Pharmaceutical validation

PHARMACEUTICAL VALIDATION (MQA 202T)
SMT. B.N.B SWAMINARAYANPHARMACY COLLEGE SALVAV, VAPI. Page 1
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Prepared by: Dhruvi Parmar
M. Pharmacy (Semester II)
Department of Quality Assuarance

INDEX
SR.NO. CONTENT PAGE NO.
1 Introduction 3
2 Procedure of process validation 4
3 Documentation of process validation 6
4 Types of process validation
5 Process validation of various formulation:- 17
a) Coated tablet 17
b) Capsules 24
c) Ointment/creams 26
d) Liquid orals 30
e) Aerosols 32
6 Aseptic filling: media fill validation 36
7 USFDA guidelines on process validation 39
8 Analytical method validation 44
9 References 50

INTRODUCTION
• Process Validation is the analysis of data gathered throughout
the design and manufacturing of a product in order to confirm
that the process can reliably output products of a determined
standard.
• Regulatory authorities like EMA and FDA have published
guidelines relating to process validation.
• The purpose of process validation is to ensure varied inputs lead
to consistent and high quality outputs.
• Process validation is an ongoing process that must be frequently
adapted as manufacturing feedback is gathered.
• End-to-end validation of production processes is essential in
determining product quality because quality cannot always be
determined by finished-product inspection.
• Process validation can be broken down into 3 steps: process
design, process qualification, and continued process verification.

PROCESS OF PROCESS VALIDATION

 Process Validation Protocol
 Detailed chemical synthesis of product
 List of approved vendors
 Reference of R&D and pilot scale up studies and technology
 List of EQ/Instruments used and its qualification/Calibration
status
 Critical process steps and CPP
identification/description/justification
 Sampling and testing plans (pictorials)
 Validated analytical methods for IP and Int/final product
 ACC with scientific rationale
 List of validation members
 Deviations/ conclusions/ Recommendations/certification &
Report pattern

 DOCUMENTATION OF PROCESS VALIDATION
• Validation Master Plan (VMP)
• Protocols
• Reports
Validation Master Plan (VMP)
• Contains key elements of the validation programme.
• Concise, clear, contain at least:
 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)
 Planning and scheduling
 Change control and references to existing documents
Importance of the VMP:
 The VMP describes clearly and concisely the company’s
philosophy, expectations and approach to be followed..
• Identifies the systems and controls to be validated.
• The level of testing required.
• Covers all aspects of the project as equipment qualification.
• Developed in the early stages of a production.
• Object and allow a logical progression from plan to validation
schedule.
• The VMP can also assist in monitoring and tracking the progress
of the project by performing periodic audit reviews v/s the
approved version of the VMP.
Contents of typical VMP:
• Following are the contents of VMP :
• Introduction,
• Purpose,
• Scope,

• Overview /Description of system to bevalidated,
• Responsibilities,
• Validation methodology,
• Acceptance criteria, Validation report,
• Change control, Validation project milestone,
• Deliverables.
Benefits of VMP:
• It provides the total pictures of the project.
• It is a management tool for tracking progress.
• Assignment of responsibility, which promote team work.
• It identifies acceptance criteria before the start of validation.
Qualification and validation protocols
• Describe the study to be performed and include as a minimum:
 The objectives of the study
 The site of the study
 The responsible personnel
 Description of sops to be followed
 Equipment to be used
 Standards and criteria for the products and processes
 The type of validation

 The processes and/or parameters
 Sampling, testing and monitoring requirements
 Predetermined acceptance criteria for drawing conclusions
• Description (how results will be analyzed)
• Protocol approved prior to use - changes approved
prior to implementation of the change
Qualification and validation reports
• Written reports on the qualification and validation performed
• Reflect protocols followed and include at least:
 Title and objective of the study; reference to the protocol;
details of material
 Equipment, programs and cycles used; procedures and test
methods
• Results 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 are accepted, this should be justified. Where necessary
further studies should be performed
• Responsible departments and QA to approve completed report,
including the conclusion
Qualification stages
• There are four stages of qualification:

 Design qualification (DQ);
 Installation qualification (IQ);
 Operational qualification (OQ); and
 Performance qualification (PQ).
• All SOPs for operation, maintenance and calibration should be
prepared during qualification
• Training provided and records maintained
 Design qualification(DQ):
 Defines the functional and operation specification of the
instrument, program, or equipment and details the rationale for
choosing the supplier
 DQ should ensure that instruments have all the necessary
functions and performance criteria that will enable them to be
successfully implemented for the intended application and to
meet user requirements.
DQ considerations include:
 Description of the analysis problem.
 Description of the intended use for the equipment.
 Description of the intended environment.
 Preliminary selection of the functional and performance
specification (technical, environmental, safety).
 Preliminary selection of the supplier.
 Final selection of the supplier and equipment.
 Development and documentation of final functional and
operational specifications.

 Installation qualification:
Provides documented evidence that the installation was complete
and satisfactory
• During IQ:
 Purchase specifications, drawings, manuals, spare parts lists and
vendor details should be verified
 Control and measuring devices should be calibrated
Important IQ considerations are:
 Equipment design features (i.e. materials of construction clean
ability, etc.)
 Operational qualification:
Provides documented evidence that utilities, systems or equipment
and all its components operate in accordance with operational
specifications
• 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.
 Performance qualification:
Provides documented evidence that utilities, systems or equipment
and all its components can consistently perform in accordance with
the specifications under routine use
• Test results collected over a suitable period of time to prove
consistency
 Requalification

• In accordance with a defined schedule
• Frequency to be determined (e.g. on the basis of factors such as
the analysis of results relating to calibration, verification and
maintenance)
• Periodic and after changes
 e.g. changes to utilities, systems, equipment; maintenance work;
and movement
• Part of change control procedure
 TYPES OF PROCESS VALIDATION
1. PROSPECTIVE VALIDATION
2. CONCURRENT VALIDATION
3. RETROSPECTIVE VALIDATION
4. REVALIDATION VALIDATION
1. PROSPECTIVE VALIDATION
• Prospective validation is carried out during the development stage
by means 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 might lead to
critical situations.
• Carried out prior to distribution of a new product or an existing
product made under a revised manufacturing process where such
revision may affect product specification or quality characteristics.
• It is executed before the process is put into commercial use.
• Also called as Premarket validation.
• Determine the critical parameters.

