Pharmaceutical Process Validation: A Key Requirement for Quality Attribute


Sukhada Kulkarni*, Amrita Panda, Ravi Tiwari

Department of Pharmaceutical Chemistry, SVKM’s NMIMS, School of Pharmacy and Technology Management Shirpur Dist. Dhule 425405 Maharashtra, India

*Corresponding Author E-mail:




The rationale of this article is to present a preface and general idea on process validation of pharmaceutical manufacturing process. In order to achieve the highest quality of a manufactured drug, process validation is regarded as crucial step in achieving and maintaining the quality of the final product. Quality techniques must be built into the product at every step and not just tested for final product. Thus regulatory gives certain specific guidelines to focus on strict quality control. 


KEYWORDS: Process Validation, Regulatory Guidelines, Quality Control




To meet the requirements of Good Manufacturing Practices (GMPs) in pharmaceutical industries process validation is most discussed and recognized subject that ensures the targeted product quality. When we talk about any pharmaceutical product quality is at utmost priority that decides effectiveness and efficiency of that product. Hence, quality of a product is an imperative prerequisite which is assured through process validation in a product development cycle. Process validation is defined as collection as well as evaluation of data from different stages of product development that provides scientific evidence for robustness of the process. The concept was initially proposed by two FDA officials Ted Byers and Bud Loftus, in the mid 1970’s. The main objective of process validation is that the quality is built in product at each stage of its development and not at the end stage only. There are different validation protocols for different dosage forms. [1]

Process validation starts with the planning an overview of the entire organizational structure, validation operation, its content and planning. Then comes installation qualification that involves establishing documented evidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. Operational qualification includes an exercise oriented to the engineering function, generally referred to as commissioning.


Process qualification is establishing documented evidence that the process is effective and reproducible. Process monitoring is required in order to ensure whether the process which is planned is according to established parameters. And lastly comes revalidation that is if there is any quality characteristic(s) indicating negative trend in the process, then it needs to be revalidate the designed process. [2] Generalized view of process validation is given in the following figure 1.


Figure 1: General view of process validation

Types of Process Validation

Prospective Validation

This process usually takes place in the time when the new formula of a product is to validate before commencement of the pharmaceutical process. In this before moving into the commercial process the validation is done. The production process of a product should be broken down into individual steps so as to carry out validation properly. These processes are thus evaluated on the basis of past experiments and theoretical basis so as to know some critical solutions. In this the risk are evaluated, potential causes are investigated and probability are counted, trials and priority are been setup. Thus further trials are performed to check if the process is satisfactory or unsatisfactory; if it is unsatisfactory then they are modified until validation proves to be satisfactory. This type of validation helps to remove the risk occurring in the production process. [3]


Concurrent Validation

It is basically recertifying, requalification and revalidating the normal process which is going on. This validation arises due to sudden change in manufacturing, equipment, facilities or batch size procedure. This validation can be taken as practical approach as in many cases where the previously manufactured process is to be transferred to a manufacturer.[4]


Retrospective Validation

It examines all the past records from already completed production work, which provides evidence that process is done in a controlled manner. Although it measures all the process but is not a quality assurance measure and should be never considered for any new process or procedure. It is only valid or can be taken into consideration when new validation process is being established.  It is basically used in establishing priorities to the validation process. If the retrospective evaluation is positive that means the process does not require much attention and can be used as per daily needs. It can be best used during tablet compression and not to be used for sterile products. [5]



It is needed to ensure that the process or other related matter are hampered may be intentional or unintentional then it does not affect the product quality or its process. This is divided into two categories:

1.      Revalidation after any changes

2.      Periodic revalidation carried after every interval


Revalidation after changes: It is based on some tests and activities performance which is carried out during the original validation.


Periodic validation: There are always chances that operators or equipment works may have some defect during process so there should be regular validation done. [4]

The types of process validation are summarized in the following figure 2.


