Sie sind auf Seite 1von 161

Contents

Glossary: ....................................................................................................................................................... 5
1. Introduction to validation .................................................................................................................. 9
1.1 Definition ............................................................................................................................................ 9
1.2 History of validation ......................................................................................................................... 10
1.2.1 Equipment Qualification and Process Qualification: ................................................................. 11
1.3 Why validation? ................................................................................................................................ 13
1.4 What has to be validated? ................................................................................................................. 14
1.5 Scopes of Validation ......................................................................................................................... 15
1.6 Pre-Requisites for Successful Validation .......................................................................................... 17
1.7 Approaches of Validation ................................................................................................................. 18
1.8 Phases in Validation .......................................................................................................................... 18
1.9 Validation Decision Tree: ................................................................................................................. 20
2. Organizing for Validation ................................................................................................................ 22
2.1 Staffing issues ................................................................................................................................... 22
2.2 Department interactions .................................................................................................................... 22
2.3 Master planning or planning for Validation ...................................................................................... 24
2.4 Benefits of Master Planning .............................................................................................................. 24
2.5 Validation Process ............................................................................................................................ 25
2.6 Validation Plan .................................................................................................................................. 25
2.7 Typical validation master plan structure ........................................................................................... 26
2.8 Validation Protocol ........................................................................................................................... 27
2.9 Validation set up ............................................................................................................................... 29
2.10 Relationship between validation and qualification ......................................................................... 29
2.10.1 Design Qualification (DQ) ....................................................................................................... 30
2.10.2 Installation Qualification (IQ) .................................................................................................. 32
2.10.3 Operational Qualification (OQ) ............................................................................................... 33
2.10.4 Performance Qualification (PQ) .............................................................................................. 34
2.10.5 Component Qualification (CQ) ................................................................................................ 35
2.10.6 Requalification ......................................................................................................................... 35
2.10.7 Revalidation ............................................................................................................................. 35
2.10.8 Revalidation after change ......................................................................................................... 36
A REVIEW ON PHARMACEUTICAL VALIDATION
2

2.10.9 Change Control ........................................................................................................................ 36
2.11 Documentation ................................................................................................................................ 37
3. Areas of Validation ........................................................................................................................... 43
3.1 Process Validation ............................................................................................................................ 44
3.1.1 Pilot Scale-Up and Process Validation ...................................................................................... 45
3.1.2 Priority Order in Process Validation .......................................................................................... 46
3.1.3 Stages of Process Validation ...................................................................................................... 47
3.1.4 Types of process validation ........................................................................................................ 52
3.1.5 Process Validation Decision ...................................................................................................... 59
3.1.6 Sterilization Validation .............................................................................................................. 62
3.2 Analytical method validation ............................................................................................................ 66
3.2.1 Why analytical methods need to be validated? .......................................................................... 67
3.2.2 Types of analytical procedures to be validated .......................................................................... 67
3.2.3 Advantages of analytical method validation .............................................................................. 67
3.2.3 Strategy for validation of methods ............................................................................................. 68
3.2.4 Analytical procedure .................................................................................................................. 68
3.2.5 Validation Parameters ................................................................................................................ 69
3.2.6 Data Elements Required for Validation ..................................................................................... 76
3.3 Facilities Validation .......................................................................................................................... 77
3.3.1 The Engineering Design Process for a Facility .......................................................................... 77
3.3.2 Conceptual Design: .................................................................................................................... 77
3.3.3 Purposes: .................................................................................................................................... 78
3.3.4 Qualification Activities .............................................................................................................. 79
3.3.5 Qualification Cost ...................................................................................................................... 79
3.3.6 Design Development: ................................................................................................................. 79
3.3.7 Facility Qualification Plan ......................................................................................................... 80
3.3.8 Qualification .............................................................................................................................. 81
3.4 Computer System Validation ............................................................................................................ 86
3.4.1 History of computer system validation in brief .......................................................................... 86
3.4.2 Importance of CSV .................................................................................................................... 87
3.4.3 Typical Computer System Validation ........................................................................................ 87
3.4.4 Advantages of CSV .................................................................................................................... 89
3.4.5 Software validation .................................................................................................................... 90
A REVIEW ON PHARMACEUTICAL VALIDATION
3

3.4.6 Software Life Cycle ................................................................................................................... 90
3.4.7 Construction or coding ............................................................................................................... 94
3.4.8 Testing by the Software Developer ............................................................................................ 94
3.4.9 User Site Testing ........................................................................................................................ 95
3.5 Equipment Validation ....................................................................................................................... 96
3.5.1 Reason of Equipment Validation ............................................................................................... 96
3.5.2 Content of Equipment Validation .............................................................................................. 96
3.5.3 Balances and Measuring Equipment .......................................................................................... 97
3.5.4 Production equipment ................................................................................................................ 97
3.5.5 Control laboratory equipment .................................................................................................... 97
3.5.6 Washing, cleaning and drying equipment .................................................................................. 98
3.5.7 Equipment Validation Process ................................................................................................... 98
3.5.8 HPLC method calibration ........................................................................................................ 100
3.5.9 HVAC Validation .................................................................................................................... 107
3.6 Cold Chain Validation .................................................................................................................... 117
3.6.1 Uses .......................................................................................................................................... 117
3.6.2 Strategy .................................................................................................................................... 118
3.6.3 Evaluation and Reporting......................................................................................................... 119
3.6.4 Ongoing Monitoring ................................................................................................................ 119
3.7 Source Validation: .......................................................................................................................... 120
3.7.1 Methods of vendor validation .................................................................................................. 120
3.7.2 Corrective and Preventive action ............................................................................................. 123
3.7.3 Importance of Source Validation ............................................................................................. 124
3.8 Personnel Validation ....................................................................................................................... 127
3.8.1 GMP Requirement ................................................................................................................... 127
3.8.2 Responsibilities ........................................................................................................................ 127
3.8.3 Training for personnel .............................................................................................................. 129
3.9 Packaging Validation: ..................................................................................................................... 130
3.9.1 Packaging Materials ................................................................................................................. 131
3.9.2 Packaging Equipment .............................................................................................................. 131
3.9.3 Assess the GMP Risk ............................................................................................................... 132
3.9.4 Line Layout .............................................................................................................................. 132
3.9.5 Operating Procedure and Training ........................................................................................... 132
A REVIEW ON PHARMACEUTICAL VALIDATION
4

3.9.6 Conduct of Packaging Validation ............................................................................................ 133
3.9.7 Performance qualification examples ........................................................................................ 135
3.9.8 Tests that can be performed for packaging validation ............................................................. 136
3.10 Cleaning Validation ...................................................................................................................... 139
3.10.1 Necessity ................................................................................................................................ 140
3.10.2 Advantages ............................................................................................................................. 140
3.10.3 Contamination ........................................................................................................................ 140
3.10.4 Cross Contamination .............................................................................................................. 140
3.10.5 Mechanism of Contamination ................................................................................................ 141
3.10.6 Cleaning Agent selection ....................................................................................................... 141
3.10.7 Sampling Techniques ............................................................................................................. 142
3.10.8 Sampling Methods ................................................................................................................. 143
3.10.9 Level of Cleaning ................................................................................................................... 145
3.10.10 Cleaning Validation procedure ............................................................................................ 146
3.10.11 Strategy on Cleaning Validation Studies ............................................................................. 146
3.10.12 Analyzing cleaning validation samples ................................................................................ 148
3.10.13 Data analysis for estimating possible contamination ........................................................... 149
4. Future Aspects of Validation ............................................................................................................. 150
4.1. Latest Technology .......................................................................................................................... 150
4.2 Automated Inspection/Identification ............................................................................................... 150
4.3 Process Automation ........................................................................................................................ 150
4.4 Robotics .......................................................................................................................................... 151
4.5 Isolation........................................................................................................................................... 151
5. Conclusion ....................................................................................................................................... 153
6. References ........................................................................................................................................ 154






A REVIEW ON PHARMACEUTICAL VALIDATION
5

Glossary:
1. Calibration The set of operations that establish, under specified conditions, the
relationship between values indicated by an instrument or system for measuring (for e.g.
weight, temperature, 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 established.
2. Computer validation - Documented evidence which provides a high degree of assurance
that a computerized system analyses, controls and records data correctly and that data
processing complies with predetermined specifications.
3. Commissioning The setting up, adjustment and testing of equipment or a system to ensure
that it meets all the requirements, as specified in the user requirement specification, and
capacities as specified by the designer or developer. Commissioning is carried out before
qualification and validation.
4. Concurrent validation Validation carried out during routine production of products
intended for sale.
5. Cleaning validation Documented evidence to establish that cleaning procedures are
removing residues to predetermined levels of acceptability, taking into consideration factors
such as batch size, dosing, toxicology, and equipment size.
6. Design qualification (DQ) Documented evidence that the premises, supporting systems,
utilities, equipment and processes have been designed in accordance with the requirements of
GMP.
7. Good engineering practices (GEP) Established engineering methods and standards that
are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.
8. Installation qualification (IQ) The performance of tests to ensure that the installations
(such as machines, measuring devices, utilities and manufacturing areas) used in a
manufacturing process are appropriately selected and correctly installed and operate in
accordance with established specifications.
9. Operational qualification (OQ) Documented verification that the system or subsystem
performs as intended over all anticipated operating ranges.
10. Performance qualification (PQ) Documented verification that the equipment or system
operates consistently and gives reproducibility with defined specifications and parameters for
A REVIEW ON PHARMACEUTICAL VALIDATION
6

prolonged periods. (In the context of systems, the term process validation may also be
used.)
11. Process validation Documented evidence which provides a high degree of assurance that a
specific process will consistently result in a product that meets its predetermined
specifications and quality characteristics.
12. Prospective validation Validation carried out during the development stage on the basis of
a risk analysis of the production process, which is broken down into individual steps; these
are then evaluated on the basis of past experience to determine whether they may lead to
critical situations.
13. Qualification Action of proving and documenting that any premises, systems and
equipment are properly installed, and/or work correctly and lead to the expected result.
Qualification is often a part (the initial stage) of validation, but the individual qualification
steps alone do not constitute process validation.
14. Retrospective validation Involves the evaluation of past experience of production on the
condition that composition, procedures, and equipment remain unchanged.
15. Revalidation Repeated validation of an approved process (or a part thereof) to ensure
continued compliance with established requirements.
16. Standard Operating Procedure (SOP) An authorized written procedure giving
instructions for performing operations not necessarily specific to a given product or material
but of a more general nature (e.g. equipment operation, maintenance and cleaning;
validation; cleaning of premises and environmental control, sampling and inspection).
Certain SOPs may be used to supplement product-specific master batch production
documentation.
17. Validation Action of proving and documenting that any process, procedure or method
actually and consistently leads to the expected results. The aim of validation is not to correct
or detect deviations in the packed product but to prevent deviations in the final packed
products as far as is practicable and economic.
18. Validation protocol (or plan) (VP) A document describing the activities to be performed
in a validation, including the acceptance criteria for the approval of a manufacturing process
or a part thereof for routine use.
A REVIEW ON PHARMACEUTICAL VALIDATION
7

19. Validation report (VR) A document in which the records, results and evaluation of a
completed validation programme are assembled and summarized. It may also contain
proposals for the improvement of processes and/or equipment.
20. Validation master plan (VMP) - The VMP is a high-level document that establishes an
umbrella validation plan for the entire project and summarizes the manufacturers overall
philosophy and approach, to be used for establishing performance adequacy. It provides
information on the manufacturers validation work programme and defines details of and
timescales for the validation work to be performed, including a statement of the
responsibilities of those implementing the plan.
21. Verification The application of methods, procedures, tests and other evaluations, in
addition to monitoring, to determine compliance with the GMP principles.
22. Worst case A condition or set of conditions encompassing the upper and lower processing
limits for operating parameters and circumstances, within SOPs, which pose the greatest
chance of product or process failure when compared to ideal conditions. Such conditions do
not necessarily include product or process failure.
23. URS User Requirements Specification (URS) provides a clear and precise definition of
what the user wants the system to do. It defines the functions to be carried out, the data on
which the system will operate and the operating environment. The URS define also any non-
functional requirements, constraints such as time and costs and what deliverables are to be
supplied. The emphasis should be on the required functions and not the method of
implementing those functions.
24. Acceptance Criteria The criteria a product must meet to successfully complete a test
phase or to achieve delivery requirements.
25. Change Control A formal system of reviewing and documenting proposed or actual
change that might affect the validated status of a system, equipment or process followed by
action to ensure ongoing validated state.
26. Requirement It can be any need or expectation for a system. It reflects the stated or
implied needs of the customer, and may be market-based, contractual, or statutory, as well as
an organizations internal needs.
27. Specification It is a document that states requirements.
A REVIEW ON PHARMACEUTICAL VALIDATION
8

28. Quality Assurance It can be defined as the totality of the arrangements made with the
object of ensuring that pharmaceutical products are of the quality required for their intended
use. In addition, it ensures that arrangements made for the manufacture, supply and use of the
correct starting and packaging materials.
29. Quality Control It is the part of GMP concerned with sampling, specifications and testing,
and with the organization, documentation and release procedures which ensures that the
necessary and relevant tests are actually carried out and that materials are not released for
used, nor products released for sale or supply, until their quality has been judged to be
satisfactory. It is not confined to laboratory operations but must be involved in all decisions
concerning the quality of the product.

A REVIEW ON PHARMACEUTICAL VALIDATION
9

1. Introduction to validation
1.1 Definition
Validation is not a one-time event but on-going process covering all phases of a product or
process. Literally, validation in pharmaceuticals means to be valid or justifiable. Simply saying,
validation means action of proving effectiveness. According to FDA 1987 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.
1
According to European Commission- 1991, validation is an act of proving in
accordance of GMPs that any process actually leads to expected results. According to European
Commission-2000, validation is documented evidence that the process, operated within
established parameters, can perform effectively and reproducibly to produce a medicinal product
meeting its predetermined specifications and quality attributes.
Validation is the evaluating of processes, products or analytical methods to ensure compliance
with product or method requirements. Prerequisites to fulfill these requirements for analytical
laboratories are properly functioning and well documented instruments (hardware and firmware),
computer hardware and software and validated analytical methods.
2


Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an
element of the quality assurance programme associated with a particular product or process. The
basic principles of quality assurance have as their goal the production of products that are fit for
their intended use. These principles are as follows:
Quality, safety and efficacy must be designed and built into the product.
Quality cannot be inspected or tested into the product.
Each critical step of the manufacturing process must be validated. Other steps in the process
must be under control to maximize the probability that the finished product consistently and
predictably meets all quality and design specifications.
Validation of processes and systems is fundamental to achieving these goals. It is by design and
validation that a manufacturer can establish confidence that the manufactured products will
consistently meet their product specifications.
Documentation associated with validation includes:
Standard operating procedures (SOPs)
A REVIEW ON PHARMACEUTICAL VALIDATION
10

Specifications
Validation master plan (VMP)
Qualification protocols and reports
Validation protocols and reports.
The implementation of validation work requires considerable resources such as:
Time: Generally validation work is subject to rigorous time schedules.
Financial: Validation often requires the time of specialized personnel and expensive
technology.
Human: Validation requires the collaboration of experts from various disciplines (e.g. a
multidisciplinary team, comprising quality assurance, engineering, manufacturing and other
disciplines, depending on the product and process to be validated).
3


Chapman purported Validation means nothing else than well-organized, well-documented
common sense.
4


1.2 History of validation:
Validation is a subject that has grown in importance within the global healthcare industry over
the past 25 years. Its origin can be traced to terminal sterilization process failures in the early
1970s. Individuals in the US point to the LVP sterilization problems of Abbott and Baxter, while
those in the U.K. cite the Davenport incident.
5
Each incident was a result of a non-obvious fault
coupled with the inherent limitations of the end-product sterility test. As a consequence of these
events, non-sterile materials were released to the market, deaths occurred, and regulatory
investigations were launched. The outcome of this was the introduction by the regulators of the
concept of Validation.
The initial reaction to this regulatory initiative was one of puzzlement, only a limited number of
firms had encountered difficulties, and all of the problems were seemingly associated with the
sterilization of LVP containers. It took several years for firms across the industry to understand
that the concerns related to process effectiveness were not limited to LVP solutions, and even
longer to recognize that those concerns were not restricted to sterile products. From its earliest
days, validation was identified as a new regulatory requirement to be added to the list of things
that firms must do, with little consideration of its real implications. The first efforts reflected
A REVIEW ON PHARMACEUTICAL VALIDATION
11

what can be termed the scientific method of observation of an activity, hypothesis/predition of
cause/effect relationship, and experimentation followed by new observations in the form of the
experimental report. In the pharmaceutical validation model this has evolved into the validation
protocol (hypothesis and prediction), field execution (experimentation), and summary report
preparation (documented observations).
6

By 1980, it was evident to all that validation was here to stay, so pharmaceutical firms began to
organize their activities more formally. Ad hoc teams and task forces that had started the efforts
were replaced by permanent Validation Departments whose responsibilities and scope varied
with the organization but whose purpose was to provide the necessary validation for a firms
products and processes. The individuals in these departments were the first to grapple with
validation as their primary responsibility, and their methods, concepts, and practices have served
to define validation ever since as establishing documented evidence which provides a high
degree of assurance that a specific process will consistently produce a product meeting its pre-
determined specifications and quality attributes.
7

The first efforts at validation were rather crude and limited in their understanding of the full
implications but slowly made significant strides. For e.g. the first sterilization validations were
performed without prior qualification of the equipment. Once validation had been established as
discipline, methods for its execution became substantially more formalized and rigorous.
Perhaps, most important was stride was separation of activities into two major categories.

1.2.1 Equipment Qualification and Process Qualification:
It was apparent by then that validation had to be more closely integrated into the mainstream of
cGMP operations in order to maximize its effectiveness in larger organizations. A number of
areas can be identified as pre-requisites for process or system validation. The origins of these
elements can be identified in the cGMP requirements for drugs and devices (Table 1).
8

With this understanding, the industry began to recognize that validation offered advantages to the
firm and implemented validation objectives that were non-regulatory and geared for the
optimization of processes and systems. The attention being placed on validation at this time led
to important changes in how firms approached its implementation and should be integrated with
other GMP.

A REVIEW ON PHARMACEUTICAL VALIDATION
12

Table 1:- Pre-Requisites for Validation
1 Process Development [21 CFR 820.30Design Control]. The activities performed to
define the process, product or system to be evaluated.
2 Process Documentation [21 CFR 211 Subparts F - Production and Process controls and J-
Records and Reports]. The documentation (batch records, procedures, test methods,
sampling plans) and processes (software) that define the operation of the equipment to
attain the desired result.
3 Equipment Qualification [21CFR 211 Subparts C Buildings and Facilities and D-
Equipment]. The specifications, drawing, checklists and other data that support the
physical equipment (hardware) utilized for the process.
4 Calibration [21 CFR 211 Subparts D Equipment]. The methods and controls that
establish the accuracy of data.
5 Analytical Methods [21CFR 211 Subparts I Laboratory Controls]. The means to
evaluate the outcome of the process on the materials.
6 Cleaning [21 CFR 211.67Equipment Cleaning and Maintenance]. A specialized process,
the intent of which is to remove the traces of the prior product from the equipment.
7 Change Control [21 CFR 211. 100(b) Equipment Cleaning and Maintenance]. A
formalized process control scheme that evaluates changes to documentation, materials,
and equipment.

The pharmaceutical industry participated in the introduction of computers into the manufacturing
environment during the 1980s. This led to FDA concerns relative to the validation of
computerized system used within the industry. The pharmaceutical industrys response to the
FDAs new concerns regarding validation of computerized systems was somewhat different than
what had occurred previously. The Pharmaceutical Manufacturers Association established an
interdisciplinary group called the Computer Systems Validation Committee (CSVC) in late 1983
to address how the industry would address the FDAs concerns. Through the creation of the
A REVIEW ON PHARMACEUTICAL VALIDATION
13

CSVC, the industry began to assume a position of leadership regarding validation. Through the
auspices of the CSVC, an industry approach to the validation of computerized systems in the
GMP environment was established.
9
Central to the industry position, was the adoption of the
life cycle concept as an appropriate model for managing the activities needed for the
successful validation of computerized systems (Figure 1). The life cycle approach focuses on
managing a project from cradle to grave. When employing the life cycle approach, the design,
implementation, and operation of system (or project) are recognized as interdependent parts of
the whole. Operation and maintenance concerns are addressed during the design of the system
and confirmed in the implementation phase to ensure their acceptability. The adoption of the life
cycle methodology afforded such a degree of control over the complex tasks associated with the
validation of computerized systems that it came into nearly universal application within a very
short period.
Figure 1


1.3 Why validation?
First and foremost, among the reasons for validation is that it is a regulatory requirement for
virtually every process in the global healthcare industry for pharmaceuticals, biologics, and
medical devices. Regulatory agencies across the world expect firms to validate their processes.
The continuing trend toward harmonization of requirements will eventually result in a common
level of expectation for validations worldwide.
Number of tangible and intangible benefits of validation was realized (Table 2)
10
. In the
intervening years, there has been repeated affirmation of those expectations at other firms, large
A REVIEW ON PHARMACEUTICAL VALIDATION
14

and small. Regrettably, there has been little quantification of these benefits. The predominance of
compliance-based validation initiatives generally restricts objective discussion of cost
implications for any initiative. But once a process/product is properly validated, it seem that
reduced sample size and intervals could be easily justified, and thus provide a measurable return
on the validation effort. Aside from utility systems, it is hardly ever realized and represents one
of the major failings relative to the implementation of validation in pharmaceutical industry.

Table 1: Benefits of Validation
Increased throughput
Reduction in rejections and reworks
Reduction in utility costs
Avoidance of capital expenditures
Fewer complaints about process related failures
Reduced testing in process and finished goods
More rapid and accurate investigations into process deviations
More rapid and reliable startup of new equipment
Easier scale-up from development work
Easier maintenance of the equipment
Improved employee awareness of processes
More rapid automation

Validation and validation-like activities are found in a number of industries, regulated and
unregulated. Banking, aviation, software, microelectronics, nuclear power, among others all
incorporate practices closely resembling validation of health care product production. The health
care industries fixation on compliance has perhaps blinded us the real value of validation
practices.
1.4 What has to be validated?
Validation efforts in the analytical laboratory should be broken down into separate components
addressing the equipment (both the instrument and the computer controlling it) and the analytical
methods run on that equipment. After these have been verified separately they should be checked
together to confirm expected performance limits (so-called system suitability testing), and finally
A REVIEW ON PHARMACEUTICAL VALIDATION
15

the sample analysis data collected on such a system should be authenticated with suitable
validation checkouts. Other activities include checking reference standards and qualification of
people.
1) Equipment: All (computerized) equipment that is used to create, modify, maintain, archive,
retrieve, or distribute critical data for cGMP/GCP/GLP purposes should be validated.
Validation of hardware includes testing the instrument according to the documented
specifications. Even though this may include word processing systems to create and maintain
SOPs, it covers analytic systems only. If instruments consist of several modules, a modular
HPLC system for example, the entire system should be validated. Validation of computer
systems must include the qualification of hardware and software.
2) Analysis method: Validation covers testing of significant method characteristics, for e.g
sensitivity and reproducibility.
3) Analytical system: The system combines instrument, computer and analytical method. This
validation usually referred to as system suitability testing, tests the system for documented
performance specifications for the specific analysis method.
4) Data: When analyzing samples the data must be validated. The validation process includes
documentation and checks for data plausibility, consistency, integrity, and traceability. A
complete audit trail must be in place, which allows tracing back the final result to the raw
data for integrity.
5) Personnel: People should be qualified for their jobs. This includes education, training and/or
experience.
6) Reference standards: Reference standard should be checked for purity, identity,
concentrations and stability.
11


1.5 Scopes of Validation
There should be an appropriate and sufficient system including organizational structure and
documentation infrastructure, sufficient personnel and financial resources to perform
validation tasks in a timely manner. Management and persons responsible for quality
assurance should be involved.
A REVIEW ON PHARMACEUTICAL VALIDATION
16

Personnel with appropriate qualifications and experience should be responsible for
performing validation. They should represent different departments depending on the
validation work to be performed.
There should be proper preparation and planning before validation is performed. There
should be a specific programme for validation activities.
Validation should be performed in a structured way according to the documented procedures
and protocols.
Validation should be performed for:
For new premises, equipment, utilities and systems, and processes and procedures.
At periodic intervals, and
When major changes have been made.
(Periodic revalidation or periodic requalification may be substituted, where appropriate, with
periodic evaluation of data and information to establish whether requalification or revalidation is
required).
Validation should be performed in accordance with written protocols. A written report on the
outcome of the validation should be produced.
Validation should be done over a period of time, e.g. at least three consecutive batches (full
production scale) should be validated, to demonstrate consistency. Worst case situations
should be considered.
There should be a clear distinction between in-process controls and validation. In-process
tests are performed during the manufacture of each batch according to specifications and
methods devised during the development phase. Their objective is to monitor the process
continuously.
When a new manufacturing formula or method is adopted, steps should be taken to
demonstrate its suitability for routine processing. The defined process, using the materials
and equipment specified, should be shown to result in the consistent yield of a product of the
required quality.
Manufacturers should identify what validation work is needed to prove that critical aspects of
their operations are appropriately controlled. Significant changes to the facilities or the
equipment, and processes that may affect the quality of the product should be validated. A
A REVIEW ON PHARMACEUTICAL VALIDATION
17

risk assessment approach should be used to determine the scope and extent of validation
required.
12

1.6 Pre-Requisites for Successful Validation
There are some elements or tools that are required for conducting effective validations. Each are
presented and discussed in the following sections:
Understanding
The single most important element required is a good understanding of what validation is.
This understanding activity goes beyond the basic definition of validation, beyond the
concept of requiring a minimum of three runs and understanding must be anchored by
sufficient years of practical experience and knowledge. It will permit sound and logical
decisions even under most intense situations.
13

Communication
Communication is one of the best methods of improving environment understanding. It is
essential for any activity that requires more than one resource to complete. This point is
understandable considering that conducting effective validation involves multi-departments.
Co-operation and Focus
Multi departments that sometimes interact during the course of executing validation program
are project management, accounting, quality control, project engineering, process
engineering, quality assurance, facilities; regulatory etc should have a commendable co-
operation.
Experience
A firm must have resources with solid validation experience to get success in their validation
program.
Resources
Resources mean personnel who will plan and execute equipment on which validations will be
performed on materials with which to conduct validations. Laboratories that will perform
necessary analysis should provide necessary funding for the validations and allocate
sufficient time to perform validations.
14

Plan
Conducting validations within most companies will involve a number of departments and
disciplines. These disciplines need a perfect plan in order to get good team synergy.
A REVIEW ON PHARMACEUTICAL VALIDATION
18

Budget
It is important to understand that a successful validation must be done to completion and it
should not be limited by a budget assembled by personnel who have no appreciation for what
is required to successfully complete validation. Further, it is important to understand that
validations cost money.
15

Standard Operating Procedures (SOPs)
The SOPs capture activities that routinely occur within an organization. Departments charged
with abiding by or following these SOPs must first be trained against these SOPs.
Quality Control lab support
In most of the validations, some laboratory testing will be required. In most cases this testing
is handled by the QC group. QC is expected to provide results in timely manner. So often, the
wait for the receipt of analytical results cases the entire validation project to come to halt.
Because validations are based on the results obtained.

