REVIEW ARTICLE
A Review on Pharmaceutical Validation
Sudarshan Balasaheb Kakad*, Mahesh Hari Kolhe, Tushar Pradip Dukre
Department of Pharmaceutics, Pravara Rural College of Pharmacy, Pravaranagar-413736, Maharashtra, India
Received: 16th June, 2020; Revised: 12th July, 2020; Accepted: 29th August, 2020; Available Online: 25th September, 2020
ABSTRACT
Quality is the primordial intention of any industry and its products manufactured. Multiple views on obtaining such quality
are the current interest in the pharmaceutical industry, and it has been maintained by validation. Validation is documented
evidence that provides a high degree of assurance. Validation has become one of the pharmaceutical industries’ most recognized
subjects. This article provides detailed information about pharmaceutical validation and its importance. Quality is always an
imperative prerequisite when we consider the product. In this article, we discuss the types of validation, process validation,
equipment validation, cleaning, and analytical method validation. Validation is the process that is used to confirm that the
analytical procedure employed for a specific test is suitable for the intended use.
Keywords: Analytical method validation, Cleaning validation, Equipment validation, Process validation, Validation, etc.
International Journal of Pharmaceutical Quality Assurance (2020); DOI: 10.25258/ijpqa.11.3.6
How to cite this article: Kakad SB, Kolhe MH, Dukre TP. A Review on Pharmaceutical Validation. International Journal of
Pharmaceutical Quality Assurance. 2020;11(3):338-342.
Source of support: Nil.
Conflict of interest: None
INTRODUCTION simply means an assessment of validity or action of proving
Validation is the process of establishing documentary evidence effectiveness. Validation is a team effort where it involves
demonstrating that a procedure, process, or activity carried out people from various disciplines of the plant.2,3
in testing, and then production, maintains the desired level of NEED OF VALIDATION
compliance at all stages. In the pharmaceutical industry, it is
very important that in addition to final testing and compliance • The pharmaceutical industry uses expensive material,
of products, it is also assured that the process will consistently sophisticated facilities, equipment, and highly qualified
produce the expected results (Figure 1).1 personnel.
The prime objective of any pharmaceutical plant is to • Detailed study and control of the manufacturing process
manufacture products of requisite attribute and quality batch validation are necessary if failure cost is to be
consistently, at the lowest possible cost. Although validation reduced and productivity is improved.
studies have been conducted in the pharmaceutical industry • It would not be feasible to use equipment not knowing if it will
for a long time, there is an ever-increasing interest in validation produce the product we want, not to employ the people with no
owing to their industry’s greater emphasis in recent years on assurance that they can do or fail to implement process checks
quality assurance program and is fundamental to an efficient or examination to assure that product meet specifications.
production operation. The concept of validation has expanded • The efficient use of these resources is necessary for the
through the years to embrace a wide range of activities, continued success of the industry. The cost of product
from analytical methods used for the quality control of drug failures, rejects, reworks, recalls, complaints are a sufficient
substances and drug products, to computerized systems part of the total production cost.
for clinical trials, labeling, or process control, validation is • Assurance of quality and cost reduction.4
founded on, but not prescribed by regulatory requirements, TYPES OF VALIDATION
and is best viewed as an important and integral part of current
Generally, validation has four major types. These are as
good manufacturing practices (cGMP). The word validation
follows:
• Process validation
• Equipment validation
• Analytical method validation
Figure 1: Validation process • Cleaning validation (Figure 2)
A Review on Pharmaceutical Validation
a revised manufacturing process. Validation is completed, and
the results are approved prior to any product release establishing
documented evidence prior to process implementation that a
system does what it proposed to do based on pre-planned
protocols. Each prospective validation step will be described
in the qualification/validation documents.
Concurrent Validation
It is a combination of retrospective and prospective validation.
Performed against an approved protocol, but the product is
released on a lot-by-lot basis, usually used on an existing
product not previously validated or insufficiently validated.
