This document discusses the concept and types of validation of government regulation for pharmaceutical processes. It defines validation and describes the main types, including analytical method validation, equipment validation, cleaning validation, and process validation. For each type, key aspects and considerations are outlined. The history and regulatory basis for process validation are also summarized.

1. CONCEPT & TYPE OF VALIDATION OF GOVERNMENT REGULATION
DEFINITION
The concept of validation was first proposed by Food and drug administration (FDA) TED
BYERS & BUD LOFTUS in the mid 1970’s in order to improve the quality of pharmaceuticals.
The word validation means “RECTIFICATION or CONFIRMATION’’
“Documented evidence which providesa highdegreeof assurance thata specific processwillconsistently
produce a product meeting its pre- determined specificationsand quality attributes”
TYPES OF VALIDATION
1) ANALYTICAL METHOD VALIDATION
2) EQUIPMENT VALIDATION
3) CLEANINGVALIDATION
4) PROCESS VALIDATION
1) ANALYTICAL METHOD VALIDATION
 Method validation must prove that the analytical method used for a specific test is suitable for
which it is to be carried out.
Methods should be validated
 When they are to be established for routine use.
 When the method is to be changed due to change in conditions.
 Whenever the equivalence between new method and the standard are demonstrated.
TYPES OF PROCEDURES TO BE VALIDATED
1) ACCURACY
The accuracy of an analytical method refers to the closeness of agreement between the
observed value and the value which is either congenitally a true one or reference one.
2) PRECISION
The precision of an analytical method refers to the closeness of values obtained from a series of
tests.
3) REPEATABILITY
Repeatability is established when the same sample is estimated repeatedly by the same analyst
using same analytical method within the same laboratory using same instrument and performed within a
short period of time.
4) INTERMEDIATE PRECISION
When the test is repeated on different days by different persons or using different instruments
within the same laboratory, the variation is expressed in terms of intermediate precision.

2. 5) REPRODUCIBILITY
When a method is standardized, the test is carried out in different laboratories using the same
method, the precision between the laboratories is referred to as reproducibility.
6) SPECIFICITY
Specificity is the ability of a test method to measure the analyte explicitly in the presence of other
components.
7) LINEARITY
Linearity of an analytical method refers to it’s ability to measure a specific component within a
range.
8) DETECTION LIMIT
It is a individual analytical procedure is the lowest amount of analyte in a sample which can be
detected but not necessarily quantitated, under the stated experimental conditions.
DETERMINATION
Several approaches for determining the detection limit are possible, depending on weather the
procedure is a non – instrumental or instrumental.
 BASED ON VISUAL EXAMINATION
 SED ON SIGNAL TO NOISE RATIO
9) QUANTITATIONLIMIT
It is a individual analytical procedure is the lowest amount of analyte in a sample which can be
quantitatively determined with suitable precision and accuracy.
DETERMINATION
Several approaches for determining the detection limit are possible, depending on whether the
procedure is a non – instrumental or instrumental.
 BASED ON VISUAL EXAMINATION
 BASED ON SIGNAL TO NOISE RATIO
10) RANGE
It is an expression of the lowest and highest levels of analyte that have been demonstrated to be
determinable for the product.
The specified range is normally derived from linearity studies
2.EQUIPMENT VALIDATION
Equipment validation is to provide a high level of documented evidence that the equipment and the
process confirm to a standard.

3. TYPES
a) INSTALLATION QUALIFICATION (IQ)
b) OPERATIONAL QUALIFICATION(OQ)
c) DESIGN QUALIFICATION (DQ)
d) PERFORMANCE QUALIFICATION(PQ)
(a) INSTALLATIONQUALIFICATION(IQ)
It ensures that all major processing and packing equipment and ancillary systems are in conformity
with installation specification, equipment manuals, schematics.
Important IQ considerations
 Calibration, preventive maintenance
 Safety features
 Software documentation
 Equipment design features
(b) OPERATIONAL QUALIFICATION (OQ)
 It is done to provide a high degree of assurance that the equipment functions as intended.
 It is conducted in 2 stages-component operational qualification & systemoperational qualification.
Important OQ considerations
 Software procedures
 Raw material specification
 Process operation procedures
 Material handling requirements
(c) DESIGN QUALIFICATION(DQ)
It is a documented review of the design, at an appropriate stage in the project, for conformance to
operational and regulatory expectation.
Important DQ considerations
 GMP’s and regulatory requirements
 Reliability and efficiency
 Safety and environment impact
 Construct ability and installation of equipment
(d) PERFORMANCE QUALIFICATION (PQ)
It is a documented verification that all aspectsof a facility, utility or equipment perform as intended
in meeting pre-determined acceptance criteria.
Important PQ considerations
 Actual product & process parameters
 Acceptability of the product
 Process repeatability