• Prospective validation is a requirement, and therefore it makes
validation an integral part of a carefully planned, logical
product/process developmental program.
 Objective:
To prove that the process will work in accordance with a validation
protocol
 During Product development stage
• Production process broken down into individual steps
• Each steps evaluated on the basis of experience or theoretical
considerations
• Critical factors that may affect the quality of the finished
product are determined.
 Personnel involved in Prospective validation are
• Representatives from Production
• QC/QA, Engineering
• Research and Development
• It is a challenge element to determine the robustness of the
process. Such a challenge is generally referred to as a "worst
case" exercise.
 Pre-Requisite of process validation
• All equipment to be used should have been qualified
(Installation/Operational Qualification),
• The production Facility and area should be validated.
• Analytical testing methods to be used should have been fully
validated,.
• Critical support systems like water system, compressed air
system etc, should be validated.
• Raw and packaging material specifications are approved.

• Staff taking part in the validation work should have been
appropriately trained.
 ORGANIZATION
• Prospective validation requires a planned program and
organization to carry it to successful completion.
• The structure of organization will vary from company to
company.
• It makes validation an integral part of a carefully planned,
logical product/process developmental program.
 MASTER DOCUMENTATION
• An effective prospective validation program must be supported
by documentation extending from product initiation to full-scale
production.
• Contain a complete history of the final product that is being
manufactured.
• It will consist of
• Reports
• Procedures,
• Protocols,
• Specifications,
• Analytical methods,
• Any other critical documents pertaining to the formulation,
process, and analytical method development.
2. CONCURRENT VALIDATION
 Definition: Concurrent Validation means establishing documented
evidence a process does what it is supposed to do based on data
generated during actual implementation of the process.
• Validation – during routine production

• Validation involves –
 In-process monitoring
 End product testing
• Personnel – Authorized staff
• Documentation – as per Prospective Validation
• A process where current production batches are used to monitor
processing parameters. 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. Examples of these may be when:
 A previous validated process is being transferred to a third
party contract manufacturer or to another site.
 The product is a different strength of a previously validated
product with the same ratio of active/inactive ingredients.
• 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.
• The numbers of batches produced are limited.
• Process with low production volume per batch and market
demand. Drug due to shortage or absence of supply.
• In all above cases concurrent validation is valid, provided
following conditions are appropriately.
• Pre-approved protocol for concurrent validation with rational
• A deviation shall be raised with justification and shall be
approved by plant head/head process owner/Head-QMS.
Product behavior and history shall be reviewed based on
developmental/scale up/test batches.
• A detailed procedure shall be planned for handling of the
marketed product if any adverse reactions observed in
concurrent validation process.

• Concurrent validation batches shall be compiled in interim
report and shall be approved all key disciplines.
3. RETROSPECTIVE VALIDATION
• Retrospective process validation is validation of a process for a
product already in distribution based upon accumulated production,
testing and control data. Generally, process validation is a pre-
production activity.
• This is performed for all new equipment, products and processes.
• It is a proactive approach of documenting the design, specifications
and performances before the system is operational.
• Conducted fir a product already being marked, 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.
• Batches manufactured for a defined period. (minimum of 10 last
consecutive batches). Number of lots released per year.
• Batch size/ strength/ manufacturer/ year/ period.
• Master manufacturing/packaging documents.
• List of process deviations, corrective actions and changes to
manufacturing documents.
• Data for stability testing for several batches.

• Trend analysis including those for quality related complaints.
 Product Selection Criteria for Retrospective Validation
• For a product to be considered for retrospective validation, it must
have a stable process; that is, one in which the method of
manufacture has remained essentially unchanged for a period of
time.
• Products for which there is no record of a change in the method of
manufacture or control during this period can be regarded as
candidates for validation.
• The 20-to-30-batch rule originates from control chart principals,
which consider 20 to 30 points that plot within the limits as
evidence of a stable process.
• This decision making is best handled by a validation committee.
• The second step in the product selection process, addresses the
situation in which a change in the method of manufacture or
control was implemented during the last 20 or so production
batches.
• In general, a history of any one of the following changes to the
method of manufacture and control should be fully investigated
before any decision is made to validate retrospectively:
• Formulation changes involving one or more of the active
ingredients or key excipients
• Introduction of new equipment not equivalent in every respect to
that previously in use
• Changes in the method of manufacture that may affect the
product’s characteristics
• Changes to the manufacturing facility
• A product found to be unsuitable for retrospective validation
because of a revised manufacturing process is a likely candidate for
prospective validation.
• The third and last step in our selection process is to identify which
products are likely to be discontinued because of a lack of

marketing interest or regulatory consideration, to be sold, or to be
reformulated.
 Validation Protocol
• It should specify the data to be collected, the number of batches
to be included in the study, and how the data, once assembled,
will be treated for relevance.
• The criteria for acceptable results should be described.
• The value of a protocol is to control the direction of the study, as
well as provide a baseline in the event unanticipated
developments necessitate a change in strategy.
• A written protocol is also an FDA recommendation.
 Other Considerations
• Comprehensive records of complaints received either directly
from the customer or through a drug problem reporting program
should be reviewed. Furthermore, a record of any follow-up
investigation of such complaints is mandatory and should be
part of this file.
• Batch yield reflects efficiency of the operation. Because yield
figures are the sum of numerous interactions, they fail in most
cases to provide specific information about process performance
and therefore must be used with caution in retrospective
validation.
• Lot-to-lot differences in the purity of the therapeutic agent must
be considered when evaluating in-process and finished-product
test results.
• In addition to potency such qualities as particle size distribution,
bulk density, and source of the material will be of interest.

• Such information should be available from the raw material test
reports prepared by the quality control laboratory for each lot of
material received.
• These documents can provide a chronological profile of the
operating environment and reveal recent alterations to the
process equipment that may have enough impact to disqualify
the product from retrospective validation consideration.
4. REVALIDATION
Definition: Re-validation provides the evidence that changes in a
process and/or the process environment, introduced either
intentionally or unintentionally, do not adversely affect process
characteristics and product quality.
• There are two basic categories of Re-validation:
1. Re-validation in cases of known change (including transfer of
processes from one company to another or from one site to
another),
2. Periodic Re-validation carried out at scheduled intervals
 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.
 Changes that are likely to require Re-validation are as follows:
• Changes in raw materials (physical properties such as density,
viscosity, particle size distribution, and moisture, etc., that may
affect the process or product).
• Changes in the source of active raw material manufacturer.
• Changes in packaging material (primary container/closure
system).

