The Pharma Innovation Journal 2015; 4(3): 01-07 

ISSN: 2277- 7695

TPI 2015; 4(3): 01-07
© 2015 TPI
Prospective Validation: A Review
www.thepharmajournal.com
Received: 24-07-2014
Accepted: 25-03-2015
Monika Sharma, Shikha Agarwal, Shweta Agarwal, Manoj Sharma

Monika Sharma  Abstract

L.R. Institute of Pharmacy, Validation is the art of designing and practicing the designed steps alongside with the documentation.
Vill. Jabli-Kyar, P.O. Oachghat, Process validation emphasize on process design elements and maintaining process control during
Distt. Solan (H.P.), India. commercialization and communicate that process validation is an ongoing program and align process
validation activities with product lifecycle. Process validation also emphasizes the role of objective
Shikha Agarwal  measures and statistical tools & analyses and emphasizes knowledge, detection, and control of variability
L.R. Institute of Pharmacy,
and gives assurance on consistent of quality/productivity throughout life cycle of product. According to
Vill. Jabli-Kyar, P.O. Oachghat,
Distt. Solan (H.P.), India.
GMP, validation studies are essential part of GMP these are required to be done as per predefined
protocols. The process validation is establishing documented evidence which provides high degree on
Shweta Agarwal assurance that a specific process consistently produced a product meeting its predetermined specifications
L.R Institute of Pharmacy, and quality characteristic. The validation study provide the accuracy, sensitivity, specificity and
Vill. Jabli-Kyar, P.O Oachghat, reproducibility of the test methods employed by the firms, shall be established and documented. Thus the
Distt. Solan (HP), India. validation is an essential part of the quality assurance. Lending importance to validation is increasingly
profound in recent years.
Manoj Sharma
L.R. Institute of Pharmacy, Keywords: Process Validation, GMP, specifications, consistent, documented
Vill. Jabli-Kyar, P.O. Oachghat,
Distt. Solan (H.P.), India.
1. Introduction
The objective of the design and manufacture of the compressed tablet is to deliver orally the
correct amount of drug in the proper form, over a period of time and in the desired location,
and to have its chemical integrity protected to that point. The prime objective of any
pharmaceutical plant is to manufacture products of requisite attribute and quality consistently,
at the lowest possible cost. Numerous features are required to ensure product quality, such as
chemical and physical stability, suitable preservation against microbial contamination if
appropriate, uniformity of dose of drug, acceptability to users including prescriber and patient,
as well as suitable packing, labeling, and validation [1]. It is through careful design and
validation of both the process and process controls that a manufacturer can establish a high
degree of confidence that all manufactured units from successive lots will be acceptable.
Successful validation of a process may reduce the dependence upon intensive in-process and
finished product testing. In most cases, end-product testing plays a major role in assuring that
quality assurance goals are met; i.e., validation and end-product testing are not mutually
exclusive [2]. The FDA in Guidelines on General Principles of Process Validation defines
process validation as "establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product meeting its predetermined
specifications and quality characteristics". According to EMEA, “Process validation can be
defined as documented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a medical product meeting its predetermined
specifications and quality attributes”[3].
Tablet as a dosage form comprises a mixture of active substances and excipients, usually in
powder form, pressed or compacted into a solid. The excipients can include binders, glidants
(flow aids) and lubricants to ensure efficient tableting; disintegrants to promote tablet break-up
in the digestive tract; sweeteners or flavors to enhance taste; and pigments to make the tablets
visually attractive. A polymer coating is often applied to make the tablet smoother and easier to
swallow, to control the release rate of the active ingredient, to make it more resistant to the
Correspondence: environment (extending its shelf life), or to enhance the tablet's appearance. The manufacturing
Monika Sharma of tablets involves extensive powder handling. The powder must be blended for uniformity and
L.R. Institute of Pharmacy,
Vill. Jabli-Kyar, P.O. Oachghat,
converted into the dosage form either through compression. Typical requirements include
Distt. Solan (H.P.), India. weighing, blending, mixing/granulation areas, compression, and coating areas [4].

