PHARMACEUTICAL VALIDATION

REVIEW ARTICLE Shubhrajit Mantry et.al / IJIPSR / 2 (10), 2014, 2476-2497

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com September Issue 2476

AN OVERVIEW: PHARMACEUTICAL VALIDATION

1Shubhrajit Mantry*,

2L.Ramya,

3S.Anil Kumar

Department of Pharmaceutics, Kottam Institute of Pharmacy, Mahaboobnagar, Telangana,

INDIA

Corresponding Author:

L.Ramya

Department of Pharmaceutics,

Kottam Institute of Pharmacy,

Mahaboobnagar, Telangana, INDIA

Email: [email protected]

Mobile: +91 900861163

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

The current objective of this review is to understand the types of validation, its basic concept and

applicability in the pharmaceutical industry. Validation is the art of designing and practicing the

designed steps alongside with the documentation. Process validation also emphasizes the role of

objective measures and statistical tools & analysesand emphasizes knowledge, detection, and control

of variability and givesassurance on consistent of quality/productivity throughout life cycle of

product. Cleaning Validation providing documented evidence that the cleaning methods employed

within a facility consistently controls potential carryover of product including intermediates and

impurities, cleaning agents and extraneous material into subsequent product to a level which is below

predetermined levels. Analytical Validation is to demonstrate that it is suitable for its intended

purpose. A tabular summation of the characteristics applicable to identification, control of impurities

and assay procedures is included. As applied to Computer Systems, regulations are intended to ensure

that the systems used support, the safety, efficacy, purity, and quality of regulated products, and

require that systems be validated.

Key words: Pharmaceutical Validation, Process, Analytical, Cleaning, Computer System

Validation




INTRODUCTION

Definition of validation [1]: Validation is carried device, food, blood products , biological

products, tissues establishments , clinical trials conducting documentary evidence demonstrating

that a procedure, process or activity carried out in production or testing maintains the desired

level of compliance at all stages.

History of Validation [1]:

The concept of validation was first proposed by two food and drug administration (FDA)

Officials, Ted byers and Bud loftus, in the mid of 1970’s in order to improve the quality of

pharmaceuticals [1]. The concept of validation was first developed for equipment and processes

and derived from the engineering practices used in delivery of large pieces of equipment that

would be manufactured, tested delivered and accepted. In 2005an individual wrote a standard

bywhich the transportation process could be validated for cold chain products [2].

Fig. 1: Flow chart pharmaceutical validation pathway [4].




WHY VALIDATION [2]:

First and certainly foremost, among the reasons for validation is that it is a regulatory requirement

for virtually every process in the global health care industry for pharmaceuticals, biologics and

medical devices, validation and validation like activities are found in a number of industries,

regulated and unregulated. Banking, aviation, software, microelectronics, nuclear power, among

others are incorporate practices closely resembling validation of health care product production.

The pharmaceutical industry uses expensive material sophisticated facilities and equipment and

highly qualified personals. Detailed study and controlled of the manufacturing process batch

validation is necessary if failure cost is to be reduces and productivity is improved. The efficient

use of these resources is necessary for the continued success of industry. The cost of product

failure, rejects, reworks, recalls, complaints are the sufficient part of total product cost. Assurance

of quality, cost reduction.

Essentials of pharmaceutical validation:

1. To reduce batch to batch variations.

2. To achieve reproducible products of the same quality, purity and strength.

3. To assure safety and efficacy and to minimize hazardous effects.

4. To reduce the chance of product recall from market.

5. To save the cost that arises because of lengthy investigation procedures in case of product

variances.

Validatin should be considered in the following situation [1]:

1. Totally new process

2. New equipment

3. Process and equipment which has been altered to suit changing priorities

4. Process where the end product test is poor and unreliable indication of product quality.

Validation steps [2]:

The validation steps recommended in GMP guidelines can be summarized as:

1. As a pre-requisite, all studies should be considered in accordance with a detailed, pre-

established protocol or series of protocols, which is the subject to formal change control

procedure.

2. All data generated during the course of studies should be formally reviewed and certified

as evaluated against predetermined criteria.

3. Suitable testing facilities, equipment, instruments and methodology should be available.




4. Suitable clean room facilities should be available in both local and background

environment. These should be assurance that the clean room environment as specified is

secured through initial qualification and subsequently through the implementation of

programme of retesting in process equipment should be properly installed qualified and

maintained.