• Changes in the process (e.g. mixing time, drying temperatures
and batch size).
• Changes in the equipment (e.g. addition of automatic detection
system).
• Changes of equipment which involve the replacement of
equipment on a “like for like” basis would not normally require
a revalidation except that this new equipment Must be qualified.
• Changes in the plant/facility.
• Variations revealed by trend analysis (e.g. process drifts).
 VALIDATION PROTOCOL
• Detailed protocol for performing validations are essential to
ensure that the process is adequately validated.
• Process validation protocols 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,
revalidation.
• 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.
PROCESS VALIDATION OF FORMULATION
1. COATED TABLETS
2. CAPSULES
3. OINTMENT/CREAMS
4. LIQUID ORALS & AEROSOLS
1. Coated tablet
Some Common Variables InTheManufacture Of Tablet
Products
• Particle size of drug substance
• Bulk density of drug substance/excipients
• Powder load in granulator
• Amount and concentration of binder
• Mixer speed and mixing times
• Granulation moisture content
• Milling conditions
• Lubricant blending times
• Tablet hardness
• Coating solution spray rate
Validation protocol for manufacturing of tablets

Industrial Process overview of Solid dosage form
• Steps & process parameter are following-
1. Mixing or Blending-Material have similar physical properties will
be easier to form a uniform mix or blend as compare to difference
properties.
Techniques-
• Diffusion(tumble)
• Convection(planetary or high intensity or fluid bed.
 Mixing or blending depending on various factor-
(a)Mixing speed-mixing the drug & excipient will
 require more intense mixing than adding the
 lubricant to the final blend.
(b)Mixing time-mixing time will be dependent on the mixing
technique & speed.
 If over mixed occured at the result demixing or segregation of
the material.

(c)Drug uniformity- handling of the material are key in
 Obtaining valid content uniformity results .
 Segregation of the sample can occur by handling resulting
inaccurate results.
 Sample should be equivalent to the weight of a single tablet.
(d)Excipient uniformity-excipient need to be uniform in the
granulation.
Two keys excipient are-
 LUBRICANT- lubricant needs to be distributed uniformly in
the mixture/granulation for high speed compression operation .
 Uneven distribution of the lubricant can result in picking &
sticking problem during compresion.
 Color- evenly distributed in the mixture so the tablets have a
uniform appreance (color,hue& intensity)
 Uniform dispersed in the blend prior to compression to avoid
shading(molting).
(e)Equipment capacity/load
 The bulk density of Material will affect the capacity of the
equipment .
 Undercharging or overcharging a blender can result in poor drug
or tablet lubricant distribution.
2. Wet granulation
(a)Binder addition-
 should be added as a granulating solution or dry like other
excipients.

 Adding the binder dry avoids the need to determine the optimal
binder conc.
(b)Binder conc.-
 If the binder conc. are high they are not ejected by spray nozzle
then the binder needs to be dilute enough so that it can be
pumped through the spray nozzle.
(c)Amount of binder solution /granulating solvent-
 Too much binder or solvent solution will over wet the material
&prolong the drying time.
 Amount of binder solution is related to the binder conc.
(d)Granulation end point –how is the granulation end point
determined? is it determined by granulation end point equipment(eg-
ammeter or wattmeter)
(3) wet milling
 does the wet granulation need to be milled to break up the
lumps & enhance drying of the granulation
o FACTORS-
(a)Equipment size & capacity-
 Mill should be enough large to delump the entire batch within
a resonable time period to min. manufacturing time.
(b) Screen size
 screen needs to be small enough to delump the material but
not too small to cause excesssive heating of the mill at the
result drying of granulation occurred.
(c)Mill speed
 sufficient speed without causing staining the equipment.
(d) Feed rate- of the wet granulation is interelated to screen
size ,mill size & speed

(4) Drying
type of drying technique
a) Tray dryer
b) Fluid bed
c) Microwave
 Changing dryer techniques could affect such tablet properties
such as hardness, disintegration ,dissolution & stability
 High moisture content can result in-
1. Tablet picking or sticking to tablet punch surfaces
2. Poor chemical properties as a result of hydrolysis .
 An over dried granulation could result in poor hardness
&fraibility.
Moisture content are analysed by following method –
1. Near I.R
2. Loss of drying
3. Karl fischer
o FACTORS-
(A) Inlet/outlet temp. The inlet temp is the temp of the
incoming air to dryer ,while the outlet temp is the temp leaving
the unit.
(B)
&affect the chemical stability.
(C)
the granulation. Drying also affect the moisture in the
granulation.
(D) Equipment capability/capacity
(5) Milling

 Milling operation will reduce the particle size of the dried
granulation.
 An optimal particle size/size distribution for the formulation will
need to determined .
o FACTORS-
(a)Mill type- what mill type should be used(impact or screen)?
(b) Screen size- A smaller screen size will produce a small
particle size & a greater number of fines.
(c)Mill speed- what is the optimal mill speed?
 Higher speed will result in a smaller particle size &possilbly
a wider particle size distribution.
(d) Feed rate- is dependent on the mill capacity ,screen
size,mill speed
(6) Lubrication
(a) Selection of lubricant- what kind of lubricant should be used?
 Grade of lubricant used
 Compatibility with other ingredient.
(b) Amount of lubricant- how much amount lubricant is required?
 Too much lubricant will form hyrophobic layer on the tablet
resulting dissolution problem.
(c)Mixing time- how much should the material is mixed to ensure
proper formation?
• Should mixing stop after the addition of the lubricant or should
additional mixing be required ?
• If not mixed long enough from problems like chipping ,capping
etc.
(7) Tablet compression

 the material should readily flow from the hopper onto the feed
frame & into the dies.
 Inadequate flow can result in ‘RAT HOLING’in the hopper.this
can cause tablet weight &uniformity problem.
FACTORS
(A) Tolling- The size ,shape&concavity of the tooling should
be examined based formulation properties &commercial
specification.
(B) Compression speed- range of compression speed to
determine the operating range of the compressor.
 The adequacy of the material’sflow into the dies will be
determined by examining the tablet weights.
 Is a force feeder required to ensure that sufficient material feed
into the dies.
(C) Compression or ejection force- determined optimal
compression force to obtain the desired tablet hardness.
The following in-process tests should be examined during the
compression stages
• Appearance
• Hardness
• Tablet weight
• Friability
• Disintegration
• Weight uniformity
In process tests-
• Moisture content of dried granulation
• Granulation particle size distribution

• 3Blend uniformity
• Individual tablet/capsule weight
• Tablet hardness
• Tablet thickness
• Disintegration
• Impurity profile
(8) Tablet coating-
Tablet coating can occur by different techniques(eg-sugar,film or
compression)
• Key area to consider for tablet coating include the following-
(a) Tablet properties –the tablet needs to be enough to withstand the
coating process.
• If tablet attrition occurs ,the tablets will have rough surface
appearance
• Round shape easily coated than multiple sides.
(b)Equipment type- coater will need to be selected.
• Conventional or perforated pan & fluid bed coaters are
potential.
(c)Coater load-what is the acceptance tablet load range of the
equipment?
Too high load at the result attrition occurred.
(d)Pan speed- what is the optimal pan speed?
It is interelated to coating parameter such as inlet temp., spray
rate & flow rate.
(e) Spray guns- number & types of guns should be determined in
order to efficiently coat the tablet.

