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Process validation of tablet dosage form: A comprehensive review

Article · January 2018

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 The Pharma Innovation Journal 2018; 7(3): 433-438

ISSN (E): 2277- 7695

ISSN (P): 2349-8242
NAAS Rating: 5.03 Process validation of tablet dosage form: A
TPI 2018; 7(3): 433-438
© 2018 TPI comprehensive review
www.thepharmajournal.com
Received: 15-01-2018
Accepted: 16-02-2018 Kiranbala Jain and Meenakshi Bharkatiya
Kiranbala Jain
Bhupal Noble’s Institute of Abstract
Pharmaceutical Sciences, B.N. Validation is one of the important steps in achieving and maintaining the quality of the final product. If
University, Sewashram Road, each step of production process is validated we can assure that the final product is of the best quality.
Udaipur, Rajasthan, India Process validation is an essential component for the safety of drug product and also to maintain the
quality of the product. Validation is establishing documented evidence which provides a high degree of
Meenakshi Bharkatiya assurance that a specific process for manufacturing of tablets will consistently produce a product meeting
Bhupal Noble’s Institute of
its pre-determined specifications and quality attributes. Validation and quality assurance will go hand in
Pharmaceutical Sciences, B.N.
hand, ensuring the quality for the products. The present article gives an introduction and general
University, Sewashram Road,
Udaipur, Rajasthan, India overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing
process.

Keywords: Validation, process validation, solid dosage form, tablets

Introduction
Validation is a concept that has been evolving continuously since its first formal appearance in
the United States in 1978. The concept of validation has expanded through the years to
encompass a wide range of activities from analytical methods used for the quality control of
the drug substances and drug products to computerized systems for clinical trials and is the
important step in gaining and maintaining the quality of the final product [1].
Validation can also be said as- “The collection and assessment of data, from the process design
stage all the way through production, which establishes logical indication that a process is
capable of consistently delivering quality products” [2].
The concept of validation was first proposed by two Food and Drug Administration officials,
Ted Byers and Bud Loftus in the mid 1970’s in order to improve the quality of
pharmaceuticals [3].
According to US FDA in 1978, “A validation manufacturing process is one which has been
proved to do what it purports or is represented to do. The proof of validation is obtained
through the collection and evaluation of data, preferably, beginning from the process
development phase and continuing the production phase. Validation necessarily includes
process qualification (the qualification of materials, equipment, system, building, personnel),
but it also includes the control on the entire process for repeated batches or runs [4].”
USFDA defined process validation as “establishing documented evidence which provides high
degree of assurance that a specific process will consistently produce a product meeting its
predetermined specifications and quality characteristics [5]”.

Why is validation required?

 It would not be feasible to use the equipment without knowing whether it will produce the
product we wanted or not.
 The pharmaceutical industry uses expensive materials, sophisticated facilities &
equipment and highly qualified personnel. The efficient use of these resources is
necessary for the continued success of the industry.
 The cost of product failures, rejects, reworks, and recalls, complaints are the significant
parts of the total production cost.
Correspondence  Detailed study and control of the manufacturing process i.e. validation is necessary if
Kiranbala Jain failure to be reduced and productivity improved.
Bhupal Noble’s Institute of
Pharmaceutical Sciences, B.N.
 Therefore the pharmaceutical industries are concerned about validation because of the
University, Sewashram road, following reasons.
Udaipur, Rajasthan, India
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 Assurance of quality. company's overall philosophy, intentions and approaches to

 Cost reduction. be used for establishing performance adequacy. The
 Government regulation [6, 7] validation master plan should be agreed upon by
management.
When process validation is required? Validation in general requires meticulous preparation and
The process validation should be performed whenever there careful planning of the various steps in the process. In
is- addition, all work should be carried out in a structured way
 New product or existing products as per SUPAC changes. according to formally authorized standard operating
 Change in site of manufacturing. procedures. All observations must be documented and where
 Change in batch size. possible must be recorded as actual numerical results.
The validation master plan should provide an overview of the
 Change in equipment.
entire validation operation, its organizational structure, its
 Change in process existing products.
content and planning. The main elements of it being the list
 Change in composition or components.
inventory of the items to be validated and the planning
 Change in the critical control parameters. schedule. All validation activities relating to critical technical
 • Change in vendor of API or critical excipient. operations, relevant to product and process controls within a