Figure 2: Types of Process validation


Strategy of Process Validation

The strategy should always be simple and easy to understand. In process validation mainly involves five important steps:

1.      Mixing or blending speed: Intensity and speed determination is most important for determining shear speed for mixing the drug with excipients. This mixing requires more intensity than addition of lubricants.

2.      Mixing and blending time: Mixing and blending time dependent on its technique and the speed which help to obtain uniform mixture. Experiments are being performed to determine whether materials are over mixed or causes de-mixing or segregation. Particle size distribution and density are the physical properties due to whose difference de-mixing occur. Many a times de-mixing occur in direct compression in which drug substance is micronized and excipients are granular.

3.      Drug uniformity: Content uniformity is performed to determine uniformity of drug throughout the mixing and blending process. Valid content uniformity can be obtained by sampling technique and handling of the materials. Segregation can occur by over handling which gives an inaccurate result. [6]

Five other points can also be involved:

a.       Different raw materials lots should be included. These different raw materials are active drug substances and major excipients.

b.      Batches to be run in different shifts and in succession.

c.       Batches should be manufactured in equipments and facilities for commercial production.

d.      Critical process variable should be set and not exceed their upper or lower limit during process operation.

e.       When the requirement of validation protocol fails with respect to product input and output then should be subjected to process requalification and subsequent revalidation. [7]



Steps involved in process validation:


Figure 3: Steps involved in Process Validation


The steps involved in process validation are given in figure 3and aredescribed as follow:


Process Design

a.       Building and capturing process knowledge and understanding

According to the ICH Q10 pharmaceutical Quality System the drug design experiments should be in accordance with the sound scientific methods and principles. Decisions and justifications of the controls should be documented and reviewed for use in lifecycle of product and process. Product development activities provide key inputs for designing as quality attributes, intended dosage form. Commercial manufacturing equipment functionality and limitations should be checked for the variability. Designing an effective process with effective control approach is based on process knowledge and understanding is obtained. Documentation should be made about activities and studies in the process. [8]

b.      Establish a strategy for process control

Knowledge and understanding is the basis for establishing an process control for each and every unit and also for overall process. Strategies can be designed for input variation during process. Controls consist of analysis of material and equipment auto processing. The control records containing the operational limits and strategy should be stored for future reference.

Process Qualification

a.       Design of a facility and qualification of utilities and equipment

It is essential that activities performed to have proper facility design. The activities undertaken to demonstrate equipment and its utilities suitable for intended use and performance is termed as qualifications. Qualification includes the following activities:

1.      Selection of the equipment for the construction of materials, performance characteristics based on the specific use.

2.      Verifications of equipment for its installation with design specifications.

3.      Verifying that the operation is in accordance with process requirements in all operating ranges.

Qualifications can be considered under individual plans or as part of overall project plan.

b.      Process Performance Qualifications

This step combines the facilities, utilities and equipment, procedures and components to produce products. This will define the process design and demonstrate the process performances. Success at this stage signals an important step ahead for product lifecycle. Before commercial distribution of drug one should successfully complete PPQ. [9][10]


Process Verification

In 1987 it was called as revalidation. This gives an assurance that process will remain in control state during manufacturing. Evaluation provides data about the problems in process performance and helps to take some actions to prevent so that process remains in control. A program should be set up so that proper control and analysis of the product and process is done so that quality of product is well established. The information gathered should help to verify that quality attributes are being controlled throughout the process. In this on- going sampling is a part of the program:

1.      In first phase of commercial production: Continued monitoring at every level during process qualification stage

2.      In second phase of commercial production: When sufficient data is available to have significant variability and estimate it.

Process optimization: In this stage data must be known about any improvement or optimization of the process. The information includes product performance and manufacturing experience. This all are required to know if any change in experiments procedure are applicable or not. [11]


Regulatory background for process validation

The concept of process validation came in early 1970s through the regulatory aspects of cGMP regulations and also its application to quality assuarance, production, pilot plant and various other analytical considerations. In 1990 a concept of preapproval inspection came into existance and one of the basic requirements was of commercial batch validation data. Initially the focus of validation was directed towards the prescribtion of drug but further FDA expanded it upto  adulterated if the method or facility used for processing, packaging or hyandeling of that product were not administered in confirmity with the CGMP, this as according to Section 501(a)(2)(B) of the FD&C Act of legal authority.