5. The process should be revalidated at intervals, and comprehensive documentation should

be available to define support and record the overall validation process.

Importance of validation [5]:

1) Assurance or quality

2) Time bound.

3) Process optimization

4) Reduction of quality cost

5) Nominal mix-up’s and bottlenecks

6) Minimal batch failures, improved efficiently and productivity

7) Reduction in rejections

8) Increased output

9) Avoidance of capital expenditure.

10) Fewer complains about process related failures

11) Reduced testing in process

12) More rapid and reliable start-up of new equipments

13) Easier scale-up from development work

14) Easier maintenance of equipment

15) Improved employee awareness of process

16) More rapid atomization

17) Government regulation compliance with validation requirement is necessary for obtaining

approval to manufacture and to introduce new product

Types of pharmaceutical validation:

1) Process validation

2) Analytical validation

3) Cleaning validation

4) Computerized validation




PROCESS VALIDATION

Introduction [5]:

The quality system regulation defines process validation as establishing by objectives evidence

that a process consistently produces a result or product meeting its predetermined specifications

(Or)

Process validation is establishing documented evidence which provides high degree of assurance

that a specific process will consistently produce a product.

Advantages of process validation [2]:

1) Expanded real time monitoring and adjustment of process

2) Enhanced ability to statistically evaluate process performance and product variables eg

:indiduals mean, range, control limits.

3) Enhanced data and evaluation capabilities and increased confidence about process

reproducibility and product quality.

4) Improved ability to set target parameters and control limits for routine production,

correlating with validation results.

5) Enhanced reporting capability.

Basic principle [5]:

1) Establish that the process equipment has the capacity of operating within required

parameter.

2) Demonstrate that controlling, monitoring , and measuring equipment and instrumentation

are capable of operating within the parameters prescribed for the process equipment.

3) Requalification or revalidation, installation qualification.

4) Election of methods, process and equipment to ensure the product meets specifications.

Operational qualification objectives of process validation [2]:

1. The manufacturing process, in addition to the individual equipment, must be validated.

2. The goal is to create a robust manufacturing process that consistently produces a drug

product with minimal variation that adheres to quality criteria of purity, identity and

potency.

3. In the end, process validation will ensure a robust product that is highly reproducible over

time.




4. A validation plan for the manufacturing process should be drafted and executed by

engineers in order to satisfy guidelines. The validation plan usually involves just a

performance qualification section.

Fig. 2: Flow chart of process validation

Sifting

Dispensing

Binding agent

prepared Shifter

Rapid Mixer Granulator Dry Mixing

Rapid Mixer Granulator Granulation

Fluid Bed Dryer Drying

Mutimill, Sifter, Siftercum Dry Milling & Sifting

Blending Blending Content Uniformity

R&D Octagonal Blender

Compression Compression Machine Precompression

Machine Speed

Shopper Study

Desaription

Group

Standard

Variation

Hardness etc.

Sub Coating Inlet

Sexhaust

Tempeature

Weight Build

Up

Enteric Coating

Packing




Type of process validation [2]

1) Prospective validation

2) Concurrent validation

3) Retrospective validation

4) Re-validation

Prospective validation:

Conducted prior to the product made under modified production process. Where the modifications

are significant and may affect the product characters. It is preplanned scientific approach and

includes the initial stages of validation. Developing in process tests sampling plans designing of

batch records, defining raw materials specifications.Completion of pilot runs, transfer of

technology from scale-up batches to commercial size batches. In prospective validation the

validation protocol is executed before the process is put into commercial use. It is generally

considered acceptable that three consecutive batches/ runs within the finally agreed parameters,

giving product of the desired quality would constitute a proper validation of the process.

Concurrent validation:

A process where current production batches are used to monitor. It gives of the present batch

being studied. And offers limited assurance regarding consistency of quality from batch to batch.

concurrent validation may be the practical approach under certain circumstances.

Example:

1. A previous validation 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 number 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. Process of manufacturing urgently needed drug due to storage and absence of supply. A

deviation shall be raised with justification and shall be approved be plant head/ head

process owner /head –QMS. A detailed procedure shall be planned for handling of the

marketed product if any adverse reactions observed in concurrent validation process.