Change in specification on input material [3] firm should be included in the validation master plan. It
should comprise all prospective, concurrent and retrospective
Validation Protocol validations as well as re-validation.
For performing the process validations the detailed protocols The validation master plan should be a summary document
are required for ensuring that the process is been adequately and should therefore be brief, concise and clear. It should not
validated. repeat information documented elsewhere but should refer to
The protocol should contain the following components: existing documents such as policy documents, SOP's and
a. The purpose and scope of the validation. validation protocols and reports.
b. Validation team with their qualifications and The format and content should include:
responsibilities.  Introduction: validation policy, scope, location and
c. Type of validation: Prospective, Concurrent, schedule
Retrospective, Re-validation  Organizational structure: personnel responsibilities
d. Total Number batches should be validated.
 Plant/ process /product description: rational for inclusions
e. A complete list of equipments and apparatus to be used;
or exclusions and extent of validation
with their parameters
 Specific process considerations that are critical and those
f. Installation Qualification and Operation Qualification of
requiring extra attention
equipments.
 List of products/ processes/ systems to be validated,
g. The calibration criteria for all instruments.
summarized in a matrix format, validation approach
h. All possible critical process parameters with their criteria.
i. All the process variables/ attributes with their risk and  Re-validation activities, actual status and future planning
management should be given.  Key acceptance criteria [10].
j. Production related all processing details should be clearly
described in the form of master documents. Process validation for solid dosage forms
k. Sampling schedule with all details of sampling points, The critical parameters considered during the process
methods and sampling plans. validation of tablets are
l. Statistical tools to be used in the analysis of data. 1. Mixing or Blending
m. Training schedule for operators 2. Granulation
n. Validated test methods to be used in in-process testing 3. Wet milling
and for the finished product. 4. Drying
o. Specifications for raw and packaging materials and test 5. Milling
methods. 6. Compression
p. All performs for documenting the results, conclusions 7. Coating
and for approval of study results should be given [8].
Mixing or Blending
Responsible Authorities for Validation Materials that have similar physical properties will be easier
The validation working party is convened to define progress, to form a uniform mix or blend and will not segregate as
coordinate and ultimately, approve the entire effort, including readily as materials with large differences.
all of the documentation generated. A. Mixing or blending technique: Diffusion (tumble),
The working party would usually include the following staff convection (planetary or high intensity), or pneumatic
members, (fluid bed) techniques can be used to mix or blend
 Head of quality assurance. materials. Determine the technique that is required for the
formulation or process objective. It may be different.
 Head of engineering.
B. Mixing or blending speed: Determine the intensity
 Validation manager.
(low/high shear) and/or speed (low/high/optimal shear)
 Production manager.
(rpm) of the mixing or blending. Mixing the drug and
 Specialist validation discipline: all areas [9]. excipient will require more intense mixing than adding
the lubricant to the final blend.
Validation Master Plan C. Mixing or blending time: How much mixing or
A validation master plan is a document that summarizes the blending is required to obtain a uniform mixture? The
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mixing or blending time will be dependent on the mixing I. What type of wet granulation technique will be used?
or blending technique and speed. If the materials are Will it be low shear (e.g., Hobart), high shear (e.g.,
overmixed, this would result in demixing or segregation Diosna, GEI Collette) or fluid bed (e.g., Glatt, Fluid Air)?
of the materials. Demixing can occur due to difference in Each technique will produce granules with different
the physical properties (e.g., particle size distribution and physical properties and will require monitoring of
density). different processing parameters.
D. Drug uniformity: Content uniformity is usually II. Binder addition: Should the binder be added as a
performed to determine the uniformity of drug granulating solution or dry like the other excipients?
throughout the mix or blend. Representative samples Adding the binder dry avoids the need to determine the
should be taken throughout the mix or blend. The optimal binder concentration and a separate manufacture
sampling technique and handling of the materials are key for the binder solution.