1.7 Approaches of Validation
According to the WHO, there are two basic approaches to validation; one is based on evidence
obtained through testing (prospective and concurrent validation), and another is based on the
analysis of accumulated (historical) data (i.e. retrospective validation). Whenever possible,
prospective validation is preferred. Retrospective validation is no longer encouraged and is, in
any case, not applicable to the manufacturing of sterile products.
Both prospective and concurrent validation may include following:
Extensive product testing, which may involve extensive sample testing (with the estimation
of confidence limits for individual results) and the demonstration of intra- and inter-batch
homogeneity.
Simulation process trials
Challenge/ worst case tests, which determine the robustness of the process, and
Control of process parameters being monitored during normal production runs to obtain
additional information on the reliability of the process.
16

1.8 Phases in Validation
17
:
The activities relating to validation studies may be classified into three phases mainly. They are
as follows:
A REVIEW ON PHARMACEUTICAL VALIDATION
19

1. Pre-validation Qualification Phase: It covers all activities related to product research and
development, formulating pilot batch studies, scale-up studies, technology transfer to
commercial scale batches, establishing stability conditions and storage, and handling of in-
process and finished dosage forms, equipment; operational and installation qualification,
master production document and process capacity.
2. Process validation phase: It is designed to verify that all established limits of the critical
process parameters are valid and satisfactory products can be produced even under worst
conditions.
3. Validation Maintenance phase: It requires frequent review of all process related documents,
including audit reports, to assure that there have been no changes, deviations, failures and
modifications to the production process and that all SOPs, including change control
procedures have been followed. At this phase, the validation comprising of members from all
major departments assures that there have been no changes/deviations that should be resulted
in requalification and revalidation. A careful design and validation of systems and process
controls can establish a high degree of confidence that all lots of batches produced will meet
their intended specifications. Thus, its assumed that throughout manufacturing and control,
operations are conducted in accordance with the principle of GMP both in general and in
specific reference to sterile product manufacture.
The validation steps recommended in GMP guidelines can be summarized as follows
18
:
As a pre-requisite, all studies should be conducted in accordance with a detailed, pre-
established protocol or series of protocols, which in turn is subject to formal change control
procedures.
Both the personnel conducting the studies and those running the process being studied should
be appropriately trained and qualified and be suitable and competent to perform the task
assigned to them.
All data generated during the course of studies should be formally reviewed and certified as
evaluated against pre-determined criteria.
Suitable testing facilities, equipment, instruments and methodology should be available.
Suitable clean room facilities should be available in both the local and background
environment. There should be assurance that the clean room environment as specified is
secured through initial commissioning (qualification) and subsequently through the
A REVIEW ON PHARMACEUTICAL VALIDATION
20

implementation of a programme of re-testing in-process equipment should be properly
installed, qualified and maintained.
When appropriate attention is paid to above, the process, if aseptic, may be validated by
means of process simulation studies.
The process should be revalidated at specific time intervals.
Comprehensive documentation should be available to define support and record the overall
validation process.

1.9 Validation Decision Tree:
This model describes a decision tree that helps manufacturer decide on whether processes need
to be validated or not. It is one of the easiest models under consideration.

















Each process should have a specification describing both the process parameters and the desired
output. The tree is described below:
A
Is process
Output
Verifiable
B
Is Verification
Sufficient &
Cost Effective
C
Verify &
Control the
Process
D
Validate
E
Redesign
Product and/or
Process
NO NO
Yes YES
Figure- 2: Validation Decision Tree
A REVIEW ON PHARMACEUTICAL VALIDATION
21

A. The manufacturer should consider whether the output can be verified by subsequent
monitoring or measurement.
B. If the answer is positive, then the consideration should be made as to whether or not
verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution.
C. If yes, the output should be verified and the process should be appropriately controlled.
D. If the output of the process is not verifiable then the decision should be to validate the
process.
E. The product or process should be redesigned to reduce variation, improve product or process
and decrease risk or cost to a point where verification is acceptable decision.

A REVIEW ON PHARMACEUTICAL VALIDATION
22

2. Organizing for Validation
Validation and its role within a pharmaceutical organization have come a long way from its
inception in the 1970s, when the effort was primarily focused on sterilization validation and
demonstrating that the conditions to achieve sterility were met. As a result, it was managed from
within the sterile manufacturing unit using a small team. In the 1980s, validations organizations
were created and began interacting with other groups such as Research, Engineering, Production,
Manufacturing, and Quality Assurance.
Formulating a mission is essential to ensure proper definition of a department role in the
formation. Although there is broad diversity of validation department missions within the
pharmaceutical industry, the mission that is general to all validation departments is the satisfying
of the regulatory requirement to have processes validated. Certainly the validation mission is
influenced by the size of the company as well as its product lines.
2.1 Staffing issues
When staffing a validation group, the mission and the organization exert a degree of influence,
primarily in the academic backgrounds of the members. Because of the aforementioned diversity,
a considerable variety of academic backgrounds are usually found among validation
professionals, such as members having degrees in chemistry, microbiology, pharmacy, statistics,
computer science, biochemistry as well as engineering disciplines. For e.g. when the mission is
directed toward a sterile products focus, having a microbiology degree would be beneficial. In
general sense, the more important than the actual academic background are these 3 skills:
problem-solving capability, interpersonal skills, and oral and written communication abilities.
The technical talent to recognize and solve problems is fundamental to validation. Finally, it is
targeted that the validation members be able to effectively express the validation objectives and
concerns both orally and in written form. If the professional can successfully communicate
orally, esp. during an FDA visit, the strength of validation package is expected to be even
greater.
2.2 Department interactions
Once missions of departments have been formalized and the validation operations are organized,
the main challenge is to implement the plan, which requires interaction with many peer groups.
Within the company, other departments involved in validation taskforce are as follows:
A REVIEW ON PHARMACEUTICAL VALIDATION
23

1. R & D: It is involved with new product and process development and often existing process
improvements. Their key responsibility in validation is to ensure the acceptability (and thus
validatability) of new products or improved process in the manufacturing area. They must
be aware of the validation plan and resulting acceptance criteria.
2. Engineering: It is involved with new or modified equipment or facilities and their start-ups.
Their role is to ensure the acceptability of the processes later on, so their concern must be
built in at the design phase and continued through construction.
3. Production: It is concerned with processes that require validation and stress the benefits of a
validation program.
4. Maintenance: Its concerned with change control, calibration, and preventative maintenance.
This occurs at the instant when an undocumented change is made to a validated piece of
equipment.
5. Quality Control: Its involved with the testing laboratories and ensures that laboratory
personnel know not only the number and type of tests required for the study but also how the
testing fits into the overall validation program.
6. Quality Assurance: Its concerned with GMP compliance to ensure a firms regulatory
compliance. Through the technical competency of the validation staff and the GMP
compliance expertise existing within the QA group, these efforts should be successful. The
key point is to communicate so that the regulatory compliance objective of validation is met.
Whether the process is a bulk process or one of the finishing steps; whether it is a proprietary
purification process, a steam sterilization process, or a conventional non-sterile process; whether
the focus is a clinical manufacturing lot or commercial production; or whether the effort is
accomplished within the firm, contracted out in conjunction with an outsourced manufacturing
agreement, or with the assistance of a consultant, the validation staff must possess 4 things:
i. Technical expertise, allowing a thorough understanding of the process being reviewed.
ii. Understanding of the fundamentals of validation and the ability to apply them to the process.
iii. Interpersonal skills necessary to deal with all of the organizations within and outside of the
firm.
iv. Support from management, which positions the validation effort as a critical element in the
companys success.
These basics ensure that the validation effort is successfully accomplished.
19

A REVIEW ON PHARMACEUTICAL VALIDATION
24

2.3 Master planning or planning for Validation
The validation master plan (VMP) has become common practice for all large capital projects
within the global healthcare industry. The master plan has come into vogue to ensure that the
validation requirements for major facilities are adequately addressed. Although its often
described as a regulatory requirement, there is in fact no such requirement in any of the worlds
cGMP regulations; nevertheless, its real value is as a management tool to be used to coordinate
the validation effort. It is an indispensable tool that delineates how the validation effort is to be
executed. The utility of plan diminishes with facility size and complexity, but even small projects
may benefit from the structure that a master plan brings to the validation effort.
20

VMP is a good practice to document all validation activities in a document. The FDA does not
specifically demand a validation master plan however; inspectors want to know what the
companys approach towards validation is. So, VMP is an ideal tool to communicate this
approach internally and to inspectors.
21
The validation master plan should provide an overview
of the entire validation operation, its organizational structure, its content and planning. All
validation activities relating to critical technical operations, relevant to product and process
controls within a firm should be included in the VMP. It should comprise all prospective,
concurrent and retrospective validations as well as revalidation.
22
The VMP should reflect the
key elements of the validation programme. It should be concise and clear and contain at least the
following:
A validation policy
Organizational structure of validation activities
Summary of facilities, systems, equipment and processes validated and to be validated.
Documentation format (e.g. protocol and report format)
Planning and scheduling
Change control
References to existing documents

2.4 Benefits of Master Planning
Numerous benefits are derived from a VMP which can substantially enhance the firms
validation posture for the project. A well-structured plan will provide following advantages to a
firm:
A REVIEW ON PHARMACEUTICAL VALIDATION
25

i. Codify decisions regarding how cGMP requirements will be satisfied.
ii. Allow detailed definition of validation activities necessary for the successful operation of the
facility.
iii. Serve as an important document in regulatory compliance and interaction.
iv. Serve as a communication document on the validation for use with third parties.
v. Be easily converted into a Drug Master File
vi. Serve as an excellent tool for audit preparation (either internal or external).
vii. Define project execution through the definition of requirements.
viii. Help determine resource needs for personnel, materials, equipment, components and
laboratory analysis.
ix. Ease protocol and report preparation through the definition of accepted formats.
x. Be used as a bid document when soliciting bids for contract execution.

2.5 Validation Process
Each part of the validation process should be documented. There should be a written plan for
performing each validation to specify who is responsible for managing and performing the
various validation tasks such as production of validation protocols and approvals of validation
documentation. Validation protocols should be written for each phase of the validation to include
acceptance criteria. The validation plan and the validation protocols may be combined into a
single document. The outcome of each phase of validation should be recorded and the overall
conclusions, with a scientific assessment of any failures should be documented in a validation
summary report. The validation records and summary report must be reviewed and approved
before putting the process or system affected into use.

2.6 Validation Plan
The plan should first identify the following things:
What is being validated
Where the validation will take place
Why the validation is taking place providing reference to any relevant change control
records, risk assessments, URS and FDS.
The validation stages required
A REVIEW ON PHARMACEUTICAL VALIDATION
26

Validation time-frames
The plan should also identify the validation team and define responsibilities for :
Overall management of the validation
Production of protocols
Performing the validation and recording the outcome
Reviewing and approving the protocols and validation records
Reviewing the validation outcomes and signing off the validation as acceptable.
23


2.7 Typical validation master plan structure
There is no standard format for master plans. Various authors used different types of plans with
appropriate adaptations to suit to specific requirements of a particular project. The most
successfully used plans basic template is given in table below (table 3)
24
. It can be readily
modified to different project types and scales. With changes in the facility type, there is a
corresponding change in the focus of the master plan.
Table 3 Validation master plan template
Introduction Introduction to the project scope, location, and timing. Includes
responsibilities for protocol, SOP, report and other documentation
preparation and approval. Identifies who is responsible for the
various activities. A general validation SOP or policy statement may
be included.
Plant/Process/Product
Development
A concise description of the entire project is provided. It will
provide information on layout and flow of personnel, materials, and
components; utility and support systems; description of the
processes to be performed and products to be made in the facility.
Major equipment is also described.
Computerized System
and Process Control
Description (If needed)
Computerized information, laboratory and process control systems
are described in sufficient detail to delineate the validation
requirements. This section may be omitted if the level of automation
is minimal.
A REVIEW ON PHARMACEUTICAL VALIDATION
27

List of Systems/
Processes/Products to
be validated
Equipment, systems, and products are listed in a matrix format that
describes the extent of validation required (i.e. IQ, OQ, or PQ) as
part of the project. Additional breakout of computerized, cleaning
and sterilization validation requirements can be added.
General and Specific
Acceptance Criteria
Key acceptance criteria (general and specific) for the items listed in
the prior section are provided. Emphasis should be placed on
quantitative criteria throughout. To merely state the general
requirements provides no substantial benefit to either those
responsible for the validation or for those involved in the design
process.
Special Issues (if
needed)
Sections can be included describing in greater detail the validation
requirements of an element of the project where additional
clarification may be warranted. Typical subjects include automation,
cleaning, containment, isolation, or lyophilization.
Protocol and
Documentation format
The format to be used for protocols, reports, and operating
procedures is described. This particularly useful in a new
organization where such formats have not yet been defined. It can
also be beneficial when working with an outside contractor to ensure
that all documentation is in the correct format.
Required procedures List of SOPs (new or existing) necessary to operate the facility.
Manpower planning
and scheduling
An estimate of the staffing requirements to complete the validation
effort described in the plan. A preliminary schedule of required
activities is prepared to help estimate appropriate manning levels.

2.8 Validation Protocol
Validation protocol is the step that comes after validation plan. It is an integral element of the
validation plan. The protocol describes:
The qualification/validation phase (IQ,OQ, PQ or method process validation)
A REVIEW ON PHARMACEUTICAL VALIDATION
28

The tests that will be performed
The test procedures
The objectives of the validation in terms of acceptance criteria for each test
Records to be completed.
What needs to be tested, how many tests to do and the acceptance criteria at each validation
phase will be specific to each validation and must be founded on the scientific and technical
basis of the processes and systems involved. It should be possible to establish the specific
requirements by reference to the relevant risk assessments, URS, FDS, published standards,
regulations & guidelines.
25

The detailed protocols for performing validations are essential to ensure that the process is
adequately validated. It should include the following elements:
Objectives, scope of coverage of the validation study.
Validation team membership, their qualifications and responsibilities.
Type of validation: prospective, concurrent, retrospective, re-validation.
Number and selection of batches to be on the validation study.
A list of all equipment to be used; their normal and worst case operating parameters.
Outcome of IQ, OQ for critical equipment.
Requirements for calibration of all measuring devices.
Critical process parameters and their respective tolerances.
Process variables and attributes with probable risk and prevention shall be captured.
Description of the processing steps: copy of the master documents for the product.
Sampling points, stages of sampling, methods of sampling, sampling plans.
Statistical tools to be used in the analysis of data.
Training requirements for the processing operators.
Validated test methods to be used in in process testing and for the finished product.
Specifications for raw and packaging materials and test methods.
Forms and charts to be used for documenting results.
Format for presentation of results, documenting conclusions and for approval of study
results.
A REVIEW ON PHARMACEUTICAL VALIDATION
29

There should also be a description of the way in which the results will be analyzed. The protocol
should be approved prior to use. Any changes to a protocol should be approved prior to
implementation of the change. The validation protocol and report may also include copies of the
product stability report or a summary of it, validation documentation on cleaning, and analytical
methods.

2.9 Validation set up
Validation set up is very essential to establish the desired attributes. These attributes include
physical as well as chemical characteristics. In the case of parenterals, these attributes should
include stability, absence of pyrogens, and freedom from visible particles.
Acceptance specifications for the product should be established in order to attain uniformity and
consistently the desired product attributes, and the specifications should be derived from testing
and challenge of the system on sound statistical basis during the initial development and
production phases and continuing through subsequent routine production.
The process and equipment should be selected to achieve the product specification. For e.g.
design engineers; production and quality assurance people may all be involved. The process
should be defined with a great deal of specificity and each step of the process should be
challenged to determine its adequacy. These aspects are important in order to assure products of
uniform quality, purity and performance.
26


2.10 Relationship between validation and qualification
Validation and qualification are essential components of the same concept. The term
qualification is normally used for equipment, utilities and systems, and validation for processes.
In this sense, qualification is part of validation. Qualification is pre-requisite of validation. There
are four phases/stages of qualification for process, equipment, facilities or systems:
Design qualification (DQ);
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
Component qualification (CQ), only sometimes stated.
A REVIEW ON PHARMACEUTICAL VALIDATION
30

All SOPs for operation, maintenance and calibration should be prepared during qualification.
Training should also be provided to operators and training records be maintained.

2.10.1 Design Qualification (DQ)
DQ is defined as Providing documented verification that all key aspects of the design,
procurement and installation adhere to the approved design intention and that all the
manufacturers recommendations have been suitably considered.
27
It defines the functional and
operational specifications of the instrument and details the conscious decisions in the selection of
the supplier.
28
DQ covers all aspects of the design and procurement of facility and equipment. It
is intended to encompass all those activities that might take place in the design phase, detailed
and development, including activities associated with procurement of equipment and checkout at
the suppliers works. It is a verification that the design meets user requirements with a particular
focus on those requirements that relate to GMP and product quality. The extent of DQ may
depend on the contract arrangements. Design may be subcontracted to suppliers or
subcontractors and how this is covered should be defined in the plan. DQ is not a regulatory
requirement but a smart activity to include in the qualification process. It is essential that aspects
of design are demonstrated in the qualification process as the existing regulations require that
facility and equipment are of suitable design and appropriate to purpose.
DQ should also provide documented evidence that the design specifications were met. Any
validation should start with setting and documenting the specifications for user requirements,
instrument functions and performance. The specifications of the instruments design should be
compared with the user requirement specifications. It is a simple rule of thumb: without
specifications there is no validation. DQ is the most important step in the validation process.
Errors made in this phase can have a tremendous impact on the workload during later phases.
Steps for design qualification: The recommended steps that should be considered for inclusion in
a design qualification are listed below:
Description of the analysis problem.
Selection of the analysis technique.
Description of the intended use of the equipment.
Preliminary selection of functional and performance or operational specifications (technical,
environmental, safety).
A REVIEW ON PHARMACEUTICAL VALIDATION
31

Preliminary selection of the supplier.
Instrument tests (if the technique is new).
Final selection of the equipment.
Final selection of the supplier.
Development and documentation of the final functional and operational specifications.
Role of vendor for design qualification
Although the user of a system has ultimate responsibility for validation, the vendor also plays a
major role. The validation covers the complete life of a product, starting with the design and
development. For commercial off the shelf systems, the user has hardly any influence on how the
software is being developed and validated, but he can check through documentation to see if the
vendor followed in acknowledged quality process.
Tasks of the vendor: The vendor should
Develop and validate software following documented procedures.
Test the system and document test cases, acceptance criteria and test results.
Retain the tests protocols and source code for review at the vendors site.
Provide procedures for IQ and OQ/PV.
Implement a customer feedback, change control and response system.
Provide fast telephone, e-mail and/ or on-site support.
Qualification of the vendor
As a part of the qualification process, the vendor should be qualified. The question is, how
should this be done? Is an established and documented quality system enough, for e.g. ISO
9001? Should there be a direct audit? Is there another alternative between these two extremes?
There may be situations where a vendor audit is recommended: for e.g. when computer systems
are being developed for a specific user. However, this is rarely the case for analytical equipment.
Typically, off-the-shelf systems are purchased from a vendor with little or no customization for
specific users.
The exact procedure to qualify a vendor depends very much on the individual situation, for e.g.
is the system in mind employing mature or new technology? Is the specific system in widespread
use either within your own laboratory or your company, or are there references in the same
industry? Does the system include complex computer hardware and software?

A REVIEW ON PHARMACEUTICAL VALIDATION
32

2.10.2 Installation Qualification (IQ)
It can be defined as process of obtaining and documenting evidence that equipment has been
provided and installed in accordance with the specification. IQ establishes that the instrument is
received as designed and specified, that it is properly installed in the selected environment, and
that this environment is suitable for the operation and use of the instrument. This involves
verification of good engineering practice in installation of equipment, and should consider
electrical safety, safety issues, location siting, and maintenance/calibration schedules and should
confirm that the installation has been carried out as specified with the appropriate supporting
documentation. This activity can be delegated to the supplier, provided that the content of the IQ
document is approved in advance by the laboratory.
IQ should provide documented evidence that the installation was complete and satisfactory. It
should also clearly define those areas and items of equipment systems that are to be qualified.
The purpose specifications, drawings, manuals, spare parts lists and vendor details should be
verified during installation qualification. Also, control and measuring devices be calibrated.
Steps for IQ: Steps for IQ include activities prior and during installation of the equipment. The
recommended steps are as follows:
a) Before installation
Obtain manufacturers recommendations for installation site requirements.
Check the site for the fulfillment of the manufacturers recommendations (utilities such
as electricity, water and gases and environmental conditions such as humidity,
temperature and dust).
Allow sufficient shelf space for the equipment, SOPs, operating manuals and software.
b) During installation
Compare equipment, as received, with purchase order (including software, accessories,
spare parts)
Check documentation for completeness (operating manuals, maintenance instructions,
and standard operating procedures or testing, safety and validation certificates).
Check equipment for any damage.
Install hardware (computer, equipment, fittings and tubings for fluid and gas connections
columns in HPLC and GC, power cables, data flow and instrument control cables).
A REVIEW ON PHARMACEUTICAL VALIDATION
33

Switch on the instruments and ensure that all modules power up and perform an
electronic self-test.
List equipment manuals and SOPs.
Prepare an installation report.

2.10.3 Operational Qualification (OQ)
It can be defined as process of obtaining and documenting evidence that installed equipment
operates within predetermined limits when used in accordance with its operational procedures.
OQ is the process of demonstrating that an instrument will function according to its operational
specification in the selected environment. It should provide documented evidence that utilities,
systems or equipment and all its components operate in accordance with operational
specifications. Tests should be designed to demonstrate satisfactory operation over the normal
operating range as well as at the limits of its operating conditions (including worst case
conditions). Operation controls, alarms, switches, displays and other operational components
should be tested and measurements made in accordance with a statistical approach should be
fully described.
29
It should prove that the instrument is suitable for its intended use. It is not
required to prove that the instrument meets the manufacturers performance specifications.
Frequently, people misunderstand and prefer to use the manufacturers specifications because
usually these are readily available.
Moreover, this is the verification of process, equipment and facilities over its operating range and
is assessed against the specifications as defined in the URS. During this stage, a range of tests
will be carried out to demonstrate the integrity and functionality of the system, including the
ability to operate under worst case conditions. Confirmation that all calibration, operating and
cleaning processes have been defined and tested will be required. Definition of the required
programme of planned preventative maintenance (PPM) should be considered. It can be carried
out by the supplier and/or by laboratory, or a combination of both. In any case, this must be
performed using and agreed OQ protocol.

Steps for OQ
Define intended functions to be tested.
A REVIEW ON PHARMACEUTICAL VALIDATION
34

Define test cases and acceptance criteria. For an HPLC system such tests include precision of
retention times and peak areas, wavelength accuracy of UV detectors, gradient accuracy and
precision, system carry over, baseline noise and detector linearity.
Perform tests and compare the results with the acceptance criteria.

2.10.4 Performance Qualification (PQ)
It is defined as process of obtaining and documenting evidence that the equipment, as installed
and operated in accordance with operational procedures, consistently performs in accordance
with predetermined criteria and thereby yields product meeting its specifications. Successful
completion of IQ and OQ is followed by PQ. It can also be defined as documented verification
that all aspects of a facility, utility or equipment perform as intended in meeting predetermined
acceptance criteria. This is performed to demonstrate that the process, equipment or facility
performs as required under routine operational conditions and as defined in the URS. This is
sometimes referred to as Process validation and is the stage of the exercise when the equipment
or process is assessed in its practical application, with operational outputs/product being assessed
for acceptability.
30
It should provide documented evidence that utilities, systems or equipment
and all its components can consistently perform in accordance with the specifications under
routine use.
This is generally applicable to those systems that require extended testing over a period of time
such as water systems, heating, and ventilation systems such as those applicable to clean rooms
and the actual performance of the clean room to meet the defined standards of operation over
periods of time. Some organizations may include PQ in the OQ.
PQ should include following, however, it is not exclusive.
Tests using production materials, substitutes or simulated product.
Tests to include condition(s) with upper and lower limits. It will be useful to briefly discuss
process capability design and testing and process qualification.
Check actual product and process parameters and procedures established in OQ.
Test acceptability of the product.
Check process repeatability, and long term process stability.


A REVIEW ON PHARMACEUTICAL VALIDATION
35

2.10.5 Component Qualification (CQ)
It is relatively new term developed in 2005. This refers to the manufacturing of auxiliary
components to ensure that they are manufactured to the correct design criteria. This could
involve packaging components such as folding cartons, shipping cases, labels or even phase
change material. All of these components must have some type of random inspection to ensure
that the third party manufacturers process is consistently producing components that are used in
the world of GMP at drug or biologic manufacturer.
31


2.10.6 Requalification
Requalification should be done in accordance with a defined schedule. The frequency of
requalification may be determined on the basis of factors such as the analysis of results relating
to calibration, verification and maintenance. There should be periodic requalification, as well as
requalification after changes (such as changes to utilities, systems, equipment; maintenance
work; and movement). It should be considered as part of the change control procedure.

