Wazade et al., IJPSR, 2012; Vol.

3(9): 3007-3022 ISSN: 0975-8232

IJPSR (2012), Vol. 3, Issue 09 (Review Article)

Received on 28 May, 2012; received in revised form 12 June, 2012; accepted 17 August, 2012

AN OVERVIEW OF PHARMACEUTICAL PROCESS VALIDATION AND PROCESS CONTROL VARIABLES OF TABLETS

MANUFACTURING PROCESSES IN INDUSTRY

Mahesh B. Wazade*, Sheelpriya R. Walde and Abhay M. Ittadwar

Department of Quality Assurance, Gurunanak College of Pharmacy, Nagpur-440 026, Maharashtra, India

Keywords: ABSTRACT
Pharmaceutical process validation,
Drug production, Validation is an integral part of quality assurance; the product quality is
Process control variables,
derived from careful attention to a number of factors including selection of
Manufacturing process
quality parts and materials, adequate product and manufacturing process
Correspondence to Author:
design, control of the process variables, in-process and end-product testing.
Mahesh B. Wazade Recently validation has become one of the pharmaceutical industrys most
recognized and discussed subjects. It is a critical success factor in product
Research Scholar, Department of Quality approval and ongoing commercialization, facilities and processes involved in
Assurance, Gurunanak College of
Pharmacy, Nagpur-440 026, Maharashtra, pharmaceutical manufacturing process impact significantly on the quality of
India the products. Process controls are mandatory in good manufacturing practice
(GMP). The purpose is to monitor the on-line and off-line performance of the
E-mail: [email protected]
manufacturing process, and hence, validate it.

INTRODUCTION: Pharmaceutical process validation is a predetermined specifications and quality

key element in assuring that these quality assurance characteristics 1.
goals are met. It is through careful design and
validation of both the process and process controls History of Validation: The concept of validation was
that a manufacturer can establish a high degree of first proposed by two FDA officials, Ted Byers and Bud
confidence that all manufactured units from successive Loftus, in the mid 1970s in order to improve the
lots will be acceptable. Successfully validating a quality of pharmaceuticals (Agalloco 1995). It was
process may reduce the dependence upon intensive in- proposed in direct response to several problems in the
process and finished product testing. It should be sterility of large volume parenteral market. The first
noted that in all most cases, end-product testing plays validation activities were focused on the processes
a major role in assuring that quality assurance goals involved in making these products, but quickly spread
are met; i.e., validation and end-product testing are to associated process of pharmaceutical.
not mutually exclusive.
QUICK RESPONSE CODE
The U.S. Food and Drug Administration (FDA) has IJPSR:
proposed guidelines with the following definition for ICV- 4.57
process validation: Process validation is establishing
Website:
documented evidence which provides a high degree of
www.ijpsr.com
assurance that a specific process (such as the
manufacture of pharmaceutical dosage forms) will
consistently produce a product meeting its

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U.S.F.D.A. was the pioneer in advocating the concept

of process validation, but till 29th September 1978 the The first edition of the Orange Guide the British
definition of process validation did not appear in any version of GMPs, which was published in 1971 contains
part of literature of U.S.F.D.A. no cGMP regulations a section titled "Verification of Procedures" that states,
talked anything about process validation. "Procedures should undergo a regular critical appraisal
to ensure that they are remain capable of achieving
Process validation and its role within a pharmaceutical the results which they are intended to achieve". This
organization have come a long way from its inception term now here appeared in the U.S.F.D.A.
in the 1970s. At that time, the effort was primarily documentation, this was not defined in law; it was only
focused on sterilization validation and demonstrating in a F.D.A. The compliance programmed entitled "Drug
that the conditions to achieve sterility were met. As a Process Inspections" issued in June 1978 (before
result, the mission was often managed from within the publication of the revised cGMP Regulations) 3.
sterile manufacturing organization using a small team.
In the 1980s validation organizations were created and Process validation is defined as the collection and
began interacting with the other traditional groups evaluation of data, from the process design stage
such as Research, Engineering, Production, through commercial production, which establishes
Manufacturing, and Quality Assurance 2. scientific evidence that a process is capable of
consistently delivering quality product. Process
The term process validation was first used is validation involves a series of activities taking place
debatable, as the concepts underlying the term are over the lifecycle of the product and validation process
quite old and the use of synonyms such as verification as shown in Figure 1. This guidance describes process
and confirmation appears to predict the use of validation activities in three stages which discusses
validation. later.

