Validation and Calibration

Dr. Saima Amin

 Pharmaceutical Validation
Validation is a scientific study of a quality assurance which
provides confirmation of the facilities, systems, equipments,
manufacturing processes, software and testing methods
that have an impact on product quality, safety and efficacy.
FDA-guidelines:
“Validation is establishing 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.”

EU-guidelines
“Action of proving, in accordance with GMP principles that
any procedure, process, equipment, material, activity or
system actually leads to the expected results.”
https://youtu.be/hTFh17WJ4m8
Types of validation
a. Retrospective validation
b. Prospective validation
c. Concurrent validation
d. Revalidation
Retrospective validation
ü Establishing documented evidence prior to process
implementation that a system does what it is proposed to do
based on preplanned protocols.
ü This approach to validation is normally undertaken whenever
the process for a new formula must be validated before routine
pharmaceutical production commences.
ü In fact, validation of a process by this approach often leads to
transfer of the manufacturing process from the development
function to production.
ü Its done for the process for a product already in distribution,
example stability studies
Prospective validation

Ø It is used for facilities, processes, and process controls in

operation use that have not undergone a formally
documented validation process.
Ø Validation conducted prior to distribution either of a new
product, or a product made under a revised manufacturing
process.
Ø Validation is completed and the results are approved prior to
any product release establishing documented evidence prior
to process implementation that a system does what it
proposed to do based on pre-planned protocols.
Ø Each prospective validation step is described in
qualification/validation documents.
Ø Its done for first three commercial batches.
Concurrent validation

Ø It is a combination of retrospective and prospective validation.

Ø Performed against an approved protocol but product is
released on a lot-by-lot basis.
Ø Usually used on an existing product not previously validated or
insufficiently validated.
Ø Concurrent validation is used for establishing documented
evidence that a facility & processes do what they purport to do,
based on information generated during actual implementation
of the process.
Revalidation
It means repeating the original validation effort or any part of it,
and includes investigative review of existing performance data.
Ø This approach is essential to maintain the validated status of
the plant, equipment, manufacturing processes and computer
systems.
Ø Possible reasons for starting the revalidation process include:
- The transfer of a product from one plant to another.
-The necessity of periodic checking of the validation
results.
- Significant increase or decrease in batch size.
- Change of the product, plant, process that could affect
its quality.
- Sequencial batches that failed to meet the specifications.
- When existing method is modified.
- Change in composition of a formulation.
- Change in route of synthesis of the API
Validation Master Plan
Ø It is used to describe the key elements of the process that are to be
conrtrolled.
Ø It also discloses the committment to maintain validation status.

Team of VMP
Validation Master Plan

Ø A Validation master plan is the document that shapes the company’s

overall philosophy, purpose and approaches to be used for starting
performance adequacy.
Ø Validation in general needs careful preparation and meticulous planning of
the various steps in the process.
Ø The WHO GMP explains that all the content of validation program should
be clearly mentioned and documented in validation master plans.
Ø It is an internally approved plan, which include validation policies,
structure of organization, summary of facilities like list of equipments to be
used, steps used in validation, formats for documentation, sampling
schedules, process variable, change control, analytical method to be used,
acceptance criteria, references and validation option (prospective,
concurrent and retrospective validations as well as revalidation)
Journal of Drug Delivery & Therapeutics. 2016; 6(4):79-8
Ø In addition, all work should be carried out in a planned way according to
formally allowed standard operating procedures (SOP).
Ø All inspection must be documented and all possible observations must be
recorded as actual numerical results.
Ø The validation master plan should issue an outline of the complete
validation operation, its organizational structure, its content and its
planning.
Ø It should be a summary document and it should therefore be brief, concise
and understandable.
Ø It should not replicate the information documented but should refer to
existing documents such as the policy documents, SOP’s and validation
protocols and reports.
Ø The format and the content should include all these things:
1. Introduction: validation policy, scope, location and schedule.
2. Organizational structure: personnel responsibilities.
3.Plant/process/product description: rational for inclusions or
exclusions and extent of validation.
4. Specific process considerations that are critical and those requiring
extra attention.
5. List of products/ processes/ systems to be validated, summarized
in a matrix format, validation approach.
6. Type of validation procedures employed.
7. Re-validation activities, actual status and future planning.
8. Key acceptance criteria.
9. Documentation format.
10. Reference to the required SOP’s.
11. Time plans of each validation project and sub-project
Elements of Equipment Validation

ü Pre-approved written protocols are used for validation

activities.
ü The facility, utilities, major manufacturing equipment and
laboratory instruments should be qualified by performing
Design Qualification (DQ)/ Installation Qualification
(IQ)/Operational Qualification (OQ)/Performance Qualification
(PQ) as per the approved protocols.
ü Protocol is either be designed by the user department or
supplied by the vendor.
ü Preferably the skilled personnel engaged internally or
externally conduct equipment / instrument qualification.
Design Qualification

