About Author: R. C. PATEL, C. K. BHUVA, MR. R. P. SINGH, MR. ABHISHEK DADHICH, MR. ANIL SHARMA.
Department of Quality Assurance, Gyan Vihar School of pharmacy,
Suresh Gyan Vihar University,
Jaipur, Rajasthan, India-302025
Reference ID: PHARMATUTOR-ART-1053
Abstract
Validation has become one of the pharmaceutical industry’s most recognized and discussed subjects. It is a critical success factor in product approval and ongoing commercialization. This article provide brief introduction about the pharmaceutical process validation and its importance according to regulatory provision, also provide the answer of question like why to do, when to do and how to do it. This work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process. Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. In pharmaceutical industry, Process Validation performs this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.
THE REGULATORY BASIS FOR PROCESS VALIDATION
Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a)(2)(B) of the FD&C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with CGMP. Assurance must be given that the drug would meet the requirements of the act as to safety and would have the identity and strength and meet the quality and purity characteristics that it purported or was represented to possess. That section of the act sets the premise for process validation requirements for both finished pharmaceuticals and active pharmaceutical ingredients, because active pharmaceutical ingredients are also deemed to be drugs under the act.
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. Although these regulations do not include a definition for process validation, the requirement is implicit in the language of 21 CFR 211.100, which states: “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”
THE REGULATORY HISTORY OF PROCESS VALIDATION
Although the emphasis on validation began in the late 1970s, the requirement has been around since at least the 1963 CGMP regulations for finished pharmaceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved in 1962 with Section 501(a) (2) (B) as an amendment. Prior to then, CGMP and process validation were not required by law. The FDA had the burden of proving that a drug was adulterated by collecting and analyzing samples. This was a significant regulatory burden and restricted the value of factory inspections of pharmaceutical manufacturers. It took injuries and deaths, mostly involving cross-contamination problems, to convince Congress and the FDA that a revision of the law was needed. The result was the Kefauver–Harris drug amendments, which provided the additional powerful regulatory tool that FDA required to deem a drug product adulterated if the manufacturing process was not acceptable. The first CGMP regulations, based largely on the Pharmaceutical Manufacturers Association’s manufacturing control guidelines, were then published and became effective in 1963. This change allowed FDA to expect a preventative approach rather than a reactive approach to quality control. Section 505(d)(3) is also important in the implementation of process validation requirements because it gives the agency the authority to withhold approval of a new drug application if the “methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that FDA must inspect every drug manufacturing establishment at least once every 2 years. At first, FDA did this with great diligence, but after the worst CGMP manufacturing situations had been dealt with and violations of the law became less obvious, FDA eased up its pharmaceutical plant inspection activities and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s involved first conducting a massive sampling and testing program of finished batches of particularly important drugs in terms of clinical significance and dollar volume, then taking legal action against violative batches and inspecting the manufacturers until they were proven to be in compliance. This approach was not entirely satisfactory because samples are not necessarily representative of all batches. Finished product testing for sterility, for example, does not assure that the lot is sterile. Several incidents refocused FDA’s attention to process inspections. The investigation of complaints of clinical failures of several products (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found significant content uniformity problems that were the result of poorly controlled manufacturing processes. Also, two large-volume parenteral manufacturers experienced complaints despite quality control programs and negative sterility testing. Although the cause of the microbiological contamination was never proven, FDA inspections did find deficiencies in the manufacturing process and it became evident that there was no real proof that the products were sterile. What became evident in these cases was that FDA had not looked at the process itself—certainly not the entire process—in its regulatory activities; it was quality control- rather than quality assurance-oriented. The compliance officials were not thinking in terms of process validation. One of the first entries into process validation was a 1974 paper presented by Ted Byers, entitled “Design for Quality”. The term validation was not used, but the paper described an increased attention to adequacy of processes for the production of pharmaceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Association in 1978 entitled “Validation and Stability”—discussed the legal basis for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation was written for the pharmaceutical, device, and veterinary medicine industries. It has been effective in standardizing the approach by the different parts of the agency and in communicating that approach to manufacturers in each industry.
WHAT IS PROCESS VALIDATION DEFINITION
According to USFDA
In 1978,
“A validated 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 through the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, personnel), but it also includes the control on the entire process for repeated batches or runs.”
