U.S.F.D.A. was the pioneer in the concept of process validation. Validation had proven to be an important tool for quality management of pharmaceutical according to ISO 9000:2000.

1. Pharmaceutical validation

2. Introduction
 U.S.F.D.A. was the pioneer in the concept of process validation.
 Validation had proven to be an important tool for quality
management of pharmaceutical according to ISO 9000:2000.
 Food and Drug Administration (FDA) definition :- validation refers
to establishing documented evidence that a process or system
when operated within established parameters, can perform
effectively and reproducibly to produce a medicinal product
meeting its pre-determined specifications and quality attributes.
 ISO definition : Validation is the confirmation by examination and
the provision of objective evidence that the particular
requirements for a specific intended use are fulfilled.

3. Scope of Validation
 Pharmaceutical validation is a vast area of work and it practically covers
every aspect of pharmaceutical processing activities
 The pharmaceutical application will point out at least the following areas
for pharmaceutical validation.
 For e.g
 1) Analytical test methods
 2) Instrument Calibration
 3) Process Utility services
 4) Raw materials
 5 ) Equipment
 6) Facilities
 7) Manufacturing operations
 8) Product Design
 9)Packaging material
 10) Cleaning
 11) Operators.

4.  1) Analytical test methods-
 The analytical test method requires demonstration of the following
characteristic in it.
 E.g
 Accuracy
 Precision
 Specificity
 Limit of detection
 Limit of Quantitation
 Linearity
 Range
 Ruggedness
 Robustness
 2) Instrument Calibration:
 Measurement of various parameter is a prime activity in pharmaceutical processing and
hence, it demands a very high level of accuracy in such measurement.
 Some of the common measurements involved are temp. , pressure, relative humidity,
conductivity, time, rotations, current, voltages, pH, Volume, Weight and so on.
 All device which are used to measure such parameter, require calibration of these
devices, so that level of the process become very high

5.  3) Process Utility services-
 Process Utility services support the manufacturing process and the plant is require to operate
them regularly.
 Some important process utility services are as follows
 1) Different types of water
 E.g.- Raw water
 Soft water
 Purified water
 Water for injection
 2) Steam
 E.g. Plant steam
 Pure steam
 3) HVAC systems
 E.g- Heating
 Ventilation
 Air conditioning
 4) Different gases
 E,g- Nitrogen
 LPG
 Oxygen
 Carbon dioxide
 5) Drainage System-

6.  4) Raw materials and Packaging Material-
 Qualification of R.M. and P.M. requires two stages programme.
 Stage 1- defining specification for each and every items of R.M / P.M. and it
also require the pharmacopoeia requirement.
 Stage 2- vendor certification- to study and certify vendor who can supply the
desired quality of material, required quantity at expected time and at
affordable price.
 5) Equipment-
 The equipment qualification programmers starts with users requirement
specifications.
 This will follow the installation, operational and performance qualification
and finally verification of qualification at pre-specified interval.
 You need to design protocol for each of the above qualification activities.
 The equipment qualification programme should also cover the S.O.P.
identification and verification for cleaning, operation and maintenance of
the equipments.

7.  6) Facilities:
 Qualification of pharmaceutical facilities involve the following
phase namely,
 1- defining user requirement in term of user requirement specification
 2- functional requirement specification
 3- deriving design qualification
 4- construction of facilities
 5- certification of constructed facility
 6- ongoing building maintenance
 7) Manufacturing-
 Pharmaceutical formulation are divided into various dosage forms.
 Each dosage form has various processes involved in it.
 Each such process must be validated.