points in obtaining valid content uniformity results. For III. Binder concentration: The optimal binder concentration
the final blend (blend prior to compression), the sample will need to be determined for the formulation. If the
taken should be equivalent to the weight of a single binder is to be sprayed, the binder solution needs to be
tablet. dilute enough so that it can be pumped through the spray
E. Excipient uniformity: Besides drug uniformity, nozzle. It should also be sufficiently concentrated to form
excipients need to be uniform in the granulation or blend. granules without over wetting the materials.
IV. Amount of binder solution/granulating solvent: How
Two key excipients are much binder or solvent solution is required to granulate
I. Lubricant: The lubricant needs to be distributed the material? Too much binder or solvent solution will
uniformly in the mixture/granulation for the high-speed over wet the materials and prolong the drying time. The
compression operation. Uneven distribution of the amount of binder solution is related to the binder
lubricant can result in picking and sticky problems during concentration.
compression. It can also lead to tablet low dissolution due V. Binder solution/granulating solvent addition rate:
to excessive lubricant in some tablets. Define the rate or rate range at which the binder solution
II. Color: The colorant(s) need(s) to be evenly distributed in or granulating solvent can be added to the materials. Can
the mixture so that the tablets have a uniform appearance the granulating solution be dumped into the mixer or does
(e.g., color, hue, and intensity). The coloring agent may it have to be metered in at a specific rate?
need to be prescreened or more uniformly dispersed in VI. Mixing time: How long should the material is mixed to
the blend prior to compression to avoid speckling or ensure proper formation of granules? Should mixing stop
shading of the color. after the addition of the binder or solvent solution or
F. Equipment capacity/load: The bulk density of materials should additional mixing be required? Granulations that
or granules will affect the capacity of the equipment. If are not mixed long enough can form incomplete or weak
an excipient in the formulation affects the density of the granules. These granules may have poor flow and
final blend to a greater extent than any other ingredient, compression properties. On the other hand, over mixing
then a well-controlled density specification for that the granulation can lead to harder granules and a lower
excipient may be warranted. Test different-sized loads in dissolution rate.
the mixer/blender (e.g., 30, 50, and 70% of working VII. Granulation end point: How is the granulation end
volume) for optimal mixing or blending. Undercharging point determined? Is it determined or controlled by
or overcharging a blender can result in poor drug or tablet granulation end point equipment (e.g., ammeter or
lubricant distribution [11, 12]. wattmeter)? Is it controlled by specifying critical
processing parameters? For example, a drug or excipients
Granulation mixture may be granulated by adding a predetermined
If a powder blend's properties do not suit direct compression amount of water (granulating solution) at a certain rate.
tabletting, manufacturers will turn to granulation processes to The granulation is completed after mixing for a set time
create the desired flowability and low dustability. These after the water has been added [15, 16, 17].
characteristics are required to minimize tablet weight
variations, and ensure high density for high tablet filling B. Dry granulation: In the dry granulation method the
weight and high mouldability for hard tablet manufacture. granulation is formed not by adding a binder. Here
However, granulation is a more time-consuming technique compacting large mass of the mixture and subsequently
compared with direct compression and there is also a risk of crushing and sizing these pieces into smaller granules
product cross-contamination and product loss during the takes place. The primary powder particles are aggregated
different processing steps (granulation, drying, sieving). All under high pressure. There are two main processes. Either
of these factors can increase costs compared with direct a large tablet (known as a slug) is produced in a heavy-
compression [13]. duty tablet press (a process known as slugging) or the
powder is squeezed between two rollers to produce a
A. Wet Granulation sheet of material (roller compaction).
In wet-granulation, a liquid binder solution is combined with
a bed of mixed powders to mass the particles together into Wet Milling
granules. The damp mass is then screened, dried and milled to Does the wet granulation need to be milled to break up the
the desired size. The mass may also be dry screened, lumps and enhance drying of the granulation? Wet granules
lubricated and compressed or extruded through a perforated that have a wide aggregate range can lead to inefficient drying
screen and then dried [14]. (long drying times and partially dried large granules or
lumps).