Figure 2: Types of validations Concurrent validation is used for establishing documented
evidence that a facility and processes do what they purport to
do, based on information generated during actual imputation
of the process.
Revalidation
It means repeating the original validation effort or any part of
it, and includes an investigative review of existing performance
data. This approach is essential to maintain the validated status
of the plant, equipment, and manufacturing. Possible reasons
for starting the revalidation process include:
• The scope of revalidation procedures depends on the extent
of the changes and the effect upon the product.
Figure 3: Types of process validation • Significant increase or decrease in batch size.
Process Validation • The necessity of periodic checking of the validation results.
• The transfer of a product from one plant to another (Figure 3).7
The process validation is a component of the coherent
prerequisites of a quality management system. Process Equipment Validation
validation is the most essential and perceived parameters Design Qualification (DQ)
of current good manufacturing practices. The objective of a
The documented verification that the proposed design of the
quality system is to produce items that are matched with their
facilities, systems, and equipment is suitable for the intended
proposed use uniformly. Process approval is a key component
purpose (Figure 4).
in guaranteeing that these standards and objectives are met.5,6
In this qualification, compliance of design with GMP
• Retrospective validation
should be demonstrated. The principles of design should
• Prospective validation
be such as to achieve the objectives of GMP with regard to
• Concurrent validation
equipment. Mechanical drawings and design features provided
• Revalidation
by the manufacturer of the equipment should be examined.
Retrospective Validation
Installation Qualification (IQ)
Establishing documented evidence prior to process implemen-
Establishing confidence that process equipment and ancillary
tation that a system does what it proposed to do based
systems are capable of consistently operating within
on pre-planned protocols. This approach to validation is
established limits and tolerances food and drug administration
normally undertaken whenever the process for a new formula
(FDA). The documented verification that the facilities, systems,
must be validated before routine pharmaceutical production
and equipment as installed or modified complies with the
commences. Validation of a process by this approach often
approved design and the manufacturer’s recommendations.
leads to the transfer of the manufacturing process from
Installation qualification should be carried out on new or
the development function to production. The retrospective
modified facilities, systems, and equipment. The following
validation is used for facilities, processes, and process
main points should be included in the installation qualification:
controls in operation use that have not undergone a formally
• Checking of installation of equipment, piping, services,
documented validation process.
and instrumentation.
Prospective Validation • Collection of supplier’s operating working instructions
It is used for facilities, processes, and process controls in and maintenance requirements and their calibration
operation use that have not undergone a formally documented requirements.
validation process. Validation was conducted prior to the • Verification of materials of construction.
distribution of either a new product or a product made under • Sources of spares and maintenance.
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A Review on Pharmaceutical Validation
application. Validation is required for any new or altered
procedure to verify that it is fit for giving predictable and
dependable outcomes, once used by various administrators by
the usage of comparable instrumentation inside the similar or
absolutely distinct laboratories.12
Method validation is a reported program that offers that
the processing system will give a high level of affirmation to
meet its predicated acceptance basis.13
It consists of mainly five different steps which are as
follows:
• Qualification of the system
• Sampling
• Preparation of sample
• Analysis of sample
• Assessment of data14
The main aim of method validation is to produce proof that the
method will do what it is supposed to do, accurate, reliable,
Figure 4: Process of equipment validation
and consistent. The validation parameters as per International
Operational Qualification (OQ) Conference on Harmonization (ICH) guidelines are described
The documented verification that the facilities, systems, and below15:
equipment, as installed or modified, perform as intended Accuracy: Accuracy is expressed as the nearness of agreement
throughout the anticipated operating ranges. Operational between the values found and values that are already available.