8.  8) product Design:
 In the pharmaceutical validation process product design is the
first stage.
 The whole process generally goes something like this
 Formulation development
 Primary packaging studies
 Defining specification for R.M./ P. M.
 Defining the process
 Quality control specification and test methods
 Pilot plant studies
 Trial commercial batches
 Commercial production
 Concurrent validation
 revalidation

9.  9) Cleaning
 Cleaning in pharmaceutical operations involves mainly three areas namely
 Equipment and process container
 Product container
 Facility
 The cleaning validation should cover the following point namely;
 Cleaning limit
 Material used for cleaning
 Cleaning method
 Trace analysis, method and limits.
 Frequency of cleaning wherever applicable.
 10) Operators:
 Operator is a vital link in the whole validation process.
 Unless and until the operator is trained , no process can be expected to deliver
the desired goods.
 The training of operator involves three factor namely;
 1- knowledge: Technical, GMP related, Safety, productivity etc.
 2_ Skills- Technical, safety and skill to apply the available knowledge in other areas.
 3- Attitudes: A positive and constructive attitude towards every work he is doing.

10. Importance / Benefit of Validation
 Validation activity must give the industry some advantages, some benefit
and some added value.
 Dr. Robert G. Kiefler has identified four major advantages of validation
namely:
 1- reduction of quality cost
 2- process optimization
 3- Assurance of quality
 4- Safety
 1- Reduction of quality cost:
 Traditionally , quality costs are divided into four categories, they are
 A- Preventive cost
 B- Appraisal cost
 C- Internal failure costs and
 D- External failure costs

11.  A- Preventive cost
 Preventive costs are costs incurred in order to prevent failures and/ or reduce
the appraisal costs.
 They involve the following
• Quality planning
• Vendor approval system
• Training
• Documentation, SOPs, monograph
• Preventive maintenance
• Calibration
• Process validation
• Quality assurance audit and self inspection
• Annual review of data or trend analysis.
 B- Appraisal costs:
 Appraisal costs are costs of inspection, testing and quality evolution. Some
example are
 Inspection/ testing of raw and packaging material
 Inspection/ testing of in process material
 Inspection/ testing of finished product
 Stability testing.

12.  C- Internal Failure Costs:
 Internal failure costs associated with non-confirming material that does
not meet quality standards-still in the company’s possession
 Some example of internal failure costs are
 Rejects
 Reworks
 Re-inspection
 Retests
 Wastage/scrap
 Sorting substandard material
 D) External failure costs:
 External failure costs are costs associated with a non-conformance
condition after has left the company's ownership.
 Some example of external failure costs are
 Recalls
 Complaints
 Returns due to quality related problems.

13.  2- process optimization
 Process optimization means make the process effective, efficient, perfect or
useful as possible at the minimum cost.
 Some areas where experience show that optimization is possible as a result of
validation studies are the following
 1- optimum batch sizes relative to availability of equipment and personnel and size of
facility
 2- decrease down time of equipment
 3- reduced sterilization times due to studies
 4- Reduced mixing time
 5- faster and more accurate analytical test procedure.
 6-Better product and component specification
 7- reduced energy costs.
 3- Assurance of quality-
 Validation is an extension of quality assurance
 Validation and process control are at the heart of GMPs.
 4- Safety-
 Validation can also result in increased operation safety.

14. Types of validation
 What are the Four Main Types of Validation?
 There are 4 main types of validation:
 1) Prospective Validation
 2) Concurrent Validation
 3) Retrospective Validation
 4) Revalidation (Periodic and After Change)

15.  What is Prospective Validation?
 Prospective validation is carried out during the development stage.
 It includes the division of the production process into separate steps,
and the analysis of potentially critical points in the manufacturing
process e.g. mixing times, or temperature.
 This particular type of process validation is normally carried out with
the introduction of new products and manufacturing processes.
 Before this validation can take place, the following requirements need
to be satisfied:
 The facilities & equipment must be qualified
 The operators running the validation batches must have an understanding
of the process
 The design and optimization must be completed
 The pilot laboratory batches must be completed
 Product stability information is available
 At least one pilot batch has been completed which shows no significant
deviations from the expected performance of the process.