Size of spray nozzle properly to ensure even distribution over
the tablet bed & to prevent clogging of the nozzles.
(f) Spray rate- spray rate should be determined .
Spraying too fast will cause the tablets to become over
wet,resulting in clumping of the tablets & possible dissolution of
the tablet surface.
• Spray too slowly will cause the coating material to prior to
adhesion to the tablets, result in rough & poor coating
efficiency.
(g)Tablet flow-flow of the tablets in the coater should be examined
to ensure proper flow.
• The addition of baffles may be required adequate movement of
the tablet for coating.
(h)Inlet/outlet temp &air flow-parameter should be set to ensure
that the atomized coating solution reaches the tablet surface &
then is quickly dried.
(i) Coating solution-the conc. & viscosity of the coating solution
will need to be determined.
The stability of the coating solution should be investigated to
establish its shelf life.
(j) Coating weight-a min. & max. Coating weight should be
established for the tablet
(k)Residual solvent level-if solvents are used for tablet coating ,the
residual solvent level will need to be determined.
APPEARANCE TESTING FOR TABLET COATING-
1. Cracking or peeling of the tablet
2. Intagliation fill-in
3. Color uniformity
4. Coating efficiency should be determined for the coating
operation

Finished product tests-
1. Appearance
2. Assay
3. Content uniformity
4. Tablet hardness
5. Tablet friability
6. Impurity profile
7. Dissolution
• Process validation testing is generally done on the first three
batches of product made in production –size equipment.
• Revalidation testing is only done when a significant change has
occured.
2. CAPSULES
VALIDATION OF RAW MATERIALS AND EXCIPIENTS
 The validation process of solid dosage form begins with the
validation of raw materials both API and excipients.
 Preformulation is one of the critical step to be validated in
product validation
 Physical characters such as drug and particle size can affect
material flow and blend uniformity.
 Chemical characters like impurities can effect stability of drug.
 The hygroscopic nature is important in both handling and
reproducibility of the manufacturing process.

VALIDATION OF EXCIPIENTS
 Excipients can represent less then 1% of a tablet formula
 Factors to be aware of are
I. The grade and source of the excipients
II. Particle size and shape characteristics and
 Lot-to-lot variability
 Microcrystalline cellulose(MCC) used as diluents shows
significant changes in the chemical composition, crystalinity,
particle size b/w different lots.
 Differences in particle size of MCC can effect wet
granulation/blend uniformity of tablet formulation.
 In direct compression formulations differences in particle size
distribution b/w lots can result in
 Non uniformity in initial mix
 Materials segregate during compression
CAPSULE COMPOSITION-
Capsule shell provide :
 The reason for the presence of each ingredient in the capsule
formulae.
 Justify the level and grade of each ingredient .
 Explain the selection of the capsule size and shape
 Discuss the need for capsule identification(color).
Capsule shell contents-
 Establish the compatibility of the capsule shell and the
capsule contents.
 Determine the hygroscopic nature of the capsule formulation

 For example : A hygroscopic formulation(API
/excipients)can pull water from the capsule shell, which could
effect the API stability.
PROCESS EVALUATION AND SELECTION
 The process to manufacture the contents of a hard gelatin
capsule is the same as the tablet.
 It may required only a blending step, such as a direct
compression tablet, or several unit operations, such as a wet
granulation tablet (e.g. mixing, wet milling, drying, dry milling
and blending).
 In either case, the materials are then encapsulated in a capsule
shell.
ENCAPSULATION SPEED
 The formulation should be encapsulated at a wide range of
speeds to determine the operating range of the encapsulation.
ENCAPSULATION
 Encapsulation is a critical step in the production of capsules,
similar to the compression for tablet dosage forms.
 The materials to be encapsulated will need to have good flow
properties and a consistent density.
QUALITY CONTROL TESTS ARE DIVIDED INTO
1. PHYSICAL TEST
 Disintegration test
 Weight variation
2. CHEMICAL TEST
 Dissolution test
 Assay
 Content uniformity
 Stability testing Moisture permeation test

3. OINTMENT/CREAMS
Validation of Semisolids
Semisolids:
 A pharmaceutical dosage form category that includes
ointments, cream emulsions, pastes, gels, and rigid foams.
Their common property is the ability to cling to the surface of
application for reasonable duration before they are washed or
worn off. The adhesion is due to plastic rheologic behavior,
which allows the semisolid to retain shape and cling as a film
until acted upon by an outside force, in which case it will
deform and flow.
Pre-validation Requirements :
 Cleaning Validation
 Preventive Maintenance for Facilities and Utilities
 Calibration of Equipment
 Equipment Qualification
 Raw Materials/Components/Test Methods
 Process Justification
 Documentation
 Change Control
 Training operators
All must be proven suitable and reliable for the manufacturing
process before the process can be validated
Critical Parameters – Semi- Solids Critical

Equipment Critical Process Parameter
 Mixing Speed
 Homogenizing Speed
 Mixing Time
 Heating / Cooling Time
 Pumping Speed (Flow Rate)
 Vacuum

Critical Processing Parameter
Product Testing
 Validation testing of bulk and F/G must be based on testing
standard release criteria and in-process testing criteria
 Routine QC release testing should be performed on a routine
sample. These samples should be taken separately from the
validation samples.
Validation Batch:
 New products and product transfer, Prospective validation is
required
 Manufacturing Process, Formula, Equipment and Batch Size
have to be fixed during the validation trials.

 Batch Size should be the same size as commercial production
batch
 The batch size must be fixed for production. However, it can be
changed up to 10% with the on-going study by using the same
equipment.
 Different lots but same manufacturer of active ingredients
should be used during validation trials
 At least 2 portions of this bulk quantity must be filled in to 2
batches of any size container. The portions should be from
different bulk trials.
 1 entire bulk should filled in to 1 batch of the smallest container
size to demonstrate the largest filling run time.
 The validation study should include the smallest and largest size
of the same type of filled container.
 Raw materials, in-process product and finished product must
pass all in process and testing standard release requirements.
 Cleaning procedure for all relevant equipment must be evaluated
for cleaning validation.
 Product may not be released to the market until the validation
report is approved and issued.
In-process Monitoring
 Record temperature of melted ingredients, mixtures,
incoming liquids and final product, and rates of heating or
cooling for comparison against the product development
batch information.
 Record critical processing parameters for pumping, mixing,
comminution and transfer of the product.
 Check the product for foaming, presence of unusual lumps, or
discoloration. Determine if there is any residue in the tanks
after emptying. Examine the filters and screens for unmixed
or undissolved material.