FIGURE: Error! No text of specified style in document.. VALIDATION LIFE CYCLE

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This particular definition did not appear in any of the procedure, process, equipment, material, activity or
yearly revision of that particular compliance system actually leads to expected results.
programmed but until March 29, 1983 it was the only
official definition of process validation on March 29, This includes in particular, the manufacture of
1983 draft on guidelines entitled Guidelines on investigational products and the scaling up of
General Principles of Process Validation was made processes from pilot plant to production unit. This is
available and the same was finalized in May, 1987 4. most important when processes go into routine full-
scale production follows pharmaceutical development
This guidance aligns process validation activities with a and pilot-plant operations. With a view to facilitating
product lifecycle concept and with existing FDA subsequent validation and its assessment in the course
guidance, including the FDA/International Conference of quality audits or regulatory inspections, it is
on Harmonisation (ICH) guidances for industry, Q8 recommended that all documentation reflecting such
(R2) Pharmaceutical Development, Q9 Quality Risk transfers be kept together in a separate file
Management and Q10 Pharmaceutical Quality System (technology transfer document) 7.
5
.
Scope of Validation: Pharmaceutical Validation is a
Bernard T. Loftus was director of drug manufacturing vast area of work and it practically covers every aspect
in the Food and Drug Administration (FDA) in the of pharmaceutical processing activities, hence defining
1970s, when the concept of process validation was first the Scope of Validation becomes a really difficult task.
applied to the pharmaceutical industry and become an However, a systematic look at the pharmaceutical
important part of current good manufacturing operations will point out at least the following areas
practices M (CGMPs). for pharmaceutical validation;

In process validation theres a lot common sense, you 1. Analytical

need to fully understand the process as you use it to 2. Instrument Calibration
make your product (FDA) 6. 3. Process Utility services
4. Raw materials
What is process Validation: The term process 5. Packaging materials
validation is not defined in the Food, Drug and 6. Equipment
Cosmetic Act (FD&C) Act or in FDAs CGMP regulations. 7. Facilities
Many definitions have been offered that in general 8. Manufacturing operations
express the same idea, that a process will do what it 9. Product Design
purports to do, or represent to do that the process 10. Cleaning
works and the proof is documented. 11. Operators 8

Validation is defined as confirmation, through the The regulatory basis for Process Validation: Once the
provision of objective evidence, that the requirements concept of being able to pre-directs process
for a specific intended use or application have been performance to meet user requirements evolved, FDA
fulfilled. In contrast with verification, validation rather regulatory officials established that there was a legal
focuses on the question whether a system can perform basis of requiring process validation. The ultimate legal
its desired functions. authority is in section 501(a)(2)(B) of the FD&C Act,
which states that a drug is deemed to bead ultimate
The word validation simply means assessment of differ the methods used in or the facilities or controls
validity or action of proving effectiveness. According to used for its manufacture, processing, packing or
European community for medicinal products, holding do not conform to or administrated in
validation is action of proving in accordance with the conformity with CGMP. The CGMP regulations for
principals of good manufacturing practices that any finished pharmaceuticals 21CFR 210 and 211 were
promulgated to enforce the requirements of the act,