2.10.7 Revalidation
Revalidation can be defined as repeating the original validation effort or any part of it, which
includes investigative review of existing data. It is essential to maintain the validated status of
the plant, equipment, manufacturing processes and computer systems. Processes and procedures
should be revalidated to ensure that they remain capable of achieving the intended results. There
should be periodic revalidation, as well as revalidation after changes. It should be done in
accordance with a defined schedule. The frequency and extent of revalidation should be
determined using a risk based approach together with a review of historical data.
Periodic revalidation should be performed to assess process changes that may occur gradually
over a period of time, or because of wear of equipment. The following should be considered
when periodic revalidation is performed:
Master formulae and specifications
SOPs
Records (e.g. of calibration, maintenance and cleaning)
Analytical methods

A REVIEW ON PHARMACEUTICAL VALIDATION
36

2.10.8 Revalidation after change
Revalidation should be performed following a change that could have an effect on the process,
procedure, quality of the product and/or the product characteristics. Revalidation should be
considered as part of the change control procedure. The extent of revalidation will depend on the
nature and significance of the changes. Changes should not adversely affect product quality or
process characteristics. The changes requiring revalidation should be defined in the validation
plan, and it may include following:
Changes in starting materials (including physical properties, such as density, viscosity or
particle size distribution that may affect the process or product)
Change of starting material manufacturer
Transfer of processes to a different site (including change of facilities and installations which
influence the process)
Changes of primary packaging material (e.g. substituting plastic for glass)
Changes in the manufacturing process (e.g. mixing times or drying temperatures)
Changes in the equipment (e.g. addition of automatic detection systems, installation of new
equipment, major revisions to machinery or apparatus and breakdowns);
Production area and support system changes (e.g. rearrangement of areas, or a new water
treatment method)
Appearance of negative quality trends
Appearance of new findings based on current knowledge, e.g. new technology
Support system changes.
Changes of equipment which involve the replacement of equipment on a like-for-like basis
would not normally require revalidation. For e.g. installation of a new centrifugal pump to
replace an older model would not necessarily require revalidation.
32


2.10.9 Change Control
Process capability design, testing and process qualification
Process capability can be defined as the study of critical parameters/operating variables that
influence process output and the range of data for each of the critical process parameters that will
result in acceptable process output. The objectives of process capability design and testing are:
A REVIEW ON PHARMACEUTICAL VALIDATION
37

Determination of number of critical parameters in a process that affect the quality of process
output and their relative importance,
To show that the generated numerical data for each critical parameter are within atleast
statistical quality control limits (i.e. 3standard deviations) and that there is no assignable
cause of variation in the process data.
Process qualification is the study of trials conducted to show that all systems/subsystems or unit
manufacturing operations perform as intended that all critical process parameters remain within
assigned control limits; and that such studies and trials are verifiable and certifiable through
documentation. Process qualification is also referred to as operational or performance
qualification. Such studies or trials form the basis of process capability design and testing.
33


2.11 Documentation
It is essential that the validation program is documented and is properly maintained. So a written
protocol should be established that specifies how qualification and validation will be conducted.
The protocol should be reviewed and approved. The protocol should specify critical steps and
acceptance criteria.
34
Each stage of the validation process should be fully documented, reviewed,
authorized and signed off. There should be a formal review of each stage of validation and
documented approval before proceeding to the next stage.
The reports should reflect the protocols followed and include atleast the title and objective of the
study; reference to the protocol; details of material, equipment, programmes and cycles used;
procedures and test methods. The results should be evaluated, analyzed and compared against the
pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations
and out-of-limit results should be investigated. If these deviations are accepted, this should be
justified and where necessary further studies should be performed. Usually, the department
responsible for the qualification and validation work should approve the completed work. And
the conclusion of the report should state whether or not the outcome of the qualification and/or
validation was considered successful. The quality assurance department approves the report after
the final review. The criteria for approval should be in accordance with the companys quality
assurance system. Any deviations found during the validation process should be acted upon and
documented as such and corrective actions be taken, where required.
35

A REVIEW ON PHARMACEUTICAL VALIDATION
38

Usually, a report that cross-references the qualification and/or validation protocol is prepared
summarizing the results obtained, commenting on any deviations observed, and drawing
necessary conclusions, including recommending changes necessary to correct deficiencies. For
e.g. in routine production, it is important to adequately record process details (e.g. time, speed,
temperature, & equipment used) and any changes which have record. A maintenance log is also
maintained, which is useful in performing failure investigations concerning a specific
manufacturing lot.
The document (i.e. validation report) on completion of the installation and operation
qualification consists of:
Validation plan and protocols.
User requirement and functional specifications.
Evidence of vendor qualification.
The IQ document (includes description of hardware and software).
Operating and maintenance manuals and SOPs for testing.
Qualification test reports with signatures and dates.
Summary of test results and a formal statement that the system has been accepted.
Approval of user, validation department and quality assurance.
36

The samples of check-lists for different qualifications are given below:












A REVIEW ON PHARMACEUTICAL VALIDATION
39

Installation Qualification (IQ)
Name of company: The White Horse Pharmaceuticals
Address: Raj-fulbaria, Savar, Dhaka.
Check list for installation Qualification for: HPLC
Qualification Protocol No:WHP: 002 Date:10-11-2013
Has the equipment been delivered according to
purchase order?

Yes

No
Has the equipment been checked for damage
(Equipment should be undamaged).

Yes


No
Has the required documentation been supplied? Is it
of correct issue and identified properly by model
number, serial number and date?

Yes

No.
Have details of all the services and utilities required
to operate equipment been provided?

Yes

No.
Have methods and instructions for maintenance been
provided along with spare parts and contact points for
service?

Yes

No.
Is the selected environment suitable for the
equipment? Have appropriate utilities (e.g. electricity,
gas, steam, water, etc.) been provided?

Yes

No.
Has information regarding health, safety and
environment in relation to the operation of the
equipment been provided?

Yes

No.










A REVIEW ON PHARMACEUTICAL VALIDATION
40








In case of OQ and PQ, qualification protocol has to be prepared which will include:
SOP for OQ and PQ
References to SOPs for:
o Calibration of measuring devices, if the equipment has them
o Operators training;
o Preventive maintenance;
o Cleaning and sanitization;
Formats for documentation and certification.
{Formats suggested below are based on WHO publication. A WHO guide to Good
Manufacturing Practice (GMP) requirements Part 2; Validation.}


Signature:
Name of the person:
Designation:
Date:
(On the behalf the company)

Signature:
Name of the person:
Designation:
Date:
(On the behalf of manufacturer of
equipment)
A REVIEW ON PHARMACEUTICAL VALIDATION
41

Operational Qualification (OQ)

Name and address of Company: The White Horse Pharmaceuticals
Validation Protocol No: WHP 006
Operational Qualification:
Name of Equipment /System: Mass Mixture
A. Materials, Equipments, Documents:
List of Calibration equipment required.
Materials and Supplies needed to perform OQ.
SOPs and Data Sheets for normal operation of equipment/System.
Records of training of operators.
Manuals for equipment.

B. Procedure:
Test and record calibration data for such instruments which need calibration.
Test and record operation conditions of control points and alarms (e.g. temp., rotation,
velocity, etc.).
Test and record output.
Measure and record the results of Challenge to the system in normal and worst case
situation where required.
Following:
o Record any deviations to the procedure, if made.
o Prepare a deviation report giving justification of acceptance of deviation and its
impact on operation.
o Report.
Prepare a report on OQ.
Submit to QA for review and approval.
37




A REVIEW ON PHARMACEUTICAL VALIDATION
42

Performance Qualification (PQ)

Name and Address of Company:
Validation Protocol No:
Performance Qualification:
A. Materials, Equipments, Documents:
List of Materials.
List of equipment.
List of SOPs
(SOPs which are specific to the performance tests including data sheets, charts predetermined
specifications and acceptance limits)
B. Procedure:
Equipments: Run three times employing normal procedure for each uses (configuration
or load) and records the data on data sheet. Also record deviation to the procedure, if
made.
System: Run for 20 consecutive working days and record data on datasheet. Also record
deviation to procedure, if made. (Prepare summary of the data).

C. Evaluation:
Perform required calculation and statistical analyses,
Compare the results with acceptance limits.
If there has been deviation to the procedure, prepare deviation report including
justification of acceptance and its impact on performance.
Prepare a PQ report.
Submit PQ document to QA for approval and review.
38

A REVIEW ON PHARMACEUTICAL VALIDATION
43

3. Areas of Validation

Manufacturing pharmaceutical products is a highly controlled process, whether the end product
is aseptic, terminally sterilized, lyophilized, or even an originating bulk ingredient. Therefore,
the environments in which the activities of manufacture are performed must be controlled and
through monitoring proven to be in control. In a pharmaceutical industry, several of its areas are
regularly validated as per the requirements. Such validation entails detailed measuring of various
physical parameters throughout the sterilization process and assessing and comparing these
results to relevant international standards. The list of areas of validation is as follows:

1. Process validation
2. Analytical method validation
3. Facilities validation
4. Computer system validation
5. Environmental validation
6. Equipment validation
a. HVAC validation
b. HPLC validation
7. Raw material or vendor validation
8. Cleaning validation
9. Cold chain validation
10. Personal validation

A REVIEW ON PHARMACEUTICAL VALIDATION
44

3.1 Process Validation
US FDA defines process validation as establishing documented evidence which provides a high
degree of assurance that a specified process will consistently produce a product meeting its pre-
determined specifications and quality characteristics.
In recent days, FDA modified the definition of process validation 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.
ICH defined process validation as the means of ensuring and providing documentary evidence
that processes within their specified design parameters that are capable of repeatedly and reliably
producing a finished product of the required quality.
WHO defined it as the documented act of proving that any procedure, process, equipment,
material, activity or system actually leads to expected results.
39

The term process validation should be reserved for the final stage(s) of the product/process
development sequence.














Process validation is assigned at the end of the sequence so that the specific exercise of process
validation should never be designed to fail. If the process validation assignment is failed, it is
Product design
Product characterization
Product selection (go formula)
Process design
Product optimization
Process characterization
Process optimization
Process demonstration
Process validation program
Product/process certification
A REVIEW ON PHARMACEUTICAL VALIDATION
45

considered that processs capability (what the process can and cannot do under a given set of
operational) is monitored incompletely.

3.1.1 Pilot Scale-Up and Process Validation
Before preparation of the first pilot-production batch following development activities are
performed.
1. Formulation design, selection, and optimization.
2. Preparation of the first pilot-laboratory batch.
3. Conduct initial accelerated stability testing.
4. If the formulation is deemed stable, preparation of additional pilot laboratory batches of the
drug product for expanded nonclinical and/or clinical use.
A. Laboratory Batch
It is the selection of a suitable preliminary formula for more critical study. It is a testing based on
certain agreed-upon initial design criteria, requirements, and/or specifications. The work is
performed in the development laboratory.

Batch Size:
usually 310 kg of a solid or semisolid
310 liters of a liquid
3000 to 10,000 units of a tablet or capsule.
B. Laboratory Pilot Batch
After passing the accelerated stability testing (e.g., 1 month at 45C or 3 months at 40C or
40C/80% RH), the next step in the scale-up process is the preparation of the (10 ) laboratory
pilot batch.
Batch Size:
30100 kg of a solid or semisolid
30100 liters of a liquid
30,000 to 100,000 units of a tablet or capsule.
The number and actual size of the laboratory pilot batches may vary in response to one or more
of the following factors:
1. Equipment availability
2. Active pharmaceutical ingredient (API)
A REVIEW ON PHARMACEUTICAL VALIDATION
46

3. Cost of raw materials
4. Inventory requirements for clinical and nonclinical studies.
C. Pilot Production
This phase may be carried out either as a shared responsibility between the development
laboratories and its appropriate manufacturing counterpart or as a process demonstration by a
separate, designated pilot-plant or process-development function.








Figure: Main piloting options (Top). Separate pilot plant functionsengineering concept.
(Bottom) Joint pilot operation.
It targeted to scale the product and process by another order of magnitude (e.g. 100 ) to change
batch size significantly for required additional validation studies.
The number of batches can depend on several factors including but not limited to:
1. The complexity of the process being validated;
2. The level of process variability; and
3. The amount of experimental data and/or process knowledge available on the specific process.

3.1.2 Priority Order in Process Validation
The following order of importance or priority with respect to validation is suggested:
A. Sterile Products and Their Processes:
1. Large-volume parenterals (LVPs)
2. Small-volume parenterals (SVPs)
3. Ophthalmics, other sterile products, and medical devices
B. Non-sterile Products and Their Processes:
1. Low-dose/high-potency tablets and capsules/transdermal delivery systems (TDDs)
Development
Laboratory
Pilot
Plant

Production
Development
Laboratory

Production
Pilot Batch
Request
Pilot Batch
Completion Report
A REVIEW ON PHARMACEUTICAL VALIDATION
47

2. Drugs with stability problems
3. Other tablets and capsules
4. Oral liquids, topicals, and diagnostic aids.

3.1.3 Stages of Process Validation
Process validation involves a series of activities taking place over the lifecycle of the product and
process. Process validation activities describes in three stages.

Stage 1 Process Design
It is the activity of defining the commercial manufacturing process that will be reflected in
planned master production and control records. At this stage, a process suitable for routine
commercial manufacturing that can consistently deliver a product that meets its quality attributes
is designed.
A. Building and Capturing Process Knowledge and Understanding
1. Design of Experiment (DOE) studies
o For justification of establishing ranges of incoming component quality,
equipment parameters, and in-process material quality attributes.
2. Revealing relationships of multivariate interactions, between the variable inputs (e.g.,
component characteristics or process parameters) and the resulting outputs (e.g., in-
process material, intermediates, or the final product).
3. Risk analysis tools to screen potential variables for DOE studies.
o To minimize the total number of experiments conducted while maximizing
knowledge gained.
4. Experiments or demonstrations at laboratory or pilot scale.
o To evaluate certain conditions and prediction of performance of the commercial
process.
o To provide information that can be used to model or simulate the commercial process.
5. Computer-based or virtual simulations of certain unit operations or dynamics.
o Provide process understanding.
o Help avoid problems at commercial scale.
A REVIEW ON PHARMACEUTICAL VALIDATION
48

6. Studding documentation procedure of activities and studies resulting in process
understanding
o Reflect the basis for decisions made about the process.
o E.g. variables studied for a unit operation and the rationale for those variables is
useful during the process qualification and continued process verification stages.
B. 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. To reduce and adjust input variation during
manufacturing is the objective of process control.
Recommendations:
1. Control both examination of material quality and equipment monitoring.
2. Control the process through operational limits and in-process.
When the product attribute is not readily measurable due to limitations of sampling or
detectability (e.g., viral clearance or microbial contamination).
When intermediates and products cannot be highly characterized and well-defined
quality attributes cannot be identified.
3. Timely analysis and control loops to adjust the processing conditions so that the output
remains constant.
4. Controls operational limits.
The planned commercial production and control records, which contain the operational limits
and overall strategy for process control, should be carried forward to the next stage for
confirmation.

Stage 2 Process Qualification
During this stage, the process design is evaluated to determine if it is capable of reproducible
commercial manufacture. For commercial distribution, successful completion of Stage 2 is
necessary.
40
Products manufactured during this stage, if acceptable, can be released for
distribution. This stage has 3 elements:
A. Design of a Facility and Qualification of Utilities and Equipment
Qualification of utilities and equipment generally includes the following activities:
1. Selecting utilities and equipment construction materials, operating principles.
A REVIEW ON PHARMACEUTICAL VALIDATION
49

2. 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.
3. 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
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.
B. Process Performance Qualification (PPQ)
It combines the actual facility, utilities and equipment (each now qualified). It also combines the
trained personnel with the commercial manufacturing process, control procedures, and
components to produce commercial batches.
Criteria:
1. PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process
performance.
2. The level of monitoring and testing should be sufficient to confirm uniform product quality
throughout the batch.
3. The increased level of scrutiny, testing, and sampling should continue through the process
verification stage as appropriate, to establish levels and frequency of routine sampling and
monitoring for the particular product and process.
C. PPQ Protocol
It is a written protocol that specifies the manufacturing conditions, controls, testing, and expected
outcomes is essential for this stage of process validation. Protocols discuss the following
elements:
1. The manufacturing conditions, including operating parameters, processing limits, and
component (raw material) inputs.
2. The data to be collected, when and how it will be evaluated.
A REVIEW ON PHARMACEUTICAL VALIDATION
50

3. Tests to be performed (in-process, release, characterization) and acceptance criteria for
each significant processing step.
4. The sampling plan, including sampling points, number of samples, and the frequency of
sampling for each unit operation and attribute.
5. Criteria and process performance indicators that allow for a science- and risk-based decision.
The criteria should include:

A description of the statistical methods to be used in analyzing all collected data (e.g.,
statistical metrics defining both intra-batch and inter-batch variability).
Provision for addressing deviations from expected conditions and handling of
nonconforming data.
6. Design of facilities and the qualification of utilities and equipment, personnel training and
qualification, and verification of material sources.
7. Status of the validation of analytical methods used in measuring the process, in-process
materials, and the product.
8. Review and approval of the protocol by appropriate departments and the quality unit.
D. PPQ Protocol Execution and Report
After review and approved by all appropriate departments, including the quality unit execution of
the PPQ, protocol should begin. If any deviations, it must be justified and approved by all
appropriate departments and the quality unit before implementation.
Criteria followed during PPQ Execution
1. The commercial manufacturing process and routine procedures must be followed during PPQ
protocol execution.
2. The PPQ lots should be manufactured under normal conditions by the personnel routinely
expected to perform each step of each unit operation in the process.
Normal operating conditions include
the utility systems (e.g., air handling and water purification)
material
personnel
environment
manufacturing

A REVIEW ON PHARMACEUTICAL VALIDATION
51

Report
A report should be prepared in a timely manner after the completion. This report should:
1. Discuss and cross-reference all aspects of the protocol.
2. Summarize data collected and analyze the data, as specified by the protocol.
3. Evaluate any unexpected observations and additional data not specified in the protocol.
4. Describe in sufficient detail any corrective actions or changes that should be made to
existing procedures and controls.

Stage 3 Continued Process Verification
At this stage, it is assured that the process remains in a state of control (the validated state)
during commercial manufacture and the unplanned departures from the process is designed. In
this phase, undesired process variability is detected and evaluated which identifies problems and
determines whether action must be taken to correct, anticipate, and prevent problems to control
process.
41

Recommendations:
1. Procedures should describe how trending and calculations are to be performed and should
guard against overreaction, and failure to detect unintended process variability.
2. Production data should be collected to evaluate process stability and capability. The quality unit
should review this information.
42

3. The data should be statistically trended and reviewed by trained personnel.
A statistician develop :
The data collection plan and statistical methods
Procedures used in measuring and evaluating process stability and process
capability.
43

4. The quality units meet periodically with production staff to evaluate data, discuss possible trends
or undesirable process variation, and coordinate any correction or follow-up actions by
production.
44

5. The equipment and facility qualification data should be assessed periodically to determine
whether re-qualification should be performed.
6. Once established, qualification status must be maintained through routine monitoring,
maintenance, and calibration procedures and schedules.
A REVIEW ON PHARMACEUTICAL VALIDATION
52

3.1.4 Types of process validation
3.1.4.1 Prospective process validation
It is defined as the established documented evidence that a system does what it purports to do
based on a preplanned protocol. Its objective is to prove or demonstrate that the process will
work in accordance with validation protocol prepared for the pilot production trials.
Prospective validation requires a planned program and organization to carry it to successful
completion. The organization must have clearly defined areas of responsibility and authority for
each of the groups involved in the program. In this type, structure must be tailored to meet the
requirements and an effective project management structure will have to be established.
Master Documentation:
An effective prospective validation program must be supported by documentation extending
from product initiation to full-scale production. The master documentation file should contain all
information that was generated during the entire product development sequence to a validation
process.
Product Development
It begins when an active chemical entity shows the necessary attributes for a commercial
product. This activities form the foundation upon which the subsequent validation data are built.
This can sub-divide into formulation and process development, along with scale-up
development.
A. Formulation Development
It provides the basic information on the active chemical, the formula, and the impact of raw
materials or excipients on the product.
1. Preformulation profile or characterization of the components of the formula.
2. Formulation profile, which consists of physical and chemical characteristics required for
the products, drug-excipient compatibility studies, and the effect of formulation on in
vitro dissolution.
3. Effect of formulation variables on the bioavailability of the product.
4. Specific test methods.
5. Key product attributes and/or specifications.
6. Optimum formulation.
7. Development of cleaning procedures and test methods.
A REVIEW ON PHARMACEUTICAL VALIDATION
53

B. Process Development
They may occur after the formulation has been developed simultaneously. Major activities occur
either in the pilot plant or in the proposed manufacturing plant. It should have following
objectives:
1. Develop a suitable process to produce a product that meets all product specifications,
economic constraints and cGMPs.
2. Identify the key process parameters that affect the product attributes.
3. Identify in-process specifications and test methods.
4. Identify generic and/or specific equipment that may be required.
Cleaning procedures should at least be in the final stages of development.
Process development can be divided into several stages.
a. Design: It includes following -
1. Prepare flow diagram.
2. Prepare influence matrix.
3. Establish experimental procedure.
4. Establish design criteria.
5. Prepare study plan and protocols.
b. Challenging of critical process parameters:
1. Identify critical variables for unit and overall operation.
2. Establish maximum tolerance for process variables.
These studies determine:
The feasibility of the designed process.
The criticality of the parameters.
c. Process characterization:
1. Modify study plan and protocols.
2. Establish nominal values for critical values.
3. Establish tolerances for critical variables.
The objectives of these studies are -
1. Confirm critical process parameters and determine their effects on product quality attributes.
2. Establish process conditions for each unit operation.
3. Determine in-process operating limits to guarantee acceptable finished product and yield.
A REVIEW ON PHARMACEUTICAL VALIDATION
54

4. Confirm the validity of the test methods.
d. Process Verification:
1. Modify study plan and protocols
2. Determine product variability under constant processing conditions
3. Prepare process transfer documents
4. Finalize product specification
e. Development Documentation:
The developmental document to support the validation of the process may contain the following:
Process challenging and characterization reports
Development batch record
Raw material test methods and specifications
Equipment list and qualification and calibration status
Process flow diagram
Process variable tolerances
Operating instructions for equipment (where necessary)
In-process quality control program
Critical unit operation
Final product specifications
Special production facility requirements
Cleaning Procedure for equipment and facilities
Test methods
Stability profile of the product
Produced during process development
Primary packaging specification
Development of Manufacturing Capability
There must be a suitable production facility for every manufacturing process that is
developed. This facility includes buildings, equipment, staff, and supporting functions.
Full-Scale Product/Process Development
The development of the final full-scale production process proceeds through the following steps:
a. Process scale-up studies
A REVIEW ON PHARMACEUTICAL VALIDATION
55

Careful planning and implementation requires during transition of successful pilot-scale process
or research scale to a full-scale process.
b. Qualification Trials
After completing scale-up studies it may be necessary to manufacture one or more batches at full
scale to confirm that the entire manufacturing process can be carried out smoothly. This may
occur prior to or after the regulatory submission, depending on the strategy used in filing.
c. Process Validation Runs
After completing the qualification trials, the protocol for the full-scale process validation runs
can be written. Current industry standard for the validation batches is manufactured for both
process parameters and specifications.
FDA has determined that the minimum number of validation batches should be three.

Master Product Document
An extensive quantity of documents is generated at each stage of the development and validation
of the final production process. Some of these documents will be directly related to the
manufacture of the final products.
The documents that are required for manufacturing the product then become the master product
document. Items that will normally be included in the master product document are-
1. Batch manufacturing record
2. Master formulation
3. Process flow diagram
4. Master manufacturing instructions
5. Master packaging instructions
6. Specifications
7. Sampling (location and frequency)
8. Test methods
9. Process validation data
Defining Experimental Programs
Its purpose is to examine experiments or combinations of related experiments for developing
justification of formulation. Topics to be discussed include -
1. Defining program scope
A REVIEW ON PHARMACEUTICAL VALIDATION
56

The definition of specific experimental objectives can be a continuing activity throughout
product development.
The effect and impact of time, resources, and budget should be incorporated into the
experimental program to avoid critical program objectives.
2. Process summary
Flow Diagram

Provide a focal point of early program planning activities.
Provides a convenient basis on which list of variables and responses is developed.
Variables and Responses
Once properly identified, the list of variables and responses for the process is not
likely to change appreciably.
Cause-and-Effect Diagram
Principle factors of each process step that can cause or influence the effect are drawn
as sub branches of each branch, until a complete cause-and-effect diagram is
developed.
























Figure 3: Cause-and-effect diagram (granulated product).
A REVIEW ON PHARMACEUTICAL VALIDATION
57

3. Experimental design and analysis
Many different experimental designs and analysis methods can be used in development
activities. In general, designs that are usable offer different levels of efficiency, complexity,
and effectiveness in achieving experimental objectives.
4. Experiment documentation
5. Program organization

3.1.4.2 Concurrent Validation
It is a process where current production batches are used to monitor processing parameters. It
gives assurance of the present batch being studied, and offers limited assurance regarding
consistency of quality from batch to batch.
43
Concurrent Validation may be the practical approach under certain circumstances. Examples of
these may be when:
1. A previous validated process is being transferred to a third party contract manufacturer or to
another site.
2. The product is a different strength of a previously validated product with the same ratio of
active/inactive ingredients.
3. The numbers of lots evaluated under the Retrospective Validation were not sufficient to
obtain a high degree of assurance demonstrating that the process is fully under control.
4. The numbers of batches produced are limited.
5. Process with low production volume per batch and market demand.
6. Process of manufacturing urgently needed drug due to shortage or absence of supply.
In all above cases, concurrent validation is valid, provided following conditions are
appropriately.
1. Pre-approved protocol for concurrent validation with rational
2. A deviation shall be raised with justification and shall be approved by plant head /head
process owner/Head-QMS.
3. Product behavior and history shall be reviewed based on developmental/scale up /test
batches.
4. A detailed procedure shall be planned for handling of the marketed product if any adverse
reactions observed in concurrent validation process.
A REVIEW ON PHARMACEUTICAL VALIDATION
58

5. Concurrent validation batches shall be compiled in interim report and shall be approved all
key disciplines.
44


3.1.4.3 Retrospective Validation
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.
45

Some of the essential elements for Retrospective Validation are:
1. Batches manufactured for a defined period (minimum of 10 last consecutive batches).
2. Number of lots released per year.
3. Batch size/strength/manufacturer/year/period.
4. Master manufacturing/packaging documents.
5. List of process deviations, corrective actions and changes to manufacturing documents.
6. Data for stability testing for several batches.
7. Trend analysis including those for quality related complaints.

3.1.4.4 Process 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.
45
Re-Validation becomes necessary in certain situations. The following are examples of some of
the planned or unplanned change that may require re-validation:
1. Changes in raw materials (physical properties such as density, viscosity, particle size
distribution, and moisture, etc., that may affect the process or product).
2. Changes in the source of active raw material manufacturer.
3. Changes in packaging material (primary container/closure system).
A REVIEW ON PHARMACEUTICAL VALIDATION
59

4. Changes in the process (e.g., mixing time, drying temperatures and batch size).
5. Changes in the equipment (e.g. addition of automatic detection system).
6. Changes of equipment which involve the replacement of equipment on a like for like basis
would not normally require a revalidation except that this new equipment
Must be qualified.
Changes in the plant/facility.
Variations revealed by trend analysis (e.g. process drifts).
46


3.1.5 Process Validation Decision
45

a) Process Validation Decision Tree for change in process controls of manufacturing process of
drug products:





A REVIEW ON PHARMACEUTICAL VALIDATION
60

b) Process Validation Decision Tree for Change in Manufacturing Site of Drug Product:




c) Process Validation Decision Tree for Change in Batch size of drug Product:







d) Process Validation Decision Tree for Change in Equipment:












A REVIEW ON PHARMACEUTICAL VALIDATION
61

e) Process Validation Decision Tree for Change in Source of Active Pharmaceutical Ingredients
(API).












f) Process Validation Decision Tree for Change in Source of Excipient














A REVIEW ON PHARMACEUTICAL VALIDATION
62

3.1.6 Sterilization Validation
Sterilization processes require periodic validation to demonstrate that they are working correctly
and functioning within established norms. Such validation entails detailed measuring of various
physical parameters throughout the sterilization process and assessing and comparing these
results to relevant international standards.
The production of sterile preparations should be carried out in clean areas, entry to which should
be through airlocks for personnel and/or for equipment and materials. Clean areas should be
maintained to an appropriate standard of cleanliness and supplied with air that has passed
through filters of the required efficiency.
Manufacturing operations are divided here into two categories
a. Those where the product is terminally sterilized,
b. Those which are conducted aseptically at some or all stages.