16.  What is Concurrent Validation?
 Concurrent validation is carried out during normal production. It
requires a full understanding of the process based on prospective work.
 It involves very close and intensified monitoring of all the
manufacturing steps and critical points in at least the first three
production-scale batches
 Examples of in-process testing include:
 pH Value
 Tablet Hardness
 Weight Variation
 Dissolution Time
 Content Uniformity
 Viscosity or Density
 Colour or Clarity
 Particle Size Distribution
 Average Unit Potency

17.  What is Retrospective Validation?
 Retrospective validation is the analysis of accumulated results from past
production batches manufactured under identical conditions to assess
the consistency of a process.
 It includes trend analysis on test results and a close examination of all
recorded process deviations and their relevant investigation reports.
 This type of validation is applied to established products who are
considered stable where prospective validation programs cannot be
justified.
 Using either data-based computer systems or manual methods the
following method can be used to perform retrospective validation:
 Gather the numerical data from completed batch records
 Organize this data in sequence i.e. Batch Manufacturing Date
 Include the data for at least 20-40 batches, if the number is less than 20
include all of the data available
 Learn the data by eliminating all of the non-critical numerical information
 Subject this data to statistical evaluation
 Analyse the state of control of the manufacturing process
 Generate a report of all findings

18.  What is Revalidation?
 Periodic revalidation offers the opportunity to check that the
systems are still operating as originally validated and that no
unintended changes have affected the process, system or piece of
equipment and the end result.
 Conditions requiring revalidation can be summarized into 5 main
categories:
 A change to a critical raw material involved with the drug make-up
 A change or replacement of a critical piece of equipment
 A change to the facility
 A significant increase or decrease in batch size
 Sequential products that that fail to meet product and process
specifications

19. Documentation Involved in validation /
Validation Master plan (VMP)
 Validation master plan (VMP) is the key document in an organization’s
validation programme.
 The validation master plan should provide an outline of the entire
validation operation, its organizational structure, its content and planning.
 The main element of it is the list of the items to be validated and the
planning schedule.
 The VMP serve as the validation roadmap, setting the course, justifying
the strategy, outlining the preliminary test and acceptance criteria and
documenting the necessary programs that ensure a containing state of
validation
 Definition of VMP-
 The VMP must present an overall picture of the company facility,
organization and capability.

20.  Scope of VMP:
 All validation activities relating to
 Reduce rework
 Reduce cost
 Reduce rejected
 Relevant to product
 Corporate legal protection Scope
 Critical technical operations
 Corporate image
 Satisfactory inspections
 Secure third-party contracts
 lots Avoid recalled
 lots Helps in new drug approval
 Process controls within a firm should be included in VMP
 A VMP should comprise all prospective, concurrent, retrospective validations as well as
re-validations
 In case of large projects like the construction of a new facility, often the best approach
is to a separate VMP.
 Financial gain

21.  Why to Perform VMP?:
 VMP is not a requirement of FDA ,but it has become almost an
industry standard .
 Who Performs VMP?:
 Validation Manager
 Quality Assurance Department
 Member from Production
 Member from Engineering (Utilities)
 Member from Calibration Laboratory
 Member from Quality Control Laboratory
 Member from Maintenance Member from HVAC Department
 Member from Product Development Laboratory

22.  Which factors are considered in VMP?:
 Contents of VMP:
 1) Introduction
 2) Methodology
 3) Qualification:DQ,IQ,OQ,PQ
 4) Personnel
 5) Schedule
 6) Preventative maintenance
 7) Change control Procedure
 8) Documentation
Introduction :
 It include following details: A description of facility, premises,
equipment, & its purpose
 Scope of validation
 Policies on regulatory bodies like GMP, cGMP, WHO