Retrospective validation:

Conduct for a product already being marketed. And is based on extensive date accumulated over

several lots and overtime. Retrospective validation may be used for older products which are not

validated by the fabricator. At the time that may were first marketed. Part c of the regulation to F

& D Act retrospective validation is only acceptable for well established detailed process and will

be appropriate where there have recent changes in the formulation of the product. Operating

procedures, equipment &faclility.

1) Batches manufactured for a defined period

2) Number of lots released per year.

3) Batch size /strength /manufacturer /year/period.

4) Packaging documents

5) List of process deviations, corrective actions and changes to manufacturing documents

6) Data for stability testing for several batches .are essential elements of retrospective

validation.

Process re-validation:

Required when there is a change in any of the critical process parameters. Formulation primary

packaging components, raw material fabricator major. Equipments or premises failure to meet

product and process specifications in batches would also require

Process re-validation:-

Example:

1. changes in raw material physical properties (density, viscosity, particle size)

2. Changes in the source of active raw material manufacturer.

3. Changes in the packaging material.

4. Changes in the process (eg:-mixing time, drying, temp. etc)

5. Changes in equipments.

6. Changes in plant / facility.




ANALYTICAL VALIDATION

Introduction [6]:

Identification, limit test, quality & quantity test. Analytical validation provides recommendations

on how applicant , can submit analytical procedures it provides the data of the identity , strength,

quality, purity and potency of drug substances and drug products covered in new drug

applications (NDA`S) abrivated new drug applications (AND`S)biologics license applications

(BLA`S) and supplements to these applications. The revalidation of existing analytical methods

may need to be considered when the manufacturing process changes during the products life

cycle.

Validation is defined as finding or testing the truth of something. Analytical methods validation is

just one type of validation required during drug development and manufacturing. Pharmaceutical

company should have an overall validation policy which documents how validation will be

performed.

Principle /Scope [7]:

A description of the basic principles of the analytical tests/ technology (separation, detection etc)

target analytes and samples types.( drug substance drug product , impurities or compounds in

biological fluids etc) change is covered by existing validation

Redevelopment of the

Mehtod requried due to

change

revalidation requried due to

change

changes not covered by

existing validation

Fig. 3: Flow chart for the life cycle of on analytical validation

DEVELOPMENT OF THE

METHOD

VALIDATION OF THE

METHOD

METHOD IN ROUTINE USE

CHANGE TO METHOD:

EVALUATE THE EFFECT




Types of analytical procedures to be validated:

1) Identification tests.

2) Quantitative test impurities content.

3) Limit tests for the control of impurities

4) Quantitative tests of the active moiety in sample of drug substance product or other

selected compounds in drug product.

Identification tests:-

Identification tests are intended to ensure the identity of an analyte in a sample. This is normally

achieved by comparison of a property of the sample to the reference standard ( spectrum ,

chromatography , chemical reactivity).

Testing of impurities:-It may be quantitative test or a limit test for the impurity of the sample

Assay procedures are intended to measure the analyte present in a given sample.Assay represents

a quantitative measurement of major components in the drug substance

i) Specificity [8]:

(one compound identification sample)

Specificity is defined as ability to asses unequivocally the analyte in the presence of components

which may be present (impurities, matrix, etc)

To carryout identification , purity tests Assay methods.

ii) Linearity [9]:-

Linearity if defined as ability (which a specified range) to obtain test results which are Directly

proportional to the concentration of analyte in the sample It may be demonstrated directly on drug

(standard) and separate weighings of Drug Components using the proposed procedure .linearity

should be evaluated by visual Inspection of a plot of signals for the establishment of linearity, a

minimum of concentration Is recommended (continuation left) If there is a linear relationship,test

results should be evaluated by appropriate statistical methods,

Example:

Calculation of a regression line the method of least squares.

In some cases , to obtain linearity between assays and sample concentration , the test data may

need to be subjected to a mathematical transformation prior to the regression analysis. Data from

the regression line itself may be helpful to provide mathematical estimates of the degree of

linearity.




iii) Range [9]: Range is defined as the interval between upper and lower concentration of the

analyte. The specified range is normally derived from linearity studies and depends on the

intended application of procedure.