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2. Objectives of process validation environment, processing site, method of production or testing
 In addition to the individual equipment, the manufacturing or any other change that may affect product quality or support
process must be validated. system operations. Any proposals for changes should be
 The goal is to create a robust manufacturing process that drafted, reviewed, and approved by the appropriate
consistently produces a drug product with minimal organizational units, and reviewed and approved by the quality
variation that adheres to quality criteria of purity, identity, control unit [7, 10]. Major Phases in Validation are: Phase 1: Pre-
and potency. Validation Phase or the Qualification Phase Phase 2: Process
 Engineers should draft and execute a validation plan for Validation Phase (Process Qualification phase) Phase 3:
the manufacturing process in order to satisfy guidelines. Validation Maintenance Phase [11, 12].
The validation plan usually involves just a PQ section.
 Just as equipment validation, after the initial validation, 6. The regulatory basis for process validation
major changes will result in the need for subsequent The concept of process validation from its beginnings in the
revalidation. early 1970s through the regulatory aspects associated with
 Process validation will ensure a robust product which is current good manufacturing practice (cGMP) regulations and
highly reproducible over time. the application thereof to various analytical, quality assurance,
pilot plant, production, and sterile product and solid dosage
3. Reason for Process Validation forms considerations. In the early 1990s, the concept of pre-
The possible reason of performing process validation may approval inspection (PAI) was born and had as one of its basic
include: tenet 'the assurance' that approved validation protocols and
New product or existing products as per SUPAC changes. schedules were being generated and during comprehensive
 Change in site of manufacturing. development i.e. scale-up of pilot batch to commercial batch
 Change in batch size. validation data were required in order to achieve a successful
 Change in equipment. regulatory PAI audit. There are several important reasons for
 Change in process existing products. validating a product and/or process. First, manufacturers are
 Change in composition or components. required by law to conform to cGMP regulations. Second,
 Change in the critical control parameters. good business dictates that a manufacturer avoids the
 Change in vendor of API or critical incipient. possibility of rejected or recalled batches. Third, validation
 Change in specification on input material. helps to ensure product uniformity, reproducibility, and
 Abnormal trends in quality parameters of product through quality. Although the original focus of validation was directed
review during Annual Product Review (APR). towards prescription drugs, the FDA Modernization Act of
 Trend of Out of Specification (OOS) or Out of Trend 1997 expanded the agency's authority to inspect establishments
(OOT) in consecutive batches [5]. manufacturing over-the-counter (OTC) drugs to ensure
compliance with cGMP. Once the concept of being able to
4. Benefits of process validation predict process performance to meet user requirements
 Consistent through output. evolved, FDA regulatory officials established that there was a
 Reduction in rejections and reworks. legal basis for requiring process validation. The ultimate legal
 Reduction in utility cost. authority is Section 501(a)(2)(B) of the FD&C Act, which
 Avoidance of capital expenditures. states that a drug is deemed to be adulterated if the methods
 Fewer complaints about process related failure. used in, or the facilities or controls used for, its manufacture,
 Reduced testing process and finished goods. processing, packing, or holding do not conform to or were not
 More rapid and accurate investigations into process operated or administrated in conformity with cGMP. The
deviation. cGMP regulations for finished pharmaceuticals, 21 CFR 210
 More rapid and reliable start-up of new equipment. and 211, were promulgated to enforce the requirements of the
 Easier scale-up from development work. act. FDA has the authority and responsibility to inspect and
 Easier maintenance of equipment. evaluate process validation performed by manufacturers. The
 Improve employee awareness of processes. cGMP regulations for validating pharmaceutical (drug)
 More rapid automation [6]. manufacturing require that drug products be produced with a
high degree of assurance of meeting all the attributes they are
5. Types of process validation [7, 8, 9] intended to possess.
The guidelines on general principles of process validation
mentions four types of validation: A) Prospective validation 7. Validation of solid dosage forms
B) Concurrent validation The strategy selected for process validation should be simple
C) Retrospective validation and straightforward. The following five points gives strategy
D) Revalidation Change Control for process validation:
A consistent achievement of product quality is dependent on  The use of different lots of raw materials should be
the availability of defined/approved/ validated procedures and included. i.e. active drug substance and major excipients.
the application and adherence to these procedures by trained  Batches should be run in succession and on different days
personnel. In the event that any change is to be introduced into and shifts (the latter condition, if appropriate).
the production operation, it is important to evaluate its  Batches should be manufactured in the equipment and
potential impact and where necessary provide appropriate facilities designated for eventual commercial production.
evaluation and/or actions. Written procedures should be in  Critical process variables should be set within their
place to describe the actions to be taken if a change is proposed operating ranges and should not exceed their upper and
to a product component, process equipment, process lower control limits during process operation. Output
 