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which states that: There shall be written procedures 1. It deepens the understanding of processes,
for production and process control designed to assure decreases the risks, processing problems.
that the drug products have the identity, strength, 2. It assures the smooth running of the process.
quality and purity they purport or are represented to
3. It decreases the risks of defect costs.
possess 9.
4. It decreases the risks of regulatory non-
Need of Validation: Quality is always an imperative compliance.
prerequisite when we consider any product; it 5. A fully validated process may require less in-
becomes primes when it relates to life saving products process control and end product testing.
like pharmaceuticals. Although it is mandatory from 6. It optimizes the process.
the government and regulatory bodies but it is also a 7. It gives assurance of quality and safety12.
fact that quality of a pharmaceutical product can not 8.
Each step of a manufacturing process is
be adequately controlled solely by pharmacopoeia
analysis of the final product. controlled to assure that the finished product
Validation gives confident over the product meets all quality attributes including in
manufacturing process. specifications.
Its give assurance to the product quality as per 9. Product selection
customer requirements. 10. Process design
Validation mandatory as per regulatory 11. Process/ Product characterization
requirements10.
12. Process/ Product optimization
If we are not going for validation then following
13. Process validation program
problems can be occur
Low process capability 14. Product/process certification13.
Scrap, Rework Types of Validation:
Protracted production cycle times and low
capacity utilization 1. Process validation
Resolution of process related problems slow 2. Analytical method validation
and difficult 3. Cleaning validation
High cost of compliance 4. Computer system validation
Risk of
Drug shortages Document regarding Validation:
Releasing a poor quality product, Recalls
Delay in approval of new drugs 1. Getting started
Quality problems confounding clinical trial data 2. Protocol development
3. User requirements specification (URS)
So, as to minimize these problems we need to do
4. Design qualification (DQ)
validation 11.
5. Installation qualification (IQ)
Importance of Validation: Effective process validation 6. Operational qualification (OQ)
contributes significantly to assuring drug quality, the 7. Performance qualification (PQ) 14.
basic principle of quality assurance is that a drug
Types of Process Validation: Depending on when it is
should be produced that is fit for its intended use. The
performed in relation to production, validation can be
most compelling reasons to optimize and validate
prospective, concurrent, retrospective and revalidation
pharmaceutical productions and supporting processes
(Repeated Validation). It would normally be expected
are quality assurance and cost reduction. The basic
that process validation be completed prior to the
principles of quality assurance have as their goal and
distribution of a finished product that is intended for
the production of articles that are fit for their intended
sale (Prospective Validation). Where this is not
use.

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possible, it may be necessary to validate processes All equipment, the production environment and
during routine production (Concurrent Validation). analytical testing methods to be used should have
Processes which have been in use for some time been fully validated (Installation/ Operational
without any significant changes may also be validated Qualification). Staff taking part in the validation work
according to an approved protocol (Retrospective should have been appropriately trained, in practice,
Validation) 15. operational qualification may be carried out using
batches of actual product. This work may also fulfil the
Prospective Validation: Prospective Validation is requirements of prospective validation 18.
carried out during the development stage by means of
a risk analysis of the production process, which is Concurrent Validation: Concurrent Validation is
broken down into individual steps; these are the carried out during normal production. This method is
evaluated on the basis of past experience to determine effective only if the development stage has resulted in
whether they might lead to critical situations. a proper understanding of the fundamentals of the
process. The nature and specifications of sub sequent
It can be performed when a new formulation is in-process and final tests are based on the evaluation
developed or during critical changes like change in the of the results of such monitoring.
batch size is done since here multiple parameters are
changed like quantities of materials, equipment size, Concurrent validation carried out during normal
manufacturing process and parameters. The trials are production, it is together with a trend analysis
then performed and evaluated and an overall including stability should be carried out to an
assessment is made, if at the end the results are appropriate extent throughout the life of the product
acceptable the process is satisfactory 16. 19
.

These experiments may incorporate a challenge Concurrent validation may have the practical approach
element to determine the robustness of the process. under certain circumstances. Examples of these may
Such a challenge is generally referred to as a worst be:
case exercise. Each experiment should be planned and
documented fully in an authorised protocol. This When a previously validated process is being
document will have the following elements; transferred to a third party contract
A description of the process / experiment manufacturer or to another manufacturing site.
Details of the equipment / facilities to be used Where the product is a different strength of a
(including measuring / recording equipment) previously validated product with the same
together with its calibration status ratio of active / inactive ingredients.
The variables to be monitored When the number of lots evaluated under the
The samples to be taken -where, when, how retrospective validation were not sufficient to
and how many obtain a high degree of assurance
The product performance characteristics / demonstrating that the process is fully under
attributes to be monitored, together with the control.
test When the numbers of batches produced are
Methods limited (e.g. orphan drugs).
The acceptable limits
Time schedules It is important in these cases however, that the
Personnel responsibilities systems and equipment to be used have been fully
validated previously. The justification for conducting
Details of methods for recording and evaluating
concurrent validation must be documented and the
results, including statistical analysis 17.
protocol must be approved by the validation team.

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A report should be prepared and approved prior to the Subject the resultant data to statistical analysis
sale of each batch and a final report should be and evaluation.
prepared and approved after the completion of all
concurrent batches. It is generally considered Draw conclusions as to the state of control of the
acceptable that a minimum of three consecutive manufacturing process based on the analysis of
batches within the finally agreed parameters giving the retrospective validation data.
product the desired quality would constitute a proper Issue a report of your findings (documented evidence)
validation of the process 20. 22
.

