

❖ Validation under document of cGMP covers procedure, process qualification,
equipment and facilities.

❖ 211.68: Validation of automated process.

❖ 211.84(d)(2): Validation of supplier’s test results for components.

❖ 211.84(d)(3): Validation of supplier’s test results for containers and closures.

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❖ 211.110(a):Validation of manufacturing process to ensure content
uniformity and integrity..

❖ 211.113(b): Validation of sterilization process.

❖ 211.165: Validation of analytical methods.

❖ By June 2010, the same GLP/GMP Validation requirements will apply to
all manufacturers of dietary supplements.

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VALIDATION REQUIREMENT UNDER WHO:

❖WHO(World Health Organization) cGMP Guidelines: Validation studies are
an essential part of current Good Manufacturing Practice(cGMP) and should
be conducted in accordance with predefined protocols.

❖WHO Validation definition:

The documented act of proving any procedure, process, equipment, material,
activity or system which actually leads to the expected results.

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VALIDATION REQUIREMENT UNDER EU:

❖ The European Union Requirements for validation is an extract from ICH Q8,Q9,Q10
documented guidelines and helps to study continuous process verification

❖ EU Validation Definition:

❖ Strategies of validation under EU includes:

1. Traditional process Verification(TPV)

2. Continuous Process Validation(CPV)

3. Critical Process Parameters(CPP)

4. Critical Quality Attributes(CQA)

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1) TRADITIONAL PROCESS VERIFICATION(TPV)
Process validation should focus on the control strategy, which primarily includes

critical process parameters and other relevant studies demonstrating that the process is
capable of delivering the desired product quality.

2) CONTINUOUS PROCESS VALIDATION(CPV)
An alternative approach to process validation in which manufacturing process

performance is continuously monitored and evaluated.

3) CRITICAL PROCESS PARAMETERS(CPP):
A process parameter whose variability has an impact on a critical quality attribute

and therefore should be controlled to ensure the process produce the desired quality.

4)CRITICAL QUALITY ATTRIBUTES(CQA):
A physical, chemical, biological or microbiological property should be within an

appropriate limit, range to ensure product quality.

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VALIDATION QUALIFICATION UNDER PIC/S:

❖ According to EU Guidelines to Good Manufacturing Practice for Medicinal
Products in Annex 15, the principles of qualification and validation of the
PIC/S is given under document PIC/S PI 006-3.

PIC/S – Pharmaceutical Inspection Co-operation Scheme.

❖ Doc states: GMP for medicinal products, recommendations on Validation
master plan, Installation and Operational Qualification can assist with the
interpretation and the implementation.

❖ This document applies primarily to inspectorates of the PIC/S member for
whom it is intended as instruction for preparing an inspection and as an
advanced training aid for qualification/ validation.

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URS, DQ, IQ, OQ AND PQ OF
FACILITIES

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QUALIFICATION:

❖ It is the act of planning, carrying out, and recording the results of tests which is
performed on equipment to confirm the capability of its working. Normally
qualification should be performed before process validation.

❖ Qualification is part of validation, but individual qualification step alone do not
constitute process validation.

❖ Stages of qualification should normally start with the preparation of User Requirement
Specifications (URS).

❖ Depending on the function and operation of the utility, equipment or system this is
followed by as appropriate, different stages in qualification such as Factor Acceptance
Test(FAT), Site Acceptance Test(SAT),Design Qualification(DQ), Installation
Qualification(IQ), Operational Qualification (OQ) and Performance Qualification(PQ).

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FACILITIES QUALIFICATIONS:

❖ Facility qualification validates the overall manufacturing/ testing/production environment.

❖ All equipment and utilities used in the process area must be listed in the Facilities
Qualification

❖ Facilities should have following five documents regarding validation.

1) User Requirement Specification(U.R.S)

2) Design qualification

3) Installation Qualification

4) Operational Qualification

5) Performance qualification
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❖ Facilities will handle following categories of products e.g..