23.  Methodology:
 Predetermined requirement to identifying the standards.
 Development of the acceptance criteria that are used to judge the validation
 It is also involve planning and execution of documents such as protocols,
records,reports, or other
 The std will involve three elements :
 Regulatory and guidance documents
 National standards
 Company standards
 Qualification:
 Includes all the aspects of design
 It is important to ensure that the organization is consistent and cover all the
aspect of validation process for specific project.
 The validation structure and organization is clear to any inspection authority.
 Design qualification providing documented evidence that the design of
facility and equipment meet the requirements of the user specification
&GMP

24.  Personnel:
 The CFR 21 states; “each person engaged in and each person
responsible for supervising the manufacture processing, packaging, or
holding of a drug product shall have the education, training, and
experience. or a combination thereof ,to enable that person to
perform the assigned functions”
 principles for personnel requirements.
 experience of personnel in house training reports, etc
 Schedules:
 Essential
 Prepared at early stage
 A good plan contains all necessary features which are to be
considered during execution of plan and determines the control of
the project.
 It ensures that the personnel involved in the VMP are not only aware
of the engineering targets, but also the validation targets.

25.  Preventive maintenance:
 This is the responsibility of site maintenance and operation dept.
 The activity should be performed during the design phase, and documentation required
should be, included in requisition.
 Change control procedure:
 Essentials for continuous operation of the system, process ,or equipment and provides a
formal mechanism for monitoring changes during the continued operation of system
 The proposed changes that can affect the validated status of a system are reviewed by
the validation team or responsible personnel and the proposed corrective action is
approved
 Sufficient detailed documentation is necessary for each critical change to maintain
control over the system with the passage of time
 Various changes can be categorized as follow:
 Process equipment and system hardware change control
 Software change control
 Process change control
 Multiple changes Emergency changes
 Planned changes
 Repetitive changes
 Pending changes

26.  Documentation: This section usually to identify the
documentation that should be produced for the processing like;
 Engineering drawing
 Equipment supplier drawing and documents
 Factory acceptance document
 IQ documents
 OQ documents
 PQ documents

27.  How VMP is prepared?:
 Developing validation master plan: Documentation The VMP is used , managed, and enforced
throughout the life of a process to ensure quality.
 The document the validation approach, specifies the responsibilities of each of the validation
team member, and important effort at the beginning of a project
 The Description of following system are necessary to control validation activities as well as the
ongoing operation of the system , process, or equipment: Protocol and documentation prep
 Protocol execution
 Documentation control
 Change control
 Protocol:
 VMP includes the information into formal written protocols, which serve as guides for executing
appropriate validation activities.
 Protocol should be developed for IQ,OQ,PQ
 The information included in specific protocols are: Description of system Qualification objective
 Scope
 Responsibility and data collection procedures
 Test procedures- specific acceptance criteria
 Documentation procedures
 Summary and deviation report

28.  Installation qualification IQ:
 It is perform to verify that the installed components are the ones
specified, that they are properly identified, and so on, as stated in
the construction documents in accordance with specific
requirement of the user.
 IQ protocol includes:
 Spec ref, including purchase orders and contracts nos
 Verification and calibration of critical installed components
 Verification of procedures
 Verification of major component
 Verification of control and monitoring devices
 Verification of utilities connections
 Lubricants
 Final drawing reference manuals

29.  Operation qualification: OQ
 This involves the testing of various components of the system,
process or equipment to document proper performance of these
components.
 OQ Protocol includes:
 Verification of test equipment calibration
 Verification of controls and indicators
 Computer control system testing
 Verification of sequence of operation
 Verification of major components of operations
 Verification of alarms Power failure/recovery testing
 Functionality testing of distribution system valves etc
 System initial sampling

30.  Performance Qualification :PQ
 This involves challenging the system, process , or equipment to
provide evidence of appropriate and variable operation
 PQ protocol includes:
 System sampling
 Equipment cold start tests System invasive tests
 Operating procedures:
 Procedures must be for prepared for all operations to be performed
during the executions of protocol Called as validation operating
procedures, SOP’s, operating manuals
 Ensures that system process or equipment is operated consistently
during validation and exactly as it should during normal operation
conditions