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responses should be well within finished product 10.4 Drying
specifications. The type of drying technique (e.g., tray, fluid bed, and
 Failure to meet the requirements of the Validation protocol microwave) required for the formulation needs to be
with respect to process input and output control should be determined and justified. The type of technique may be
subjected to process requalification and subsequent dependent on such factors as drug or formulation properties
revalidation following a thorough analysis of process data and equipment availability. Changing dryer techniques could
and formal discussion by the validation team [12, 13]. affect such tablet properties as hardness, disintegration,
dissolution, and stability. The optimal moisture content of the
8. Guidelines for process validation of solid dosage forms dried granulation needs to be determined. High moisture
Numerous factors should be considered when developing and content can result in tablet picking or sticking to tablet punch
validating solid dosage forms. As a means of providing a broad surfaces and poor chemical stability as a result of hydrolysis.
overview of these validation criteria, the following An over dried granulation could result in poor hardness and
checklist/guideline as in Table 1, is provided for tablets and friability. Moisture content analysis can he performed using the
dry-filled capsules for inclusion in an in depth validation conventional loss-on-drying techniques or such state-of-the-art
program. Some of these unit operations will not be applicable techniques as near infrared (NIR) spectroscopy. Factors to be
for every solid dosage form (e.g., direct compression tablets considered are:
and uncoated tablets). 1. Inlet/outlet temperature
2. Airflow
9. Steps for validation and acceptance criteria 3. Moisture uniformity
The following steps (Table 6) are used in industry for 4. Equipment capability/capacity
validation of tablets in wet granulation process [12, 16]. 5. Milling

10. Industrial process evaluation and selection for tablets The milling operation will reduce the particle size of the dried
Determine the unit operations needed to manufacture the granulation. The resultant particle size distribution will affect
tablets. such material properties as flow, compressibility,
disintegration, and dissolution. An optimal particle size/size
10.1 Mixing or blending distribution for the formulation will need to be determined.
Mixing or blending ensures production of uniform mixture of Factors to consider in milling are:
active pharmaceutical ingredients and excipients that do not  Mill type
segregate post blending. So this step is carefully scrutinized  Screen size
and validated. Parameters to consider:  Mill speed
 Mixing or blending technique.  Feed rate
 Mixing or blending speed.
 Mixing or blending time. 10.5 Lubrication
 Drug uniformity. Lubricants are added to reduce the friction during tablet
 Excipient uniformity. ejection between the walls of the tablet and die cavity in which
 Equipment capacity/load. the tablet was formed. Factors like amount of lubricant added,
grade of lubricant used, compatibility with other ingredients
10.2 Wet Granulation and mixing time must be considered.
Different types of wet granulation techniques can be used such
as low shear (e.g., Hobart), high shear (e.g., Diosna, GEI- 10.6 Tablet Compression
Collette) or fluid bed (e.g., Glatt, Fluid Air). Each technique Compression is a critical step in the production of a tablet
will produce granules with different physical properties and dosage form. The materials being compressed will need to
will require monitoring of different processing parameters. Wet have adequate flow and compression properties. The material
granulation parameters to be considered during development should readily flow from the hopper onto the feed frame and
and validation are: into the dies. Inadequate flow can result in "rat holing" in the
 Binder addition hopper and/or segregation of the blend in the hopper/feed
 Binder concentration frame. This can cause tablet weight and content uniformity
 Amount of binder solution/granulating solvent problems. As for the compressibility properties of the
 Binder solution/granulating solvent addition formulation, it should be examined on an instrumented tablet
 Mixing time press. Factors to consider during compression are as follows:
 Granulation end point  Tooling
 Compression speed
10.3 Wet Milling  Compression/ejection force
The wet granulation might need to be milled to break up the
lumps and enhance drying of the granulation. Wet granules that The following in-process tests should be examined during the
have a wide aggregate range can lead to inefficient drying compression stage:
(long drying times and partially dried large granules or lumps).  Appearance
Factors to consider are:  Hardness
 Equipment size and capacity  Tablet weight
 Screen size  Friability
 Mill speed  Disintegration
 Feed rate  Weight uniformity
 

