VALIDATION OF

PHARMACEUTICAL
INDUSTRY IN GENERAL
KELAS A
KELOMPOK 3
1. FITRI (1211012003)
2. DIDI M IKHSAN (1211012004)
3. RIRI ADE KURNIA ( 1211012005)
4. ARIEF CHANDRA ABBAS
(1211012006)
5. LEFRINA GUSRIANI (1211012007)

VALIDATION
Validation is documented evidence
that provides a high degree of
assurance that a specific process will
consistently produce a product meeting
its predetermined specifications and
quality attributes
(FDA,1987)

CONCEPT OF VALIDATION
GMP-definition is the validation of
"establishing documented evidence
that establishes a high degree of
certainty that a particular process
will consistently a product that
provides the previously established
specifications and quality attributes
are available

IMPORTANCE OF VALIDATION
1. Assurance of quality
2. Time bound
3. Process optimisation
4. Reduction of quality cost.
5. Nominal mix-ups, and bottle necks
6. Minimal batch failures, improved efficiently and productivity.
7. Reduction in rejections.
8. Increased output.
9. Avoidance of capital expenditures
10. Fewer complaints about process related failures.
11. Reduced testing in process and in finished goods.
12. More rapid and reliable start-up of new equipments
13. Easier scale-up form development work.
14. Easier maintenance of equipment.
15. Improved employee awareness of processes.
16. More rapid automation.
17. Government regulation (Compliance with validation requirements is necessary
for obtaining approval to manufacture and to introduce new products)
(Nandhakumar,2012)

Appropriate and complete documentation is recognized as

crucial for the validation. Standard Operating Procedures
(SOPs), production formulas, detailed documentation batch
changeControl, experimental reporting systems, analytical
documents, reports development, validation protocols and
reports are an integral part of validation philosophy. The
validation of the documentation provides a source of
information for the ongoing operation of the plant and is a
resource that is used in the subsequent process of
development or modification activities.
All test activities will take a level of impact assessment to
ensure that systems, services andProducts were determined
directly affected by the test.
A revalidation program should be implemented on a
permanent equipment on the revalidation requirements and
change control.

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 lifecycle of
the product and process.
(FDA, 2011)

PLANNING FOR VALIDATION

All validation activities should be planned.
Should be clearly defined and documented in validation master plan (VMP)
or equivalent documents.
The VMP should be a summary document, which is brief, concise and
clear.
The VMP should contain data on at least the following:
1. Validation policy.
2. Organisational structure of validation activities.
3. Summary of facilities, systems, equipment and processes to be
validated.
4. Documentation format: The format to be used for protocols and reports.
5. Planning and scheduling.
6. Change control.
7. Reference to existing document.
8. Incase of large projects, it may be necessary to create separate
validation master plans.
(Nandhakumar,2012)

TYPES OF VALIDATION
Prospective validation
Establishing documented evidence that a device / process
or system to do what they do, on a pre-planned series of
scientific investigations within the meaning of validation
sets basedPlan.
Concurrent validation
Is used when an existing process can be shown to be in a
state of control by use of tests on samples taken at
strategic points in a process, and at the end of the process.
All data are collected simultaneously with the
implementation of the process, to demonstrate sufficient
information to process reproducibility.

Retrospective Validation
Establishing documented evidence that a process does notwhat
it purports to do, based on review and analysis of historical data.
Design Qualification (DQ)
The intent of the DQ is in the planning and commissioning
process met with a number of mechanisms, including:
- Generation of User Requirement Specifications
- Verification of this type corresponding user requirement
specifications.
- Supplier Evaluation / Audit
- Check the Challenge of the design by GMP audits
- Product Quality ImpactAssessment
- Specifying Validation documentation requirements of suppliers
- Agreements with the suppliers about the performance targets
- Factory Acceptance Test (FAT), Site Acceptance Test (SAT) and
commissioning procedures
- Definition of construction and installation documentation) to
assist with Installation Qualification (IQ.