The following minimum specified range should be considered

1. For the assay of drug substance or finished product: Normally from 80 to 120 % of the

test concentration

2. For content uniformity test: 70-130% of test concentration

3. For dissolution testing: 20 % over the specified range

4. For the determination of an impurity: from the reporting level of an impurity to 102 % of

the specifications.

Note: for validation o impurity test procedure carried during development of may be

necessary to consider the range around suggested limits.

Accuracy:

Accuracy is the difference between the true value and the value obtained .accuracy should be

established across the specified range of the analytical procedure . Application of an analytical

procedure to an analyteof known purity.

Methods of expressing accuracy [10]:

Absolute error: The difference between the true value and the measured value , with regard to

the sign ,is knows as absolute error

Example: If a2.72gm of sample of material analyzed to be 2.662g. the absolute error is -0.10gm

the error is also called mean error

Relative error: The absolute or mean error expressed as percentage of th true value is known as

the relative error.

Precision [6]:

Precision is defined as the closeness of agreement between a series of measurements Obtain from

multiple sampling of the homogenous sample.

Repeatability: precision under the same operating condition over a short interval of time

Method:

1. A determination covering the specified range

2. 6 determination at 100% of the test concentration




Intermediate Precision:

Express within laboratory variations.

Method:

1. Depends on circumstance o using of methods.

2. Should include variation in days ,analysts, columns .

Reproducibility:

Precision between laboratories.

Method:

1. Depends on usage of method

2. Should include interlaboratory study

Robustness [6]:

The evaluation of robustness should be considered during the development phase and depends on

the type of procedure under study. It should show the reliability of an analysis respect to

deliberate variations in method parameters

If measurements are susceptible to variation in analytical conditions, the analytical condition

should be suitably controlled or a precautionary statement should be include in the procedure one

consequence of the evaluation of robustness should that a series of system suitability parameters

is established to ensure that validity of the analytical procedure is maintained whenever used .

Eq: of typical variation:

1) stability of analytical solution

2) extraction time .

3) influence of variation of P4 in mobile phase

4) influence of variation in mobile phase composition

5) different columns

6) temperature

Standard deviation[8]:-

Sample standard deviation , is defined as the standard deviation of a small subset of this

large data set, then it is found that the value calculated for the sample standard deviation . on a

number of subsets many vary considerably due to random variability in the data. The smaller the

number of data, the higher is the variability of the sample standard deviation .as a results of this ,if

recommended that the standard deviation should only be calculated for data sets n>3




Flow rate:

Robustness is the measure of capacity of a method to remain unaffected by small variations in

method parameters:

Aspects:

1. To be considered during development

2. To be used for establishment of system suitability criteria

3. Include testing of stability of solution

4. To be tested by introducing small variation in method parameters.

Detection limit:

Is defined as lowest amount of an analyte in a sample which can be detected but not necessarily

quantitated.

Method

1. Based on visual evaluation

2. Based on standard deviation of response and slope

3. Report results and method of choice

Standard deviation s = s2

S= )(1

1xx

ni

S= xxn

i

(1

1)2

Quantitation limit:

Is defined as lowest amount of an analyte in a sample which can be quantitatively determined

with suitable precision and accuracy.

Method:

1) Visual evaluation

2) Based on standard deviation and slope

3) Report results and method of choice




CLEANING VALIDATION:

INTRODUCTION [12]:

Cleaning validation is primarly applicable to the cleaning of process manufacturing equipments in

the pharmaceutical industry. If the equipment is not cleaned properly it contaminate the product

which is manufactured in the same equipment.

History:

Tragedy “clixir of sulfanilamide” which killed over 100 people greatly dramatired to beoaden the

existing legislation on june 25th

1938 franklin D. Roosevelt signed the federal food drug and

cosmetic act, it required manufactures to provide scientific proof of drug safety before it could be

marketed .All these events gives rise to cleaning validation.

Objective

1) Safety of patients

2) Product contamination presents serious liability issues for any pharmaceutical

manufacturer or contract organization.

Cleaning:

Cleaning can be defined as removal of residues and contaminants. By using detergents or

degraducation products.

Table 1: Types of Cleaning Sequence

Manual Cleaning Sequence Cip (Cleaning In Place) Cleaning Sequence.