4.  Long term process stability
3) CLEANING VALIDATION
Cleaning validation ensures that there is no cross contamination in a multi-product manufacturing
plant and also prevents microbial contamination
Once a product is manufactured, the equipment is cleaned using appropriate cleaning SOP’S
established during IQ of the equipment
TYPES OF CONTAMINATIONTO BECONSIDERED IN CLEANING VALIDATION
 Cross contamination
 Microbial contamination
 Contamination by cleaning or sanitizing agent
 Contamination by other agents
4) PROCESS VALIDATION
Process validation is the means of ensuring & providing documentary evidence that processes are
capable of repeatedly & reliably producing a finished product of the required quality.
TYPES
a) PROSPECTIVE VALIDATION
b) CONCURRENT VALIDATION
c) RETROSPECTIVE VALIDATION
d) PROCESS RE-VALIDATION
(a) PROSPECTIVE VALIDATION
It is conducted prior to the distribution of either a new product or a product made under a modified
production process, where the modifications are significant & may affect the product characteristics.
It includes:
 Initial stages of formulation development & process development
 Setting of process sampling plans
 Designing of batch records
 Defining raw material specifications
 Transfer of technology from scale up to commercial size batches
 Environmental controls
Here,the validation protocol is executed before the process is put into commercial use.
It is generally considered acceptable that three consecutive batches within the finally agreed
parameters, giving product of the desired quality would constitute a proper validation of the process.
(b) CONCURRENT VALIDATION
It is a process where current production batches are used to monitor processing parameters

5. It gives of the present batch being studied, and offers limited assurance regarding consistency of
quality from batch to batch.
Examples ofthese may be when
 Aprevious validated processis being transferredto a third party contractmanufactureror to another
site
 The number of batches produced are limited
 Process with low production volume per batch and market demand
 The product is a different strength of a previously validated product with the same ratio of active
or inactive ingredients
(c) RETROSPECTIVE VALIDATION
It is conducted for a product already being marketed and is based on extensive data accumulated
over severallots and over time.
This validation may be used for older products which were not validated by the fabricator at the
time that they were first marketed.
Retrospective validation is only acceptable for well established detailed processes and will be
inappropriate when there have recent changes in the formulation of the products, operating procedures,
equipment & facility.
Some ofthe essential elements ofthis validation are
 Batches manufactured for a definite period
 Number of lots released per year
 Master manufacturing/packaging documents
 List of process deviations, corrective actions & changes to manufacturing documents
 Data for stability testing for severalbatches
(d) PROCESS RE-VALIDATION
Process re-validation is required when there is a change in any of the critical process parameters,
formulation, primary packaging components, major equipment or premises.
Examples when processre-validation is required when
 Changes in raw materials (physical properties such as density, viscosity, particle size distribution)
 Changes in source of active raw material manufacturer
 Changes in packaging material (primary container/ closure system)
 Changes in the process (Mixing time, drying temperatures & batch size)
 Changes in the equipment
 Changes in the plant/facility
GOVERNMENT REGULATION
HISTORY

6. The Kefauver-Harris Amendments to the FD&C Act were approved in1962 with Section
501(a)(2)(B) as an amendment.
The result of the amendments Provided an additional powerful regulatory tool to FDA to stop
particular manufacturing process when the drug product is deemed to adulteration.
The Drug Product Quality Assurance Program of the 1960’s and 1970’s involved first conducting
a massive sampling and testing program of finished batches.
The investigation of clinical failures of several products (including Digoxin, Digitoxin,
Prednisolone, and Prednisone) by FDA found significant content uniformity problems that were the result
of poorly controlled manufacturing processes.
REGULATORYBASIS
The regulatory basis validation program of process validation is embodied within the regulations
& guidelines provided by cGMP & FDA.
The ultimate legal authority is Sec501(a)(2)(B) by the FD&C Act, which states “Drug is deemed
to be adulterated due to the methods/ facilities used for the manufacturing, processing, packing/holding
fails to administer in conformity – cGMP”
Validation-Process validation is not just an FDA or U.S. requirement. Similar requirements
included in the World Health Organization (WHO), the Pharmaceutical Inspection Co-operation Scheme
(PIC/S),and the European Union (EU).
REGULATIONS FOR VALIDATIONUNDER USFDA
Section211.100(a): Written procedures/deviations.
“There shall be written procedures for production and process control designed to assure that the
drug products have the identity, strength, quality, and purity.”
Section 211.110: Sampling and testing of in-process materials and drug products
"control procedures shall be established to monitor the output and Validate the performance of
those manufacturing processes that may be responsible for causing variability in the characteristics of in-
process material and the drug product”
21CFR211.133: Control of Microbiological Contamination
" Appropriate written procedures, designed to prevent microbiological contamination of drug
products purporting to be sterile, shall be established and lfollowed. Such procedures shall include
Validation of any sterilization process.
FDA must inspect every drug manufacturing establishment at least once every 2 years
REGULATORYREQUIREMENT FOR VALIDATION IN cGMP
The first cGMP regulations, based largely on the Pharmaceutical Manufacturers Association’s-
manufacturing control guidelines
The Medicines Act (1968) covers most aspects of cGMP in what is commonly referred to as "The
Orange Guide"