ü The DQ is aimed to specify that the equipment, system or

facility is designed in accordance with the requirements of
the user and Good Manufacturing Practice (GMP)
guidelines.
üA protocol should be made for design
requirements/technical specifications with consultation of
the supplier and a report is documented for the same.
Installation Qualification (IQ)
Ø Upon arrival of the equipment in the plant, it is first checked to ensure that
the equipment is supplied as per the design requirements/technical
specifications.
Ø The Engineering Department verifies that the equipment and components
are supplied in accordance with the specifications mentioned in (DQ).
Ø The equipment is then shifted to its predetermined location and place as per
the equipment floor Plan.
Ø The IQ procedure comprises the following activities.
Ø The activities are Confirmation to the parameter specified in DQ.
Ø 1. Equipment description and identification.
2. Verification of major components.
3. Material of construction.
4. Utilities connections.
5. Calibration Requirements
6. Installation verification
7. IQ certification
Ø Installation Qualification is considered complete only after the equipment has
been properly installed; all the above said parameters are verified and
documented as per the approved IQ protocol.
Ø The validation team checks, identify and enlist the appropriate safety
features provided for various service lines and prepare a preventive
Operational Qualification (OQ)
o During Operational Qualification documented evidence are made to
establish that all parts of the equipment work within their specifications and
operational parameters.
o The OQ procedure typically includes the following:
1. Brief identification information
2. Visual inspection parameters
3. Functioning of switches and indicator lights
4. Check and calibration of sensor, probes, gauges, recorders, air flow
rates, directions, pressures, temperatures etc.
5. Filter integrity and efficiency test
6. Cleaning procedure
7. Control panel testing
8. Safety features testing
9. Operational testing as per process and system requirements and
challenging.
10. Training for operators and supervisors for operation and cleaning of
equipment.
o The equipment is operated for each operating component to verify that all
operating features are functioning as per the specifications.
o A special attention is paid to service line connections and safety features.
o Critical devices are identified and calibrated against a standard device.
o The completion of a successful operational qualification allow the
finalization of calibration, operating and cleaning procedures, operator
training and preventive requirements.
o It shall permit the formal "release" of the facilities, systems and
equipments.

Performance Qualification (PQ)

v Performance qualification is the final stage of qualification, which

demonstrates that how the equipment/system will perform when
challenged under simulated or actual production conditions.

v A series of tests are designed to demonstrate that the equipment / system

is capable to perform consistently and meet required specifications under
routine production operations.
Stages of Process Validation
Stage 1 – Process Design
Stage 2 – Process Validation or Process Qualification
Stage 3 – Continued Process Validation

Stage 1 – Process Design

v This is the research and development phase and involves defining a

process for manufacturing the product. It usually includes the following:

Ø Creation of a Quality Target Product Profile (QTPP)

Ø Identifying Critical Quality Attributes (CQAs)
Ø Defining Critical Process Parameters (CPPs)
Ø Conducting risk assessments

v From a regulatory point of view, an essential component of this stage is

meticulous and comprehensive record keeping.
v The data collected in this phase is used to optimise production process,
create efficiencies, and troubleshoot problems.
Stage 2 – Process Validation or Process Qualification

v This stage evaluates/qualifies the process designed earlier to ensure it

can reproduce consistent and reliable levels of quality.

v It involves collecting and evaluating data on all aspects and stages of the
manufacturing process. It includes:

ü The building and facilities, i.e. ensuring they adhere to local

regulations as well as pharmaceutical manufacturing regulations.
ü The transportation of raw materials.
ü Storage of raw materials.
ü The knowledge, training, and working practices of production line
employees.
ü Every step of the process to turn raw materials into the finished
product. This includes having pre-defined sampling points at various
stages of the process.
ü Finished product packaging, storage, and distribution.
ü Another useful component of this stage of Process Validation is to
develop contingency plans for situations where things go wrong.
Stage 3 – Continued Process Verification

v 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.

v One of the main aims of this stage is to detect and resolve process drift.

v The stage involves product sampling, analysis, and verification at

various points in the manufacturing process, and requires the
involvement of employees with quality control training.