qualification should follow IQ. It can also be defined as the closeness between the true value
OQ should include the following: and the observed value. It is sometimes called as trueness, and it
• Tests developed from the knowledge of the processes, could be determined by using at least nine determinations over
systems, and equipment. a minimum of three concentrations over the specified range.16
• Defining lower and upper operating limits. Sometimes, Precision: The exactness of an analytical procedure expresses
these are called “worst-case” conditions. the nearness of agreement (degree of scatter) between
a group of measurements obtained from the different sampling
Performance Qualification (PQ)
of a uniform sample underneath the prescribed conditions.17
“It is a documented verification that the equipment and Precision may be taken into consideration at three levels:
ancillary systems as compared together can perform effectively • Repeatability: It expresses the exactness below a similar
and reproducibly based an approved method and specification.” operating condition over a brief interval of time and is
PQ is establishing confidence that the process is effective also referred to as intra-assay precision. A minimum of
and reproducible, establishing confidence that a process six replicates test preparation of a similar or consistent
in accordance with the design qualifications. Performance sample ready at the 100% check.18
qualification is documented proof that the equipment functions • Intermediate precision: It expresses the exactness under
in your facilities exactly as intended. This is ensured by inside research laboratories, in distinct days, through
verifying the suitability of the equipment under the actual distinct analyst, and on distinct instruments/equipment.
operating conditions of the environment, and according to Two different analysts, each preparing six sample solutions,
its intended task (e.g., compliance with safety regulations as per specified method.19
for accident prevention, and traceable data transmission). • Reproducibility: It refers to the precision between different
Performance qualification reviews the critical parameters of analytical labs; every research facility set up an aggregate
the equipment using suitable test methods. These procedures of six sample solutions, according to the analytical
are documented in the form of test specifications. It is not technique.19
mandatory to perform performance qualification on all Specificity: For every stage of development, the analytical
equipment or instruments. However, performance qualification technique should demonstrate specificity. The technique should
is to be performed for all the process equipment and the have the power to unequivocally assess the analyte of interest,
equipment that is critical. The question on whether not to whereas, within the presence of all expected parts, which can
carry out performance qualification is generally done on a encompass degradants, excipients/sample matrix, and sample
case-to-case basis.9,10,11 blank peaks.20
Analytical Method Validation Limit of detection (LoD): Lowest quantity of an analyte,
Validation of an analytical approach is established through which may be detected by the chromatographic separation;
laboratory research, that the execution attributes of the however, it is not necessary that this quantity will quantify
procedure meet the requirements for the proposed scientific as a precise value. A blank resolution is injected, and peak to
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A Review on Pharmaceutical Validation
peak quantitative noise relation that we have to calculate from procedures for removal of product residues, degradation
blank chromatograms. Then, calculate the concentration at the products, preservatives, excipients and/or cleaning agents,
signal to quantitative noise relation is concerning 3:1. as well as, the control potential microbial contamination.
LoD can be expressed as, Elements of Cleaning Validation
LoD = 3.3 × SD/S
The cleaning validation should demonstrate that the procedure
Where, SD = Standard deviation of response, S = Slope of
consistently removes residues of the substance previously
calibration curve.21
manufactured down to levels that are acceptable and
Limit of quantitation (LoQ): It is characterized by the least
that the cleaning procedure itself does not contribute
quantity of an analyte that can be quantified with exactness
unacceptable levels of residual materials to the equipment. The
and precision.
limits set should be practical, achievable, and justifiable. In
LOQ can be communicated as,
API manufacture, there may be partial reactants and unwanted
LoQ = 10 × SD/S byproducts that may not have been chemically identified.
Where SD = Standard deviation of response, S = Slope of
calibration curve.22 Sampling Techniques
The selection of either of these techniques must be consistent
Linearity: Linearity may be characterized as the capacity of with sound scientific judgment and must support the objective
an analytical technique to produce outcomes that are directly of the study, which is to demonstrate that the amount of
related to the concentration of an analyte in the standard residual material in the equipment has been reduced to
solution.23 acceptable levels. There are three known sampling methods:
Range: It can be characterized as the interval amongst upper Direct Surface Sampling
and lower quantities of analyte in the sample. The minimum It involves the determination of the type of sampling methods
of the specified range to be 80 to 120% of the test sample for used and its impact on the test data to check the interference
the assay test.24 of the sampling material with the test. Therefore, early in the
Ruggedness: Ruggedness is the degree or measure of validation program, it is crucial to assure the sampling medium
reproducibility under different situations, such as, in and solvent if they are satisfactory and be readily used. The
different laboratories, different analysts, different machines, advantages of direct sampling are that areas hardest to clean
environmental conditions, operators, etc.25 and which are reasonable, acceptable, can be evaluated, leading
Robustness: It is characterized by the level of ability of an to establishing a level of contamination or residue per given
analytical technique to stay similar by minute purposely surface area.