7. Validation under document of cGMP covers procedure, process qualification, equipment, &
facilities.
211.68: validation of automated process.
211.84(d)(2): validation of supplier’s test results for components.
211.84(d)(3): validation of supplier’s test results for container and closures.
211.110(a): validation of manufacturing process to ensure content uniformity& integrity.
211.1113(b): validation of sterilization process.
211.165: validation of analytical methods. By June 2010, the same GLP/GMP Validation requirements will
apply to all manufacturers of dietary supplements.
PLANS OF FDA GMP
The FDA plans to oversee 591 national GMP inspections in 2014 and 2015, reduced from 967
performed last year.
Consequently, the agency plans to perform 30 percent more foreign GMP inspections, increasing
last year’s total of 604 to a new grand total of 843 inspections.
Companies will now be chosen for inspection using the agency’s risk-based inspection model that
equates inspection periodicity to company quality practices and procedures. This risk based on model
develop specifically for FDA GMP PLANS use, takes into account risk factors; such as, Class I recalls,
adverse events,as well as compliance history as it assigns an appropriate inspection cycle. 21
VALIDATION REQUIREMENT UNDERWHO
WHO (World Health Organization) cGMP Guidelines state Validation studies are an essentialpart
of current good manufacturing practice (cGMP) and should be conducted in accordance with predefined
protocols.
WHO validation definition:
The documented act of proving any procedure, process, equipment, material, activity or system
which actually leads to the expected results.
 DQ: Design Qualification
IQ: Installation Qualification
 OQ: Operational qualification
PQ:Performance qualification
DQ:
The compliance of the basic design (location plan) with the user requirements & regulatory
requirements should be submitted & documented.

8. IQ:
Documentary evidence to prove that the premises & equipment have been built & installed in
compliance with their specifications.
IQ include:
1) Preventive maintenance.
2) Equipment info.
3) Calibration.
4) Verification of the equipment.
OQ:
A series of tests to measure the performance capability of equipment. The OQ for HPLC system is
the operation of pump, injector & detector will be tested at this stage.
PQ:
Process to verify that the system is repeatable & capable for consistently producing a quality
product.
VALIDATION REQUIREMENT UNDEREU:
The European Union requirements for validation is an extract from ICH Q8, Q9 and Q10
documented guidelines and helps to study continuous process verification
EU Validation Definition:
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
Strategies ofvalidation under EU includes:
1) Traditional process verification
2) Continuous process validation (CPV)
3) Critical process parameter (CPP)
4) Critical quality attributes (CQA)
1) Traditional process verification
process validation should focus on the control strategy, which primarily includes critical process
parameters and other relevant studies demonstrating that the process is capable of delivering the desired
product quality.
2) Continuous process validation (CPV)
an alternative approach to process validation in which manufacturing process performance is
continuously monitored & evaluated.

9. 3) Critical process parameter (CPP)
a process parameter whose variability has an impact on a critical quality attribute and therefore
should be controlled to ensure the process produce the desired quality.
4) Critical quality attributes (CQA)
a physical, chemical, biological or microbiological property should be within an appropriate limit,
range to ensure product quality.
VALIDATION REQUIREMENT UNDERPIC/S
According the EU Guidelines to Good Manufacturing Practice for Medicinal Products in Annex 15
the principles of qualification & validation of the PIC/S is given under document PIC/S PI 006-3:
Doc states
GMP for medicinal products Recommendations on Validation Master Plan Installation and
Operational Qualification (Non-Sterile Process Validation Cleaning Validation) can assist with the
interpretation and the implementation.
This document applies primarily to inspectorates of the PIC/S member for whom it is intended as
instruction for preparing an inspection, and as an advanced training aid for qualification/validation.