Retrospective Validation: Retrospective Validation Revalidation: Revalidation is needed to ensure that
involves the examination of past experience of changes in the process and/or in the process
production on the assumption that composition, environment, whether intentional or unintentional do
procedures and equipment remain unchanged; such not adversely affect process characteristics and
experience and the results of in-process and final product quality.
control tests are then evaluated. Recorded difficulties
and failures in production are analyzed to determine Revalidation may be divided into two broad categories:
the limits of process parameters. A trend analysis may Revalidation after any change having a bearing on
be conducted to determine the extent to which the product quality.
process parameters are within the permissible range.
Periodic revalidation carried out at scheduled intervals.
Retrospective validation is obviously not a quality Revalidation after changes may be based on the
assurance measure in itself and should never be performance of the same tests and activities as those
applied to new processes or products. It may be used during the original validation, including tests on
considered in special circumstances only e.g., when sub processes and on the equipment concerned with
validation requirements are first introduced in a validation.
company, retrospective validation may then be useful
in establishing the priorities for the validation Conditions requiring revalidation study and
programme 21. documentation are listed as follows:

Using either data-based computer systems or manual 1. Changes in the source of active raw material
methods, retrospective validation may be conducted in manufacturer.
the following manner: 2. Changes in packaging material (primary
container/closure system).
Gather the numerical data from the completed 3. Changes in raw materials (physical properties such
batch record and include assay values, end as density, viscosity, particle size distribution,
product test results and in-process data. moisture etc. that may affect the process or
Organize these data in a chronological product).
sequence according to batch manufacturing 4. Changes in the process (e.g., mixing time, drying
data, using a spread sheet format. temperatures and batch size).
Include data from at least the last 2030 5. Changes in the equipment (e.g. addition of
manufactured batches for analysis. If the automatic detection system).
number of batches is less than 20, then include 6. Changes of Equipment which involve the
all manufactured batches and commit to obtain replacement of equipment on a like for like basis
the required number for analysis. would not normally require a re-validation except
Trim the data by eliminating test results from that this new equipment must be qualified.
noncritical processing steps and delete all 7. Changes in the plant/facility.
gratuitous numerical information. 8. Variations revealed by trend analysis (e.g. process
drifts).

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Periodic Revalidation: The decision to introduce Validation Maintenance Phase: It requires frequent
periodic revalidation should be based essentially on a review of all process related documents, including
review of historical data i.e., data generated during in- validation of audit reports, to assure that there have
process and finished product testing after the latest been no changes, deviations, failures and
validation, aimed at verifying that the process is under modifications to the production process and that all
control. standard operating procedures (SOPs), including
change control procedures have been followed.
During the review of such historical data, any trend in
the data collected should be evaluated. In some It is assumed that throughout manufacturing and
processes such as sterilization, additional process control operations are conducted in accordance with
testing is required to complement the historical data. the principle of good manufacturing practice (GMP)
Additionally, the following points should be checked at both in general and in specific reference to sterile
the time of a scheduled revalidation: product manufacture 24.

Changes in master formula and methods, batch Principles of Quality Assurance: Assurance of product
size, etc., if so, their impact on the product quality is derived from careful attention to a number of
should be assessed. factors including selection of quality parts and
materials, adequate product and process design,
To check whether calibrations have been made
control of the process, in-process and end-product
in accordance with the established program testing. The basic principles of quality assurance have
and time schedule. as their goal the production of articles that are fit for
Revalidation have the preventive maintenance their intended use.
been performed in accordance with the
program and time schedule. These principles may be stated as follows:
To update the required standard operating
1. Quality, safety and effectiveness must be
procedures (SOPs). designed and built into the product;
Checking the cleaning and hygiene program 2. Quality cannot be inspected or tested into the
have been carried out. finished product;
Any changes been made in the analytical 3. Each step of the manufacturing process must
control methods 23. be controlled to maximize the probability that
the finished product meets all quality and
design specifications.
Major Phases in Validation:
Process validation is a key element in assuring that
Pre-validation Qualification Phase: It covers all
these quality assurance goals are meet. It is through
activities relating to product research and
careful design and validation of both the process and
development, formulation pilot batch studies, scale-up
process controls that a manufacturer can establish a
studies, transfer of technology to commercial scale
high degree of confidence that all manufactured units
batches, establishing stability conditions and storage
from successive lots will be acceptable. Successfully
and handling of in-process and finished dosage forms,
validating a process may reduce the dependence upon
equipment qualification, installation qualification,
intensive in-process and finished product testing 25.
master production document, operational qualification
and process capacity.
WHO Concept: The World Health Organization
(WHO) defines the validation in the same way but
Process Validation Phase: It is designed to verify that
elaborates on the concept: Validation studies are
all established limits of the critical process parameter
essential part of GMP and should be conducted
are valid and that satisfactory products can be
according with predefined protocols. A written report
produced even under the worst conditions.