Dismantle the parts of equipment to be

cleaned

Prewash the parts with tap water

Pre-wash the parts in tap water

Wash the pre-washed parts with cleaning

solution

Wash the pre washed parts with cleaning

solution

Rinse the parts in tap water Blow out using compressed air

Rinse now with purified water Rinse the parts with tap water

Dry the parts using hot air Final rinse using purified water

Visual inspection is done to check whether

the equipment is clean Blow out using compressed air

Reassemble the parts finally Drying using hot and compressed air




Fig. 4: Flow chart for cleaning validation process

Mechanism of cleaning [12]:

1) Mechanical action:-It refers to the removal of residues and contaminants through

physical actions such as brushing, surubbing and using pressur i2ed water.

2) Dissolution:- It involves dissolving the residues with a suitable solvent eg :- water being

non – toxic, Acidic and alkaline solvents.

3) Detergency :- Detergent acts in four ways as welting agent, solubili2er, emulsifier and

dispersant in removing the residues and contaminants from the equipment.

4) Chemical reaction :- Oxidation and hydrolysis reactions chemically breaks the organic

residues and confaminant to make them readily remorable from the equipment.

Determination the most

appropriate cleaning procedure for

the equipment

Develop a cleaning validation

protocol for the product and the

equipment being cleaned

Develop and validate the sampling

and choosen analytical methods for

the compounds being cleaned

Interim report:

Generate interim and cleaning

validation report on clean by clean

basis detailing the acceptability of

the cleaning procedure for the

equipment and the product

Generate a cleaning validation

report detailing the acceptability of

the cleaning procedure for the

equipment and the product

The report should give a full

detailed background and

introduction

Evaluate equipmemt surface and

determined

STAGE 1 STAGE 2

STAGE 3

STAGE 4




Elements of cleaning validation:

1) Establishment of acceptance criteria.

2) Cleaning procedure.

i. Identification of the equipment.

ii. Characteri2ation of the products

iii. Determination and characteri2ation of the cleaning agents.

3) Sampling procedure and necessary validation of same

Establishment of acceptance criteria [12]:-

The cleaning validation should demonstrate that the procedure consistently removes residues of

the substance previously manufactured down to levels that are acceptable and that the cleaning

procedure itself does not contribute unacceptable levels of residual materials to the equipment.

The limits should be practical, achievable and justifiable

In active pharmaceutical ingredient manufacture there may be practical reactants and unwanted by

products which may not have been chemically identified therefore, it maybe necessary to focus on

by – products as well as the principle reactants.

Sampling methods for cleaning validation[11]:-

There are three known sampling methods :

1) Swabbing (or direct surface sampling) method.

2) Rinse sampling method.

3) Placebo method.

Swabbing technique:

Involves the use of a swabbing material often saturated with solvent, to physically sample the

surfaces.

Advantages:

1) Dissolves and physically removes the sample.

2) Economical and widely available.

3) May allow sampling of a defined area.

4) Applicable to active, microbial and cleaning agent residues




Limitations :

1) Results may be technique dependent.

2) Swab material and design may inhibit recovery and specificity of the method .

3) Evaluation of large, complex and hard to reach difficult areas (crevices,pipes, valvesetc)

Advantages :

1) Easy and simple

2) Applicable for actives , cleaning agents and excipients

3) Allows sampling of large surface area.

4) Allows sampling of unique (pores) surfaces.

Limitations:

1) May lower test sensitivity.

2) Reduced physical sampling of the surface.

Placebo sampling:

Can be used to detect residues on equipment through the processing of placebo batch

subsequent to the cleaning process it is appropriate for active residue cleaning agent,

particulars and microbial testing.

Advantages:

1) Applicable for hard to reach surfaces.

2) Requires no additional sampling steps.

Limitations:

1) Difficult to determine recovery.

2) Residues may not be homogenously distributed.

COMPUTER SYSTEM VALIDATION [13]

Computer system validation stringent quality requirements in FDA regulated industries impose

the need for specific controls and procedures throughout the software development life cycle

(SDLC).

CSV is defined as 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.




Components of a computer system [14] :

The components of a computer system include hardware, software, operating procedures,

processes, and personnel.

Requirements:

Requirements will determine the scope of the project the validation and qualification should be

the first major deliverable for any computer system.

Software :How the software is to operate.

Hardware :the hardware including the server.

Controlling system : the operating system on the server and the database used to collect the data

from the software.