3.1.6.1 Requirement of validation
Sterile Preparations refers to the intent of preventing harm and fatality to patients that could arise
from microbial contamination or excessive bacterial end toxins. But during manufacturing and
compounding, there is risk of microbial contamination despite of all the precautions taken in the
pharmaceuticals. Some sources of microbial contamination in aseptic processing area are as
follows
46
:
Personnel borne contaminants
Human error
Non-routine operations during aseptic process
Assembly of sterile equipment prior to use
Mechanical failure
Inadequate or improper sanitation
Transfer of materials within APA
Routine operations during aseptic process
Airborne contaminants
Surface contaminants
Failure of sterilizing filter
Failure of HEPA filter
A REVIEW ON PHARMACEUTICAL VALIDATION
63

Inadequate or improper sterilization.

3.1.6.2 Principles of validation of sterilization processes
1. The process equipment has the capability of operating under a controllable set of conditions.
These conditions depend on the sterilizing agent used.
2. The control equipment can operate within the limits needed to ensure reproducibility and
accuracy of the parameters of the sterilization equipment.
3. Replicate sterilization cycles are used to test the operational ranges of the equipment and the
impact on the probability of survival of micro-organisms.
4. Validated process will have to be monitored during routine operation and also needs to be
requalified at periodical intervals.
5. Sterilization cycles are developed then validated with the help of biological indicators (BIs)
specific for the sterilizing agent that is used.
6. Document and archive data from all the steps above in a retrievable fashion.

3.1.6.3 Clean room Certification
47
:
The certification state of the clean room must be determined in advance of testing; three states
exist within the manufacturing facility, such as:
As Built: A completed room with all services connected and functional, but without
production equipment or personnel within the facility.
At Rest: A room where all the services are connected, all the equipment is installed and
operating to an agreed manner, but no personnel are present.
Operational: All equipments are installed and are functioning to an agreed format, and a
specified number of personnel are present working to an agreed procedure.

3.1.6.4 Manufacture of sterile preparations
48

For the manufacture of sterile pharmaceutical preparations, four grades are distinguished here, as
follows:
Grade A: The local zone for high-risk operations, e.g. filling and making aseptic connections.
Normally such conditions are provided by a laminar-airflow workstation. Laminar-airflow
A REVIEW ON PHARMACEUTICAL VALIDATION
64

systems should provide a homogeneous air speed of approximately 0.45m/s 20% (guidance
value) at the working position.
Grade B: In aseptic preparation and filling, the background environment for the grade A zone.
Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile
products
To obtain air of the required characteristics, methods specified by national authorities should be
used. In order to reach the B, C and D grades, the number of air changes should be appropriate
for the size of the room and the equipment and personnel present in it. At least 20 air changes per
hour are usually required for a room with a good airflow pattern and appropriate high-efficiency
particulate air (HEPA) filters.

3.1.6.5 How to validate
The sterility test applied to the finished product should be regarded as the last step of control
measures by which sterility is assured. The test should be validated for all the products.
The sterility of the finished product is assured by the validation of the sterilization cycle in the
case of terminally sterilized products, and by media simulation or media fill runs for
aseptically processed products. Batch-processing records and, in the case of aseptic processing,
environmental quality records, should be examined in conjunction with the results of the sterility
tests.
For injectable products the water for injection and the intermediate, if appropriate, and finished
products should be monitored for endotoxins, using an established pharmacopoeial method that
has been validated for each type of product.
For large-volume infusion solutions, such monitoring of water or intermediates should always be
done, in addition to any tests required by an approved monograph for the finished product.
When a sample fails a test, the cause of the failure should be investigated and necessary action
should be taken.

3.1.6.6 Process Simulation Test
It uses a nutrient medium (media fill). Selection of the nutrient medium is made based on dosage
form of the product and selectivity, clarity, concentration and suitability for sterilization of the
nutrient medium. It is performed by running three consecutive satisfactory simulation tests.
A REVIEW ON PHARMACEUTICAL VALIDATION
65

These tests should be repeated at defined intervals and after any significant modification to the
heating, ventilation and air-conditioning (HVAC) system, equipment or process. It should
incorporate activities and interventions known to occur during normal production as well as the
worst-case situation. The process simulation tests should be representative of each shift and shift
changeover to address any time-related and operational features.
The number of containers used for media fills should be sufficient to enable a valid evaluation.
For small batches, the number of containers for media fills should at least equal the size of the
product batch. The target should be zero growth and the following should be applied:
When filling fewer than 5000 units, no contaminated units should be detected.
When filling 5000 10000 units,
o One contaminated unit should result in an investigation, including consideration of a
repeat media fill;
o Two contaminated units are considered cause for revalidation following investigation;
When filling more than 10000 units:
o One contaminated unit should result in an investigation;
o Two contaminated units are considered cause for revalidation following investigation.

All sterilization process should be validated. Before choosing/adopting the sterilization process,
its suitability for the product and its efficacy to achieve desired sterilized conditions should be
demonstrated by physical measurements and by biological indicators, where appropriate. The
validity should be verified at scheduled intervals, at least annually, and whenever significant
modifications have been made. Records should be kept of all results.

A REVIEW ON PHARMACEUTICAL VALIDATION
66

3.2 Analytical method validation
Analytical method validation is the process to confirm that the analytical procedure employed for
a specific test is suitable for its intended use.
49
It is the process of proving that an analytical
method is acceptable for its intended purposes.
METHOD VALIDATION = ERROR ASSESSMENT
ISO defines method validation as confirmation by examination and provision of evidences that
the particular requirements for a specified intended use are fulfilled.
For pharmaceutical world, the meaning of analytical methods validation is the process to confirm
that a method does what it purports to do, that is, to document through laboratory studies that the
measurement procedure can reliably assess the identity, strength, and/or quality of a bulk drug
substance, excipient or finished product. It should follow a life cycle approach (Figure below).
Following this approach, validation activities should be performed and completed prior to release
of Phase I clinical material and continually be updated, as needed, throughout product
development, culminating in the validation for regulatory filing for licensing.

















Figure 3: Schematic of test
method life cycle
A REVIEW ON PHARMACEUTICAL VALIDATION
67

3.2.1 Why analytical methods need to be validated?
Methods need to be validated or revalidated as follows:
1. Before their introduction into routine use.
2. Whenever the conditions change for which the method has been validated (e.g., instrument
with different characteristics).
3. Whenever the method is changed, and the change is outside the original scope of the method.
4. When quality control indicates an established method is changing with time.
5. In order to demonstrate the equivalence between two methods (e.g., a new method and a
standard).

3.2.2 Types of analytical procedures to be validated
Discussion of the validation of analytical procedures is directed to the four most common types
of analytical procedures:
1. Identification tests
Intended to ensure the identity of an analyte in a sample.
Normally achieved by comparison of a property of the sample (e.g., spectrum,
chromatographic behavior, chemical reactivity, etc.) to that of a reference standard
2. Quantitative tests for impurities content

3. Limit tests for the control of impurities
Either a quantitative test or a limit test for the impurity in a sample.
Quantitative test or a limit test are Intended to accurately reflect the purity
characteristics of the sample.
4. Quantitative tests of the active moiety in samples of drug substance or drug product or
other selected component(s) in the drug product
3.2.3 Advantages of analytical method validation
1. It builds a degree of confidence, not only for the developer but also to the user.
2. It results inexpensive, eliminates frustrating repetitions and leads to better time management
in the end.
3. Method validation absorbs the shock of changes in the conditions such as reagent supplier or
grade, analytical setup.
A REVIEW ON PHARMACEUTICAL VALIDATION
68

3.2.3 Strategy for validation of methods
The validity of a specific method should be demonstrated in laboratory experiments using
samples or standards that are similar to the unknown samples analyzed in the routine. The
preparation and execution should follow a validation protocol, preferably written in a step by
step instruction format.
Possible steps for a complete method validation are listed below:




















3.2.4 Analytical procedure
The analytical procedure refers to the way of performing the analysis. It should describe in detail
the steps necessary to perform each analytical test. This may include but is not limited to: the
sample, the reference standard and the reagents preparations, use of the apparatus, generation of
the calibration curve, use of the formulae for the calculation, etc.
Develop a validation protocol or operating procedure for the validation

Define the application, purpose and scope of the method

Define the performance parameters and acceptance criteria
Define validation experiments
Verify relevant performance characteristics of equipment
Qualify materials, e.g. standards and reagents
Perform prevalidation experiments
Adjust method parameters or/and acceptance criteria if necessary
Perform full internal (and external) validation experiments
Develop SOPs (standard operating procedures) for executing the method in the routine
Define criteria for revalidation
Define type and frequency of system suitability tests and/or analytical quality control
(AQC) checks for the routine
Document validation experiments and results in the validation
A REVIEW ON PHARMACEUTICAL VALIDATION
69

3.2.4.1 Assay Characteristics/parameters to be validated
The table below shows the validation parameters required for different types of methods per ICH
Q2A and Q2B for commercial validation


3.2.5 Validation Parameters
A. Specificity
Specificity is the ability to assess unequivocally the analyte in the presence of components which
may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
Lack of specificity of an individual analytical procedure may be compensated by other
supporting analytical procedure(s). This definition has the following implications:
Identification: to ensure the identity of an analyte.
Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement
of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual
solvents content, etc.
Assay (content or potency):
To provide an exact result that allows an accurate statement on the content or potency of an
analyte in a sample.
B. Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the value
which is accepted either as a conventional true value or an accepted reference value and the
A REVIEW ON PHARMACEUTICAL VALIDATION
70

value found.
50
The accuracy of an analytical procedure is the closeness of test results obtained by
that procedure to the true value.
51

Methods:
1. Analyzing a sample of known concentration of well characterized (e.g., reference standard)
and comparing the measured value to the true value.
2. Spiked placebo (product matrix) recovery method: A known amount of pure active
constituent is added to formulation blank [sample that contains all other ingredients except
the active(s)], the resulting mixture is assayed and the results obtained are compared with the
expected result.
3. Standard addition method
49
:








Recommended Data:
Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3
concentration levels covering the specified range (e.g., 3 concentrations/3 replicates each of the
total analytical procedure).
48

Calculation:
Accuracy is calculated as the percentage of recovery by the assay of the known added amount of
analyte in the sample, or as the difference between the mean and the accepted true value,
together with confidence intervals.
Assessment:
It can be accomplished in a variety of ways such as
1. Evaluating the recovery of the analyte (percent recovery) across the range of the assay.
2. Evaluating the linearity of the relationship between estimated and actual concentrations.
A sample is assayed
A known amount of pure active constituent is added
Sample is again assayed
The difference between the results of
The two assays is compared with the expected answer

A REVIEW ON PHARMACEUTICAL VALIDATION
71

The confidence interval for the slope be contained in an interval around 1.0, or alternatively, that
the slope be close to 1.0.
49

C. Precision
Precision expresses the closeness of agreement (degree of scatter) between a series of
measurements obtained from multiple sampling of the same homogeneous sample under the
prescribed conditions.
48
It is the degree of agreement among individual test results when the
procedure is applied repeatedly to multiple samplings of a homogeneous sample.
52

Precision should be investigated using homogeneous, authentic samples. If not possible to obtain
a homogeneous sample, it may be investigated using artificially prepared samples or a sample
solution.
The precision of an analytical procedure is usually expressed as the variance, standard deviation
or coefficient of variation of a series of measurements.
Precision may be considered at three levels: repeatability, intermediate precision and
reproducibility.
1. Repeatability
Repeatability expresses the precision under the same operating conditions over a short interval of
time. Repeatability is also termed intra-assay precision.
48
It involves analysis of replicates by the
analyst using the same equipment and method and conducting the precision study over short
period of time.
Repeatability should be assessed using a minimum of 9 determinations covering the specified
range for the procedure (e.g., 3 concentrations/3 replicates each); or a minimum of 6
determinations at 100% of the test concentration.
The RSD(relative standard deviation) values are important for showing degree of variation.
RSD below 1% for built drugs
RSD below 2% for assays in finished product.
2. Intermediate precision
Intermediate precision expresses within-laboratories variations: different days, different analysts,
different equipment, etc.
Effects of random events on the precision of the analytical procedure should be studied
Typical variations to be studied include days, analysts, equipment, etc.
The use of an experimental design (matrix) is encouraged.
A REVIEW ON PHARMACEUTICAL VALIDATION
72

3. Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually
applied to standardization of methodology).
48

It involves precision study at different occasions, different laboratories and different
batch of reagent, different analysts and different equipment.
49

Reproducibility is assessed by means of an inter-laboratory trial (by different analysts, by
the use of different equipment, or by carrying out the analysis at different times).
48

D. Limit of Detection
The Limit of Detection is the lowest amount of analyte in a sample which can be detected but not
necessarily quantitated as an exact value. It is a limit that specifies whether or not an analyte is
above or below certain value.
48
The Limit of Detection is usually expressed as the concentration
of analyte (e.g., percentage, parts per billion) in the sample.
There are two methods of determining the limit of detection. They are as follow:
1. Non instrumental procedures
The detection limit is generally determined by -
a. The analysis of samples with known concentrations of analyte
b. Establishing the minimum level at which the analyte can be reliably detected.
2. Instrumental procedures
In this method, measured signals from samples with known low concentrations of analyte are
compared with those of blank samples. The minimum concentration at which the analyte can
reliably be detected is established. Typically acceptable signal-to-noise ratios are 2:1 or 3:1. The
signalto noise ratio is determined by dividing the base peak by the standard deviation of all data
points below a set threshold.
Calculation:
Limit of detection is calculated by taking the concentration of the peak of interest divided by
three times the signaltonoise ratio.
49

E. Limit of Quantitation.
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a
sample which can be quantitatively determined with suitable precision and accuracy. The
quantitation limit is a parameter of quantitative assays for low levels of compounds in sample
matrices, and is used particularly for the determination of impurities and/or degradation products.
A REVIEW ON PHARMACEUTICAL VALIDATION
73

It is determined by analyzing samples containing known quantities of the analyte and
determining the lowest level at which acceptable degrees of accuracy and precision are
attainable. In the case where final assessment is based on an instrumental reading, it is
determined from the magnitude of background response by analyzing a number of blank samples
and calculating the standard deviation of this response.
The standard deviation multiplied by a factor (usually 10) provides an estimate of the limit of
quantitation. In many cases, the limit of quantitation is approximately twice the limit of
detection.
F. Linearity
The linearity of an analytical procedure is its ability (within a given range) to obtain test results
which are directly proportional to the concentration (amount) of analyte in the sample.
48
Thus
linearity refers to the linearity of the relationship of concentration and assay measurement.
Linearity should be established across the range of the analytical procedure.
1. It should be established initially by visual examination of a plot of signals as a function of
analyte concentration of content.
2. If there appears to be a linear relationship, test results should be established by appropriate
statistical methods (e.g., by calculation of a regression line by the method of least squares).
3. Data obtained from the regression line itself may be helpful to provide mathematical
estimates of the degree of linearity.
49

For the establishment of linearity, a minimum of 5 concentrations is recommended.
48

The working sample concentration and samples tested for accuracy should be in the linear range.
Data is processed by linear least square regression declaring the regression coefficient and b of
the linear equation, y = ax + b together with the correlation coefficient of determination r. For
the method to be linear the r value should be close to 1.
49
G. Range
The range of an analytical procedure is the interval between the upper and lower concentration
(amounts) of analyte in the sample (including these concentrations) for which it has been
demonstrated that the analytical procedure has a suitable level of precision, accuracy and
linearity.
The following minimum specified ranges should be considered:
A REVIEW ON PHARMACEUTICAL VALIDATION
74

1. For the assay of a drug substance or a finished (drug) product: normally from 80 to 120
percent of the test concentration;
2. For content uniformity: covering a minimum of 70 to 130 percent of the test concentration,
unless a wider more appropriate range, based on the nature of the dosage form (e.g., metered
dose inhalers), is justified.
3. For dissolution testing: +/-20 % over the specified range. e.g., if the specifications for a
controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours,
the validated range would be 0-110% of the label claim.
4. For the determination of an impurity: Impurity must be within 1 120% of the
specification. For impurities known to be unusually potent or to produce toxic or unexpected
pharmacological effects, the detection/quantitation limit should be commensurate with the
level at which the impurities must be controlled;
5. If assay and purity are performed together as one test and only a 100% standard is used,
linearity should cover the range from the reporting level of the impurities1 to 120% of the
assay specification.
H. Robustness
It is a measure of its capacity to remain unaffected by small, but deliberate variations in method
parameters and provides an indication of its reliability during normal usage.
48
The robustness of
a method is evaluated by varying method parameters such as percent organic solvent, pH, ionic
strength, temperature and determine the effect (if any) on the results of the method.
53

The evaluation of robustness should be considered during the development phase and depends on
the type of procedure under study. If measurements are susceptible to variations in analytical
conditions, the analytical conditions should be suitably controlled or a precautionary statement
should be included in the procedure. Examples of typical variations are:
Stability of analytical solutions;
Extraction time.
In the case of liquid chromatography, examples of typical variations are:
influence of variations of pH in a mobile phase;
influence of variations in mobile phase composition;
different columns (different lots and/or suppliers);
temperature;
A REVIEW ON PHARMACEUTICAL VALIDATION
75

flow rate.
In the case of gas-chromatography, examples of typical variations are:
different columns (different lots and/or suppliers);
temperature;
flow rate.
48

I. Ruggedness.
The ruggedness of an analytical method is the degree of reproducibility of test results obtained
by the analysis of the same samples under a variety of normal test conditions such as different
laboratories, different analysts, using operational and environmental conditions that may differ
but are still within the specified parameters of the assay.
It is normally suggested when the method is to be used in more than one laboratory.
Normally expressed as the lack of the influence on the test results of operational and
environmental variables of the analytical method.
For the determination of ruggedness, the degree of reproducibility of test result is determined as
function of the assay variable. This reproducibility may be compared to the precision of the assay
under normal condition to obtain a measure of the ruggedness of then analytical method.
51

J. Stability and system suitability tests.
Stability of the sample, standard and reagents is required for a reasonable time to generate
reproducible and reliable results. For example, 24 h stability is desired for solutions and reagents
that need to be prepared for each analysis.
System suitability test provide the added assurance that on a specific occasion the method is
giving, accurate and precise results. System suitability test are run every time a method is used
either before or during analysis.
The results of each system suitability test are compared with defined acceptance criteria and if
they pass, the method is deemed satisfactory on that occasion. The nature of the test and the
acceptance criteria will be based upon data generated during method development optimization
and validation experiments.
Document of system suitability can be accomplished by using software specifically designed for
the task to provide a review of method development and to summarize the data regarding
reproducibility.
54


A REVIEW ON PHARMACEUTICAL VALIDATION
76

3.2.6 Data Elements Required for Validation
There are various analytical methods used for the examination of pharmaceutical materials.
Here only the most common categories of tests for which validation data should be required is
described. These categories are as follows:
Category I Analytical procedures for quantitation of major components of bulk drug
substances or active ingredients (including preservatives) in finished pharmaceutical products.
Category II Analytical procedures for determination of impurities in bulk drug substances or
degradation compounds in finished pharmaceutical products. These procedures include
quantitative assays and limit tests.
Category III Analytical procedures for determination of performance characteristics. (e.g.
Dissolution, drug release).
Category IV Identification tests.
For each category, different analytical information is needed. Listed in table below are data
elements that are normally required for each of these categories.
Analytical
Performance
Characteristics
Assay
category I
Assay
category II
Assay
category III
Assay
category
IV
Quantitative
tests
Limit
Tests
Accuracy Yes Yes * * No
Precision Yes Yes No Yes No
Specificity Yes Yes Yes * Yes
Detection Limit No No Yes * No
Quantitation
Limit
No Yes No * No
Linearity Yes Yes No * No
Range Yes Yes * * No


Where, * indicates that may be required depending on the nature of the specific test.
Table 4: Characteristics required for assay validation as per USP

A REVIEW ON PHARMACEUTICAL VALIDATION
77

3.3 Facilities Validation
The design, construction, and commissioning of a new facility for the pharmaceutical industry is
a complex process that involves the interaction of a wide variety of engineering, process and QA,
and control disciplines and may proceed through a series of different phases from a conceptual,
feasibility study, through to the final detailed design, construction, commissioning, and final site
validation activities.
The consequence of this for the facility designer is that he or she must use design and
engineering methods that will comply with and demonstrate that the facility, when complete,
does meet the requirements of cGMP.
55

The key basis to successfully qualify a facility is to plan the qualification from the earliest stage
of the facility design by the development of a clear validation strategy that will develop into a
plan for validation throughout the project.
3.3.1 The Engineering Design Process for a Facility
The engineering design process typically follows a series of phases:
Conceptual design
Design development, front-end design or basic/preliminary engineering
Detailed engineering
Procurement
Construction
Pre commissioning
Commissioning
Each of these phases has its own engineering objectives and consequently, the qualification
requirements have both a different scope and extent at each phase. The concepts for qualification
will be described for each phase.

3.3.2 Conceptual Design:
Production of clinical trial material will have moved from laboratory facilities to pilot-scale
operations. Experience gained at this pilot-scale production will normally give sufficient
information to enable a process definition to be prepared. The marketing organization will also
have some early projections for demand levels and the type of formulations that will be required.
These key elements will give a basis for a conceptual design study.
A REVIEW ON PHARMACEUTICAL VALIDATION
78

The collection of process data for subsequent full-scale PV will also already have begun. Clearly,
the current regulatory bodies emphasis on proof of drug equivalence, i.e., final production
batches must be equivalent in biological and chemical activity to those used in the clinical trial
and any subsequent submissions (typically for the NDA) will already have some significant
effect on the manufacturing route, engineering design, and equipment selection.
The conceptual study must consider all these aspects and incorporate their requirements into this
early design. Consequently a plan is required to ensure that GMP, qualification, and process
requirements are incorporated.

3.3.3 Purposes:
The main purposes of a conceptual study are as follows:
1. An agreed basis for the design philosophy to be able to proceed to the next phase of
development.
2. To provide an initial capital cost estimate, usually for a preliminary budget sanction by senior
management.
3. The typical deliverables of this phase are as follows:
Statement of basis of design
GMP statement
Process block flow diagrams or schematics
Major equipment item list
Conceptual layout and accommodation schedule
Building and HVAC philosophy
Outline of utility systems
Outline of control philosophy
Safety considerations
Budget estimate
Usually, the conceptual study is run as a mixed disciplinary team bringing together research and
development, production, and engineering disciplines led by a study manager. Although QA
does not have a major role to play at this stage, it is important that the team has access to
appropriate personnel.

A REVIEW ON PHARMACEUTICAL VALIDATION
79

3.3.4 Qualification Activities
At this stage, the qualification of the facility is in its earliest phase and the emphasis must be on
the qualification of the design. This can be completed by reviews of the proposed design against
defined user requirements criteria. The preliminary nature of the study limits the depth of review.
It should address critical issues against the user specification and the GMP requirements.

3.3.5 Qualification Cost
Clearly if the conceptual phase is to provide a cost estimate for the project, then the qualification
must be similarly estimated at this stage. Some form of qualification statement and policy is
required to at least determine its future scope. Some may prefer to develop a very preliminary
facility and equipment. The decision of which route to take may be determined by the extent of
the study and company policy.
Without significant details of the facility and its contents, specific costs for the key qualification
tasks cannot be easily determined unless access to similar projects costs is available. At this
stage, it is probably more normal to make an allowance based on in-house or the design
engineers experience. It is important to have an estimate that reflects that of the study.

3.3.6 Design Development:
Usually, by this phase of the project, the pharmaceutical company believes that it is highly
probable that the project will precede subject perhaps to certain restrictions, usually based on
schedule and total final cost.
39

The answers of the following questions have significant bearing on the route adopted towards
design development:
Should this phase be done in house?
Involve an external design construction consultancy?
An Engineering Management Contractor?
Can the designer meet and demonstrate that the design complies with GMP?
Are you going to use a single engineering organization to manage the project through design,
procurement, construction, commissioning, and qualification?
Are the systems in place to aid qualification?
A REVIEW ON PHARMACEUTICAL VALIDATION
80

3.3.6.1 Purposes
The main objectives of this design development phase are as follows:
1. To establish a basis for detailed design.
2. To progress the design to establish the technical, capability, and safety aspects of the project.
3. To provide the necessary design data to evaluate subsequently and comply with the regulatory,
environmental, and planning requirements of a project with the relevant authorities.
4. To provide an improved cost estimate and so enable sanction of the project.
5. Typical design development deliverables are as follows:
Process flow diagrams
Process and equipment specifications
Utility specifications
Control and automation user requirements specification
Preliminary process PID
Floor plans and equipment layouts
Facility and equipment qualification plan
List of systems
Building evaluation
Building finishes
HVAC schematics and routings
Safety and GMP reviews
Environmental considerations
Project schedule
Estimate

3.3.7 Facility Qualification Plan
To be able to execute facility validation, a plan is essential. For a single system, this is achieved
through a protocol, which in simple terms is a plan, followed by its execution. For a whole
facility and its operation, we require a plan that encompasses all aspects of validation and
qualification and this is usually termed a Validation Master Plan. It would cover facility and
equipment, automation, cleaning, process and Laboratory and analytical systems. These would
A REVIEW ON PHARMACEUTICAL VALIDATION
81

often have their own sub plan and in the case of facility we have termed this the facility and
equipment qualification (FEQ) plan.
56

The typical contents of an FEQ are as follows:
Introduction
Methodology
Qualification
DQ
IQ
OQ
PQ
Personnel and responsibilities
Schedule
Preventative maintenance
Change control
Procedures
Documentation
Appendices
The plan needs to be developed and to focus on those standards that must be met including
regulatory requirements. The standards will normally comprise the following three elements:
Regulatory and guidance documents
National standards (or equivalent)
Company standards

3.3.8 Qualification
57

The primary objective of qualification is a critical review of the system, equipment, or facility
against the design documents (especially specifications and P&IDs drawings) to confirm that the
user requirements have been satisfied. One important issue is how to select the acceptance
criteria for the various tests that are performed. For example, a shelf dryer is being used for
drying of tablet granulation. The URS states the dryer to be capable of 5C, so vendor provides
A REVIEW ON PHARMACEUTICAL VALIDATION
82

a dryer that has maximum variation of 2C. It is recommended that putting the tighter
specification is better to be included. The reasons for doing so are as follows:
If the system cannot meet this claim by the vendor perhaps there are other critical claims that
the unit cannot meet.
A future product may be introduced that will require a tighter range and, if confirmed
initially, there is no need to retest the dryer.
Having paid for a dryer that can maintain a tighter range, the owner should confirm that
performance.