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summarizing results and conclusions should be Change control

recorded, prepared and stored. Particular attention Reference to the existing documents
should be accorded to the validation of processing,
testing and cleaning procedures. Critical processes In case of large projects, it may be necessary to create
should be validated with prospective and retrospective separate validation master plans 27.
validation.
Pilot Scale-Up and Process Validation: The following
The cGMPs may also be viewed as consisting of the operations are normally carried out by the
following four essential elements: development function prior to the preparation of the
first pilot-production batch. The development activities
Personnel: The people system and manpower are listed as follows:
required to carry out the various tasks within
the manufacturing and control function. Formulation design, selection, and optimization
Parts: The raw materials and components used Preparation of the first pilot-laboratory batch
in connection with the manufacturing and Conduct initial accelerated stability testing
packaging of the drug product as well as the
materials used in association with its control. If the formulation is deemed stable, preparation of
Process: The buildings, facilities, equipment, additional pilot laboratory batches of the drug product
instrumentation and support system with the for expanded non-clinical and/or clinical use.
manufacturing process and its control.
Procedures: The paper work, documentation The pilot program is defined as the scale-up operations
and records used in connection with the conducted subsequent to the product and its process
manufacturing process and its control. leaving the development laboratory and prior to its
acceptance by the full scale manufacturing unit.
Thus, the four elements of cGMPs listed above may be
combined with the four elements of pharmaceutical Thus, product and process scale-up should proceed in
process validation (i.e., qualification, validation, control graduated steps with elements of process validation
and revalidation) to form a 44 matrix with respect to (such as qualifications) incorporated at each stage of
the all the activities that may be considered in the piloting program.
connection with the manufacturer and the control of
the each drug product 26. Laboratory Batch: The first step in the scale-up process
is the selection of a suitable preliminary formula for
Validation Master Plan (VMP): All validation activities more critical study and testing based on certain
should be planned. The key elements of the validation agreed-upon initial design criteria, requirements
program should be clearly defined and documented in and/or specifications. The work is performed in the
validation master plan (VMP) or equivalent documents. development laboratory. The formula selected is
designated as the (1 ) laboratory batch. The size of
The VMP should have summary of document, which is the (1 ) laboratory batch is usually 310 kg of a solid
brief, concise and clear. The VMP should contain data or semisolid, 310 litres of a liquid or 3000 to 10,000
on at least the following: units of a tablet or capsule.

Validation policy Laboratory Pilot Batch: After the (1 ) laboratory batch

Organizational structure of validation activities is determined to be both physically and chemically
Summary of the facilities, systems, equipments stable based on accelerated, elevated temperature
and processes to be validated testing (e.g., 1 month at 45C or 3 months at 40C or
Documentation format: the format to be used 40C/80% RH), the next step in the scale-up process is
for protocols and reports the preparation of the (10 ) laboratory pilot batch.
Planning and scheduling

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The (10 ) laboratory pilot batch represents the first

replicated scale-up of the designated formula. The size
of the laboratory pilot batch is usually 30100 kg, 30
100 litres, or 30,000 to 100,000 units. It is usually
prepared in small pilot equipment within a designated
cGMPs approved area of the development laboratory

Pilot Production: The pilot-production phase may be

carried out either as a shared responsibility between
the development laboratories and its appropriate
manufacturing counter part or as a process
demonstration by a separate, designated pilot-plant or
process-development function.