Validation Batch: Bulk Sampling and Testing
 Take 10 samples from the mixer, tank, or during product
transfer to the storage/filling vessels. The samples must
represent the top, middle and bottom of the vessel.
 If sampling from the mixer/tank using an specific equipment,
samples should be taken immediately adjacent to blades,
baffles, and shafts where product movement during mixing
may restricted.
 The bottom of the tank and any potential dead spots should
be sampled and examined for unmixed or undissolved
material, if possible.
Qualification of Maximum Bulk Hold Time
 The maximum period of time which the bulk can be held
prior to fill
 One full scale bulk batch should be held for most practical
maximum time period prior to filling.
 If there is not enough support information / qualification
done. The period of 24 hours will be used.
 Hold time qualification must simulate actual in-process
conditions and handling.
 The qualified hold time used in routine production must be
specified in the manufacturing batch record.
Finish Product Testing
o Net Contents
 Perform testing on filled containers across the filling run.
 Perform testing per testing standard
o Microbiology
 Samples from each of the beginning and end of the filling run
and perform testing per Testing Standard
 Preservative Efficacy testing should be tested.

o Content Uniformity
o Other Testing
 • Assay, pH, Viscosity, Preservative Content etc.
4. Process Validation Of Liquids
 They are liquid preparation in which the drugs are dissolved,
suspended or disperse in a suitable vehicle and generally several
doses are contained in the bottle.
 Types Of Oral Liquids
• Syrups
• Solutions
• Suspension
• Eye drops
• Nasal drops etc
 Validation Includes Mainly Following Tests
1. Particle size and size distribution
2. Particle shape or morphology
3. Microbial count
4. Rheology of solvent or vehicle
5. PH of the solvent or vehicle
Monitoring outputs Some outputs to be monitored are as under:
a. Appearance
b. pH
c. Viscosity
d. Specific gravity
e. Microbial count
f. Content uniformity
g. Dissolution testing

a. Appearance of the final product indicates the signs of instability
and degradation. For e.g. settling of solid particles in case of
suspension and turbidity in case of emulsion.
b. Time for mixing or agitation and temperature of process can
affect the appearance greatly.
c. PH of aqueous oral formulations should be taken at a given
temperature and only after equilibrium has been reached in
order to minimize the PH drift.
d. Viscosity affects the settling rate of suspended particles in
suspension and coalescence of globules of internal phase in
emulsions and also in case of oral solutions it affects the overall
appearance of the final product so it must be measured and
validated properly.
e. Specific gravity: A decrease in specific gravity of the product
like suspensions indicates the presence of air within the
structure of the formulation.
f. Microbial count for the final product is essential to validate
because by performing microbial count we can select the
preservative for the final product storage. There are
specifications for each liquid oral product for the bio burden
content.
g. Content uniformity affects the dose uniformity in case of multi
dose formulations and also affects the homogeneity of the drug
within solvent system.

Summary table for validation of liquid dosages form
5. Process validation of AEROSOLS
 Inhalation aerosols have been used for the delivery of drugs to
the respiratory system since the mid-1950s. The most common
dosage form for inhalation is the metered-dose inhaler (MDI),
by which the drug is delivered from a pressurized container
using a liquefied gas propellant. Medication delivered via this
dosage form has allowed for a quick therapeutic response to the
symptoms of asthma, emphysema, and chronic obstructive
pulmonary disease (COPD), and has resulted in an improvement
in the quality of life for millions of asthma sufferers.
 In Pharmaceutical organizations, validation is a fundamental
segment that supports a company commitment to quality
assurance. Validation is a tool of quality assurance which
provides confirmation of the quality in equipment systems,
manufacturing processes, software and testing methods.
Pressurized Metered Dose Inhalers (pMDI)
 These are the most common device for administration of
aerosolized drugs.In this technique, a medication is mixed in a
canister with a propellant, and the preformed mixture is expelled
in exact measured amounts upon actuation of the deviceFig.01.

 Correct use of MDIs requires that patients learn how to organize
exhalation and inhalation with actuation of the device.
 By using the spacer device it may solve the problem moderately
the bulky size of the device can be prevention for patients who
have need of use of MDIs outside their homes.
Validation should be considered in the following situation;
o Totally New Process.
o New Equipment.
o Process and Equipment which have been altered to suit
changing priorities.
o Process where the end product test is poor and an
unreliable indication of product quality.
o Extensive product testing.
o Simulation process trials.
o Challenge/worst case trials.
o Controls of process parameters (mostly physical)
Validation Team

 A multidisciplinary team is primarily responsible for conducting
and supervising validation studies. Personnel qualified by
training and experience in a relevant discipline may conduct
such studies. The working party would usually include the
following staff members such as;
o Head of quality assurance.
o Head of engineering.
o Validation manager.
o Production manager.
o Specialist validation discipline: all areas.
 The validation team must be prepared the site validation master
plan with the specific requirements as per the company policy.
o Meet regularly, In accordance with a defined schedule, to
discuss the progress and compliance with the validation
plan and schedule.
o Determine the systems / equipment to be qualified /
validated and the extent of validation to be carried out.
o Determine the frequency of validation.
o Prepare and evaluate the suitability of the protocols.
o Verify the adequacy of the tests used for proving that the
objectives are achieved.
o Complied reports should be checked and approved by
validation team members.
o Assurance of progress in terms of validation plan and
schedule.
Retrospective validation
 It involves the examination of past experience of production on
the assumption that composition, procedures, and equipment
remain unchanged; such experience and the results of in-process
and final control tests are then evaluated.

 Recorded difficulties and failures in production are analysed to
determine the limits of process parameters. A trend analysis may
be conducted to determine the extent to which the process
parameters are within the permissible range. Some of the
essential elements for the retrospective validation are;
• Batches manufactured for defined period (minimum of 10
last consecutive batches).
• Number of lots released per year.
• Batch Size/Strength/Manufacturer/year/period.
• Master manufacturing/packaging documents.
• Current specification of active materials/Finished products.
• List of deviations, corrective actions and Changes to
manufacturing documents.
• Data for stability testing of several batches.
Concurrent validation
It may be the practical approach under certain circumstances.
Examples of these may be:
 When a previously validated process is being transferred to a
third party contract manufacturer or to another manufacturing
site.
 Where the product is a different strength of a previously
validated product with the same ratio of active / inactive
ingredients.
 When 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.
 When the numbers of batches produced are limited. It is
important in these cases however, that the systems and
equipment to be used have been fully validated previously.