( originally published in the spring 2009 issue of journal of validation technology )

Objectives of validation [15]:

1) The computer system has been built and installed on in compliance with their deign

specifications. This constitutes installation qualification (I Q)

2) The computer system operates in accordance with its design specification. This constitutes

operational qualification (O Q)

3) A specific process supported by a computer system will consistently operate in accordance

with its predetermined specifications and quality attributes in the live environment this is

called performance qualification (P Q)

Computer systems used in planning specification programming, testing, document operation,

monitoring and modifying.

System validation provides evidence and confidence.

System specifications (control document) [16]: it states

1) Objectives of a proposed computer system.

2) The data to be entered and stored.




3) The flow of data.

4) How it interacts with other systems and procedures.

5) The operating programme and test programme.

System elements :-

1) Hardware (equipment)

2) Software (procedures)

3) People (users)

Functional specification (performance specifications)

1) Provide instruction during testing, operating and maintaining the system.

2) While using system we should consider

- Location

- Power supply

- Temperature

- Magnetic disturbance

Gmp requirements for computer system :-

1) After a suitable period of running a new system it should be verified and revalidated.

2) Data should be checked periodically

Security: Security should be maintained during

1) Production and quality control.

2) Data entry by Qthori2ed persons

3) Independent verification and release for use by second Quthori2ed person.

The system is secured to prevent. Manipulation of data Sop’s for entering data, changing or

amending incorrect entries and creating back up’s the security procedures must be maintained in

records / writing form.

Back ups: Regular back ups of all files and data are carries out .Secure storage to prevent

intentional or accidental damage.




Validation of hardware :

Fig. 5: Flow chart for Hardware validation

1) Hardware is considered to be equipment .

Focus on location, maintenance, and calibration as part of the qualification.

2) It should prove

b) Appropriate capacity

ii) Operational limits

iii) reproducibility consistency

3) If records kept by supplier ,manufacturer still has to have sufficient records to allow

Assessment of the adequacy of the validation

Validation of software:

1) It is the term used to describe the complete set of programmer used by a computer

And which should be listed in menu.

2) Records are considered as software

3) Focus should be placed on

Accuracy, security, access, retention of records, review, doublechecks, documentation

and accuracy of reproduction.

Hardware

types

Input

Devices Output

Devices

Peripheral

devices

Signal

converter

Distribution

system

Central

processing unit




Fig. 6: Flow chart for software validation

Points to be considered:

i) Consistency in performance

ii) Function

iii) Repeats

iv) Documentation

v) Revalidation

(Supplementary training modules on GNP, Who .Technical reports series)

CONCLUSION

From the study it can be stated that pharmaceutical Process Validation is the most important and

recognized parameters of cGMP and It is the full fledged quality attributing tool for the

pharmaceutical industries. Validation of analytical methods is a critical element in the

development of pharmaceuticals. Success in these areas can be attributed to several important

factors, which in turn will contribute to regulatory compliance. A cleaning validation programme

should contain the assessment of equipment andproducts, assessment of the impact of a process

on routine process, determinationof an appropriate cleaning agent and method, determination of

acceptance criteriafor the residues, determination of a degree of evaluation required to validate

theprocedure, decisive on the residues to be tested based on solubility and toxicity,development

of sampling Computer sytem 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.

Programme

Over rides Software

identification

Language

Edits, inputs

manipulation

Name

function

Fixed and

variable set

points

Input

output




ACKNOWLEDGEMENT

The authors are thankful to Mr. Shubhrajit Mantry, Dept. of Pharmaceutics, Kottam Institute of

Pharmacy, for his encouragement for carrying out this review work.

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(www..mournetraing servies .co.uk preview- book methods).

8. Http www.ikev.orghaber beuvingall.pdf.2pdf.

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10. Instrumental methods of chemical analysis by gurdeep R.chatwal , sham KAnand .

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12. IjPQA (International journal of pharmaceutical quality assurance)April –june 2010,vol-2

.issue 2(26-30).

13. Http www..Stsv.compdfsts-CSV-article .pdf.pdf.

14. Originally published in the spring 2009 issue of journal of validation technology.

15. Httpwww.pestestware.comdata upload sbe-file file .location.

16. WHO. Technology reports series ,No:937,2009 Annex4

http://www.pdh/

http://www.ich.org/

http://www.ikev.orghaber/

PHARMACEUTICAL VALIDATION

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