In 1987,
“Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.”
In January 2011,
“Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.”
According to EMEA
“Validation is the act of demonstrating and documenting that a procedure operates effectively. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.”
WHY VALIDATION?
First, and certainly foremost, among the reasons for validation is that it is a regulatory requirement for virtually every process in the global health care industry for pharmaceuticals, biologics, and medical devices. Regulatory agencies across the world expect firms to validate their processes. The continuing trend toward harmonization of requirements will eventually result in a common level of expectation for validations worldwide. Utility for validation beyond compliance is certainly available. The emphasis placed on compliance as a rationale has reduced the visibility of the other advantages a firm gleans from having a sound validation program. Some years ago, identified a number of tangible and intangible benefits of validation realized at his employer at the time. In the intervening years, there has been repeated affirmation of those expectations at other firms, large and small. Regrettably, there has been little quantification of these benefits. The predominance of compliance-based validation initiatives generally restricts objective discussion of cost implications for any initiative. But once a process/product is properly validated, it would seem that reduced sample size and intervals could be easily justified, and thus provide a measurable return on the validation effort. Aside from utility systems, this is hardly ever realized and represents one of the major failings relative to the implementation of validation in our industry. Validation and validation-like activities are found in a number of industries, regulated and unregulated. Banking, aviation, software, microelectronics, nuclear power, among others all incorporate practices closely resembling validation of health care product production. That such verification activities for products, processes, and systems have utility in other areas should not be surprising. The health care industries fixation on compliance has perhaps blinded us to the real value of validation practices.
PROCESS VALIDATION: ORDER OF PRIORITY
Because of resource limitation, it is not always possible to validate an entire company’s product line at once. With the obvious exception that a company’s most profitable products should be given a higher priority, it is advisable to draw up a list of product categories to be validated. The following order of importance or priority with respect to validation is suggested:
A. Sterile Products and Their Processes
1. Large-volume parenterals (LVPs)
2. Small-volume parenterals (SVPs)
3. Ophthalmics, other sterile products, and medical devices
B. Nonsterile Products and Their Processes
1. Low-dose/high-potency tablets and capsules/transdermal delivery systems (TDDs)
2. Drugs with stability problems
3. Other tablets and capsules
4. Oral liquids, topicals, and diagnostic aids
WHAT ARE THE PROCESS VALIDATION OPTIONS?
The guidelines on general principles of process validation mention Options:
(1) Prospective process validation (also called premarket validation),
(2) Retrospective process validation,
(3) Concurrent validation and
(4) Revalidation
(1) Prospective Process Validation
In prospective process validation, an experimental plan called the validation protocol is executed (following completion of the qualification trials) before the process is put into commercial use. Most validation efforts require some degree of prospective experimentation to generate validation support data. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily:
1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements (completion of installation qualification)
2. The operators and supervising personnel who will be “running” the validation batch(es) have an understanding of the process and its requirements
3. The design, selection, and optimization of the formula have been completed
4. The qualification trials using (10 × size) pilot-laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have been provided
5. Detailed technical information on the product and the manufacturing process have been provided, including documented evidence of product stability
6. Finally, at least one qualification trial of a pilot-production (100 × size) batch has been made and shows, upon scale-up, that there were no significant deviations from the expected performance of the process.
The strategy selected for process validation should be simple and straightforward. The following factors are presented for the reader’s consideration:
1. The use of different lots of components should be included, i.e., APIs and major excipients.
2. Batches should be run in succession and on different days and shifts (the latter condition, if appropriate).
3. Batches should be manufactured in equipment and facilities designated for eventual commercial production.
4. Critical process variables should be set within their operating ranges and should not exceed their upper and lower control limits during process operation. Output responses should be well within finished product specifications.
5. Failure to meet the requirements of the validation protocol with respect to process inputs and output control should be subjected to requalification following a thorough analysis of process data and formal review by the CMC Coordination Committee.
(2) Retrospective Validation
The retrospective validation option is chosen for established products whose manufacturing processes are considered stable and when on the basis of economic considerations alone and resource limitations, prospective validation programs cannot be justified. Prior to undertaking retrospective validation, wherein the numerical in-process and/or end-product test data of historic production batches are subjected to statistical analysis, the equipment, facilities and subsystems used in connection with the manufacturing process must be qualified in conformance with CGMP requirements. The basis for retrospective validation is stated in 21CFR 211.110(b): “Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.”