The object of the pilot-production batch is to scale the FIGURE: 2. PROCESS FLOW STEPS
product and process by another order of magnitude
(100 ) to, for example, 3001,000 kg, 3001,000 litres, Process Description: Manufacturing of Tablets includes
or 300,0001,000,000 dosage form units (tablets or the following processes;
capsules) in size. Usually large production batch scale-
up is undertaken only after product introduction. 1. Premixing & Sifting
Again, the actual size of the pilot-production (100 ) 2. Granulation
batch may vary due to equipment and raw material 3. Drying
availability 28. 4. Sifting & Milling of Dried granules
5. Blending
Prerequisites for Process Validation: Before process 6. Sifting of Lubricants & Lubrication
validation can be started, the manufacturing 7. Compression
equipment and control instruments, as well as the 8. Film Coating Suspension Preparation
formulation, must be qualified. The formulation 9. Film Coating
pharmaceutical product should be studied in detail and
qualified at the development stage, i.e. before the
Mixing or Blending: The mixing or blending unit
application for the marketing authorization is
operation may occur once or several times during the
submitted. This involves pre-formulation studies,
tablets manufacture. For example, a direct
studies on the compatibility of active ingredients and
compression formulation may involve one blending
excipients of final drug product, packaging material,
step in which the drug and the excipients are blending
stability studies, etc.
together prior to compression.
Other aspects of manufacture must be validated,
including critical services (water, air, nitrogen, power A wet granulation formulation may require two
supply, etc.) and supporting operations, such as mixing/blending steps:
equipment cleaning and sanitation of premises. Proper
training and motivation of personnel are prerequisites Prior to granulating to have a uniform
to successful validation. drug/excipient mixture
After milling the dried granulation to add other
Evaluation and Selection of Process Control Variables excipients, such as the lubricant
Following unit operations should be needed to The following physical properties of the drug
determine during the manufacturing of the tablets and and excipients are factors in creating a uniform
steps involved as shown in fig. 2 29. mix or blend:
Bulk density

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Particle size distribution

Surface area Mill type
Mixing or blending operation parameters to be Screen size
considered during development and validation Mill speed
are: Feed rate 31
Mixing or blending technique
Mixing or blending speed/ time Tablets Compression: Compression is a critical step in
Drug uniformity the production of a tablets dosage form. The materials
Excipient uniformity being compressed will need to have adequate flow and
Lubricants compression properties.
Distribution of Colorant(s) Compression process parameters to be considered
Equipment capacity/load30 during development and validation are:

Wet Granulation: The type of granulation technique to Tooling

be used is to be decided, on the basis of low shear Compression speed
(e.g., Hobart), high shear (e.g., Diosna, GEI-Collette) or Compression/ejection force
fluid bed (e.g., Glatt, Fluid Air). Each technique will The following in-process tests (as discussed
produce granules with different physical properties above) should be examined during the
and will require monitoring of different processing compression stage:
parameters as listed below: Appearance
Hardness
Wet massing: Friability
Disintegration
Binder addition Weight uniformity
Binder concentration
Amount of binder solution/granulating solvent Tablet Coating: A basic understanding of rheology and
Binder solution/granulating solvent addition surface chemistry, two primary sciences of liquid flow
rate and solidliquid interaction is necessary for
Mixing time understanding coating and printing processes and
Granulation end point materials. A generally qualitative treatment of these
subjects will suffice to provide the insight needed to
use and apply coatings and inks and to help solve the
Wet Milling: problems associated with their use, of pan coating.
Tablet coating process parameters to be considered
Equipment size and capacity of mill during development and validation are:
Screen size
Mill speed Pan load
Feed rate Inlet/exhaust temperature/ humidity
Pan speed
Drying: Spray nozzle size
Atomizing pressure
Inlet/Outlet temperature
Air flow Spray rate
Moisture uniformity Spray angle
Equipment capability/capacity Gun to bed distance
Tablets core characteristics 32, 33.
Dry Milling:

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TABLE: 1. PROCESS CONTROL VARIABLES AND METHOD RESPONSES

Process Step Control Variables Measured Responses

Dry Mixing Load size, Impeller & Chopper Speed, Mixing Time Motor Power Load (Amperage)
Load size, Binder Addition Time, Impeller & Chopper Speed,
Wet Granulation Motor Power Load (Amperage)
Quantity of purified Water, Total Granulation Time
Loss On Drying (LOD), Exhaust Air
Drying Load Size, Inlet Air Temperature
Temperature
Milling Screen Size .
Description, Assay, Blend Uniformity,
Blending Load Size, Pre blending Time, Final Blending Time Tapped Density, Untapped Density,
Particle Size Distribution, LOD
Description, Average Weight,
Individual Weight Variation, Thickness,
Compression Compression speed, Compaction Force, Pre Compression Force
Hardness, Friability, DT, CU &
st
Dissolution test of 1 batch
Number of spray guns, Spray nozzle diameter, Gun to bed distance, Description, Average Weight,
Film Coating Pan RPM, Product Temperature, Inlet air temperature, Spray rate, Individual Weight Variation, Thickness,
Atomization Air Pressure, Fan width air pressure DT & Dissolution Profile of 1st batch