Table 5: Validation priorities for process and facility systems
High: IQ/OQ/PQ (or PV) Moderate: IQ/OQ Low: Commission only
Breathing Air
Water for injection/purified
water
Clean steam
Product contact gases
Classified environments
CIP system
Solvent distribution systems
Process piping
Deionized water
Vacuum (if used in the
process)
Controlled temperature rooms
Process drains (biotech)
Process drains (except
biotech)
Non-process water
Sanitary drains
Electrical systems
Comfort HVAC
Cooling water/jacket services
Instrument air

Design Qualification
It is performed to make a risk analysis and to check the design documents of a technical system
to ensure that they fulfill the user requirements. It forms the basis for defining tests in the IQ, OQ
and PQ phases.
Installation Qualification
The things that are considered in this phase are as follows:
Provide as-built documentation (e.g. P&ID check).
Check training reports.
Check that documentation is complete.
Check calibration reports.
A REVIEW ON PHARMACEUTICAL VALIDATION
83

Identify piping and instrumentation.
E.g. A sterile filling unit might include the following
41

Premises Layout Flow of personnel, product, raw materials, and such
Finishes of walls, ceilings and floors
Utility services Drains Water systems (e.g., cooling, hot and cold)
Services gases (e.g., instrument air)
Electrics
HVAC class 100 systems
Class 10,000 systems
Class 100,000 systems
Process services USP and WFI
Process gases: nitrogen, propane, and others
Clean steam
Equipment Steam sterilizer
Stopper washersterilizer
Tray washerautoclave
Dry heat sterilizer
Vessels
Hot air tunnel sterilizer
Ampoule or vial washing machine
Filling and capping machines
Lyophilizer
Inspection line
Labeler
Packing (primary)

Operational Qualification:
The typical tests in this phase include the following:
Alarm tests
Behavior of the system after energy breakdown
Accuracy of filling lines
A REVIEW ON PHARMACEUTICAL VALIDATION
84

Transportation speed in a sterilization tunnel
Temperature distribution in an autoclave
Performance of a washing machine
Accuracy of a weighing system.
The types of systems identified will be dependent on the nature of the facility, but a typical
example list for a secondary sterile facility is given as follows:
58

Facility
HVAC class 100, 10,000, 100,000
WFI water
Process gases: air, nitrogen, CO2
Propane
SIP systems
CIP systems
Vial washer
Vial tunnel sterilizer
Vial filler and stopper machine
Lyophilizer
Vial capper
Vial inspection
Vial primary packing
Autoclave
Dry heat sterilizer
Stopper washerautoclave
Solution preparation system
Performance Qualification
This is generally applicable to those systems that require extended testing over a period of time
such as water systems, heating, and ventilation systems such as those applicable to clean rooms
and the actual performance of the clean room to meet the defined standards of operation over
periods of time.
42
The technical systems that need to be performance-tested and qualified are as follows
41
:
A REVIEW ON PHARMACEUTICAL VALIDATION
85

High purity water systems (monitoring of the quality parameters: pH, TOC, conductivity,
CPU, temperature)
HVAC systems (temperature, pressure, humidity)
Complex connected systems (e.g. filling line, BPI production line; performance parameters).

A REVIEW ON PHARMACEUTICAL VALIDATION
86

3.4 Computer System Validation
Computer system validation involves validation of Computer Related Systems (any place),
Computer Systems & Operating procedures, Design, Installation, Performance etc. This
method is to verify whether the computer systems are delivering their part. It includes hardware,
software and the firmware. This method requires detailed documentation of the software or
application used by the manufacturing process in the Pharmaceutical Company.
59

A computer is a machine and like all other machines, it is normally used because it performs
specific tasks with greater accuracy and more efficiency than people. Computers accomplish this
by having the capacity to receive, retain, and give up large volumes of data and process in in a
very short time. An understanding of computer operation, and the ability to use a computer, does
not require a detailed knowledge of either electronics or the physical hardware construction. An
overall view of the computer organization with emphasis on function is sufficient.
60


3.4.1 History of computer system validation in brief
61

1978 Validation for GMP concept developed by FDA.
1979 The USA issue Federal Regulations for GMP including validation of automation
equipment.
1983 FDA Blue Book for computer system validation.
1985 US PMA published guideline for validating new and existing computer systems.
1987 FDA technical report on developing computer systems.
1988 FDA conference paper on inspecting computer systems.
1989 EU Code for GMP including Annex 11 on computerized systems.
1991 EU Directive for GMP based on EU Code for GMP.
1994 GAMP first draft Distributed to U.K. for comments.
1995 U.S. PDA publishes validation guideline for manufacturers.
1995 The USA amends GMP regulations affecting automation.
1995 U.K. FORUM revise draft guidelines to suppliers.
March of 1997, FDA issued final part 11 regulations
First Draft July, 2000 (GAMP Ameriacas)
Version 1 Quarter 2, 2001 (Co-Publication with PDA)
A REVIEW ON PHARMACEUTICAL VALIDATION
87

GAMP4, December 2001, major revision and new content in line with regulatory and
technological development.
February 4, 2003, FDA withdrew the draft guidance for industry, 21CFR Part 11.

3.4.2 Importance of CSV
62

There are two key reasons why CSV is extremely important in the Life Science sector. They are
as follows:
1. Systematic CSV helps prevent software problems from reaching production environments. A
problem in a life science software application that affects the production environment can
result in serious adverse consequences. Besides the obvious humanistic reasons that the life
science sector strives to prevent such harm to people, the business consequences of a
software failure affecting people adversely can include lawsuits, financial penalties and
manufacturing facilities getting shut down. The ultimate result could be officers getting
indicted, the company suffering economic instabilities, staff downsizing, and possibly
eventual bankruptcy.
2. FDA regulations mandate the need to perform CSV and these regulations have the impact of
law. Failing an FDA audit can result in FDA inspectional observations (483s) and warning
letters. Failure to take corrective action in a timely manner can result in shutting down
manufacturing facilities, consent decrees, and stiff financial penalties. Again, the ultimate
result could be loss of jobs, indictment of responsible parties (usually the officers of a
company), and companies suffering economic instabilities resulting in downsizing and
possibly eventual bankruptcy.
Cutting corners on doing validation might save a little money in the short term but these saving
will look minute and inconsequential in comparison to the costs and impacts of not doing
validation correctly.

3.4.3 Typical Computer System Validation
63

Document Name Function of Document in Validation
User requirements
Specifications (URS)
Defines clearly and precisely what the user wants the system to do
and states any constraints (e.g. regulatory) under which the system
must operate.
A REVIEW ON PHARMACEUTICAL VALIDATION
88

Validation Plan Defines the objectives of the validation and the activities, procedures
and responsibilities for accomplishing the objectives of the validation.
The validation plan should also deal with the approach for
maintaining the validation status. This will generally involve
referencing the organizations Quality Management System
documentation that deals with such issues as Configuration
Management, Change Control, and System Retirement.
Project Plan Details the tasks and timeline for the project.
Documentation
justifying Selection of
System including
Supplier Audit Report
Outlines the reasons for choosing the system including the results of
auditing the suppliers quality management system.
Functional
Specifications
Detailed specifications showing the functions that the system
performs.
Design Specifications Detailed specification showing how the system performs the
functions documented in the Functional Specifications.
Supplier Test Plans
and Results
Documentation of Supplier Testing
Task Reports Documentation of Design/ Specification/ Testing Reviews,
Walkthroughs, and Inspections.
Traceability Matrix Analysis document that shows mapping between URS, Functional
Specs, Design Specs and test cases in IQ, OQ, PQ.
Risk Assessments A Risk Assessment (sometimes called Failure Mode and Effects
Analysis), is an analysis of failure scenarios associated with each of
the functions and sub functions of a system. Each failure scenario is
examined for potential business impact and likelihood of occurrence
in order to determine the relative risks associated with each function
and sub function of the system. Risk assessments may need to be
performed at multiple strategic points in the SDLC.
Network and
Infrastructure
Documentation that shows that the network and infrastructure
hardware/software supporting the application System being validated
A REVIEW ON PHARMACEUTICAL VALIDATION
89

Qualification has been installed correctly and is functioning as intended.
64

Installation
Qualification Scripts
and Results
Test cases for checking that system has been installed correctly in
User environment.
Results of executing scripts.
Deviations from expected results (if any).
Operational
Qualification Scripts
and Results
Test cases for checking that system has been installed correctly in
User environment.
Results of executing scripts.
Deviations from expected results (if any).
SOPs, Training
Material, and Training
Records
Documented procedures for users, system administrators, and IT
related functions such as Backup & Restore and Archiving. Training
records must be kept to show the appropriate people were trained in
the correct operation of the system.
Performance
Qualification Scripts
and Results
Test cases for checking that System does what it is intended to do
with trained people following SOPs in the production environment
even under worst case conditions.
Results of executing scripts.
Deviations from expected results (if any).
Validation Report This includes:
A review of all activities and documents against the Validation
Plan.
Evidence that deviations (if any) have been addressed and the
system is validated.
The plan for ongoing activities to maintain validation status.

3.4.4 Advantages of CSV
65

To obtain the benefits of computer system validation it is important to implement a structured
and professional validation process right from the start of the project. This will:
Reduce cost and time you need in order to achieve compliance.
Ensure delivery on time, on budget with the necessary quality standards.
Satisfying the user immediately and in the long term.
A REVIEW ON PHARMACEUTICAL VALIDATION
90

Ensure compliance with GxP and 21CFR Part 11 regulations (all automated systems that may
have an impact on product quality, safety, identity or efficacy are subject to GxP rules).
Contribute to total product safety and traceability.
Improve change control and reduced support costs.

3.4.5 Software validation
The Quality system regulation treats verification and validation as separate distinct terms
whereas software engineers often use them interchangeably, or in some cases refer to software
verification, validation, and testing (VV&T) as if it is a single concept.
Software verification provides objective evidence that the design outputs of a particular phase of
the software development life cycle meet all the specified requirements for that phase. It looks
for consistency, completeness, and correctness of the software and its supporting documents, as
it is being developed, and provides support for a subsequent conclusion that software is
validated.
Software validation is a part of the design validation project for the project, but is not separately
defined in the Quality System regulation. FDA considers it to be confirmation by examination
and provision of objective evidence that software specifications conform to user needs and
intended uses, and that the particular requirements implemented through software can be
consistently fulfilled. In practice, it may occur both during as well as end of the software
development life cycle to ensure that all requirements have been fulfilled. It helps in developing
a level of confidence that the application meets all requirements and user expectations for the
software automated functions.

3.4.6 Software Life Cycle
Software validation takes place within the environment of an established software life cycle.
Software life cycle contains software engineering tasks and documentation necessary to support
the software validation effort. It also contains specific verification and validation tasks that are
appropriate for the intended use of the software.
The life cycle model selected should cover the software from its birth to its retirement. A series
of activities and tasks are planned and executed at various stages of the software development
A REVIEW ON PHARMACEUTICAL VALIDATION
91

lifecycle. During each of the activities; verification, testing and other tasks that support software
validation occur.
A typical software life cycle model includes the following
66
:
1. Quality Planning
2. System Requirements Definition
3. Detailed Software Requirements Specification
4. Software Design Specification
5. Construction or Coding
6. Testing
7. Installation
8. Operation and Support
9. Maintenance

3.4.6.1 Quality Planning
The plan should include following
The specific tasks for each life cycle activity
Enumeration of important quality factors
Methods and procedures for each task
Task acceptance criteria
Criteria for defining and documenting outputs in terms that will allow evaluation of their
conformance to input requirements
Inputs for each task
Outputs from each task
Roles, resources, and responsibilities for each task
Risks and assumptions
Documentation of user needs.
The typical tasks of quality planning includes following:
Risk (Hazard) Management Plan
Configuration Management Plan
Software Quality Assurance Plan
Software Verification and Validation Plan
A REVIEW ON PHARMACEUTICAL VALIDATION
92

Verification and Validation Tasks, and Acceptance Criteria
Schedule and Resource Allocation (for software verification and validation activities)
Reporting Requirements
Formal Design Review Requirements
- Other Technical Review Requirements
- Problem Reporting and Resolution Procedures
Other Support Activities

3.4.6.2 Requirements
The typical software requirements specify the following:
All software system inputs
All software system outputs
All functions that the software system will perform
All performance requirements that the software will meet
The definition of all external and user interfaces, as well as any internal software-to-system
interfaces
How users will interact with the system
What constitutes an error and how errors should be handled
Required response times
The intended operating environment
All ranges, limits, defaults, and specific values that the software will accept
All safety related requirements, specifications, features, or functions that will be
implemented in software.
The typical task includes:
Preliminary Risk Analysis
Traceability Analysis
Software Requirements to System Requirements (and vice versa)
Software Requirements to Risk Analysis
Description of User Characteristics
Listing of Characteristics and Limitations of Primary and Secondary Memory
A REVIEW ON PHARMACEUTICAL VALIDATION
93

Software Requirements Evaluation
Software User Interface Requirements Analysis
System Test Plan Generation
Acceptance Test Plan Generation
Ambiguity Review or Analysis

3.4.6.3 Design
The software design specification should include following:
Software requirements specification, including predetermined criteria for acceptance of the
software
Software risk analysis
Development procedures and coding guidelines (or other programming procedures)
Systems documentation (e.g.,a narrative or a context diagram) that describes the systems
context in which the program is intended to function, including the relationship of hardware,
software, and the physical environment
Hardware to be used
Parameters to be measured or recorded
Logical structure(including control logic) and logical processing steps (e.g., algorithms)
Data structures and data flow diagrams
Definitions of variables (control and data)and description of where they are used
Error, alarm, and warning messages
Supporting software (e.g., operating systems, drivers, other application software)
Communication links (links among internal modules of the software, links with the
supporting software, links with the hardware, and links with the user)
Security measures (both physical and logical security).
The typical tasks include:
Updated Software Risk Analysis
Traceability Analysis - Design Specification to Software Requirements (and vice versa)
Software Design Evaluation
Design Communication Link Analysis
A REVIEW ON PHARMACEUTICAL VALIDATION
94

Module Test Plan Generation
Integration Test Plan Generation
Test Design Generation (module, integration, system, and acceptance)

3.4.7 Construction or coding
Software are constructed either by coding (i.e. programming) or by assembling together
previously coded software components (e.g. from code libraries, off the-shelf software, etc.) for
use in a new applications. Coding is the lowest level of the abstraction for the software
development process where detailed design specification is implemented as source code.
The tasks include:
Traceability Analyses
Source Code to Design Specification (and vice versa)
Test Cases to Source Code and to Design Specification
Source Code and Source Code Documentation Evaluation
Source Code Interface Analysis
Test Procedure and Test Case Generation (module, integration, system, and acceptance)

3.4.8 Testing by the Software Developer
It is important for early planning in order to be effective and efficient, although its time-
consuming, difficult, and imperfect activity. Test plans and test cases should be created as early
as possible in development process identifying schedules, environments, resources,
methodologies, cases, documentation, and reporting criteria.
The tasks include following -
Test Planning
Structural Test Case Identification
Functional Test Case Identification
Traceability Analysis - Testing
Unit (Module) Tests to Detailed Design
Integration Tests to High Level Design
System Tests to Software Requirements
Unit (Module) Test Execution
A REVIEW ON PHARMACEUTICAL VALIDATION
95

Integration Test Execution
Functional Test Execution
System Test Execution
Acceptance Test Execution
Test Results Evaluation
Error Evaluation/Resolution
Final Test Report.

3.4.9 User Site Testing
It is an essential part of software validation. The term user site testing encompasses terms
such as beta test, site validation, user acceptance test, installation verification, and installation
testing and any other testing that takes place outside of the developers controlled environment.
This should take place at a users site with the actual hardware and software that will be part of
the installed system configuration. It is accomplished either by actual or simulated use of
software being tested within context in which it is intended to function.
Typical tasks include following:
Acceptance Test Execution
Test Results Evaluation
Error Evaluation/ Resolution
Final Test Report
67





A REVIEW ON PHARMACEUTICAL VALIDATION
96

3.5 Equipment Validation
Equipment validation comprehensively establishes in a documented way the instrument is
working accurately. A validation process offers evidence that the components critically
contributing to accurate functioning of the equipment consistently meet the predefined
specifications and operational attributes.
68
Equipment must be located, designed, constructed,
adapted and maintained to suit the operations to be carried out successfully. Equipment layout
and design must aim to minimize risks of error to permit effective cleaning and maintenance and
also to avoid cross-contamination, dust and dirt build-up any adverse effect on the quality of
products.
69

Equipment must be qualified to minimize risks of error and to minimize risks of contamination.
Equipment validation through inspection, testing and documentation assures that:
The correct equipment has been installed
The equipment has been properly installed
The equipment performs according to pre-established, written specifications.
70


3.5.1 Reason of Equipment Validation
1. Validation of equipment is not just desirable, it is rather a necessity. All measuring
instruments, whether they are used in factories, industries, need to be validation on a periodic
basis to ensure they are offering accurate results.
2. Equipment validation is the hallmark of assurance that certifies the accurate functioning of an
instrument under the prescribed range of operating environment and conditions, while
steadfastly adhering to the correct operating specifications.
3. The non-compliance to GMP or other regulatory bodys requirements may render the
instrumentation of a company ineligible for industry use. This can spell significant losses for
the company, further underlining the necessity of validation.
55


3.5.2 Content of Equipment Validation
a. Application of SOPs
b. Utilization list
c. Process description
d. Test instrument utilized to conduct test
A REVIEW ON PHARMACEUTICAL VALIDATION
97

e. Test instrument calibration
f. Test function
71


3.5.3 Balances and Measuring Equipment
Appropriate range and precision available
Mostly uses in production and quality control
Calibrated
scheduled basis
checks
records maintained

3.5.4 Production equipment
Appropriate design
easily and thoroughly cleaned on a scheduled basis
procedures and records
No hazard to the products
contact parts of suitable non-reactive materials
non additive and
not absorptive
Defective equipment
removed, or
labelled to prevent use
Closed equipment used when possible
Open equipment, or when equipment opened, precautions taken to prevent
contamination
Non-dedicated equipment cleaned according to validated cleaning procedures
between different products
Current drawings of critical equipment and support systems maintained
3.5.5 Control laboratory equipment
Equipment and instruments
suitable for the tests to be performed
A REVIEW ON PHARMACEUTICAL VALIDATION
98

Defective equipment
removed
labelled
3.5.6 Washing, cleaning and drying equipment
Equipment used for washing and drying not the source of contamination
Equipment design should promote easy cleaning
Cleaning on scheduled basis, procedures and records
Washing and cleaning
manual
automated (Clean in place (CIP), Steam in place (SIP))
72


3.5.7 Equipment Validation Process
73
:

Figure 6: Equipment Qualification Process
A REVIEW ON PHARMACEUTICAL VALIDATION
99

DQ considerations included:
Determine specified requirement of equipments
Defined capabilities e.g capacity, speed, range, temperature
Defined requirements e.g. size, power need, resistance to cleaning material
Additional Features e.g. ease of use, reputation, prior experience to same model,
warranty, manufacturers support.
74

IQ considerations included:
Equipment design features (i.e. material of construction clean ability, etc.)
Installation conditions (wiring, utility, functionality, etc.)
Calibration, preventative maintenance, cleaning schedules.
Safety features.
Supplier documentation, prints, drawings and manuals.
Software documented.
Spare parts list.
Environmental conditions (such as clean room requirements, temperature, and humidity).
OQ considerations include:
Process control limits (time, temperature, pressure, line speed, setup conditions, etc.)
Software parameters.
Raw material specifications
Process operating procedures.
Material handling requirements.
Process change control.
Training.
Short term stability and capability of the process, (latitude studies or control charts).
Potential failure modes, action levels and worst-case conditions.
The use of statistically valid techniques such as screening experiments to optimize the process
of equipment can be used during this phase.
PQ considerations include:
Actual product and process parameters and procedures established in OQ.
Acceptability of the product.
Assurance of process capability as established in OQ.
A REVIEW ON PHARMACEUTICAL VALIDATION
100

Process repeatability, long term process stability by installed the equipment.
75


3.5.8 HPLC method calibration
HPLC is a form of liquid chromatography used to separate compounds that are dissolved in
solution.
HPLC instruments consist of
a reservoir of mobile phase,
a pump,
an injector,
a separation column,
a detector.

Compounds are separated by injecting a sample mixture onto the column. The different
component in the mixture passes through the column at different rates due to differences in their
partition behavior between the mobile phase and the stationary phase. The mobile phase must be
degassed to eliminate the formation of air bubbles.
76
HPLC system calibration includes the
pump, the detector, the auto sampler, and the column oven. Calibration procedures are often
similar to those used in the initial operational qualification of each module of the HPLC system.
While each company's procedure might differ in the details, most share these common strategies.
77

By Whom:
An analyst, a metrologist, or a qualified contractor can perform the calibration, though all must
follow the company's prescribed standard operating procedure (SOP) and acceptance criteria.
The cost effectiveness of using outside contractors or an internal metrology department is
dependent on company size and the number of HPLC systems in the laboratory.
77

When:
Most HPLC systems in pharmaceutical laboratories are calibrated every 6-12 months. The
calibration gaps longer than 12 months are not recommended. And, the gaps shorter than 3
months are deemed unnecessary, because each HPLC system is also subjected to a daily system
suitability check to ensure sufficiency for the application.

A REVIEW ON PHARMACEUTICAL VALIDATION
101

How
A list of common strategies in selecting calibration procedure and adopting acceptance criteria is
given below:
1. Annual preventive maintenance, in which most wearable items such as pistons, seals, lamps,
and filters are replaced, is to be scheduled before calibration.
2. Before calibration, each module is shut down and powered-up to evoke built-in diagnostics
for detecting problem situations.
3. The calibration order is: detector ~ pump ~ auto sampler (as the detector is often used to
calibrate other modules).
4. Common performance characteristics to be verified for each module are:
UV detector : Wavelength accuracy, absorbance linearity, and sensitivity;
Pump : Flow rate accuracy and precision, and compositional accuracy;
Auto sampler : Sampling precision and accuracy;
Oven : Temperature accuracy;
Overall system: System dwell volume and instrumental bandwidth.
5. Acceptance criteria generally mirror the manufacturer's specifications though many are
necessarily relaxed to accommodate diversified models and aging components.
6. The calibration standard employed should be National Institute of Standards and Technology
(NIST) traceable and easily obtainable.
77


Validation program Overview in Picture:










Figure 7: Schematic diagram showing the overall validation strategy
A REVIEW ON PHARMACEUTICAL VALIDATION
102

HPLC Chromatography Calibration Procedure
Check HPLC chromatography (Pump) for the following:
I. Check point: Leakage test (By Pressure Drop)
II. Flow rate calibration

Check point: Leakage test (By pressure drop)
1. Ensure that, the instrument is ready for calibration and Start-up procedure is followed.
2. Place inlet tubing of the Pump in to the Water HPLC grade through suction filter.
3. Allow mobile phase to flow for about 5 min.
4. Block Pump outlet with the block screw.
5. The pressure rises and on crossing the 300 bar, ERROR P-MAX appears on the display
window. Note the time. Press CE key and observe the pressure drop for 5 min.
6. After 5 min., record the pressure in calibration Log.
7. Make entry of the column usage in the Column Usage Log Register.
8. Make entry of the usage in to the Instrument Usage Log Register.
9. Compare the result for its compliance against limit given in the Calibration Log and put the
remark regarding the HPLC chromatography Calibration Status.
10. In case of non-compliance, follow the Maintenance Program.
80


Flow rate calibration
1. Ensure that, the instrument is ready for calibration and Start-up procedure is followed.
2. Ensure that, the Pump is passing the Leakage Test (By Pressure Drop).
3. Keep the Drain tube in such a way that the mobile phase (Water) drops falls in to 10 ml
clean, dry volumetric flask without touching the walls of the flask and start immediately the
stopwatch when first drop falls in to the flask.
4. Wait till the collected mobile phase reaches 10 ml mark of the volumetric flask and Stop the
stopwatch. .
5. Record the time required to collect the 10 ml mobile phase in calibration Log.
6. Repeat the procedure for 1.0 ml, 1.5 ml and 2.0 ml/ min. flow rates.
7. Repeat the step 3 to 6 but using Methanol HPLC grade as mobile phase instead of water.
A REVIEW ON PHARMACEUTICAL VALIDATION
103

8. Compare the results for its compliance against limits given in the Calibration Log and put the
remark regarding the Calibration Status.
9. Make entry of the usage of the instrument and column in the Instrument Usage Log Register
and Column Usage Log Register respectively.
10. Prepare Calibration Status Label and display on the instrument at the designated place.
11. In case of non-compliance, follow the Maintenance Program.
78


Calibration Parameters of HPLC:
1. Flow rate capacity
2. Injector accuracy
3. System Precision
4. Wavelength Accuracy
5. Detector linearity
6. Injector linearity
7. Gradient performance check
8. Column oven temperature accuracy

1. Flow rate Accuracy:
Run all the solvent lines with Milli Q water (i.e. HPLC grade water).
Set the flow rate 0.500ml/min.
Wait for about 15 min to stabilize the system and ensures that the pressure is stable.
Insert the outlet tubing into a 10 ml volumetric flask and start stop watch simultaneously.
Stop the stopwatch when the lower meniscus reaches the 10 ml mark on the flask.
Record the elapsed time.
Similarly, check the flow for 1.0ml/min and 2.0ml/min
Acceptance criteria: The time taken to collect the water should be within 2.0% of the actual
value.
79

2. Injector Accuracy:
Connect the pump and detect inlet with union.
Prepare mobile phase consisting of a mixture of water and methanol.
Set a flow rate of 0.5ml/min and run time of 1 min.
A REVIEW ON PHARMACEUTICAL VALIDATION
104

Set the column temperature at 25(+/-) 2 o c.
Fill a standard HPLC vial to 2/3 rd with water. Seal the vial properly with a cap.
Weigh the vial and record the weigh as W1 grams.
Place the vial in the chromatographic system and perform 6 injections of 50 microlitre
volume from this vial.
Weigh the vial again and note the weigh after injection As W
2
grams.
Calculate the mean volume injected per injection as follows:
Mean injected volume :( w
1
-w
2
)*100/6.
Acceptance Criteria: the mean injected volume should be 50.0(+/-) 1.0 microlitre.
79

3. System precision:
Standard preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml
volumetric flask. Dissolve and dilute to the volume with mobile phase. Transfer 10 ml of this
solution into a 100ml volumetric flask and dilute to the volume with mobile phase.
Procedure: Inject blank, followed by standard preparation in 6 replicates. Note down the areas
and retention times. Now calculate the% RSD of retention time and peak areas for 6 replicates
injection.
Acceptance Criteria: The % RSD of retention time and peak area should be less than 1.0%
4. Wavelength Accuracy:
Procedure: Create and instrument method with a wavelength in nm and inject blank, followed by
standard preparation and note down the height or absorbance.
Acceptance criteria: the maximum absorbance should be at (+or -) 2nm.
5. Detector Accuracy:
Select 3d mode and set the wavelength ranges 200-400nm. Inject 20 microlitre of standards
preparation once into the chromatographic system. Extract and record the chromatographic at
wavelength of 202 to 208 nm with an interval of 1 nm to 269 to 275 nm with an interval of 1nm.
Note down the height or absorbance.
Acceptance Criteria: The maximum absorbance should be at 205(+/-) 2 nm and 272(+/-) 2nm.
Standard preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml
volumetric flask. Dissolve and dilute to the volume with mobile phase.
Now prepare the following solution:
Detector linearity solution 1 (0.06mg/ml)
A REVIEW ON PHARMACEUTICAL VALIDATION
105

Detector linearity solution 2 (0.048mg/ml)
Detector linearity solution 3 (0.03mg/ml)
Detector linearity solution 4 (0.24mg/ml)
Detector linearity solution 5 (0.012mg/ml)
Procedure: Inject blank, followed by detector linearity solutions and record the peak response of
caffeine standard plot between the concentration vs the peak responses.
Acceptance criteria: The plot should be linear and regression coefficient should not be less than
0.99.
6. Injector linearity:
Standard Preparation: Accurately weigh and transfer about 60 mg of caffeine into a 100ml
volumetric flask. Dissolve and dilute to the volume with mobile phase. Transfer 10 ml of
standard preparation into a 100ml volumetric flask and dilute to the volume with mobile phase.
Procedure: Inject 5 microlitre of the mobile phase as blank injection. Inject 5, 10, 20,50and 80
microlitre of the standard preparation and record the peak areas. Plot a curve for the volume
injected vs peak area.
Acceptance criteria: The plot should be linear and regression coefficient should not be less than
0.99.
7. Gradient performance check:
Add 5ml of acetone to 1000 ml of methanol filter and degas. Connect the pump and detector inlet
with union. Set the detector wave length at 254 nm. Place channels A and C in methanol and
channel B and D in 0.5% acetone in methanol. Set gradient program as show below for channels
A, B, C and d individually
Acceptance criteria: The calculated percentage composition should be within 1.0% of the set
composition.
8. Column oven temperature accuracy
It is evaluated with a calibrated digital thermometer at 30 0c and 60C.Place and thermometer
probe in the column oven and set the column oven temperature at 30 C. Wait till the
temperature stabilizes. Record the temperature displayed on the thermometer. Similarly performs
the column oven temperature accuracy test at 60 C.
Acceptance criteria: The resulting oven temperature from the thermometer display should be
within 2C of the set temperature.
A REVIEW ON PHARMACEUTICAL VALIDATION
106

Summary of Calibration Tests and Acceptance Criteria
80


HPLC
module
Test Procedure Acceptance Criteria
Detector
PDA or
UV/Vis
Wavelength
accuracy
Maximum absorbance of anthracene
solution (1 g/mL).
251_+3 nm
340_+ 3 nm 2
Pump Flow accuracy Run pump at 0.3 and 1.5 mL/min
(65%acetonitrile/water) and collect 5 mL
from detector into a volumetric flask.
Measure time.
< + 5%
Compositional
accuracy
Test all solvent lines at 2 mL/min with
0.1% acetone/water, step gradients at
0%, 10%, 50%, 90% and 100%. Measure
peak heights of respective step relative to
100% step.
1% absolute
Column
Oven
Temperature
Accuracy
Check actual column oven temperature
with validated thermal probe.
35+/-2"C
Auto
Sampler
Precision Determine the peak area RSD of10-1uL
injection of ethyl paraben (20
microgm/mL)
RSD <+0.5%
Linearity Determine the coefficient of linear
correlation of one injection of 5-, 10-, 40-
and 80-microlitre of ethylparaben
solution.
R > 0.999


A REVIEW ON PHARMACEUTICAL VALIDATION
107

3.5.9 HVAC Validation
HVAC is the abbreviated form of - Heating, Ventilating and Air Conditioning which is a system,
which provides conditioned air by providing Heating, Cooling & Ventilation. HVAC system
plays an important role in product, personnel, environment, instruments and machine protection.
HVAC utility is designed to control the level of viable and non-viable particulate exposure that a
drug or medicinal device might receive in addition to regulating temperature and relative
humidity conditions. It is qualified to demonstrate operating conditions of the area. The areas
serviced by the HVAC utility are classified based on viable and non-viable particulate levels
during static operating conditions and dynamic operating conditions.
81

The parameters of HVAC include the following:
Temperature
Relative Humidity
Air Class
Room to room Pressure Gradient
Air Quality
Sound level.