1. Beta Lactam products

2. Steroids

3. Vaccines

4. General pharmaceutical products etc.

❖ Facilities should have

• Manufacturing facility

• Warehousing Facility

• Q.C/R and D lab/Pilot plant

• Utility block etc
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USER REQUIREMENT SPECIFICATIONS-URS

❖ Requirements regarding equipment is given by users called as URS. It includes,
– Size of equipment
– Speed of equipment
– Effectiveness of equipment
– Availability of spares, change parts
– Low dust and sound facilities
– Auto control systems
– Lesser breakdowns
– Overall good construction

❖ The requirement and specifications for the utility of equipment should be
defined by the user and documented in the URS.

❖ The URS should be used when selection of the required utility or equipment
from an approved supplier and to verify suitability throughout the subsequent
stages of qualification.

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The following guidelines should be followed during the production of the URS :

• Each requirement statement to be uniquely referenced, and no longer than 250 words.

• Requirement statements should not be duplicated nor contradicted.

• The URS should express requirements and not design solutions.

• Each requirement should be testable.

• The URS must be understood by both user and supplier; ambiguity and jargon should be
avoided.

• The use of diagrams is often useful.

• Wherever possible, the URS should distinguish between mandatory/regulatory
requirements and desirable features.

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❖ U.R.S. for facilities is a statement spelling out, what the user wants in terms of the
facilities , he wants to create for the manufacturing of the pharmaceutical
formulations. It can expressed in the following manner.

❖ The facility will be used for the manufacture of the following formulation and
volumes, namely:

1) Tablets-Coated 10L/Shift

2) Tablets-Uncoated 20L/Shift

3) Hard gelatin capsules 5L/Shift

4) Small volume parenterals 50K Amp/Shift

5) Large volume parenterals 20Kbottles of 500 ml/Shift

6) Ointments/ Cream 20K tubes of 10g/Shift
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FACTORY ACCCEPTANCE TEST

• Inspection before delivery to the user site- FAT
• During this user should test,

❑ Every component of machine for the operation and functioning
❑ Drawing of machine
❑ Calibration
❑ Safety controls
❑ Signal and critical control points

SITE ACCEPTANCE TEST

• The equipment at the user site for any change, damage and shipping before
installation of machine.

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❖ Steps include,

-Compound unpacking
-Inspection & storage
-Installation & power-up
-Instrument calibration
-Functional testing

OPERATIONAL QUALIFICATION

❖ Documented verification that the system or subsystem operates as intended
overall anticipated operation ranges. This refers to the validation of the equipped
but non-operational premises

❖ This should be done mainly to see if there is any problem related to lighting,
drainage, sewage, sanitation, cleaning and maintenance.

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DESIGN QUALIFICATION

❖ Creating D.Q document is the responsibility of the authorized project team
responsible for the creation of the facility.

❖ The team should consists of people from various functional areas like Engineering,
production, quality management, project, personnel etc.

❖ A typical D.Q. of the facilities for the pharmaceutical plant should cover :

• Introduction

• Address of location

• Plot drawing with Dimensions

• Planned capacity of the plant.

• Area statement and layout

• Room Data sheets etc. 77

INSTALLATION QUALIFICATION

➢ It should refer the validation of empty premises.

➢ This should clearly indicate whether the premises meet the physical environment as
specified in the D.Q.

➢ I.Q involves verification of following things:

• Size verification of each room, corridors

• Surface finishes of the flooring, walls, ceilings etc.

• Ease of cleaning, maintenance and operation as detailed in D.Q

• Installed HVAC in place

• Terminal HEPA filters are in place.

• Environmental air system 78

• Verification of lighting intensity, sound limits

• Floor drainage system

• Plumbing, sewage

• Building and building surroundings sanitation and maintenance etc.

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PERFORMANCE QUALIFICATION

❖ This refers to validation of fully equipped and operational premises.

❖ This is the last of the qualifying test.

❖ Evaluate the premises suitability with equipment in operation, materials being
handled etc.

❖ Documented verification that the equipment or system performs consistently and
reproducibly with in defined specifications and parameters in its normal operation
environment (i.e.in the production environment).

PQ is synonymous with OQ to some extent.

OQ is performance of system without load.

PQ is performance of system with load.

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