Installation Qualification (IQ)

IQ is a proof that the equipment or system has been
documented in developeddelivered and installed in
accordance with design drawings, vendor recommendations
and in-house requirements. Moreover, IQ, that a record of the
main features of the equipment or system is installed, how
available and ensure that they are supported by sufficient and
appropriate documentation to implement satisfactory
operation, maintenance and control of changes.
Operational Qualification (OQ)
OQ is documented proof that operates the facilityas provided
in the above design, operation or approved acceptance range
of equipment, as applicable. In cases where process steps are
considered an appropriate placebo batch is used to
demonstrate device functionality.
All new devices should be fully taken into service before the
start of OQ to ensure that at least be sure to use the device,
complete with all mechanical assembly and pre-qualification
checks are that the device is fully functional and
thatDocumentation is complete.

Performance Qualification (PQ)

The goal of PQ is documented proof that the
equipment can always be achieved while producing
the specifications for a longer period at a defined
operating point, a product of the specified quality. The
specification will make reference to process
parameters, in-process and product specifications. PQ
requires three product batches available for all
acceptanceCriteria for in-process and product testing.
For supply PQ requires the benefits of medium to
fulfill all the data over a longer period of sampling.
The PQ documentation should be on standard
manufacturing procedures and batch records and
describe the methodology of sampling and testing to
be.

PROCESS VALIDATION ACTIVITIES IN THREE STAGES

Stage 1 Process Design : The commercial

manufacturing 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 evaluated to determine if the process
is 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.

(FDA, 2011)

STAGE 1 PROCESS DESIGN

Process design is the activity of defining the

commercial manufacturing process that will be
reflected in planned master production and control
records. The goal of this stage is to design a
process suitable for routine commercial
manufacturing that can consistently deliver a
product that meets its quality attributes.
1. Building and Capturing Process knowledge and
understanding
2. Establishing a Strategy for Process Control
(FDA, 2011)

1. BUILDING AND CAPTURING PROCESS KNOWLEDGE

AND UNDERSTANDING
Generally, early process design experiments do not need to
be performed under the CGMP conditions required for drugs
intended for commercial distribution that are manufactured
during Stage 2 (process qualification) and Stage 3
(continued process verification). They should, however, be
conducted in accordance with sound scientific methods and
principles, including good documentation practices. This
recommendation is consistent with ICH Q10 Pharmaceutical
Quality System. 12 Decisions and justification of the
controls should be sufficiently documented and internally
reviewed to verify and preserve their value for use or
adaptation later in the lifecycle of the process and product
(FDA, 2011)

2. ESTABLISHING A STRATEGY FOR PROCESS CONTROL

Process knowledge and understanding is the basis for
establishing an approach to process control for each unit
operation and the process overall. Strategies for process
control can be designed to reduce input variation, adjust for
input variation during manufacturing (and so reduce its
impact on the output), or combine both approaches.
Process controls address variability to assure quality of the
product. Controls can consist of material analysis and
equipment monitoring at significant processing points (
211.110(c)). Decisions regarding the type and extent of
process controls can be aided by earlier risk assessments,
then enhanced and improved as process experience is gained
(FDA, 2011)

(Nandhakumar,2012

STAGE 2 PROCESS QUALIFICATION

During the process qualification (PQ) stage of process
validation, the process design is evaluated to determine if it
is capable of reproducible commercial manufacture. This
stage has two elements:
(1) design of the facility and qualification of the equipment and
utilities
(2) process performance qualification (PPQ).
During Stage 2, CGMP-compliant procedures must be
followed. Successful completion of Stage 2 is necessary
before commercial distribution. 15 Products manufactured
during this stage, if acceptable, can be released for
distribution
(FDA, 2011)

1. DESIGN OF THE FACILITY AND QUALIFICATION OF

THE EQUIPMENT AND UTILITIES

Proper design of a manufacturing facility is

required under part 211, subpart C, of the CGMP
regulations on Buildings and Facilities. It is
essential that activities performed to assure
proper facility design and commissioning
precede PPQ. Here, the term qualificationrefers
to activities undertaken to demonstrate that
utilities and equipment are suitable for their
intended use and perform properly. These
activities necessarily precede manufacturing
products at the commercial scale
(FDA, 2011)