Recommended limit of the above HVAC Parameters are mentioned below:
Temperature: 205C
Relative Humidity: It is recommended to maintain RH within 505 % in all manufacturing
areas, unless there is any specific recommendation for any special operation. For example,
for Effervescent product manufacturing it is recommended to maintain the relative humidity
around 20%.
Air Class: As per International standards; i.e. Federal standards, ISO standards; British
standards etc.
Pressure Gradient: It should be maintain relatively negative unless there is any special
requirements. E.g. For sterile areas.
Air Quality: It should be Dust and Odor free.
Sound level: It should be maintained within 20 db.
A REVIEW ON PHARMACEUTICAL VALIDATION
108

Pharmaceutical rules and specifications are often contains very precise but also generally
formulated requirements of air conditioning technology such as temperature, humidity and
ventilation of premises should be adequate.
Two basic types are distinguished by the terms of
Room Ventilation Technology and
Process Air Conditioning Technology.
Both types are found and required in the pharmaceutical manufacturing sites. The essential task
of a ventilation system is to guarantee that the desired room conditions such as temperature,
humidity and cleanliness.
In contrast, the process air systems must guarantee the required process parameters.

Quality standards:
The HVAC system must supply quality air which should be in compliance to all standards
according to:
ISO EN 14644.5:2004: Clean room and associated controlled environments, part 5: clean
room operations
PIC/S Guideline to GMP for medicinal product
ISPE Baseline guide volume 3, sterile manufacturing facility
AS 1386.31989 Clean rooms and clean workstation part 1&3
EU GMP Guide, Volume IV GMP for medicinal products section 3 premises and
equipment
21CFR part 11 Subpart C building and facility and subpart D
United States Pharmacopeia USP 32
European Pharmacopeia Ph Euro 7th Edition
ISO/IEC 17025 General requirements for the competence and testing of calibration and
testing laboratories.
57

System boundaries:
The physical boundaries are defined as follows:
Source of air handling units (AHUs) and air conditioning units (ACUs) including other forms
of air pretreatment (e.g., heating/cooling, dehumidification/ humidification).
A REVIEW ON PHARMACEUTICAL VALIDATION
109

AHUs require externally supplied heating and cooling sources such as steam, hot water or
chilled water.
ACUs are self-contained with respect to heating and cooling and generally employ a
refrigeration-based heat pump. They may be reversible and both heat and cool the supply
airflow.
AHUs, ACUs and associated ductwork, which supply air to critical and controlled
areas/rooms are included while AHUs, ACUs and related ductwork, which supply non-GMP;
uncontrolled areas (e.g. offices, cafeterias) are not included.
Supply air and return air ductwork up to but not including grills inside rooms or areas.
Support utility interfaces (e.g. electrical connections at disconnect points) for heating/cooling
water supplies etc.
82


Area Description:
This area is defined to use only sterile oriented products for manufacturing. The aseptic process
involves the handling of sterile components until they are sealed in their final containers.
Aseptic area is designed, constructed and engineered to comply with pharmaceutical compliance
standards and to prevent microbial contamination.
58

The clean room for the aseptic area is classified according to the required characteristics of the
environment in four ways, such as:
A. Federal Standard
B. British Standard
C. ISO standard
D. EU CGMP








A REVIEW ON PHARMACEUTICAL VALIDATION
110

A. Table: Federal Standard 209E, Clean room classification


B.Table: British Standard 5295:1989





A REVIEW ON PHARMACEUTICAL VALIDATION
111

C. ISO airborne particulate cleanliness classes
Class maximum number of particles In each cubic meter equal to or greater than the
specified size
0.1m 0.2m 0.3m 0.5m 1m 5m
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1000 237 102 35 8
ISO 4 10000 2370 1020 352 83
ISO 5 100000 23700 10200 3520 832 29
ISO 6 1000000 237000 102000 35200 8320 293
ISO 7 352000 83200 2930
ISO 8 3520000 832000 29300
ISO 9 35200000 8320000 293000

D. Table: According to EU cGMP
Grade At Rest(b) In Operation(b)
Maximum permitted number of particles/m3 equal to or above(a)
0.5m(d) 5m 0.5m(d) 5m
A 3,520 20 3,500 20
B(c) 3,520 29 35,000 2,900
C(c) 35,200 2,900 352,000 29,000
D(c) 3,520,000 29,000 Not defined(f) Not defined(f)
A REVIEW ON PHARMACEUTICAL VALIDATION
112

The in-operation and at rest states should be defined for each clean room or suites as
mentioned in the below-mentioned grade:

Grade A: The local zone for high-risk operations includes aseptic filling zone, stopper bowls,
open vials and making aseptic connections. This zone is equipped with laminar flow systems
with homogenous air speed in a range of 0.36 to 0.54m/s.
Grade B: This is the background environment for grade A zone.
Grade C: This is the clean areas for carrying out less critical processes in the manufacture of
sterile products.
Grade D: This area is unclassified as it is meant for capping gowning room and black/grey
change room.

Cleanliness Phase:

Cleanliness grade A
(FS 209 E class 100 at rest) ISO 5
US class 100 in operation
SI M* 3.5
The local zone for operations with a high level of
risk, for example in the filling area, assembly of
the filling apparatus (pump, filter, etc.), aseptic
connections (equipment, tubes, couplings) under
laminar airflow of 0.45 m/s, 20%.
Microbiological limit <1 CFU/m3
In the case of faults, controlled, brief intervention
by personnel from cleanliness grade B is
permitted.
Cleanliness grade B
(FS 209 E class 100 at rest) ISO 5
US class 10.000 in operation
SI M* 5.5
The presence of appropriately dressed personnel
is permitted.
Turbulent airflow is permitted.
Microbiological limit 10 CFU/m3 (action limit)
(FS 209 E class 10 000 at rest) ISO
7
US class 100.000 in operation
SI M* 6.5
The presence of appropriately dressed personnel
is permitted.
Turbulent airflow is permitted.
Microbiological limit 100 CFU/m3 (action limit)
Cleanliness grade D
(FS 209 E class 100 000 at rest)
ISO 8
US class: not classified
The presence of appropriately dressed personnel
is permitted.
Turbulent airflow is permitted.
Microbiological limit 200 CFU/m3 (action limit
SI M represents the classification on the basis of 0.5m particles

A REVIEW ON PHARMACEUTICAL VALIDATION
113

HEPA filter:
High efficiency particulate air (HEPA) filters are essential to the correct performance of a clean
room. Composed of various fibers (mainly glass) bonded with resin or acrylic binders. Filter
consists of a continuous sheet of filtration material, placed between each pleat and sealed into
rigid metal frame. They are capable to remove 99.99% of particles < 1 m. Its filter efficiency is
99.97% of particles as small as 0.3m. (4)
New generations of ultrahigh efficiency filters are now available. This can retain 99.99% of
particles at 0.1 m level.
Types of HEPA filter used in sterile area:
Grade Description Type Efficiency
Cleanliness grade A H14 99.995
Cleanliness grade B H14 99.95
Cleanliness grade C H13 99.5
Cleanliness grade D H11 99.0

Requirement for Materials and Equipment:
Materials required are all the items, which will be routinely used to test air quality for
particulates and microbial counts, the manual operations, humidity, airflow, make-up air etc. etc.
Following list of devices must be calibrated before they are used during the qualification plan.
SOPs for each test method, the operation and calibrations of these equipment used, the data to be
recorded and the criteria for acceptance must be prepared and approved before beginning the
qualification plan.
83

Various components of a typical HVAC system are as follows:
1. Micro-manometer
2. Differential Pressure Gauge.
3. Thermal Anemometer
4. Vane-type Anemometer
5. Multi-parameter ventilation meter
6. Air Capture hood
7. Thermo hygrometer
8. Indoor Air Quality Meter
A REVIEW ON PHARMACEUTICAL VALIDATION
114

9. Compulsion Analyzer
10. Air Velocity Transducer
11. Micro-Ohmmeter with airflow hood
12. Particle Counter
13. Microbiological Air Sampler and Media Plates
14. Charts for the time, temperature and pressure recording.
15. Aerosol generator
16. Photometer
System Description:
HVAC system is fully integrated air conditioning and filtration system that consists of Air
Handling Unit (AHU), fans, filters, and ductwork, heating and cooling system, gauges and
control system.
Air Handling Unit: AHU is constructed in a horizontal modular, located within the plant roof
area.
Weather Louver: To prevent insect, eaves, dirt and rain from entering.
Separator: Providing primary filtration for the fresh air with steady pressure drop.
Pre-filter: Filtration of the fresh air and have resistance to heavy dust.
Mixing/Exhaust Plenums: It is fitted with parallel blade dampers which operation is extended via
drive spindles that is suitable for hand adjustment and lockable.
Electric Heating Coil: To heat the air to the proper temperature. (Fitted with over heat cutout that
is of auto-reset type.)
Cooling Unit/dehumidifier: To cool the air to the required temperature or to remove moisture
from the air.
Humidifier: To bring the air to the proper humidity, if too low
Secondary Filters: To eliminate particles of pre-determined dimensions and/or microorganisms
according to the user requirement specification.
Fan: The fan is multivane backward curved centrifugal, to suite the volume/pressure
characteristics required with double inlet, double width impeller.
Air Cooled Chillers: The chiller has two refrigerant circuits allowing for close control of the
chilled water circuit serving the Air Handling Unit cooler battery and service void fan unit under
a wide range of cooling load
A REVIEW ON PHARMACEUTICAL VALIDATION
115

Ductwork: All of the supply and general extract ductwork is installed and manufactured from
galvanized mild steel in accordance with HVAC specification DW142 low-pressure
classification. (Ductwork must be kept clean during manufacturing and installation and it must
be performed in accordance with HVAC DW/TM2 intermediate level).
Terminal Filter: The final filtration within the Cephalosporin suite must be with 99.999%
efficient HEPA filters.
Pressure Indication: This continuously monitors the pressures of each room, the air handling unit
filters pressure drop, the return air filter pressure drop and typical supply HEPA filter pressure
drop, this being one of the filters in the filling room.
84

Gas fumigation system: The air handling system is controlled by sequence timers which are
adjustable, to allow for the air handling system to be shut down on commencement of fumigation
together with the closing of the airtight dampers in the main supply and return ducts.

Testing Of Clean and Aseptic Rooms:
A. Commissioning tests
B. Microbiological Test
C. Monitoring test

A. Commissioning tests: British Standard 5295 list the tests and procedures which should be
used to commission a clean or aseptic room.

Final filter installation test: This is done to demonstrate that the filter is not damaged and
that the filter mounting frame does not leak at the gasket flange or the connection to the
ducting.
Induction leak test: This test demonstrates that particles cannot enter the room from leaks in
construction joints or by back-streaming from openings.
Filter efficiency test: Aerosol photometers and the generation and detection of DOP smoke or
sodium chloride crystals are usually used for these tests.
Particulate contamination control test: This is used to demonstrate that the number and size
distribution of particles in the clean room air do not exceed the levels specified for the
A REVIEW ON PHARMACEUTICAL VALIDATION
116

particular class of room. Microscopic techniques and direct reading light scattering
photometers are used in this type of test.
Air pressure test: This test determines the differential pressure between the clean area and
adjacent areas. This is usually measured using a sensitive manometer.
Temperature and humidity tests: Measurements are usually made with a sling psychrometer,
repeat readings being taken after 30 seconds' whirling of the instrument until stable wet and
dry bulb temperatures are obtained.
Air flow tests: Air flow within ducts can be measured with a Pitot tube and manometer. Air
change rates can be demonstrated by tracer gas decay rate or
Noise level tests: British Standard stipulates a maximum level of 65 dB.
Lighting test: The quality of the general illumination within the area and also at the work
bench is measured using a portable photoelectric photometer. Recommended lighting levels
at the work surface are <300 lux (28 ft candles) for the British Standard and 100 150 ft
candles (1076 1614 lux) for the US Standard.
B) Microbiological tests:
Settle plates
Agar contact plates and swabs
Process simulation tests
Sterility tests
C) Monitoring test:
Air pressure, temperature, and humidity measurements should be recorded continuously.
Particulate contamination should be determined daily for aseptic (Class 1) rooms and weekly
for clean (Class 2) rooms
Tests for air flow velocity and uniformity should be carried out at 3-monthly intervals.
Tests for filter efficiency should be conducted yearly. Tests should also be repeated after
repairs or maintenance
Settle plates, agar contact plates and swabs, and sterility tests should be carried out during
each work shift.
It is recommended that process simulation tests should be conducted at 3- monthly
intervals.
85


A REVIEW ON PHARMACEUTICAL VALIDATION
117

3.6 Cold Chain Validation
It is a system of transporting and storing vaccines
within a recommended temperature range of +2 to
+8C. This temperature range has been selected by the
WHO.
86

A cold chain is a temperature-controlled supply chain.
An unbroken cold chain is an uninterrupted series of
storage and distribution activities which maintain a
given temperature range.
87

Cold chain products are the products which require special temperature controlled storage. Cold
chain storage system is used to store vaccines, certain injectable preparations. Maintaining the
temperature is necessary not only during the manufacturing but the product has to be stored up to
the destination (patient).To enhance quality assurance of vaccine distribution by public health
programs various methods for packing vaccines were validated.
Validation involved both tests in an environmental chamber and actual shipping of packages by
commercial overnight delivery service.
Cold Chain Consultants specialize in operational qualification of temperature sensitive supply
chains and logistics routes. Validating or revalidating key components will highlight abnormal
behaviors in a supply chain.
Cold Chain Consultants offer end to end temperature sensitive supply route mapping services to
collect temperature data and prepare reports and recommendations. Cold chain Consultants use
state of the art technology and a comprehensive range of unique tools including wireless
monitors to collect data without breaking seals on packaging containers, trucks or trailers.
Cold Chain Consultants have a unique internet collection temperature data system to collect data
for qualification of shipping routes from anywhere in the world without the receivers having
access to this data.
88

3.6.1 Uses
1. It is used to help extend and ensure the shelf life of products such as fresh agricultural
produce, seafood, frozen food, photographic film, chemicals and pharmaceutical drugs.
2. To supply vaccines during hot climate to distant places.
A REVIEW ON PHARMACEUTICAL VALIDATION
118

3. To protect heat sensitive and biological medicine such as insulin, vaccine, interferon,
etc.
88

4.
For collecting drug substances to prepare stability testing data.


3.6.2 Strategy
























Design Qualification
Investigational Qualification
Performance Qualification
Supply chain temperature mapping and thermal studies
Operational Qualification
Warehouse and cold room mapping
Cold chain shippers, packing qualification and testing
Cold chain packaging and pallet environmental chamber qualification and testing
Testing protocols, mapping procedures with qualification report
A REVIEW ON PHARMACEUTICAL VALIDATION
119

These approaches, which require materials costing less than approximately 1% of the cost of the
vaccines they protect, provide examples of packaging suitable for overnight delivery of vaccines
in the US in different seasons.
Performing thermal testing can also help with validating the cold chain.
3.6.3 Evaluation and Reporting
Data from the data loggers and interviews should be combined into a report characterizing the
incidence of freezing and the likely causes. Interview information can provide recommendations
for ways to reduce freezing.During the distribution process one should monitor that process until
one builds a sufficient data set that clearly demonstrates the process is in compliance and in a
state of control.
It is necessary to develop an internal documentation system as well as multi-party
communication standards and protocols to transfer or create a central repository or hub to track
information across the supply chain. These systems would monitor equipment status, product
temperature history, and custody chain, etc. These help ensure that a food, pharmaceutical, or
vaccine is safe and effective when reaching its intended consumer.
It is also important to have a complete chain for the entire life cycle of a product, so there is
documented evidence as to who had control of the product throughout the lifecycle of the
product, up to the final users consumption of the product.
89


3.6.4 Ongoing Monitoring
The standardized use of qualification, validation and good cold chain management practices will
be beneficial for all involved parties in handling, storing and distributing environmentally
sensitive pharmaceuticals. An ongoing monitoring programmed will provide data to make the
quality decision for each shipment.
90


A REVIEW ON PHARMACEUTICAL VALIDATION
120

3.7 Source Validation:
It is defined as the collection and evaluation of data, beginning at
the process development stage and continuing through the
production phase, which ensure that the manufacturing processes
including equipment, buildings, personnel and materials are
capable of achieving the intended results on a consistent and
continuous basis.
91
It is also known as vendor validation.
The following points should be maintained carefully in case of source validation:
1. The evidence must be documented. (The results of the validation must be recorded).
2. Validation applies to several aspects of manufacturing, including e.g. process development,
materials, personnel and equipment).
3. It should demonstrate that the system does what is expected of it.
92

Validation is carried out against a set of criteria that are defined in advance. These criteria are
detailed in predefined protocol documents.
A Vendor Validation program includes:
Qualification of all suppliers including components, ingredients, labels, etc.
Audits of suppliers and vendors
Checking that COA(Certificate Of Analysis) from vendors include specifications for identity,
description, limits on contaminants, results, strength, and acceptance limits
Confirming the test results of certificates of analysis
Re-qualifying the vendor at periodic intervals
Reviewing specifications, procedures, and lab controls
Regular reviews of vendors documentation
93


3.7.1 Methods of vendor validation
Vendor validation can be done by two ways:
1. Vendor Approval
2. Vendor Evaluation
Procedure for inclusion of vendor in approved vendor list (Raw materials)
New vendors must be qualified and approved by QA department before regular supply of raw
materials in following manner.
A REVIEW ON PHARMACEUTICAL VALIDATION
121

1. Purchase department will locate the new vendor and find out the details of products
manufactured / supplied by them. In case of existing materials, Purchase department will
provide our specification to the new vendor.
2. Purchase department will submit the samples to QA department or R&D department for
evaluation as per specifications.
3. Samples from 3 consecutive lots / batches of active ingredient should be procured as pre-
shipment sample along with certificate of analysis. For active as well as excipients,
Assurance / Declaration of compliance with TSE / BSE requirement or material is of
vegetable origin shall be taken from the manufacturer.
4. Quality Assurance or R&D department should analyze the sample.
5. After complete analysis of the sample, the analytical report along with the comments of QA
department shall be sent to Purchase department. The vendor will be included in the
temporary approved vendor list if the samples are meeting the specifications. The new
addition to the list are entered manually and approved by Head QA & QC till the list is
amended.
6. Purchase department after studying the comments of QA department shall inform the
supplier for the supply of the material manufactured by them.
7. An audit is performed by representative of Purchase department, QA department and GMP
Cell.
i. Active Raw Material / Excipients vendor audit report shall be prepared.
ii. A supplier questionnaire is sent to suppliers.
iii. However the visit and audit of vendor shall not be considered as an approving
criterion and based on the previous history, background and quality trial lots supplied
by the supplier, the vendor may be included in approved vendor list.
8. Purchase department shall carefully study the quality aspect and also the quantity and
financial aspects of the vendor, they are as follows;
i. Capability of the vendor to supply the required material within the period.
ii. Delivery schedule in order not to affect the production cycle.
iii. The rates quoted by the vendor whether they are competitive with respect to other
vendors without compromising the quality aspects.
9. Based on the product compliance and assessment, further procurement of active raw material
A REVIEW ON PHARMACEUTICAL VALIDATION
122

should be continued. On ensuring compliance with specifications the vendor shall be
included in permanent vendors list during update of list.
10. All the suppliers evaluated by R&D department on the basis of process / product
development parameters shall be considered as temporary vendors and will be included in
temporary approved vendor list. Based on the commercial production supply, they will be
transferred to approve vendor list and shall be considered as permanent approved vendors.
11. Vendors recommended by R&D having drug master file number shall be included as
temporary vendors and based on the performance on commercial supply for production
batches, will be transferred to approve vendor list.
12. Vendors approved by the product license holder or contract giver will be listed separately as
approved for product license holder products.
94


Procedure for inclusion of vendor in approved vendor list (Packaging material)
New vendors must be qualified and approved by QA department before regular supply of
packaging materials in following manner.
1. Purchase department will locate the new vendor and find out the details of products
manufactured / supplied by them. In case of existing materials, Purchase department will
provide our specification to the new vendor.
2. For printed and primary packaging materials, vendor audit is performed by representative of
Purchase department, QA department and GMP Cell.
3. Samples of printed packaging materials if necessary will be submitted to QA department for
evaluation.
4. Purchase department after studying the comments of QA department shall inform the supplier
for the supply of the material manufactured by them.
5. Purchase department shall carefully study the quality aspect and also the quantity and
financial aspects of the vendor, they are as follows;
a) Capability of the vendor to supply the required material within the period.
b) Delivery schedule in order not to affect the production cycle.
c) The rates quoted by the vendor whether they are competitive with respect to other vendors
without compromising the quality aspects.
6. Based on the product compliance and assessment, further procurement of packaging material
A REVIEW ON PHARMACEUTICAL VALIDATION
123

should be continued. On ensuring compliance with specifications the vendor shall be included in
permanent vendors list during update of list.
7. All the suppliers evaluated by R&D department on the basis of process / product development
parameters shall be considered as temporary vendors and will be included in temporary approved
vendor list. Based on the commercial production supply, they will be transferred to approve
vendor list and shall be considered as permanent approved vendors.
50

Procedure for exclusion of vendor from approved vendor list
1. The vendor shall be disqualified and removed from the approved vendors list for the
following reasons:
i) If a lot does not comply with the specification with respect to critical tests then the
vendor shall be disqualified. The vendor shall be qualified again on further evaluation
and investigation.
ii) If a lot does not comply with the specification with respect to minor tests then the
vendor shall be disqualified if it is observed for 3 consecutive lots.
iii) 3 out of 10 lots fail to comply with the specification in a specified period under
review.
iv) The delivery schedule is not met for 40% supplies.
2. The rates mentioned in Purchase Order, differs than the rates mentioned in delivery challan
and invoice.
50


3.7.2 Corrective and Preventive action
The vendor, who has been excluded from the approved vendors list, may be included again by
taking following corrective and preventive actions;
1. The vendor shall be made aware of the reasons for his exclusion and shall be asked to explain.
2. Head Purchase and Head QA&QC shall conduct facility audit of the vendor in order to ensure
that quality system exists in the organization.
3. Carry out the discussion on other non-quality issues like delivery schedule and rate, etc.
4. After satisfactory compliance of all above points, the vendor shall be included in Temporary
Vendor List.
50

A REVIEW ON PHARMACEUTICAL VALIDATION
124

3.7.3 Importance of Source Validation
1. Assurance of quality:
Quality of finished product is greatly dependent on raw material and packaging material. The
most common cause of recall is faulty packaging material. QA department tests pre-shipment
samples to see whether they match with their specification and also whether they concur with the
COA. This ensures quality of the raw/packaging material and hence that of the finished goods.
Otherwise there is chance of contamination or adulteration.
47

2. Time bound:
By using validated method it is possible to supply the finished products within a time cycle.
Purchase department evaluates capability of the vendor to supply the required material within a
defined period. If supplier is unable, then this will create chaos in the production cycle.
48

3. Process optimization:
Use of validated on-time supplier leads to process optimization. Qualification of all suppliers
including components, ingredients, labels, etc. as well as re-qualifying the vendor at periodic
intervals by QA leads to validated raw/packaging materials which aids in smooth production and
supply and hence gives rise to an optimized process. Without this, any problem from the
supplier's end at any time will hamper production and also cause possible recall.
95

4. Reduction of cost of quality:
There is no doubt that the majority of the cost related to failure to maintain quality standard can
be prevented by the validation of source material. By proper source validation quality related
cost can be effectively reduced with a corporate quality programme but without lowering the
products standard.
51

5. Minimal batch failures:
If material is from approved source, the batch failure rate is minimized. Validated qualified
materials will lead to batches of quality finished products provided the production system is
intact. Successful batches result from good raw and packaging materials which can only be
obtained from a validated vendor. This maximizes output.
96

6. Improved efficiency and productivity:
Higher quality and productivity rate are the main theme to flourish an industry. An effective
vendor validation program results in high quality materials and components from validated
vendors and significantly reduces the amount of testing that has to be done on incoming
A REVIEW ON PHARMACEUTICAL VALIDATION
125

materials thus cutting down on overall production time. Consequently, efficiency and
productivity rises.
52

7. GMP compliance:
The use of qualified starting and packaging materials is a GMP requirement. In order to meet this
requirement, it is necessary to validate suppliers. Therefore, vendor validation allows more
compliance with GMP. At the same time, it also needs to be ensured that the vendor is producing
their material under full GMP compliance.
47

8. Less chance of sanctions:
Goods from accredited source will produce standard finished products. If products are of high
quality, then the likelihood of being sanctioned (fined huge amount of money) by regulatory
authorities is considerably less. Substandard, contaminated or adulterated raw materials from
non-validated supplier lead to corrupted finished products which increases the chance of being
sanctioned and even shut-down.
51

9. Fewer complaints about process related failures:
By using validated raw material it is possible to ensure full optimization of process. So,
ultimately leads to minimum process problem. Sample is collected from potential vendor and
then the material is run through the process to ensure that the material complies with the
specification needed for the machines or processes that are validated for the consistent
production. Materials, if not checked and tested properly, can cause frequent problems in
process, costing extra man-hour as well as wasting valuable time, which in turn can delay the
market availability of the product.
51

10. Reduced testing in process and in finished goods:
Testing of IPC and QC also can be done very easily due to the fact that the results are all time
found within the range. To ensure that the vendor can supply consistent quality, the Quality
Assurance team visits the facility of the vendor to ensure they have the capacity and proper setup
to ensure consistent quality. For further assurance, samples are requested from the vendor and
tested by the Quality control of the Pharmaceutical Company and then approved if it meets all
the quality criteria. Going through this process ensures a regular consistent material delivery
from a trusted vendor.
Frequent deviations in the raw and packaging materials supplied by a vendor means it requires
more attention from IPC and QC department. It costs extra time because any deviation or Out of
A REVIEW ON PHARMACEUTICAL VALIDATION
126

specification found in any test for the material means further testing needed to be sure of, before
finally labeling it as Rejected.
48

11. Improved employee awareness of processes:
Materials and machineries are validated; this means there is nothing wrong with them. Any
problem arising now would refer to problem with personnel. So employees (especially at the
production site) have to be extra careful in order to not make any mistakes. This helps to gain
employee awareness in the overall process.
51

12. Rapid automation:
Automation in process is the ultimate goal of validation of materials both raw and packaging.
Validating a vendor or source for the raw and packaging materials refers to ensuring that the
vendor is supplying materials of consistent quality, it also sets some specification for any
particular material, thus the testing, validating and in process check becomes automatic as every
time the same material is being used.
Without automation, the production steps are needed to be adjusted for every product and
material, which costs valuable time as well as other additional cost are associated.
48

13. Government regulation:
Before launching a new product it is mandatory to submit overall information to DGDA for
approval of drug manufacturing license, which includes validation processes as well. Source
validation falls under this and so is a requirement for approval.
52



A REVIEW ON PHARMACEUTICAL VALIDATION
127

3.8 Personnel Validation
Personal Validation act as validating something, such as a certificate, that validates something;
attestation, authentication, confirmation, proof or verification.
97
Establishment and maintenance
of satisfactory system of QA and manufacturing of products and actives rely on people. So, it
must be sufficiently qualified personnel to carry out tasks. Individual responsibilities must be
clearly understood by individuals concerned and all personnel should be aware of the principles
of GMP that affect them.