change in the technique parameter. The different technique
parameters, which can be modified in high-performance Swab Sampling
liquid chromatography are pH, drift rate, the temperature of Swabbing (or direct surface sampling) method or swab
the column, and mobile phase composition.26 sampling does not cover the entire equipment surface area,
therefore, sites must be chosen with care. It is important that,
Cleaning Validation as a minimum, the swab sites represent worst-case locations on
Cleaning validation is the process of assuring that cleaning the equipment and that the result is then extrapolated to account
procedures effectively remove the residue from manufacturing for the total product contact surface area. The solvent used for
equipment/facilities below a predetermined level. Cleaning swabbing should provide good solubility for the compound and
validation primarily applicable to the cleaning of process should not encourage degradation.
manufacturing equipment in the pharmaceutical industry. The
Rinse Sampling
term cleaning validation is to be used to describe the analytical
investigation of cleaning procedures or cycle. It should also Sampling and testing of rinse samples for the residual active
explain the development of acceptance criteria, including ingredient is a commonly adopted method to evaluated
chemical and microbial specifications, limits of detection, and cleanliness. This is a fairly convenient method in many cases
the selection of sampling methods. and requires control over the solvent used for rinsing, the
contact time, and the mixing involved. The solvent should be
Objectives selected based on the solubility of the active ingredient and
The reasons for validating the cleaning procedure: should either simulate a subsequent batch of product or at least
• It is a customer requirement. provide adequate solubility.27-29
• It ensures the safety and purity of the product.
• It is a regularity requirement in active pharmaceutical CONCLUSION
ingredient (API) product manufacture. This article gives an idea that what is validation, its types,
• Pharmaceutical products and API can be contaminated why it is necessary. Validation has been proven assurance for
by other pharmaceutical products, cleaning agents, and the process efficiency and sturdiness, and it is the full-fledged
microbial contamination. The objective of the cleaning quality attributing tool for the pharmaceutical industries. The
validation is to verify the effectiveness of cleaning method validation process and minimum requirements to be
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A Review on Pharmaceutical Validation
included in a regulatory method, cleaning procedures, and steps K, Spandana BN, et al. Analytical method validation: an updated
involved in each validation type are also discussed. Validation review. Int J Pharm Sci Res 2013;4:1280.
is a necessary process in the pharmaceutical industry, and it is 14. Araujo P. Key aspects of analytical method validation and
used to assure that the quality is worked into the procedures linearity evaluation. J Chromatogr B. 2009;877:2224-34.
15. Lavanya g, Sunil M, Eswarudu mm, Eswaraiah MC, Harisudha
supporting the development of drug and production.
K, Spandana BN, et al. Analytical method validation: an updated
REFERENCES review. Int J Pharm Sci Res. 2013;4:1280.
1. Validation definition and FDA, Regulatory agencies guidelines 16. Srivastava RK, Kumar SS. An updated review: analytical method
requirement Accessed 27 Feb 2014. validation. Eur J Pharm Med Res. 2017;4:774-784.
2. Ahir BK, et. al., Overview of validation and basic concepts of 17. Nayudu ST, Suresh PV. Bio-analytical method validation–a
Process Validation. Sch.Acad. J. Pharm. 2014; 3(2):178. review. Int J Pharm Chem Res. 2017;3:283-293.