 The justification for conducting concurrent validation must
be documented and the protocol must be approved by the
Validation Team.
 A report should be prepared and approved prior to the sale of
each batch and a final report should be prepared and
approved after the completion of all concurrent batches. It is
generally considered acceptable that a minimum of three
consecutive batches within the finally agreed parameters,
giving the product the desired quality would constitute a
proper validation of the process.
Revalidation
 It may be divided into two broad categories:
 Revalidation after any change having a bearing on product
quality.
 Periodic revalidation carried out at scheduled intervals.
 Revalidation after changes, some typical changes which
require revalidation include the following:
• Changes in the starting materials. Changes in the physical
properties, such as density, viscosity, particle size
distribution, and crystal type and modification, of the active
ingredients or Excipients may affect the mechanical
properties of the material; as a consequence, they may
adversely affect the process or the product.
• Changes in the packaging material, e.g. replacing plastics
by glass, may require changes in the packaging procedure
and therefore affect product stability.
• Changes in the process, e.g. changes in mixing time, drying
temperature and cooling regime, may affect subsequent
process steps and product quality.
• Changes in equipment, including measuring instruments,
may affect both the process and the product; repair and

maintenance work, such as the replacement of major
equipment components, may affect the process.
• Changes in the production area and support system, e.g. the
rearrangement of manufacturing areas and/or support
systems, may result in changes in the process. The repair
and maintenance of support systems, such as ventilation,
may change the environmental conditions and, as a
consequence, revalidation/requalification may be
necessary, mainly in the manufacture of sterile products.
The validation protocol should contain the following elements;
 Short description of the process.
 Summary of critical processing steps to be investigated.
 In process, finished product specification for release.
 Sampling plans.
 Departmental responsibility.
 Proposed timetable.
 Approval of protocol.
The validation report should include at least the following;
 Title and objective of study.
 Reference to protocol.
 Details of material.
 Equipment.
 Programs and cycles used.
 Details of procedures and test methods.
 Result.
 Recommendations on the limit and criteria to be applied
on future basis.
ASEPTIC FILLING: media fill validation

 Aseptic processing is the process by which a sterile (aseptic)
product (typically food or pharmaceutical) is packaged in a
sterile container in a way that maintains sterility
 Sterility is achieved with a flash-heating process (temperature
between 195 and 295 °F (91 to 146 °C)), which retains more
nutrients and uses less energy than conventional sterilization
techniques such as retort or hot-fill canning.
 Pharmaceutical Sterile processing includes use of clean rooms,
bacteria retaining filters, dry or steam heat. Aseptic food
preservation methods allow processed food to keep for long
periods of time without preservatives, as long as they are not
opened.
 The aseptic packages are typically a mix
of paper (70%), polyethylene (LDPE) (24%),
and aluminum (6%), with a tight polyethylene inside layer.
 Sterile pharmaceuticals are usually packaged in plastic or glass.
Together these materials form a tight seal against
microbiological organisms, contaminants, and degradation,
eliminating the need for refrigeration
 Aseptic containers may range in size from a few fluid ounces to
a nearly 8-million-US-gallon (30,000 m3) aseptic tank on an
ocean-going ship. Aseptic processing makes worldwide export
and import of new, economical and safe food products
possible. Bag-in-box technology is commonly used because it
provides strong containers that are lightweight and easy to
handle prior to being filled.
Media fill validation
 A “media fill” (sometimes known as a “process simulation”)
is the performance of an aseptic manufacturing procedure
using a sterile microbiological growth medium in place of the
drug solution. Microbiological growth medium is used in
place of the drug solution during media fills to test whether

the aseptic procedures are adequate to prevent contamination
during actual drug production. A media fill is one part of the
validation of an aseptic manufacturing process.
 The media fill should evaluate the aseptic assembly and
operation of the critical (sterile) equipment, qualify the
operators and assess their technique, and demonstrate that the
environmental controls are adequate to meet the basic
requirements necessary to produce a sterile drug by aseptic
processing. The media fill does not validate the ability of the
filter to sterilize growth media.
The steps involved in a media fill
1. Design
 A media fill should be carefully designed to ensure that the
simulation is representative of all the aseptic manipulations
performed during production.
 These include preparation and assembly of the product
containers, transfer of the product containers to the fill area,
and all process steps downstream from the “sterilizing filter”
up to product release, including packaging into finished
product containers.
 Finished product containers with medium should then be
incubated to permit the growth of microbial contamination in
any containers.
 Microbiologically contaminated containers are expected to
exhibit observable evidence of microbiological contamination
after suitable incubation.
 The same type and source of containers should be used for
media fills as are used in routine production.
 Media fills should be conducted in the same locations where
the production occurs and employ the broadest scope of
possible manipulations that could occur during production.

 Every aseptic manipulation during production up to the point
of finished product release should be included in the media
fill. Because each PET finished product container is to be
sampled aseptically prior to release, sample withdrawal and
any adjustments should be simulated as well.
 All steps intended for aseptic manufacturing should be
reproduced in the media fill, including sampling and dilution
of the final product.
 All personnel involved in the aseptic manufacture of the drug
product should participate in at least one media fill per year.
All processing steps that the operator normally performs
during aseptic manufacturing should be simulated.
2. Preparation for the Test
 Once the media fill procedures are established, all of the
components necessary for the simulation should be
assembled, including all of the equipment used in the aseptic
part of the process. Media to be used in the simulation may
be obtained commercially or prepared on site, and should be
sterile.
 When media are prepared on site, sterilization should be
conducted using a validated process such as steam autoclave.
Filtration is not recommended to sterilize the growth
medium.
How should a media fill be performed?
 To initially qualify an aseptic process at a specific facility,
three media fills should be conducted on three separate days
at that facility using the specific production process that is
being qualified.

 Additionally, media fills should be conducted whenever
significant changes are made to the aseptic process (e.g.,
changes in personnel, components, or equipment) and
whenever there is evidence of a failure to maintain product
sterility.
 Media fills performed to validate an aseptic process at a
specific facility should be done by an operator who
previously has been trained and qualified in aseptic
techniques (e.g., proper gowning, disinfection practices,
handling sterile materials).
 Media fills are an important element of operator qualification.
 To become a qualified operator for PET drug product
production, an operator should perform three media fills on
three separate days.
 A qualified operator should perform a media fill at least
annually.
USFDA guideline on Process Validation- A life cycle
approach
 Validation of manufacturing processes is a requirement of
the Current Good Manufacturing Practice (CGMP)
regulations for finished pharmaceuticals (21 CFR 211.100
and 211.110) and is considered as an enforceable element
of Current Good Manufacturing Practice for active
pharmaceutical ingredients (APIs) under the broader
statutory CGMP provisions of section 501(a)(2)(B) of the
Federal Food, Drug and Cosmetic Act.
 The basic principle of Quality Assurance is that a drug
should be produced that is fit for its intended use.
 Process Validation is defined as the assortment and
estimation of data, from the process design stage through

marketable production, which establishes scientific
evidence that a process is capable of consistently
delivering quality product.
 USFDA process validation guideline published in 2011,
suggest three stages of validation;
1. Process design
2. Process qualification
3. Continued Process qualification
 Before marketable delivery begins, a manufacturer is
expected to have stored enough data and knowledge about
the commercial production process to support post-
approval product distribution.
 Normally, this is achieved after adequate product and
method development, scale-up studies, equipment and
system requirement, and the effective accomplishment of
the initial conformance batches.
 Conformance batches (sometimes referred to as
"validation" batches and demonstration batches) are
prepared to validate that, under standard conditions and
defined ranges of effective parameters, the commercial
scale process appears to make adequate product.
 Prior to the manufacture of the conformance batches the
manufacturer should have identified and controlled all
critical sources of changeability.
 A validated manufacturing process has a high level of
precise assurance that it will constantly produce acceptable
products.
Approach to Process Validation:

1. Stage 1: Process Design: The marketable manufacturing process
is defined during this stage based on knowledge gained through
development and scale-up activities
2. Stage 2: Process Qualification: Throughout this stage, the
method design is estimated to determine if the process is capable
of reproducible marketable business.
3. Stage 3: Continued Process Verification: Constant assertion is
gained during routine production that the process remains in a
state of control.
Stage1: Process Design:-
Constructing and Apprehending Process Knowledge and
Understanding:
 The functionality and limits of commercial manufacturing
equipment should be considered in the process design.
 Design of experiments (DOE) studies can help to develop
process knowledge by revealing relationships, including
multivariate interactions, between the variable inputs and the
resulting outputs.
 Risk analysis tools can be used to display possible variables for
DOE studies .
Creating an Approach for Process Control:
 Controls and consist of material analysis and equipment
monitoring at significant.
 These controlled records are established in the Master formula
records and control processing points.
 Records.
 The calculated commercial production and control records
should be carried forward to the next stage for confirmation.
Stage 2: Process Qualification:-

Element (1): Design of a facility and qualification of utilities and
equipment
 Ensure qualification of facility, utilities and equipment is
completed & documented prior to initiate process qualification.
Element (2): Process Performance Qualification (PPQ)
 The PPQ combines the actual facility, utilities, equipment’s and
the trained personnel with the commercial manufacturing
controls.
 A company must successfully complete PPQ before
commencing commercial distribution of the drug product.
 To understand the marketing process adequately, the
manufacturer will need to consider the effects of scale.
 Strongly recommend firms employ objective measure (e.g.
Statistical Metrics) wherever feasible and meaningful to achieve
adequate assurance.
 The increased level of inspection, testing, and sampling should
continue through the process verification stage as correct, to
establish levels and occurrence of routine sampling and
checking for the particular product and process.
 Considerations for the duration of the intensified sampling &
checking period could include (not limited to):
• Volume of production
• Process Complexity
• Level of process understanding
• Experience with similar products and process
PPQ Protocol:
Some of key elements to be captured in validation protocol as detailed
below;

Validation shall be executed as per validation protocol duly approved
by Quality unit.
PPQ Report:
 To state a clear conclusion as to whether the data indicates the
process meets the conditions established in the protocol. If not
the report should state what should be accomplished before such
a conclusion can be reached.
 This conclusion should be based on entire compilation of
knowledge and information gained from the design stage
through the PPQ stage.
The plan should include risk management to prioritize activities
and documentation
 The plan should identify
1. Studies or tests to use
2. Criteria appropriate to assess outcomes
3. Timing of qualification activities
4. Responsibilities
5. The procedures for documenting and approving the
qualification
 Change evaluation policy

 Documentation of qualification activities
 Quality assurance (QA) approval of the qualification plan.
Stage 3: Continued Process Verification:-
 To confirm that “the process remains in a state of control during
commercial manufacture.”
 An ongoing process to collect and analyze product and process
data that relate to product quality must be established.
 The results obtained should be statistically trended and reviewed
by trained personnel.
 Recommend that a person with suitable training in statistical
process control techniques develop the data collection plan and
statistical methods.
 Good process design and development should anticipate
significant sources of variability and establish appropriate
detection, control and or qualification schemes, as well as
suitable alert and action limits.
 Study of intra-batch as well as inter-batch variation is part of a
comprehensive continued process verification program.
• Deviation can be detected by the timely assessment of
• Defect complaints
• OOS findings
• Process deviation report
• Process yield variations
• Batch record & reports
 Manufacture line operatives and quality unit staff should be
encouraged to provide feedback on process performance.
 Quality unit meet periodically with production staff to evaluate
data, discuss possible trends and coordinate any correction or
follow-up actions by product.
 Data collected during this stage might recommend ways to
improve and/or optimize the process by altering some aspect of

the process or product, such as the operating conditions, process
controls, etc.
 Well justified rationale for the change, implementation plan,
quality unit approval before implementation.
Concurrent Release of PPQ batches:
 FDA expects that simultaneous release will be used rarely.
 Circumstances and reasoning for simultaneous release should be
fully described in the PPQ protocol0
 System of careful oversight of the distributed batch to facilitate
rapid customer feedback.
Analytical Method Validation
PRINCIPLE
 Validation of an analytical procedure is the process by which it
is established, by laboratory studies, that the performance
characteristics of the procedure meet the requirements for its
intended use. All analytical methods intended to be used for
analyzing any clinical samples will need to be validated.
Validation of analytical methods is an essential but
time‐ consuming activity for most analytical development
laboratories.
 It is therefore important to understand the requirements of
method validation in more detail and the options that are
available to allow for optimal utilization of analytical resources
in a development laboratory.
 There are many reasons for the need to validate analytical
procedures. Among them are regulatory requirements, good
science, and quality control requirements. The Code of Federal
Regulations (CFR) 211.165e explicitly states that “the accuracy,

sensitivity, specificity, and reproducibility of test methods
employed by the firm shall be established and documented.”
Validation of analytical method
 Parameters for Method Validation
1. Specificity
2. Selectivity
3. Precision
4. Repeatability
5. Reproducibility
6. Accuracy
7. Linearity
8. Range
9. Limit of detection
10. Limit of quantitation
11. Robustness
12. Ruggedness
1. Selectivity/Specificity
 Although it is not consistent with the ICH, the term specific
generally refers to a method that produces a response for a
single analyte only, while the term selective refers to a method
that provides responses for a number of chemical entities that
may or may not be distinguished from each other.
 If the response is distinguished from all other responses, the
method is said to be selective.
 Since there are very few methods that respond to only one
analyte, the term selectivity is usually more appropriate.
 Selectivity in liquid chromatography is obtained by choosing
optimal columns and setting chromatographic conditions, such
as mobile phase composition, column temperature and detector
wavelength.