Definition and Control Variables of Process be done by sieve analysis, which should be
Validation: Process validation can be defined a same monitored throughout the tablets validation
as of challenging a process during development to process.
determine variables that must be controlled to ensure
the consistent production of a product or Blend uniformity: Samples of the blend are taken and
intermediate. It also provides the means for an analysed to ensure that the drug is uniformly dispersed
ongoing quality audit of the process during the throughout the tablets blend. The proper blend time
marketing phase of the product to ensure its must be established so that the blend is not under or
compliance with these specifications. over mixed. The sampling technique is critical for this
test to be valid.
The activity starts at the pharmaceutical development
department. Pertinent data or informations are Individual tablets weight: the weight of individual
collected during the pre-formulation stage and tablets is determined throughout compression to
additional inputs are generated during formulation ensure the material is flowing properly and the
development and evaluation, process development equipment is working consistently. The individual
and fullscale manufacture 34. weight should be within 5% of the nominal weight.

In-Process Test Tablets hardness: Tablets hardness is determined
Moisture content of dried granulation: Loss periodically throughout the batch to ensure that the
on drying (LOD) can be used to determine tablets are robust enough for coating, packing and
whether or not the granulation solvent has shipping and not too hard to affect dissolution
been removed to sufficient level during the
drying operation (usually less than 2 % Tablets thickness: Tablets thickness is also determined
moisture). periodically throughout the batch and is indirectly
Granulation particle size distribution: An related to the hardness. It is another indication of
extremely important parameter that can affect whether or not the formulation has proper flow and
tablets compressibility, hardness, thickness and compression properties.
content uniformity. This parameter, which can

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Disintegration: Disintegration is determined Tablets composition: Identify the key

during the manufacture as a predictor of physiological properties of the drug substances
tablets performance (e.g., dissolution). that need to be considered in developing the
formulation such as the following:
Finished product tests: Solubility of the drug substance throughout the
physiological pH range: Depending on the solubility of
Appearance: The tablets should be examined the drug, a surfactant may be needed to enhance
for such problems as tablets mottling, picking dissolution.
of the monogram, tablets filming, and capping
of the tablets. If the tablets are colored, the Particle size distribution and surface area: The particle
color quality needs to be examined. size distribution of the drug may determine grade of an
Assay: This test will determine whether or not excipients (e.g., microcrystalline cellulose) to use.
the product contains the labeled amount of
drug. True and bulk density: An excipients (e.g., diluents)
Content Uniformity: Samples are taken across that has a similar bulk density as the drug may be
the batch profile (beginning, middle and end) selected to minimize segregation, especially with a
and analyzed to ensure that the dosage form direct compression formulation.
comply with compendia standards (15% of the
labeled amount) or more stringent internal Material flow and compressibility: A free flowing,
limits. It will indicate whether there is improper highly compressible material such as microcrystalline
mixing during the manufacturing operation cellulose may be used for drugs with poor flow or
(i.e., segregation during flow of granulation compressibility properties.
from a storage bin).
Tablets hardness: A critical parameter for Hygroscopicity: Special environmental working
dosage form handling and performance. conditions may be required to ensure that moisture is
Tablets friability: Friability is an important not picked up during material storage or handling and
characteristic on the tablets ability to withstand during the manufacture of the tablets dosage form.
chipping, cracking or dusting during the
packaging operations and shipping. Melting point: If the drug has a low melting point, a
Dissolution: Dissolution is important to ensure direct compression formulation may need to be
proper drug release characteristics (in vitro developed instead of a wet granulation formulation to
availability) and batch to batch uniformity. avoid drying the material and potentially melting or
These key test parameters are the yardsticks by degrading the drug.
which the major processing variables in solid
dosage form are evaluated 35. Reasons should be provided for the presence of each
ingredient in the formula. Justification of the level or
Guidelines for Process Validation of Solid dosage form range of each ingredients especially the binder,
Numerous factors should be considered when disintegrant and lubricant. The requirement of the unit
developing and validating solid dosage form. Figures 2 operations in the tablets formulation should be
and 3 are flowcharts for the validation of new and defined like the use of high shear wet granulation
existing processes. As a means of providing a broad instead of dry granulation or the coating step 36.
overview of these validation criteria, the following
checklist/ guideline is provided for tablets for inclusion
in a depth validation program.