Qualification of utilities and equipment generally includes

the following activities:
Selecting utilities and equipment construction materials,
operating principles, and performance characteristics based
on whether they are appropriate for their specific uses.
Verifying that utility systems and equipment are built and
installed in compliance with the design specifications (e.g.,
built as designed with proper materials, capacity, and
functions, and properly connected and calibrated).
Verifying that utility systems and equipment operate in
accordance with the process requirements in all anticipated
operating ranges. This should include challenging the
equipment or system functions while under load comparable
to that expected during routine production. It should also
include the performance of interventions, stoppage, and
start-up as is expected during routine production. Operating
ranges should be shown capable of being held as long as
would be necessary during routine production

2. PROCESS PERFORMANCE QUALIFICATION

The process performance qualification (PPQ) is

the second element of Stage 2, process
qualification. The PPQ combines the actual
facility, utilities, equipment (each now qualified),
and the trained personnel with the commercial
manufacturing process, control procedures, and
components to produce commercial batches. A
successful PPQ will confirm the process design
and demonstrate that the commercial
manufacturing process performs as expected.
(FDA, 2011)

STAGE 3 CONTINUED PROCESS VERIFICATION

The goal of the third validation stage is continual
assurance that the process remains in a state of control
(the validated state) during commercial manufacture. A
system or systems for detecting unplanned departures
from the process as designed is essential to accomplish
this goal. Adherence to the CGMP requirements,
specifically, the collection and evaluation of information
and data about the performance of the process, will
allow detection of undesired process variability.
Evaluating the performance of the process identifies
problems and determines whether action must be taken
to correct, anticipate, and prevent problems so that the
procless remains in control
(FDA, 2011)

RE-VALIDATION:
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 becomes necessary in certain situations. The following are examples
of some of the planned or unplanned changes that may require re-validation:
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).
Changes in the equipment (e.g. addition of automatic detection system).
Changes of equipment which involve the replacement of equipment on a like for
like basis would not normally require a revalidation except that this newequipment
Changes in the plant/facility.
Variations revealed by trend analysis (e.g. process drifts).
Alam, 2012.

BASIC CONCEPT OF PROCESS VALIDATION

Calibration, verification and maintenance of process
equipment.
Prequalification or revalidation.
Establishing specifications and performance
characteristics.
Selection of methods, process and equipment to
ensure the product meets specifications.
Qualification or validation of process and equipment.
Testing the final product, using validated analytical
methods, in order to meet specifications.
Challenging, auditing, monitoring or sampling the
recognised critical key steps of the process.

CALIBRATION

The set of operations that astablish, under

specified conditions, the relationship between
values indicated by an instrument or system for
measuring (for example, weight, temperature
and pH) recording, and controlling, or the values
represented by a material measure, and the
corresponding known values of a reference
standard. Limits for acceptance of the results of
measuring should be estabilished. Always
remember any reference standard is always used
in calibration.

DOCUMENTATION
Documentation at each stage of the process validation lifecycle is essential
for effective communication in complex, lengthy, and multidisciplinary
projects. Documentation is important so that knowledge gained about a
product and process is accessible and comprehensible to others involved in
each stage of the lifecycle. Information transparency and accessibility are
fundamental tenets of the scientific method. They are also essential to
enabling organizational units responsible and accountable for the process to
make informed, science-based decisions that ultimately support the release
of a product to commerce.
The degree and type of documentation required by CGMP vary during the
validation lifecycle. Documentation requirements are greatest during Stage 2,
process qualification, and Stage 3, continued process verification. Studies
during these stages must conform to CGMPs and must be approved by the
quality unit in accordance with the regulations (see 211.22 and 211.100).
Viral and impurity clearance studies, even when performed at small scale,
also require quality unit oversight
(FDA, 2011)

REFERECES
Alam,

Shoaib Md. Pharmaceutical Process Validation: An

Overview. Journal of Advanced Pharmacy Education &
Research. Oct-Dec 2012 Vol 2 Issue 4. page 195

FDA,

Current Good Manufacturing Practices (CGMP) Revision

1 , 2011, Process Validation: General Principles and Practices

FDA

guidelines on General Principles of Process Validation

(May 1987)

Nandhakumar,

L. et al. An overview of pharmaceutical

validation: quality assurance view point. international
journal of research in pharmacy and chemistry. IJRPC 2011,
1(4)