Using either data-based computer systems or manual methods, retrospective validation may be conducted in the following manner:
1. Gather the numerical data from the completed batch record and include assay values, end-product test results, and in-process data.
2. Organize these data in a chronological sequence according to batch manufacturing data, using a spreadsheet format.
3. Include data from at least the last 20–30 manufactured batches for analysis. If the number of batches is less than 20, then include all manufactured batches and commit to obtain the required number for analysis.
4. Trim the data by eliminating test results from noncritical processing steps and delete all gratuitous numerical information.
5. Subject the resultant data to statistical analysis and evaluation.
6. Draw conclusions as to the state of control of the manufacturing process based on the analysis of retrospective validation data.
7. Issue a report of your findings (documented evidence).
(3) Concurrent Validation
In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control.
(4) Revalidation
Almost all GMP texts recommend that whenever there are significant changes in the facility, equipment or process, revalidation should be carried out.
The FDA process validation guidelines refer to a quality assurance system in place that requires revalidation whenever there are changes in packaging (assumed to be the primary container-closure system), formulation, equipment or processes (meaning not clear) which could impact on product effectiveness or product characteristics and whenever there are changes in product characteristics.
Conditions requiring revalidation study and documentation are listed as follows:
1. Change in a critical component (usually refers to raw materials)
2. Change or replacement in a critical piece of modular (capital) equipment
3. Change in a facility and/or plant (usually location or site)
4. Significant (usually order of magnitude) increase or decrease in batch size
5. Sequential batches that fail to meet product and process specifications
BENEFITS OF PROCESS VALIDATION
• Increased throughput
• Reduction in rejections and reworks
• Reduction in utility costs
• Avoidance of capital expenditures
• Fewer complaints about process related failures
• Reduced testing in process and finished goods
• More rapid and accurate investigations into process deviations
• More rapid and reliable start-up of new equipment
• Easier scale-up from development work
• Easier maintenance of the equipment
• Improved employee awareness of processes
• More rapid automation
Conclusion
From study, it can be stated that Process validation is a major requirement of cGMP regulation for finished pharmaceutical products. It is a key element in assuring that the quality goals are met. Successfully validating a process may reduce the dependence upon intensive in process and finished product testing. Finally, it can be concluded that Process validation is a key element in the quality assurance of pharmaceutical product as the end product testing is not sufficient to assure quality of finished product.
References:
1. “Robert A .Nash, Alfred H. Wachter”, “Pharmaceutical Process Validation”, Vol.129, Third Edition, Marcel Dekker, Inc, New York, 2003.
2. “James Agalloco, Frederick J. Carleton”, “Validation of Pharmaceutical Processes”, Third Edition, Informa Healthcare USA, Inc., New York, 2008.
3. “Anurag S. Rathore, Joseph F. Noferi, Edward R. Arling, Gail Sofer, Peter Watler, and Rhona O’Leary”, “Process Validation How Much to Do and When to Do It”, BioPharm OCTOBER 2002
4. “FEDERAL FOOD DRUG AND COSMETIC ACT”, Title 21 U.S. Code, Section 501 (a) (2) (B).
5. “CODE OF FEDERAL REGULATIONS”, Title 21, Parts 210 & 211. Fed Reg 43, 1978.
6. “NOTE FOR GUIDELINE ON PROCESS VALIDATION”, The European agency for the evaluation of medicinal products, London, march 2001
CPMP/QWP/848/96
7. “FDA”, “Current Good Manufacturing Practices; Proposed Amendment of Certain Requirements for Finished Products: Supplementary Information,” Federal Register 61(87), p. 20104 (3 May 1996).
8. “Viral Kishor bhai Patel”, “Process Validation : An Essential Process In Pharmaceutical Industry”, Pharmainfo.Net Pharmaceutical Information For You 10/01/2010
9. “GUIDANCE FOR INDUSTRY: PROCESS VALIDATION”: General Principles and Practices. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), November 2008.
10. “ICH GUIDELINE”
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