Section 211.110(a): Testing  and sampling of in-process materials and drug products, requires control procedures. Hence it is required to be established to validate the performance of those manufacturing processes that may cause variability in the characteristics of in-process material and the drug product.


Section 211.110(b): Requires the in-process specifications. It shall be derived from average of previously accepted process and process variability in the process is estimated by application of suitable statistical procedures.


Section 211.160(b)(3): Sample to be validate must represent the sample under analysis.


Section 211.165(d): The product should meet the statistical quality control criteria and specificationsas condition of release and approval.


Section 211.165(a): The batch from which the sample is analysed must meet its predetermined specifications.


Sec. 211.84 (b): Representative sample of each shipment of each batch should be collected for testing. The amount of product to be taken for analysis should be based upon some statistical criteria such as degree of precision desired, component variability, confidence levels and, the past quality history of the supplier.


Section 211.180(e): Data about product quality and manufacturing experience should be periodically evaluated to determine whether there is a need for changes in specifications or manufacturing or control procedures. [12]



Since the end product solely cannot assure the quality of product hence, process validation is considered as a pathway for achieving in built and assured quality of a product. Also the process validation is a major requirement of cGMP regulation for finished pharmaceutical products. Finally, validating a process may reduce the dependence upon intensive in process and finished product testing.



1.       Sharma T, Solanki NS and Mahatma OP. Process Validation: An Essentiality in the Pharmaceutical Industry. International Journal of Pharmaceutical Research and Development. 3(10); 2011: 133–142.  

2.       Md. Shoaib A. Pharmaceutical Process Validation: An Overview. Journal of Advanced Pharmaceutical Technology and Research. 2(4); 2012: 185-200.

3.       Satyabrata J, Arjun G, Ravipati AK, Satishkumar D, Vinod KR and David B. Industrial Process Validation Of Solid Dosage Forms – An Overview. International Journal of Pharmaceutical Sciences Review and Research. 4(2); 2010: 145-154.

4.       Verma P, Satheesh MV and Gupta V K. A Review article on Pharmaceutical Validation and Process Controls. The pharma innovation journal. 7; 2012: 51-60.

5.       Mittal H and Pahuja S. Pharmaceutical Process Validation and Its Tools: A Review. Novel Science International Journal of Pharmaceutical Sciences. 1(8); 2012: 543-549. 

6.        Josee E. Process Validation: A Critical Tool in Quality Assurance. International Society of Pharmaceutical engineering. 25(2); 2005: 1-7.

7.       Shein-Chung C. Pharmaceutical Validation and Process Controls in Drug Development. Drug Information Journal. 31(4); 1997: 1195-1201.

8.       Elsie J and Augustine O. An Overview of Pharmaceutical Validation and Process Controls in Drug Development Tropical. Journal of Pharmaceutical Research. 1(2); 2002: 115-122. 

9.       Singh H, Rana AC, Saini S and Singh G. Industrial Process Validation of Solid Dosage Forms: A Review. International research journal of pharmacy. 3(4): 2012: 63-70.

10.     Parida R. Overview of Pharmaceutical Validation and Process Controls in Drug Development. Pelagia Research Library. 1(1); 2010: 11-19.

11.      Nandhakumar L, Dharmamoorthy G, Rameshkumar S and Chandrasekaran S. An Overview of Pharmaceutical Validation: Quality Assurance View Point. International Journal of Research In Pharmacy And Chemistry. 1(4); 2011: 1003-1014.

12.     U.S. Food and Drug Administration. Guideline on General Principles of Process Validation; U.S.FDA: Rockville, MD, May, 1987.





Received on 14.09.2013       Modified on 04.11.2013

Accepted on 25.11.2013      © RJPT All right reserved

Research J. Pharm. and Tech. 7(1): Jan. 2014; Page   74-77