3. Rajput RN, et al., Process Validation of Piroxicam Dispersible 18. Daksh S, goyal A, Pandiya CK. Validation of analytical
Tablets. World J Pharma. Res. 2014;3(8):1041. methods–strategy and significance. Int J Res Dev Pharm Life
4. Patel C., Desai D. g., Seth A.K., Process validation of artemether Sci. 2015;4:1489-1497.
and lumefantrine 80/480 mg tablet. Pharma Science Monitor. 19. Tijare LK, Rangari NT, Mahajan UN. A review on bioanalytical
2015;6(1):233-243. method development and validation. Asian J Pharm Clin Res.
5. Pathuri R, Muthukumaran M, Krishnamoorthy B, Nishat A. A 2016;9:6-10.
review on analytical method development and validation of the 20. Tiwari g, Tiwari R. Bioanalytical method validation: an updated
pharmaceutical technology. Curr Pharm Res. 2013;3:855-870. review. Pharm Methods. 2010;1:25-8.
6. Patil R, Deshmukh T, Patil V, Khandelwal K. Review on 21. Pasbola K, Chaudhary M. Updated review on analytical method
analytical method development and validation. Res Rev J Pharm development and validation by HPLC. World J Pharm Pharm
Anal. 2014;3:1-10. Sci. 2017;6:1612-1630.
7. Dr.B. Venkateswara Reddy*, P. Ujwala, P. Sandeep, A. Deepthi, 22. Geetha g, Raju KN, Kumar BV, Raja mg. Analytical method
Pharmaceutical Validation–A Review, International Journal Of validation: an updated review. Int J Pharm Biol Sci. 2012;1:
Research In Pharmacy And Life Sciences. 2014;2(2):236-247. 64-71.
8. Su d a r s h a n K a k a d*, K i r a n Wa le , M a h e s h B a l s a n e , 23. Ravichandran V, Shalini S, Sundram KM, Harish R. Validation
Dr.K.S.Salunkhe, Dr.S.R Chaudhari, Process Validation of of analytical methods–strategies and importance. Int J Pharm
Parenteral Formulation, World Journal Of Pharmaceutical Pharm Sci. 2010;2:18-22.
Research. 2014;3(5):241-253. 24. Shweta K, Anita S. A review on analytical method validation.
9. Zameeruddin M., Kale S. S., Jadhav S. B., Kadam V. S., Chaware Int J Pharm Res Rev. 2016;5:30-36.
S. S., Process validation of oral solid dosage form: tablet – an 25. Boque R, Maroto A, Riu J, Rius FX. Validation of analytical
overview. World Journal of Pharmacy and Pharmaceutical methods. grasas Aceites. 2002;53:128-143.
Sciences. 2015;4(12):358- 373. 26. PushpaLatha E, Sailaja B. Bioanalytical method development and
10. Satinder Kumar, Pharmaceutical Process Validation: A CGMP validation by HPLC: a review. J Med Pharm Innov. 2014;1:1-9.
Concept, Pharmatutor-Art-1269. 27. Cleaning Validation in Active Pharmaceutical Ingredient
11. Kashid V. A., Nikam V. K., Somwanshi S. B., Dolas R. T., Manufacturing Plants APIC guide to Cleaning Validation in
Dhamak K. B., gaware V. M., Kotade K. B., Brief overview of API. Sep. 1999.
pharmaceutical facility validation. Journal of Current Pharma 28. International conference on Harmonization (ICH) ( 2005, Nov.),
Research. 2014;4(2):1134-1137, Harmonised tripartite guideline Q2 (R1), validation of analytical
12. Bhardwaj SK, Dwivedi K, Agarwal DD. A review: HPLC method procedures: Text and methodology.
development and validation. Int J Anal Bioanal Chem 2015;5:76-1. 29. Code of Federal Regulations (CFR), Part 211, Current good
13. Lavanya g, Sunil M, Eswarudu mm, Eswaraiah MC, Harisudha manufacturing practice for finished pharmaceuticals.
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