v Again, comprehensive record-keeping is required at this stage, including

logging anomalies and issues with product quality.
Phases in Validation
Phase 1: This is the Pre-validation Qualification Phase
Ø All the venture relating to the results of research and its development,
formulation, pilot batch studies, scale-up studies, and transfer of technology
to commercial scale batches, stability conditions its storage, and handling
of in-process and finished product, Equipment qualification(EQ), Installation
qualification(IQ), Master production document, Operational
qualification(OQ) and process capacity.
Ø The pre-validation phase occurs during research and development.
Ø This is the planning phase where all potential parts of the manufacturing
process must be considered.
Ø This includes pilot studies, small-batches, and scale-up studies.
Ø During this time, attention must be paid to the details of the process
including the establishment of material handling protocols, storage
procedures for raw ingredients and finished product, equipment verification
and installation, and packaging and distribution of final product.
Ø Investing time and energy into this initial planning phase can pay off later in
Phase 2: It is designed to verify that all accepted limits of the critical process
parameters are sustainable and that adequate products can be produced even
under the knock off conditions.
 Phase 3: Validation Maintenance Phase
Ø Often review of all the process related documents, including validation of
audit reports, to assure that no changes, deviations, failures and
modifications to the production process has been done and that all the
standard operating procedures (SOPs), including change in control
procedures, have been followed.
§ An alert design and validation of the systems and process controls can
accept high degree of confidence that all lots or batches manufacture will
encounter their particular specifications.
§ It is supposed that through the assembling and control operations which are
conducted in accordance with the principles of Good Manufacturing Practice
(GMP).
Validation maintenance phase of pharmaceutical validation
v The maintenance phase of pharmaceutical validation occurs when the
manufacturing process is running smoothly and consistently for some
time.
v The current SOPs are producing consistent product and there are no
known problems with the process, but it is not time to just relax and let
things ride.
v In this final phase it is important to regularly review SOPs and document
any changes to the process.
v There are audits to be done and audit reports to file.
v Regular inspections and process oversight are useful as well as additional
refresher training for employees to ensure that they continue to closely
adhere to written protocols.
Approaches to Validation Process
Ø There are two elementary methods to the validation of this process.
the experimental approach and
the analysis of ancient data.
The experimental approach, which is applicable in both prospective and the
concurrent validation, it may involve: A) Extensive product testing, B) Simulation
process trials, C) Challenge/worst case trials, and D) Control of process
parameters
In the method based on analysis of ancient data, no experiments are
performed in the retrospective validation, but instead of all available ancient
data regarding a number of groups are combined and together analysed, if
production is happening easily during the period of previous validation and the
data in process examination and final testing of the product are joint and
preserved statistically.
The consequences including the result of process ability studies, trend analysis,
Validation and Calibration

The regulatory authorities like FDA and EU require that all the firms have
program for calibration and preventive maintenance for test as well as
measurement equipments.

Calibration

Ø It is a set of operation that performs under specific conditions to verify the

values/data obtained by comparison of two instruments or measuring
devices one of which is a standard of known accuracy (Traceable to
national standards).
Ø It is used to detect, correlate, report or eliminate any of the discrepancy in
accuracy of instruments or measuring devices when being compared to
the standard.
Ø Calibration is a type of comparison but it is not an adjustments.
Ø Calibration is a demonstration that, a particular Instrument or device
produces results with in specified limits by comparisons with those
produced by a reference or traceable standard over an appropriate range of
measurements.
Ø Calibration ensures that instrument or measuring devices producing
accurate results.
Ø In calibration performance of an instrument or device is comparing against
a reference standard.
Ø Shall be performed periodically, to identify the ‘drift’ of the measuring device
or equipment and make them accurate.
Ø Shall be performed as per calibration SOP.
Ø Validation is a documented program that provides high degree of assurance
that a specific process, equipment, method or system consistently produces
a result meeting pre-determined acceptance criteria.
Ø Validation provides documented evidence that a process, equipment,
method or system produces consistent results (in other words, it ensures
that uniforms batches are produced.
Ø No such reference standards are using in validation program
Ø Shall be performed when changes or modifications happen to the existing
system or once revalidation period is reached.
Ø Shall be performed as per validation protocol
CALIBRATION VALIDATION
Calibration is a demonstration that,
Validation is a documented program
a particular
that provides high degree of
Instrument or device produces
assurance that a specific process,
results with in specified limits by
equipment, method or system
comparisons with those produced
consistently produces a result
by a reference or traceable
meeting pre-determined acceptance
standard over an appropriate range
criteria.
of measurements.
No such reference standards are
In calibration performance of an
used in validation program.
instrument or device is compared
against a reference standard.
 Validation provides documented evidence
Calibration ensures that
that a process, equipment, method or
instrument or measuring
system produces consistent results (in
devices produce accurate
other words, it ensures that uniforms
results.
batches are produced).

Shall be performed
No such requirements. Shall be performed
periodically, to identify the
when changes or modifications happen to the
‘drift’ of the measuring device
existing system or once revalidation period is
or equipment and make them
reached.
accurate.

Shall be performed as per

Shall be performed as per validation protocol.
calibration SOP.
Ø Calibration program is required by the regulatory authority (FDA) under section 21
CFR part 211.68

Ø Calibration requirements for Lab instruments under section 21 CFR part 211.67 are:
specific directions, schedule, limit of accuracy and precision remedial action and
system to prevent usage of instrument which are failed to calibrate