3.8.1 GMP Requirement
1. Adequate number of qualified people with practical experience
2. An individuals responsibilities should not be so extensive as to present a risk to quality
3. Individual written job description
4. Organization Chart
5. No gaps or unexplained overlaps
6. Adequate authority to carry out responsibilities
7. Prevent unauthorized access to production, storage, quality control
8. Stop personnel who do not work in these areas using them as passageways.
98


3.8.2 Responsibilities
Key personnel (which normally should be full-time) positions include:
Head of Quality Assurance
Head of Quality Control
Head of Production
Heads of Sales and Distribution
64

Key personnel should possess the qualifications of:
1. Scientific education
For example: Bachelor of Pharmacy, chemistry, biochemistry, chemical engineering,
Microbiology, pharmaceutical sciences and technology, pharmacology and toxicology, or other
related science subjects relevant to the responsibilities to be undertaken.
2. Practical experience
under professional guidance
A REVIEW ON PHARMACEUTICAL VALIDATION
128

able to take difficult decisions in a professional and scientific way
resolve the problems encountered in manufacturing and QC
99

Heads of Production and Quality Control responsibilities:
authorization of written procedures (SOPs) and other documents, including amendments
environmental monitoring and control, and plant hygiene
process validation and calibration
training, including application and principles of QA
approval and monitoring suppliers
designation and monitoring of storage conditions
retention of records
monitoring compliance with GMP
inspection, investigation, and taking of samples to monitor factors which may affect
quality
Head of Production Responsibilities:
Product production and storage according to appropriate documentation
Approval and implementation of production instructions, in-process QC and ensure strict
implementation
Evaluate production records; signed by designated person before passing to QC
Maintenance of production department, premises and equipment
Process validation and calibration performed, recorded and reports made available
Training of production personnel; initial and continuing
Head of Quality Assurance Responsibilities:
Approval or rejection of materials, packing materials, intermediates, bulk and finished
products
Evaluation of batch records
Carrying out of necessary testing
Approval of quality control procedures: sampling instructions, specifications, test
methods, and other QC procedures
Approval and monitoring of all contract analysis
Maintenance of quality department, premises and equipment
A REVIEW ON PHARMACEUTICAL VALIDATION
129

Validation, including analytical procedure validation, and calibration of control
equipment
Initial and continuous training of QA personnel.
64


3.8.3 Training for personnel
Training, in accordance with a written programme for
all personnel whose duties take them into production; or
into control laboratories; and
for others whose activities could affect the quality of the product
On induction and continuing
on theory and practice of GMP;
approved by either the head of Production or QA as appropriate
training records should be kept
training before undertaking any new task
Staff in special areas
clean areas; or
working with highly active, toxic, infectious, sensitizing materials should be
given specific training
The concept of QA and its understanding and implementation should be fully
discussed during training
Training session to be documented
Seminar or congress in or outside the company
Training in the company
Regular department meeting dealing with quality matters
Training of SOPs
Must be informed in advance; particularly about
personal hygiene; and
protective clothing requirements
Must be accompanied and closely supervised at all times.
100


A REVIEW ON PHARMACEUTICAL VALIDATION
130

3.9 Packaging Validation:
Packaging is defined according to WHO as a process that bulk material must undergo finished
product. The basic need for packaging validation is that it enables packaging process to meet the
product and market requirements i.e. quality attributes and consumer needs in a cost effective
and consistency efficient process with minimum down time, rejects and errors. The standard
series ISO 11607 stipulates validation of the packaging processes used for industry, health care
facilities and wherever medical devices are packed and sterilized e.g. hospitals, doctors and
dentists surgeries. This guideline deals with the following packaging processes:
pouch, reel or bag sealing,
sterilization sheets folding and wrapping,
filling and closing of reusable sterilization containers.
The processes not dealt in this guideline must be validated as per ISO 11607-2.
In 2000/2001, 42% of the defects reported by MHRA in the UK related to printed packaging
components; either because they were incorrectly printed or because the wrong components were
used within the pack. So, in order to minimize the risk of defective product reaching the patient, it
is therefore vital that there is strict procedural control of artwork development, review and
approval and handling of printed components from printer to packaging line.
Validation of packaging processes is crucial to guarantee that the integrity of the packaging
system is always assured and maintained during transport and storage until the time of use.
Packaging has been defined as the art, science and technology of preparing goods for sale in a
cost effective manner.
In considering what is meant by preparing goods for sale in the context of pharmaceuticals we
should remember that the packaging must:
Preserve the product - from degradation or contamination
Contain the product - to avoid leakage
Identify the product - providing traceability and information regarding expiry date, etc.
Security - against tampering and counterfeiting
Information on use - an aide memoir for compliance.
Convenience in use - for medical staff or patient;
A marketing tool - supporting features and/or graphics appropriate to the sales medium.
A REVIEW ON PHARMACEUTICAL VALIDATION
131

All this must be ensured for the life of the product and achieved within a complex regulatory
environment.
101

The packaging materials used must be suited to and defined for the intended packaging and
sterilization processes. Suitability is determined on the basis of information provided by the
manufacturer.
There are multiple considerations to robustness of packaging process. All medicinal products
need to be protected and consequently need to be packaged in containers that conform to
prescribed standards, particularly with respect to the exclusion of moisture and light and the
prevention of leaching of extractable substances into the contents and of chemical interaction
with the contents. The limit of acceptability depends on climatic variables partially based on
selection and change in packaging.
Key areas that play a major role and impact the robustness of a packaging process and should be
considered in validation are as below:

3.9.1 Packaging Materials
Containers: Glass, metal, plastic & rubber
Closures: Metal, plastic & rubber
Foils: Metal (ALU), cellulose, paper, plastic (PVC, PVDC)

3.9.2 Packaging Equipment
The design and layout of equipment has major impact on the efficiency of the packaging line.
Well-designed equipment will lend itself to efficient production of a consistent standard, whereas
older equipment can often be inflexible and may have elements of poor design such as areas
where packaging components or product may be trapped. These traps can result in products
being incorrectly packed, e.g. a carton containing the wrong leaflet or product from a different
batch.
This represents a significant risk to the patient and is one of the major reasons for product recall
in the industry.
The greater the number of stages there are in a packaging line, the lower its efficiency will be.
With modern order patterns of short runs it may for example be better to have two slow speed
fillers feeding a single cartooned rather than a single high-speed filler.
A REVIEW ON PHARMACEUTICAL VALIDATION
132

Appropriate validation of the packaging lines will challenge the robustness of the packaging
operation establishing the conditions under which efficiency is maximized.

3.9.3 Assess the GMP Risk
Although all GMP risks are important one can specifically take into consideration product defect
class 1 (critical) defect /intolerable defect (dangerous and pose serious health hazard) leading to
product recall. E.g. the contents of the package do not match the labeling on the package,
printing errors on labels and package inserts, incorrect packaging component in the final
assembly.
102


3.9.4 Line Layout
Design considerations for a line layout should include the ability to manage quick change-over,
perform line clearance between batches of product and clean the line in an easy and controlled
manner.
The majority of problems on packaging lines are related in some way to poor line clearance; it is
therefore important to design these problems out. A typical packing line will consist of several
feeders for packaging components and product.
Devices will normally be located in critical positions on the line to detect presence or otherwise
of the materials.
For example, a device installed on the carton feeder will ensure that a carton is supplied for each
product or tray of product and a barcode reader will verify that it is the correct one. A check
weighed will make certain that under filled or overfilled bottles are identified and ensure via the
reject device that they are excluded from the batch.
The layout of the equipment should guarantee that easy access is provided for operators and the
engineers to access this equipment when adjustments and or maintenance are required.

3.9.5 Operating Procedure and Training
To manage a packaging line, adequate standard operating procedures (SOPs) will be required.
It is vital that there are clear and unambiguous instructions on how to operate, adjust, and
maintain each piece of equipment. In addition, there will be procedures to detail how a batch is
A REVIEW ON PHARMACEUTICAL VALIDATION
133

packaged, SOP usually explains how each material is received on the line and checked for
correctness, quantity, etc. by the operators.
Details of In Process Control (IPC) tests will be given in these SOPs. Involving the line operators
in developing the SOPs will result in documents that more accurately reflect what is actually
happening on a day to day basis.
Operators will also take ownership of the SOPs ensuring better compliance and hence less
problems on the line.
103


3.9.6 Conduct of Packaging Validation
104

Packaging Validation Consists of following Steps:
Installation Qualification (IQ),
Operational Qualification (OQ) and
Performance Qualification (PQ)

Installation qualification:
At this stage engineering drawings should be checked and updated as appropriate. The technical
equipment (e.g. heat sealers) is checked if they have been properly installed and users trained. In
general, packaging processes involves sterilization sheets as well as reusable sterilization
containers are purely manual processes, so its proof of IQ is based on documentation of training
of staffs.

Operation qualification:
A distinction between automated and manual processes is made here.
a) Automated process
The heat sealing process is defined on the basis of the following parameters:
sealing temperature,
contact pressure and
sealing time/speed (dwell).
The contact pressure and sealing speed or time (dwell) are generally set by the manufacturer of
the heat sealer. The optimum sealing temperature for the respective packaging material must be
determined by the user. To that effect, the technical data sheet supplied by the manufacturer of
A REVIEW ON PHARMACEUTICAL VALIDATION
134

the packaging material is needed. This must specify the sealing temperature (e. g.170 200 C).
Sealing samples must be produced for the respective lower and upper limits. The quality
properties listed in ISO 11607-2, 5.3.2 b must be assured:
intact seal for a specified seal width
no channels or open seals
no punctures or tears
no material delamination or separation
Then the sealing temperature must be specified for routine operations. in general this is
calculated from the mean value of the limit values (e. g. mean value from 170 C and 200 C is
185 C).
b) Manual process: Sterilization sheets folding and wrapping; filling and closing of reusable
sterilization containers are checked. The most critical packaging configuration is determined,
and then these are packed according to the SOPs. The quality properties are verified and
documented by means of suitable processes or tests.
Test methods for verification of quality properties
Test method Suitable for verification of the following
quality properties
Seal integrity test (e.g. dye penetration test/
Ink test, acc. to ISO 11607-1, Annex B)
Channels or open seals
Punctures or tears.
Seal integrity indicator (e.g. Seal check) Intact seal for a specified seal width
Channels or open seals
Punctures or tears
Peel test acc. To EN 868, Annex E Material delamination or separation
Visual inspection Intact seal for a specified seal width
Punctures or tears

Performance qualification:
During this, proof must be provided that after sterilization, the process is under control and
process optimally sealed or closed sterile barrier systems.
Verification is done by means of the seal strength test as per EN 868-5, Annex D. The test is
carried out as follows:
A REVIEW ON PHARMACEUTICAL VALIDATION
135

i. Cuts measuring 15 mm in width are taken of the dried samples and at an angle of 90 to the
seal seam. At least one sample of a produced seal seam must be taken from each packaging.
If only one sample of a seal seam is taken, the sample must be taken from around the centre.
ii. Simulation of the peeling process at a speed of 200 mm/min.
iii. Recording of the seal seam strength.
iv. Evaluation and documentation of the results.
In manual processes, the testing, sterilized packaging systems are taken from the running
processes. From 3 different cycles or batches, one sample is taken in each case. Then, assurance
of the quality properties is verified for each packaging system (sample).

3.9.7 Performance qualification examples
Blister Packing :
Speed & Temperature settings / range
Different materials
Different suppliers
Different products
Need to package at extreme temps & evaluate its impact on Quality
Sealing Quality
Pack appearance ( Aesthetics )
Product Quality ( Stability, purity, assay etc )
Ampoule / Vial Filling & Packing:
Fill volume variation : fill accuracy
Splashing, spillage, container damage
deoxygenate, if required (assay )
Seal quality : aesthetics, seal test ( leak test )
Labeling / information overprinting
Inspection : manual, automatic, bar code reading
Line speed.


A REVIEW ON PHARMACEUTICAL VALIDATION
136

3.9.8 Tests that can be performed for packaging validation
105

1. Microbial Barrier Test:
The aim is to assess the microbial barrier of porous packaging materials.
Reference Standard: ASTM F 1608 Standard test method for microbial ranking of porous
packaging materials (Exposure chamber method).
Test samples are placed in an exposure chamber and an aerosol of Bacillus atrophaeus spores is
applied in the chamber. Spores which passed through the test sample are collected on membranes
filter and enumerated.
2. Toluidine Blue Test:
The aim is to assess the sealing tightness.
Reference standard: ASTM F 1929 Standard test method for detecting seal leaks in
porous medical packaging by dye penetration.
A dye penetrant is injected into the package to cover all the sealing; the contact is maintained for
the 5 to 20 seconds. Then, a visual exam of the sealing area through the transparent side of the
package is carried out.
3. Visual Inspection test:
The aim is to assess the sealing tightness.
Reference standard: ASTM F 1886 Standard test method for determining integrity of seals
for medical packaging by visual inspection.
A visual exam at a distance of 30 to 40 cm is carried out to inspect the entire sealed area of the
packaging for completeness and uniformity. The defects (number and location) are identified and
recorded. E.g. of defects: unsealed areas, non-homogeneous area, channels, etc.
4. Immersion test:
The aim is to assess the tightness of the whole packaging.
Reference standard: MedicalLab Protocol ML-FSI82-006
The sample is placed in a container filled with water at a depth greater than 150 mm and is
maintained for 20 seconds. Then, it is verified that no air bubbles escape from the sealing or the
packaging.
5. Pealability test (Manual):
The aim is to assess the pealing ability of the packaging.
A REVIEW ON PHARMACEUTICAL VALIDATION
137

Reference standard: NF EN 868-5 Packaging for terminally medical devices Part 5
Sealable pouches and reels of porous materials and plastic film construction
Requirements and test methods Appendix E.
The package is peeled slowly and carefully and the seal on the entire width and length is verified.
The width of the sealing area is measured.
6. Pealability test (With tensile strength equipment):
The aim is to assess the pealing ability of the packaging.
Reference standard: French Pharmacopoeia.
Samples are cut of 15 mm width and placed in the tensile testing machine. The maximum
pealing strength is measured.

7. Sealing Strength test:
The aim is to assess the strength of the sealing.
Reference standard: ASTM F 88 Standard test method for sealing strength of flexible barrier
materials.
NF EN 868-5 Packaging for terminally medical devices Part 5 Sealable pouches and
reels of porous materials and plastic film construction Requirements and test methods
Appendix D.
The samples are cut of 15 mm width and placed in the tensile testing machine. The maximum
strength is measured.


A REVIEW ON PHARMACEUTICAL VALIDATION
138

8. Vacuum test:
The aim is to assess level of the vacuum in vacuum pouches.
Reference standard: MedicalLab Protocol.
The sample is placed in a vacuum-bell jar linked with a pressure gauge and a low vacuum pump.
The vacuum (pressure in mbar) in the pouch is quantified.
9. Accelerated Aging:
The aim is to simulate the aging of the packaging up to the expiry date.
Reference standard: ASTM F 1980 Standard guide for accelerated aging of sterile barrier
systems for medical devices.
The packaging samples are placed in the thermo-regulated chamber at 55C for accelerated
aging. During the whole aging time, temperature of the chamber is monitored. After aging, the
packaging is tested.


Figure 8: A flowchart of package process validation
A REVIEW ON PHARMACEUTICAL VALIDATION
139

3.10 Cleaning Validation
Cleaning validation is documented evidence with high degree of assurance that one can
consistently clean a system or piece of equipment to predetermined and acceptable limits, taking
into consideration such elements as batch size, dosing, toxicology, equipment size, and the like.
It is primarily applicable to the cleaning of process manufacturing equipment in pharmaceutical
industry. It is necessary to have effective cleaning programs in place because of regulatory
requirements. It is typically completed by the accomplishment of a minimum of three
consecutive successful trials. In order to ensure that all activities are scientifically established, an
orderly approach to cleaning is followed. A flowchart of these activities is shown in fig below.

Figure 9: Cleaning validation
process flow
A REVIEW ON PHARMACEUTICAL VALIDATION
140

3.10.1 Necessity
3.10.1.1 Why required
1. To produce products that are as pure and free from contamination to extent that is possible
and feasible.
106

2. To verify the effectiveness of cleaning procedures and to ensure no risks are associated with
cross contamination of active ingredient or detergents/sanitizer.
107

3.10.1.2 When required
1. Initial qualification of process/ equipment.
2. Critical change in a cleaning procedure.
3. Critical change in formulation.
4. Significant change in formulation.
5. Change in a cleaning agent.
108


3.10.2 Advantages
1. Safety: Validation can also result in increased operator safety. Properly calibrated, validated
instruments and gauge used to reduce accident and results in safety.
2. Better Customer quality: Through proper validation, market recall is avoided which results
in better customer care and quality of the product.
109


3.10.3 Contamination
A contamination is the introduction of an undesired substance (chemical, microbiological or
other) into a starting material, intermediate or finished product.
25
Carryover of other product
component such as excipients can be problematic and may degrade and final quality of product
and this is called contamination.
110


3.10.4 Cross Contamination
A cross contamination is the introduction of a starting material, intermediate or finished product
into another starting material, intermediate or finished product.
111
Cross contamination is usually
through an active ingredient from one product carrying over into subsequent manufactured
product.
94
A REVIEW ON PHARMACEUTICAL VALIDATION
141

3.10.5 Mechanism of Contamination
1. Cross contamination with active ingredient: One of the real dangers in cross
contamination of active ingredients is that by being contaminated results in a multiple
ingredient product instead of single active ingredient.
Hazards:
a. Contamination may enhance the action or negate the action
b. Contaminant may have entirely different medical effects.
2. Microbiological contamination: This form of contamination is particularly insidious
because the contamination may develop at any time even after cleaning. A major contributing
factor is the storage of equipment in a wet condition. This provides a natural medium in
which bacteria can grow.
3. Contamination by cleaning or sanitizing agents: Some pharmaceutical operations may
find it necessary to use fairly toxic materials for cleaning purpose for stubborn residues. This
is particularly true in the manufacture of active pharmaceutical ingredients (APIs).
Hazards:
a. These materials represent a potential threat as contaminants.
b. Sanitizing agents used to wipe down cleaned equipment can cause.

4. Contamination by miscellaneous other materials: In addition to the usual expected or
anticipated list of potential contamination in a pharmaceutical operation, many other less
likely materials can also contaminate products. A partial list includes equipment parts such as
excipients, bristles from brushes used in packaging filling equipment, paper filters, micron
filters, fibers and rubber particles from gloves, cleaning aids such as brush bristles, cloth, and
cotton fibers from rags and wiping materials, lubricants.

3.10.6 Cleaning Agent selection
Cleaning chemistries fall into several broad categories:
1. Water: It is the universal solvent. If water alone will effectively clean the product without
undue time or physical effort to remove the residues, by all means employ water alone.
Sometimes water alone requires an unacceptable increase in time to get the cleaning
accomplished. For these individuals, one of the other approaches must be sought.
A REVIEW ON PHARMACEUTICAL VALIDATION
142

2. Solvent: These are typically applied in processes where solvent usage is already called for by
the manufacturing process.
For example, mother liquors are typically used as the solvents for cleaning of APIs.
Advantages:
Mother liquors is known to dissolve the primary residue.
There is little risk in employing if for cleaning.
3. Commodity chemicals: Chemicals such as NaOH can be used for cleaning as well.
Their typically high alkalinity or low acidity, however, often makes them helpful in
inactivation processes.
Disadvantages:
There may be hazard issues.
Effluent issues associated with these materials.
These chemicals lack the detergency so difficult to rinse.
Taking larger volumes of water to rinse free from systems.
4. Formulated cleaning agent: It is the largest class of cleaners. This category includes solvent
based formulations and aqueous formulations. Typically formulated cleaning agents can
include one or more alkalinity or acidity sources, surfactants builders, sequestrants, chelants
and either a solvent or water.
Advantages:
These materials are formulated to be low foaming and therefore are more readily rinsable.
Appropriate for high impingement or high turbulence cleaning.

3.10.7 Sampling Techniques
3.10.7.1 Sampling sites
It was selected based on the difficult clean geometries of the equipment and these locations
are inaccessible (Their inaccessibility makes them difficult to clean therefore, before
choosing for sampling sites one must be conscious in selecting the desired sampling
locations.)
Sampling sites of equipment is characterized by-
1. Hot spot: It is the location that is likely to become dirty during the manufacturing process
and it is difficult to clean.
A REVIEW ON PHARMACEUTICAL VALIDATION
143

2. Critical sites: They are those locations if remain dirty will certainly show disproportionate
level of contamination to the next exhibit batch.
3.10.7.2 Number of Sample Locations
The number of sample locations selected for individual equipment was based on the difficult to
clean geometries, representative location were disproportionately contaminate the portion of the
next batch.
Sample locations selected were influenced by:
1. Material of construction
2. Over all scale of the piece of equipment.

3.10.8 Sampling Methods
The common sampling method employed in cleaning validation is rinse sampling and swab
sampling.
A. Swab Sampling: It usually requires materials which are absorptive & to physically wipe the
surface and recover the analyte. Because the need to physically wipe the surface was the
preferred method that is readily accessible to human hand or arm.
Advantages:
1. Dissolve and physically remove sample.
2. Adaptability to wide variety of surfaces.
3. Economically and widely available.
4. May allow sampling of a defined area.
5. Applicable to active, microbial, and cleaning agent residues.
Limitations:
1. An Invasive technique that may introduce fibers.
2. Results may be technique dependent.
3. Swab material and design may inhibit recovery and specificity of the method.
4. Evaluation of large, complex and hard to reach areas difficult.
112, 113


B. Rinse Sampling: Rinse sampling does not employ mechanical action on the surface and the
sample is collected as a final rinse or rinse applied specifically for collecting a validation
sample.
A REVIEW ON PHARMACEUTICAL VALIDATION
144

Limitation:
1. Limited information about actual surface cleanliness in some cases.
2. May lower test sensitivity.
3. Residues may not be homogenously distributed.
4. Inability to detect location of residues.
5. Rinse volume is critical to ensure accurate interpretation of results.
6. May be difficult to accurately define and control the areas sampled, therefore usually
used for rinsing an entire piece of equipment, such as vessel.
97, 114


C. Placebo Sampling: Placebo is recognized as both potential cleaning techniques and potential
sampling techniques. Placebo material comprises of all typical excipients but not the active
ingredient. And the placebo batches were passed through a same line so that it will have
possibility to scrub of the clean system.
The principle involved in placebo is that it is passed through the same pathway as the product
therefore; it will have the possibility to scrub off residual product along those pathways. And it
usually employed for measuring system cleanliness. It majorly depends on:
1. Excipients solubility in placebo.
2. Appropriate contact time of the placebo for collecting representative sample.
3. Coverage of the placebo in-process pathways ensures removal of the placebo from all
equipment location.
4. Quantity of the placebo and residue being matched should be detectable range and the
distribution of residue uniformly in the placebo ensures the detection of sample at any
portion of the placebo.

D. Direct Sampling: It is done by using FTIR or photoelectron emission techniques. By
employing these techniques, specific spectra obtained from residue remaining on the surface
will directly measure the quality of the surface.
Advantages:
1. Sampling and analysis will be taking place in one step.
2. There will be no real loss of sampling system.
A REVIEW ON PHARMACEUTICAL VALIDATION
145

In swab sampling direct analysis of the surface is limited to the area that are accessible for
inspection.