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FIGURE: 3. VALIDATION OF NEW PROCESSES

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FIGURE: 4. VALIDATION OF EXISTING PROCESSES

Strategy for Validation of Methods: The validity of a Define the performance parameters and
specific method should be demonstrated in laboratory acceptance criteria;
experiments using samples or standards that are Define validation experiments;
similar to the unknown samples analyzed in the Verify relevant performance characteristics of
routine. The preparation and execution should follow a the equipment;
validation protocol preferably written in a step-by-step Select quality materials, e.g., standards and
instruction format as follows: reagents;
Perform pre-validation experiments;
Develop a validation protocol or operating Adjust method parameters and/or acceptance
procedure for the validation; criteria, if necessary;
Define the application purpose and scope of Perform full internal (and external) validation
the method; experiments;

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Develop SOPs for executing the method The Validation Report: A written report should be
routinely; available after completion of the validation. If found
Define criteria for revalidation; acceptable, it should be approved and authorized
Define type and frequency of system suitability (signed and dated), the report should include at least
tests and/or analytical quality control (AQC) the following:
checks for the routine; and
Document validation experiments and results in 1. Title and objective of study;
the validation report 37. 2. Reference to protocol;
3. Details of material;
Approaches to Validation Process: 4. Equipment;
There are two basic approaches to the validation of the 5. Programmes and cycles used;
process itself (apart from the qualification of 6. Details of procedures and test methods;
equipment used in production, the calibration of 7. Results (compared with acceptance criteria);
control and measurement instruments, the evaluation and
of environmental factors, etc). These are the 8. Recommendations on the limit and criteria to
experimental approach and the approach based on the be applied on future basis 40.
analysis of historical data. The experimental approach,
which is applicable to both prospective and concurrent CONCLUSION: From the review validation data on
validation, may involve; pharmaceutical process validation and process control
variables of tablets manufacturing processes in
Extensive product testing, industry, it can be stated that process validation is
Simulation process trials, major requirement of cGMPs regulation for the
Challenge/worst case trials, and process efficiency and sturdiness and it is the full
Control of process parameters (mostly physical) fledged quality attributing tool for the pharmaceutical
38 industries.

Expert Evaluation: This is an evaluation of the entire Validation is the commonest word in the areas of drug
study against the protocol requirements as outlined development, manufacturing and specification of
above. It should be prepared and the conclusion drawn finished products. It also renders reduction in the cost
at each stage stated. The final conclusions should linked with process monitoring, sampling and testing.
reflect whether the protocol requirements were met. Apart from all the consistency and reliability of a
The evaluation should include an assessment of the validated process to produce a quality product is the
planned calibration and maintenance programmes for very important for an industry. For the tableting
the equipment and instrumentation to maintain the procedure, the steps that have been studied include
validated conditions. In addition, all process powder blending, granulation, particle size, and
monitoring and control procedures required to lubrication with compression, coating and drug release
routinely ensure that the validated conditions are studies. Such step-wise studies have brought light into
maintained should be reported. the impact of the parameters and their interactions
and increased the understanding of the respective
The evaluation should be signed by authorized officers processes and also to collect a complete and rational
of the organization who were members of the team database for the building of validation evidence.
establishing the protocol and who have appropriate
expertise in the area assigned to them. Overall From the review study it is concluded that
approval of the study should be authorized by the pharmaceutical validation and process controls are
head of the validation team and the head of the quality important to assure that the drug product can meet
control department 39. standards for the identity, strength, quality, purity and
stability.

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How to cite this article:

Wazade MB, Walde SR and Ittadwar AM: An Overview of
Pharmaceutical Process Validation and Process Control Variables of
Tablets Manufacturing Processes in Industry. Int J Pharm Res Sci.
3(9); 3007-3022.

Available online on www.ijpsr.com 3022