 Besides chromatographic separation, the sample preparation
step can also be optimized for best selectivity.
 Analytical techniques that can measure the analyte response in
the presence of all potential sample components should be used
for specificity validation.
2. PRECISION
 ICH defines the precision of an analytical procedure as 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. Precision
may be considered at three levels:
o Repeatability
o Intermediate precision
o Reproducibility.
Intermediate precision
 Intermediate precision expresses variations within laboratories,
such as different days, different analysts, different equipment,
and so forth.
 Intermediate precision is determined by comparing the results of
a method run within a single laboratory over a number of days.
A method’s intermediate precision may reflect discrepancies in
results obtained from:
• Different operators
• Inconsistent working practice
• Different instruments
• Standards and reagents from different suppliers
• Columns from different batches
• A combination
 The objective of intermediate precision validation is to verify
that in the same laboratory the method will provide the same
results once the development phase is over

3. REPEATABILITY
 Repeatability expresses the precision under the same operating
conditions over a short interval of time. Repeatability is also
termed intra-assay precision.
 The ICH5 requires repeatability to be tested from at least six
replicationsmeasured at 100 percent of the test target concentration
or from at leastnine replications covering the complete specified
range. For example, theresults can be obtained at three
concentrations with three injections ateach concentration.
4. REPRODUCIBILITY
 Reproducibility expresses the precision between laboratories
(collaborative studies usually applied to standardization of
methodology).
 The objective of reproducibility is to verify that the method
will provide the same results in different laboratories. The
reproducibility of an analytical method is determined by
analyzing aliquots from homogeneous lots in different
laboratories with different analysts.
 In addition, typical variations of operational and
environmental conditions that may differ from, but are still
within, the specified parameters of the method are used.
 Validation of reproducibility is important if the method is to
be used in different laboratories.
 Factors that can influence reproducibility include differences
in room temperature and humidity, or equipment with
different characteristics such as delay volume of an HPLC
system, columns from different suppliers or different batches
and operators with different experience and thoroughness.

5. ACCURACY
ICH defines the accuracy of an analytical procedure as the
closeness of agreement between the conventional true value or
an accepted reference value and the value found.
Accuracy can also be described as the extent to which test results
generated by the method and the true value agree.
The true value for accuracy assessment can be obtained in several
ways.
One alternative is to compare the results of the method with
results from an established reference method. This approach
assumes that the uncertainty of the reference method is known.
6. LINEARIY
 ICH defines linearity of an analytical procedure as its ability
(within a given range) to obtain test results that are directly
proportional to the concentration (amount) of analyte in the
sample.
 Linearity may be demonstrated directly on the test substance
(by dilution of a standard stock solution) or by separately
weighing synthetic mixtures of the test product components.
 Linearity is determined by a series of five to six injections of
five or more standards whose concentrations span 80–120
percent of the expected concentration range.
 The response should be directly proportional to the
concentrations of the analytes or proportional by means of a
well-defined mathematical calculation.
 A linear regression equation applied to the results should have
an intercept not significantly different from zero. If a significant
nonzero intercept is obtained, it should be demonstrated that this
has no effect on the accuracy of the method.

7. RANGE
 ICH defines the range of an analytical procedure as the interval
from the upper to the 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 range of an analytical method is the interval from the upper
to the lower levels (including these levels) that have been
demonstrated to be determined with precision, accuracy and
linearity using the method as written.
 The range is normally expressed in the same units as the test
results (for example percentage, parts per million) obtained by
the analytical method.
 For assay tests, ICH requires the minimum specified range to be
80 to 120 percent of the test concentration. It also requires the
range for the determination of an impurity to extend from the
limit of quantitation or from 50 percent of the specification of
each impurity, whichever is greater, to 120 percent of the
specification. Figure 6 shows graphical definition of linearity
and range.
8. LOD
 ICH defines the detection limit of an individual analytical
procedure as the lowest amount of analyte in a sample which
can be detected but not necessarily quantitated as an exact value.
 The limit of detection (LOD) is the point at which a measured
value is larger than the uncertainty associated with it. It is the
lowest concentration of analyte in a sample that can be detected
but not necessarily quantified. The limit of detection is
frequently confused with the sensitivity of the method.
 The sensitivity of an analytical method is the capability of the
method to discriminate small differences in concentration or
mass of the test analyte.

 In practical terms, sensitivity is the slope of the calibration
curve that is obtained by plotting the response against the
analyte concentration or mass.
9. LOQ
 ICH defines the limit of quantitation (LOQ) of an individual
analytical procedure as 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 or degradation products.
 The quantitation limit is generally determined by the analysis of
samples with known concentrations of analyte and by
establishing the minimum level at which the analyte can be
quantified with acceptable accuracy and precision. If the
required precision of the method at the limit of quantitation has
been specified, 5 or 6 samples with decreasing amounts of the
analyte are injected six times. The amounts range from the
known
 LOD as determined above to 20 times the LOD.
10. ROBUSTNESS
 ICH defines the robustness of an analytical procedure as a
measure of its capacity to remain unaffected by small, but
deliberate variations in method parameters. It provides an
indication of the procedure’s reliability during normal usage.
 Robustness tests examine the effect that operational parameters
have on the analysis results. For the determination of a method’s
robustness, a number of method parameters, such as pH, flow
rate, column temperature, injection volume, detection
wavelength or mobile phase composition, are varied within a

realistic range, and the quantitative influence of the variables is
determined.
 If the influence of the parameter is within a previously specified
tolerance, the parameter is said to be within the method’s
robustness range.
 Obtaining data on these effects helps to assess whether a
method needs to be revalidated when one or more parameters
are changed, for example, to compensate for column
performance over time. In the ICH document5, it is
recommended to consider the evaluation of a method’s
robustness during the development phase, and any results that
are critical for the method should be documented.
11. RUGGEDNESS
 Ruggedness is defined by the USP as the degree of
reproducibility of results obtained under a variety of conditions,
such as different laboratories, analysts, instruments,
environmental conditions, operators and materials. Ruggedness
is a measure of the reproducibility of test results under normal,
expected operational conditions from laboratory to laboratory
and from analyst to analyst. Ruggedness is determined by the
analysis of aliquots from homogeneous lots in different
laboratories.

Reference
https://www.slideshare.net/srirao3462/pv-of-api-lupin
https://en.wikipedia.org/wiki/Process_validation
https://www.slideshare.net/niralimodha3/pharmaceutical-
process-validationpptx
https://www.slideshare.net/saravananchandran712/process-
validation-56268629?qid=0d4be0ae-132d-4de6-b87b-
af1e13d3b2ac&v=&b=&from_search=4
http://www.betterchem.com/21cfr211/retrospective_validation.
htm

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