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10.7 Tablet Coating and the overall quality of the product. The PQR will capture a
Tablet coating can occur by different techniques (e.g., sugar, broader view of product data, capturing trends and will help
film, or compression). Film coating has been the most common determine the need for revalidation and changes, if any.
technique over recent years and will be the focus of this The GMPs necessitate annual evaluation of quality standards
section. Key areas to consider for tablet coating include the of a drug product to determine the need for adjustments in drug
following: product specifications, manufacturing and control procedures.
 Tablet properties Subpart J of 21 CFR 211.180 mandates establishing a written
 Equipment type procedure for the Annual Product Review process, while, and
 Coater load recommends review of a representative number of approved as
 Pan speed well as rejected batches. The Product Quality Review Report
 Spray guns should contain at least the following details:
 Tablet flow  A review of starting materials and product contact primary
 Inlet/outlet temperature and airflow packaging materials used for the product, especially those
 Coating solution from new sources.
 Coating weight  A review of critical in-process controls and finished
 Residual solvent level product results.
 A review of all batches that failed to meet established
10.8 In-process tests specification(s) and their investigation.
 Moisture content of dried granulation  A review of all significant deviations or non-
 Granulation particle size distribution conformances, their related investigations, and the
 Blend uniformity effectiveness of resultant corrective and preventive actions
 Individual tablet weight taken.
 Tablet hardness  A review of all changes carried out to the processes or
 Tablet thickness analytical methods.
 Disintegration  A review of Marketing Authorization variations
 Impurity profile submitted/granted/refused, including those for third
country (export only) dossiers.
10.9 Finished product tests  A review of the results of the stability monitoring
 Appearance programme and any adverse trends.
 Assay  A review of quality-related product returns, complaints
 Content uniformity and recalls and the investigations performed at the time.
 Tablet hardness  A review of adequacy of any other previous product
 Tablet friability process or equipment corrective actions.
 Impurity profile  For new marketing authorizations and variations to
 Dissolution marketing authorizations, a review of post-marketing
These key test parameters are the yardsticks by which the commitments.
major processing variables in solid dosage forms are evaluated.  The qualification status of relevant critical equipment and
Some processing variables are: utilities, e.g. HVAC, water, compressed gases, etc [20].
 Mixing time and speed in blenders and granulators
 Solvent addition rates in granulators 12. Conclusion
 Time, temperature, and airflow conditions in dryers and It can be stated that process validation is major requirement of
coaters cGMPs regulation for the process efficiency and sturdiness
 Screen size, feed rate, and milling speed in mills from the review validation data on pharmaceutical process
 Machine speed and compression force in tablet presses validation and process control variables of tablets
Process validation testing is generally done on the first three manufacturing processes in industry and it is the full-fledged
batches of product made in production-size equipment. quality attributing tool for the pharmaceutical industries.
Revalidation testing is only done when a significant change has Validation is the commonest word in the areas of drug
occurred. A significant change is one that will alter the in- development, manufacturing and specification of finished
process or final product specification established during the products. It also renders reduction in the cost linked with
validation program or a change in formula, process, or process monitoring, sampling and testing. The
equipment [12, 17, 18]. multidisciplinary approach to validation of solid dosage form
Basic flowchart for the validation of new and existing must identify the product and process characteristics that must
processes of tablet manufacturing is shown in Figure1. be studied and incorporate specific validation tests to ensure
that that product will meet all quality, manufacturing, and
11. Annual Product Review regulatory requirements. The validation should start with active
Annual Product Quality Review is an annual quality review of pharmaceutical ingredient (API) characteristics so that this
licensed medicinal product which is conducted with the material will be uniform batch after batch, providing a solid
objective of verifying the consistency of the existing process, footing upon which the dosage form will be built. Scientific
the appropriateness of current specifications for both starting information obtained during the pre-formulation stage can
materials and finished product to highlight any trends and to form the basis for a well-designed and comprehensive
identify product and process improvements. The Annual validation program. The parameters chosen must be relevant
Product Quality review (APQR) is an effective quality indicators of a controlled process. It is not sufficient merely to
improvement tool to enhance the consistency of the process devise a test and set specifications for it; rather, it is desirable
 

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to show a cause and effect relationship between the parameter respective processes and also to collect a complete and rational
tested and control of the quality and/or process output. database for the building of validation evidence.
For the tableting procedure, the steps studied include powder It is concluded from the review that pharmaceutical validation
blending, granulation, particle size, and lubrication with and process controls are important to assure that the drug
compression, coating and drug release studies. Such step-wise product can meet standards for the identity, strength, quality,
studies have brought light into the impact of the parameters purity and stability.
and their interactions and increased the understanding of the

Table 1: Check List of Validation and Control Documentation

Table 2: Protocol for title page in industry

Table 3: Protocol approval

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Fig 1: Validation of new processes

13. Acknowledgments process validation. International Research Journal of

Special Thank to Mrs. Shikha Agrawal assistant professor Pharmaceutical & Applied Sciences 2013; 3(1):165-168.
LR institute of pharmacy for her support, teaching and for 6. Paruchuri R, Trivedi S, Pavuluri G, Prasanthi B, Kumar
providing the opportunity to work with her. SM. Process validation of finasteride tablets.
International Journal of Pharmaceutical Chemistry &
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