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Factors to consider are Tablet Compression

A. Equipment size and capacity: The mill should be large Compression is a critical step in the production of a tablet
enough to de lump the entire batch within a reasonable dosage form. The materials being compressed will need to
time period to minimize manufacturing time and prevent have adequate flow and compression properties. The material
the material from drying during this operation. should readily flow from the hopper onto the feed frame and
B. Screen size: The screen needs to be small enough to de into the dies. Inadequate flow can result in “rat holing” in the
lump the material, but not too small to cause excessive hopper and/ or segregation of the blend in the hopper/feed
heating of the mill, resulting in drying of the granulation. frame. This can cause tablet weight and content uniformity
C. Mill speed: The speed should be sufficient to efficiently problems.
del ump the material without straining the equipment. As for the compressibility properties of the formulation, it
D. Feed rate: The feed rate of the wet granulation is should be examined on an instrumented tablet press.
interrelated to screen size and mill size and speed [16].
Factors to consider during compression are as follows
Drying A. Tooling: The shape, size, and concavity of the tooling
The type of drying technique (e.g., tray, fluid bed, and should be examined based on the formulation properties
microwave) required for the formulation needs to be and commercial specifications. For intagliated
determined and justified. The type of technique may be (embossed) tablets, factors such as the position of the
dependent on such factors as drug or formulation properties intagliation on the tablet and the intagliation depth and
and equipment availability. Changing dryer techniques could style should be examined to ensure that picking of the
affect such tablet properties as hardness, disintegration, intagliation during compression or fill-in of the
dissolution, and stability. The optimal moisture content of the intagliation during coating does not occur.
dried granulation needs to be determined. High moisture B. Compression speed: The formulation should be
content can result in tablet picking or sticking to tablet punch compressed at a wide range of compression speeds to
surfaces and poor chemical stability as a result of hydrolysis. determine the operating range of the compressor. The
An over dried granulation could result in poor hardness and adequacy of the material’s flow into the dies will be
friability. Moisture content analysis can he performed using determined by examining the tablet weights. Is a force
the conventional loss-on-drying techniques or such state-of- feeder required to ensure that sufficient material is fed
the-art techniques as near infrared (NIR) spectroscopy. into the dies?
C. Compression/ ejection force: The compression profile
Factors to be considered are for the tablet formulation will need to be determined to
 Inlet/outlet temperature establish the optimal compression force to obtain the
 Airflow desired tablet hardness. The particle size/size distribution
 Moisture uniformity or level of lubricant may need to be adjusted in order to
 Equipment capability/capacity [17] have a robust process on a high-speed compressor.
The following in-process tests should examined during the
Milling compression stage:
The milling operation will reduce the particle size of the dried
granulation. The resultant particle size distribution will affect Factors to consider during compression are
such material properties as flow, compressibility,  Appearance
disintegration, and dissolution. An optimal particle size/size  Hardness
distribution for the formulation will need to be determined.  Tablet weight
 Friability
Factors to consider in milling are
 Disintegration
 Mill type
 Weight uniformity
 Screen size
 Mill speed Tablet Coating
 Feed rate [18] Tablets may be coated for various reasons.
 Stability
Lubrication
1. Selection of lubricant: what kind of lubricant should be  Taste masking
used? Grade of the lubricant used. Compatibility with  Controlled release
other ingredients.  Product identification
2. Amount of lubricant added: How much lubricant is  Aesthetics
required? Too much lubricant will form hydrophobic  Safety–material handling
layer on the tablet resulting in dissolution problems.
3. Mixing time: How long should the material is mixed to Tablet coating can occur by different techniques (e.g., sugar,
ensure proper formation? Should mixing stop after the film, or compression). Film coating has been the most
addition of the lubricant or should additional mixing be common technique over recent years and will be the focus of
required? If not mixed long enough form problems like this section. Key areas to consider for tablet coating include
chipping, capping, etc [19]. the following:
A. Tablet properties: Tablet properties such as hardness,
Compression shape, and intagliation (if required) are important to
Tablet weight, turrent speed, main compression force, pre obtain a good film-coated tablet. The tablet needs to be
compression force, feeder speed, upper punch entry, room hard enough to withstand the coating process. If tablet
temperature, humidity [20].
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attrition occurs, the tablets will have a rough surface  Color uniformity
appearance. For shape, a round tablet will be easier to
coat than tablets will multiple sides or edges because of Coating efficiency should be determined for the coating
the uniformity of the surface. For intagliated tablets, the operation. The efficiency will determine the amount of
intagliation style and depth should be developed to coating solution overage that may be required [21, 22, 23, 24].
prevent fill-in or chipping of the intagliation.
B. Equipment type: The type of coater will need to be Conclusion
selected. Conventional or perforated pan and fluid bed Nowadays Validation is the art of designing and practicing
coaters are potential options. the designed steps together with the documentation in
C. Coater load: What is the acceptable tablet load range of pharmaceutical industry. Validation itself does not improve
the equipment? Having too large a pan load could cause processes but confirms that the processes have been properly
attrition of the tablets because of the overall tablet weight developed and are under control in achieving, maintaining the
in the coater. In the case of a fluid bed coater, there may quality of the final product. Process validation involves a
not be sufficient airflow to fluidize the tablets. series of activities taking place over the lifecycle of the
D. Pan speed: What is the optimal pan speed? This will be product and process. Validation and process control variables
interrelated to other coating parameters, such as inlet of tablets manufacturing processes in industry and it is the
temperature, spray rate, and flow rate. full-fledged quality attributing tool for the pharmaceutical
E. Spray guns: The number and types of guns should be industries. Solid dosage form validation should be part of a
determined in order to efficiently coat the tablets. The comprehensive validation program within an industry. It is
spray nozzles should be sized properly to ensure even concluded from the review that pharmaceutical validation and
distribution over the tablet bed and to prevent clogging of process controls are important to assure that the drug product
the nozzles. The location and angle of the spray gun(s) can meet standards for the identity, strength, quality, purity
should be positioned to get adequate coverage. Having and stability.
the guns positioned too close together can lead to a
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