3.10.9 Level of Cleaning
The manufacturing process of an API typically consists of various chemical reaction and
purification steps followed by physical changes. So purification and potential carryover of the
previous product would be removed. It is required in order to ensure that the API is free from
unacceptable levels of contamination by previous substances.
It varies depending on -
1. The step being cleaned
2. Next substance being manufactured in the same piece of equipment train.
The degree or level of cleaning and validation required for process in API manufacturing
depends largely on:
1. The equipment usage (i.e. dedicated equipment or not)
2. The stage of manufacture (early, intermediate or final step)
3. The nature of the potential contaminants (toxicity, solubility etc.)
115,

116

The CEFIC-APIC guide to cleaning validation recommends three levels of cleaning that may be
implemented. This approach is outlined in the table below:

Level Thorough of cleaning Cleaning validation
2 Carryover of the previous product is critical. Cleaning
required until predetermined stringent carryover limits are
met.
Essential
1 Carryover of the previous product is less critical. Cleaning
should reduce the potential carryover to a less stringent
limit as required for level 2.
Increase from not
required to necessary
(Lower acceptable
carryover limits)
0 Only gross cleaning if carryover of the previous product is
not critical
Not required


A REVIEW ON PHARMACEUTICAL VALIDATION
146

3.10.10 Cleaning Validation procedure
1. Cleaning validation studies are carried out to provide a documented evidence and actual
experimental data that the procedure being followed for cleaning of equipment and
accessories is effective and removes all residues of previous up to a predetermined
acceptance level, thereby avoiding the risk of cross contamination.
2. Cleaning validation studies conducted shall be carried to determine the leftover residue of
active ingredient for traces of cleaning agent and microbiology status of cleaned equipments.

3.10.11 Strategy on Cleaning Validation Studies
Basic elements of cleaning validation study includes
A. Evaluating of new product/equipment
1. For new product: In case there are more than one API for the new product, each API shall
be evaluated for the below detailed parameters and based on the evaluation one API shall be
selected as worst case product
a. Batch size of the product: The product which has minimum batch size should be
considered as worst case product, which makes the acceptance criteria more stringent.
b. Based on Label Claim of API: The Product with highest strength can be considered as
worst case product.
c. Dose for the product: The product having maximum daily dose can be considered as
worst case product.
d. Solubility of the API: Product having least solubility in water and higher strength can be
considered as worst case product on basis of solubility.
e. Based on Therapeutic Potency: The most Potent product can be considered as the worst
case product on the basis of therapeutic potency.
2. For new equipment: When new product is identified as worst case, the total surface area for
the equipment shall be arrived by identifying the equipment used for manufacturing.

B. Determination of limit and reporting
Calculation of MAC for Product is given by the formula:
1. By dose criteria: NMT 1/1000th dose of any product shall appear in the maximum daily
dose of another product manufactured subsequently.
A REVIEW ON PHARMACEUTICAL VALIDATION
147

MAC= STD SBS SF LDD
Here,
MAC = Maximum allowable carryover in mg;
STD = Single Therapeutic dose of previous;
SBS = Smallest batch size of next product to be manufactured in mg;
SF = Safety factor;
LDD = Largest daily dose of next product in mg

2. 10 ppm criteria: 10 ppm of any product residue shall appear in another product
manufactured subsequently.
MAC (mg) = 10 ppm SBS
Where, SBS = Smallest batch size of next product to be manufactured in mg.
C. Cleaning Procedures.
Standard cleaning procedures for each piece of equipment and process should be prepared. It is
vital that the equipment design is evaluated in detail in conjunction with the product residues
which are to be removed, the available cleaning agents and cleaning techniques, when
determining the optimum cleaning procedure for the equipment. Cleaning procedure should be
sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process.
Parameters are to be considered during cleaning procedures
1. Equipment Parameters to be evaluated include
a. Identification of the equipment to be cleaned
b. Difficult to clean areas.
c. Property of materials.
d. Ease of disassembly.
e. Mobility.
2. Residues to be cleaned
a. Cleaning limits
b. Solubility of the residues.
c. Length of campaigns
3. Cleaning agent parameters to be evaluated
a. Preferable materials that are normally used in the process.
A REVIEW ON PHARMACEUTICAL VALIDATION
148

b. Detergents available (as a general guide, minimal use of detergents recommended unless
absolutely required).
c. Solubility properties.
d. Environmental considerations
e. Health and safety considerations.
4. Cleaning techniques to be evaluated
a. Manual cleaning.
b. CIP (Clean-in- Place)
c. COP (Clean out of place)
d. Semi-automatic procedures
e. Automatic procedures
f. Time considerations.
g. Number of cleaning cycles.

3.10.12 Analyzing cleaning validation samples
There are many analytical techniques available in cleaning validation. But choosing the
appropriate analytical tool depends on a variety of factors.
1. Specific methods: A specific method detects unique compounds in the presence of potential
contaminants e.g. HPLC, AAS, Capillary Electrophoresis.
High Performance Liquid Chromatography: Almost every pharmaceutical company
has an HPLC instrument, utilizing a variety of detector.. The vast majority of techniques
described in the literature are for the determination of surfactants in concentrated
products. Analysis of anionic and cationic surfactants is done by HPLC and Capillary
electrophoresis whereas amphoteric surfactants are analyzed by HPLC.
Capillary Electrophoresis: Capillary electrophoresis can be used for many different
types of analysis, viz., separation, detection and determination of sodium lauryl sulphate
in cationic, anionic and non-ionic surfactants.
Micellar electro kinetic capillary chromatography is used for the separation of non-ionic alkyl
phenol polyoxy ethylene type surfactants.
2. Non-specific methods: Nonspecific methods are those methods that detect any compounds
that products a certain response e.g. Total organic carbon, pH and conductivity.
A REVIEW ON PHARMACEUTICAL VALIDATION
149

Total organic carbon: TOC is determined by the oxidation of an organic compound into
carbon dioxide. The oxidation can occur through a number of mechanisms depending on
the instrument being used. TOC is used for the analysis of detergents, endotoxins,
biological media and poly ethylene glycol.
Ion Chromatography: Ion chromatography can be used for the analysis of inorganic,
organic and surfactants present in the cleaners. Most cleaners contain sodium and/or
potassium. The ion chromatography detection technique of suppressed conductivity is
more sensitive to potassium ions than to sodium ions. Very low levels of cleaning agents
can be detected by using this technique.

3.10.13 Data analysis for estimating possible contamination
To support the cleaning validation study, an appropriate analytical method must be developed to
prove at a sensitivity level, at least equal to that of the acceptable residual level. For each
analytical method, values defined as minimum quantifiable quantity (MQQ) and non-detectable
(ND) are applied. A test result greater than or equal to the MQQ is considered reliable, whereas
if it lies between ND and MQQ it is considered unreliable. Therefore values reported as ND or
between ND and MQQ can be manipulated to apply for the possible contamination.












A REVIEW ON PHARMACEUTICAL VALIDATION
150

4. Future Aspects of Validation
Since mid-1970s, validation has become an integral part of the global healthcare industry. Over
all these years the nature and scope of validation has been developed and modernized in order to
fulfill the cGMP requirements and overcome various challenges. Looking to these developments,
it seems validation will further develop in order to make this field of medical sector even better
towards perfection.

4.1. Latest Technology
By developing latest technology it can be easily done to complete validation program. In an
industry like healthcare that is so dependent on new products, technological changes are ever
present. Further changes brought about by technology can be anticipated.

4.2 Automated Inspection/Identification
Requirements for inspection of materials and verification of product attributes are myriad in our
industry. For years these inspections have been performed manually for in-process materials,
labels and other items. Recognition that such inspections are slow, costly andperhaps most
important of allineffective, applications for machine vision for color, shape, fill, character
recognition will dramatically increase. Systems for material identification including bar coding
and radio frequency will become more common. Validation of all of these systems will be built
upon the proven methods for validation of automated particle inspection including accept zone
and reject zone efficiencies. Development of suitable validation sets and calibration
methodologies for these technologies might represent the greatest challenge.

4.3 Process Automation
A review of literature over the last 20 years might suggest that further automation in the industry
is unlikely for lack of applications. One has only to visit a pharmaceutical plant to realize that
despite the publicity that opportunities for automation abound. Validation of automated systems
has been considered one of the more onerous tasks in the industry, and as a consequence
implementation has lagged. Millions of dollars have been expended in efforts to meet the
expectations of this regulation that has continued to evolve at the same time as firms have
A REVIEW ON PHARMACEUTICAL VALIDATION
151

endeavored to adhere to it. The validation of these systems is certainly possible, provided the
expectations are sufficiently clear.
117


4.4 Robotics
Many industries, automotive and microelectronics are notable examples, have replaced personnel
in repetitive, arduous or hazardous tasks with robots. Along with their implementation these
industries have realized a consistency of performance unattainable by humans.

4.5 Isolation
The pharmaceutical industry first began to explore the utility of isolation technologies in the late
1970s for containment applications once the Toxic Substances Control Act mandated substantial
improvements in worker protection for toxic and potent compounds. Applications for aseptic
processing began only a few years later when the first isolators for sterility testing were
introduced. Some 30 plus years later, these technologies are increasingly commonplace for both
situations, yet surprisingly they are not considered cGMP requirements. In todays risk-based
compliance model it is safe to predict increasing numbers of these installations, and thus an
increasing need to qualify and validate these systems as they proliferate across the industry.
118


As a whole, looking towards validation since its origin, we can say that validation has been
evolved time and again accommodating the necessity of the time in order to confirm the
acceptability of design, facilities, procedures, products and system hence fulfilling its supportive
role in the global healthcare industry. So, furthermore it will continue to emerge with near
certain adapting with the new environment as it has in the years past. An old age quote goes
The only constant is change.
119


A REVIEW ON PHARMACEUTICAL VALIDATION
152


Figure 10: - Schematic life plan of validation
A REVIEW ON PHARMACEUTICAL VALIDATION
153

5. Conclusion

Identity, strength, quality, purity, stability, safety and efficacy are the prime requirement of all
the pharmaceuticals. In order to ensure all these requirements, validation is the evidence.
Validation itself means the act of proving. It is the art of designing and practicing the designed
steps alongside with the documentation. So it has become an integral part of regulatory
requirements and everyday life in the global health care environment. There are millions of
pages of validation documentation across the world. But presence of such mountains of
information is not justification for its continued existence. Its presence affords a level of
confidence in the quality of products for human health. The extent of risks to patient has been
reduced by validation effort in the pharmaceutical products. Validation and quality assurance go
hand in hand, ensuring thorough quality for the products. Every tasks accomplished in validation
process requires thorough planning, rationale, risk assessment, evaluation, documentation and
proper implementation of protocol.
From this review, we conclude that validation is important to assure that the drug product
meet standards. For this reason, every pharmaceutical industry should put their prime focus in
validation to produce quality products.
A REVIEW ON PHARMACEUTICAL VALIDATION
154

6. References

1
Fry E. Presentation at PDA Annual Meeting. Nov 1980.
2
United States FDA, General principles of validation, Rockville, MD, Center for Drug
Evaluation and Research (CDER), May 1987.
3
WHO Expert Committee on specifications for pharmaceutical preparations 40
th
ed.Annex
4.Supplementary guidelines on GMP:validation. Pg 108
4
Chapman Ken. A primer Good laboratory practice and current good manufacturing practice,
Ludwig Huber.Germany. Agilent Technologies.pg. 37
5
Chapman K. A history of validation in the US-part I. Pharm Technol Validation Comput Relat
Syst 1991;15(10).
6
James Agalloco, Frederick J. Carleton.Validation of Pharmaceutical Processes.3
rd

ed.Newyork:Informa Healthcare USA, Inc.2008.
7
FDA, Guideline on General Principles of Validation, 1985
8
Agalloco J. Validation yesterday, today and tomorrow. In: Proceedings of Parenteral Drug
Association International Symposium. Basel, Switzerland Parenteral Drug Association, 1993:1-
11.
9
FDA, Guideline on General Principles of Process Validation, Many, 1987.
10
Agalloco J. The other side of process validation. J parenter sci Technol 1986; 40(6):251-2.
11
Huber Ludwig, A primer Good Laboratory practice and current good manufacturing practice,
Agilent Technologies. p.g.37-38
12
WHO Technical Report Series 937. WHO Expert Committee on specifications for
pharmaceutical preparations 40
th
ed.Annex 4. P.g. no: 112-113.
13
Guidance for Industry, Process Validation, General Principles and Practices. U.S.
Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research
(CBER), Center for Veterinary Medicine (CVM), November 2011
14
Agalloco JP. Practical consideration in Retrospective Validation. Pharm Tech. 1983.
15
Mayer RJ. Validation of Product and Process, PPMA. Seminar on Validation of solid Dosage
form Processes. Atlanata May 1980
A REVIEW ON PHARMACEUTICAL VALIDATION
155


16
WHO Technical Report Series 937. WHO Expert Committee on specifications for
pharmaceutical preparations 40
th
ed.Annex 4. P.g. no.112.
17
Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issued for Development
and Validation. Washington DC: US FDA, 1994.
18
Elsie Jatto, Augustine and O. Okhamafe; An Overview of Pharmaceutical Validation and
Process Controls in Drug Development, Tropical Journal of Pharmaceutical Research, December
2002; 1 (2): 115-122
19
Agalloco James and Carleton J. Frederick. Validation of Pharmaceutical Processes.3
rd

ed.Newyork:Informa Healthcare USA, Inc.2008.Chapter 2.p.g.5-10
20
Agalloco and DeSantis. In: Good Design Practices for GMP Pharmaceutical Facilities by
Andrew A. Signore and Terry Jacobs: Taylor & Francis Group in 2005. Chapter 8: Validation
and Facility Design. P.g. 193-194.
21
Ludwig Huber Validation Master Plan, www.labcompliance.com/books/masterplan.htm,
April 2002
22
WHO Technical Report Series 937. WHO Expert Committee on specifications for
pharmaceutical preparations 40
th
ed.Annex 4: Supplementary guidelines on good manufacturing
practices: validation. Pg.no.112-113.
23
Guidelines for Validation & Qualification, including Change Control, for Hospital Transfusion
Laboratories. Section 11.p.g. 18.
24
Agalloco and DeSantis. In: Good Design Practices for GMP Pharmaceutical Facilities by
Andrew A. Signore and Terry Jacobs: Taylor & Francis Group in 2005. Chapter 8: Validation
and Facility Design. P.g. 196.
25
Guidelines for Validation & Qualification, including Change Control, for Hospital Transfusion
Laboratories. Section 11.p.g.19.
26
Nandhakumar et al. An overview of pharmaceutical validation: Quality assurance viewpoint.
International Journal of Research in pharmacy and chemistry 2011,1(4).ISSN:2231-2781
27
James Agalloco and Frederick J. Carleton. In Validation of Pharmaceutical Processes.3rd
edition:Informa Healthcare USA, Inc.2008. Chapter 3. Pg.no.22
A REVIEW ON PHARMACEUTICAL VALIDATION
156


28
P. Bedson and M. Sargent, The development and application of guidance on equipment
qualification of analytical instruments, Accreditation and Quality Assurance, 1 (6), 265/274
(1996)
29
WHO Expert Committee on specifications for pharmaceutical preparations 40
th
ed.Annex 4.
P.g. no. 116-117
30
Guidelines for Validation & Qualification, including Change Control, for Hospital Transfusion
Laboratories.p.g 20.
31
http://en.wikipedia.org/wiki/Validation_(drug_manufacture). Cited on: 7th, July 2014.
32
WHO Technical Report Series 937. WHO Expert Committee on specifications for
pharmaceutical preparations 40
th
ed.Annex 4. P.g. no.118.
33
http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/v4an15_en.pdf
34
Final Version of Annex 15 to the EU Guide to GMP. Title: Qualification and validation.
Published on: Brussels, July 2001. Pg.no. 4
35
WHO Technical Report Series 937. WHO Expert Committee on specifications for
pharmaceutical preparations 40
th
ed.Annex 4. P.g. no.115.
36
Huber Ludwig, A primer Good Laboratory practice and current good manufacturing practice,
Agilent Technologies. p.g.41.
37
http://www.validation-online.net/operational-qualification.html
38
http://www.validation-online.net/performance-qualification.html
39
Guidance for Industry: Process Validation: General Principles and Practices. U.S. Department
of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and
Research (CDER), Centre for Biologics Evaluation and Research (CBER), Centre for Veterinary
Medicine (CVM), January 2011.
40
ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot
Acceptance Procedure.
41
ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices, ASTM
E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and Equipment, and ASTM E2709-09 Standard
Practice for Demonstrating Capability to Comply with a Lot Acceptance Procedure.
A REVIEW ON PHARMACEUTICAL VALIDATION
157


42
Certain manufacturing changes may call for formal notification to the Agency before
implementation, as directed by existing regulations (see, e.g., 21 CFR 314.70 and 601.12).
43
Validation Guidelines for Pharmaceutical Dosage Forms (GUI-0029) / December 1, 2009
44
Guidelines for Process Validation of Pharmaceutical Dosage Form Saudi Food & Drug
Authority; Version 2; February, 1992.
45
Md. Shoaib Alam. Pharmaceutical Process Validation: An Overview. Journal of Advanced
PharmacyEducation and Research. Oct-Dec 2012. Vol. 2. Issue 4. P.g. 189 191.
46
Agalloco, J.; Akers, J. Current practices in the validation of aseptic processing1996, PDA
technical report #24. PDA. J. Pharm. Sci. Technol.1997, 51(2).
47
Clean rooms and associated controlled environments. Part 1: classification of airborne
particulates. Geneva, International Organization for Standardization, 1999.
48
U.S. Food and Drug Administration. Guideline on Sterile Drug Products Produced by Aseptic
Processing FDA, 1987.
49
Nash R. A and Wachter A. H, Pharmaceutical Process Validation an International Third
Edition. Revised and Expended, Marcel Dekkar, Inc., New York, 2003;
50
Validation of analytical procedures: text and methodology Q
2
(R
1
)
51
Validation of compendial methods, United States Pharmacopeia, 26th Revision,
52
US FDA, Guidelines for submitting samples and analytical data for method validation,
Rockville, MD, Center for Drugs and Biologics Department of Health and Human Services;
1987.
53
National Formulary, 21
st
Edition, Rockville, MD, The United States Pharmacopeial
Convention, Inc, 2440; 2003.
54
US FDA, General principles of validation, Rockville, MD, Center for Drug Evaluation and
Research (CDER); 1987.
55
Simmons PL. The design construction and commissioning of a new facility in accordance with
GMP regulations. Pharm Engin 1992; 12(5).
56
The governing of medicinal products in the European Community. Good Manufacturing
Practice for Medicinal Products. Vol. IV. Luxembourg Office for Official Publications of the
European Communities, 1992.

A REVIEW ON PHARMACEUTICAL VALIDATION
158


57
Nash A. Robert, and Wachter H. Alfred. Pharmaceutical Process Validation. An International
3
rd
ed, Revised and Expanded. Marcel Dekker, Inc. USA. Chapter 13:Equipment and facility
validation. P.g. 488-496
58
Validation of Pharmaceutical process, Third Edition, Edited by: James Agalloco and Frederick
J. Carleton. P.g.23
59
http://pharmaceuticalvalidation.blogspot.com/2011_01_01_archive.html
60
Saeed Tafreshi.Validation for pharmaceutical processes. Computerized Systems Valiation. P.g.
609
61
Saeed Tafreshi. Intelitec Corporation, Irvine, California, U.S.A. In: Validation for
pharmaceutical processes 3
rd
ed. James Agalloco and Frederick J. Carleton. Chapter 46:
Computerized Systems Valiation. P.g. 617
62
Computer System Validation Its More Than Just Testing. STS CONSULTING.
www.stsv.com
63
A typical Computer System Validation. STS CONSULTING. www.stsv.com. Pg. 5
64
McDowall, R. D.; Qualification of Computer Networks and Infrastructure; American
Pharmaceutical Review, Summer 2001 Issue.
65
http://www.pstestware.com/data/uploads/be_file/file_location/WP_Computer%20System%20V
alidation_21112005.pdf
66
Saeed Tafreshi. Intelitec Corporation, Irvine, California, U.S.A. In: Validation for
pharmaceutical processes 3
rd
ed. James Agalloco and Frederick J. Carleton. Chapter 46:
Computerized Systems Valiation. P.g. 612-613
67
General Principles of Software Validation; Final Guidance for Industry and FDA Staff
Document issued on: January 11, 2002 This document supersedes the draft document, "General
Principles of Software Validation, Version 1.1, dated June 9, 1997.
68
http://www.askaboutvalidation.com/52442-defining-calibration-validation-of-equipment
69
Equipment and Its Qualification: by- Rutendo Kuwana, Technical Officer, WHO, Geneva.
70
http://www.thermo.com/eThermo/CMA/PDFs/Various/File_21019.pdf
71
http://www.slideshare.net/gaurav11288/equipment-validation-15052240
72
Pharmaceutical Quality Operations; byMd. Abul Kalam Azad.
A REVIEW ON PHARMACEUTICAL VALIDATION
159


73
David Rudd:Qualification of Analytical Equipment. Method Validation in Pharmaceutical
Analysis A Guide to Best Practice. Joachim Ermer, John H.McB, Miller (Eds.).2005Wiley,
Weinheim.3-527-31255-2 P.g. 232
74
Pharmaceutical Quality Operations; byMd. Abul Kalam Azad.
75
Validation and Qualification; byChris Chun, Carlos Lee.
76
www.google.com /high performance liquid chromatography.wikipedia
77
Dong W. Michael: HPLC system calibration for GMP complianc: Purdue Pharma. Ardsley.
New York.
78
www.google.com/ pharmaceuticals guidelines.com
79
Parma Quality Operation; By-Md. Abul kalam Azad.
80
www.google.com/ pharmaceuticals guidelines.com
81
International Organization for Standardization. ISO 14644-1; Part 1: classification of air
cleanliness; ISO 14644-2: specifications for testing and monitoring to prove continued
compliance with ISO 14644-1; ISO/FDIS 14644-3 Part 3: test methods; ISO 14644-4 Part 4:
design construction and startup; ISO 14698-1 Biocontamination control, Part 1: general
principles and methods. Institute of Environmental Sciences and Technology (IEST),
www.iest.org
82
U.S. Pharmacopeias. Microbiological evaluation of clean rooms and other controlled
environments, 1995. Pharmacopeias Forum 21! 1116O. Rockville, MD: United States
Pharmacopeias Convention, 1995.
83
American Society of Heating, Refrigerating and Air Conditioning Engineers. Gravimetric and
dust spot procedures for testing air cleaning devices used in general ventilation for removing
particulate matter, Standard 52.1-1992; Method of testing general ventilation air-cleaning
devices for removal efficiency by particle size, Standard 52.2-1999.
84
European Standard EN 1822-1. High efficiency air filters (HEPA and ULPA) Part 1:
classification performance testing, marking. Central Secretariat, Rue de Stassart, 36, B-1050
Brussels.
85
www.google.com /pharmaceuticals guidelines/Testing of Clean and Aseptic Rooms
86
World Health Organization (2006). Temperature sensitivity of vaccines.
http://www.who.int/vaccines-documents/DocsPDF06/847 pdf.
A REVIEW ON PHARMACEUTICAL VALIDATION
160


87
Kohli, Pawanexh. "Fruits and Vegetables Post-Harvest Care: The Basics" (PDF). CrossTree
techno-visors.
88
Gyesley, S. W. (1991). Total Sysstems Approach to Predict Shelf Life of Packaged Foods.
ASTM STP 1113-EB.
89
National Health and Medical Research Council (2008). The Australian Immunization
Handbook 9th Ed. Commonwealth of Australia.
http://immunise.health.gov.au/internet/immunise/publishing.nsf/Content/handbook-home.
90
PROTOCOL FOR EVALUATING FREEZING IN THE VACCINE COLD CHAIN in the
Program for Appropriate Technology in Health April 2003
91
http://www.gmp-compliance.org/eca_news_355.html
92
http://www.instantgmp.com/DS/GMP-Compliance-Supplier-Vendor-Qualification
93
APIC Supplier Qualification & Management Guideline
94
www.google.com/pharmaceuticals guideline
95
A Guide to Supply Chain Risk Management for the Pharmaceutical & Medical Device
Industries & their suppliers- PQG
96
WHO Drug Information V0l.12, No.3, 1998
97
https://www.wordnik.com/words/validation
98
Principles for the Validation and Use of Personnel Selection Procedures Fourth Edition
99
Part one 9.7 WHO-PSM
100
http://apps.who.int/prequal/trainingresources/pq_pres/workshop_Malaysia/M01-personnel
101
Vol. 4 (3) (951), Jul Sep 2013 www.ijrpbsonline.com
102
www.google.com/packaging validation/wikipedia
103
Malukani J. Packaging Validation of Sotalol Hydrochloride Tablets, Invention journal. 2012;
1(3): 1-7.
104
Zetral Central Service . Sterilization. Guideline for the validation of packaging processes
according to ISO 11607-2. Official publication of the German Society for Sterile Supply (DGSV
e.V.). Supplement 2012.
105
Packaging validation according to ISO 11607. Medical lab. MG-FSI72-104. March 2011
A REVIEW ON PHARMACEUTICAL VALIDATION
161


106
Kumar V S, Sanjeev T: Overview of cleaning validation in pharmaceutical manufacturing
unit. International Journal of Advanced Research in Pharmaceutical & Biosciences. 2012; 1(2):
154-164.
107
Robert Fredrick: The Basic Facts of Cleaning Validation. Canada: Pharmainfo.net; 2004.
Available from http://www.pharmainfo.net/reviews/basic-facts-cleaning-validation
108
Patel Hiren Popatbhai et al: Process validation of Benzepril HCL 5 mg tablet. International
Research Journal of Pharmaceutical and applied sciences 2012; 2(4): 1-16.
109
Kathiresan K: Cleaning validation of acetaminophen tablets. Rasayan Journal 2010; 3(3):
503-506.
110
Kathiresan K: Cleaning validation of acetaminophen tablets. Rasayan Journal 2010; 3(3):
503-506.
111
http://wiki.answers.com/Q/What_is_the_difference_between_cross_contamination
112
Robert Fredrick: The Basic Facts of Cleaning Validation. Canada: Pharmainfo.net; 2004.
Available from http://www.pharmainfo.net/reviews/basic-facts-cleaning-validation
113
Bodavula Samba Siva Rao: Cleaning validation of albendazole tablet 400 mg. Pharma
Innovations. 2012; 1(4): 76-94.
114
Kumar S: A review on concept of cleaning validation in pharmaceutical Industry.
International Research Journal of Pharmaceutical Sciences 2012; 3(7): 17-19.
115
Health product and food branch inspectorate: Cleaning validation guidelines 2008; 1-16.
116
Sanjay Dey, Anindya G: Overview of cleaning validation in pharmaceutical industry. Indian
Journal of Pharmaceutical Quality Assurance 2010; 2(2): 26-30.
117
FDA, Guidance for Industry PATA Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance.
118
FDA, Pharmaceutical CGMPS for the 21st CenturyA Risk based Approach, 2004.
119
Agalloco J. Validationa new perspective. In: Medina C, ed. Compliance Handbook for
Pharmaceuticals, Medical Devices and Biologics. New York: Marcel-Dekker, 2004:83128.