A Brief History Of Parenteral Process Validation — How We Got Here

This article is based on the introduction from a new book,Principals of Parenteral Solution Validation, A Practical Lifecycle Approach, written by Igor Gorsky and Harold S. Baseman and published by Academic Press.

The term parenteral pertains to medicinal preparations that are delivered via injection through one or several layers of skin tissue. This word is derived from the Greek words para and etheron, which mean “outside of the intestine.” It typically refers to dosage forms that are administered by routes other than the topical and enteral routes. Because the administration of injectables, by definition, requires circumventing the highly protective barriers of the human body, the skin and the mucous membranes, the dosage form must achieve an exceptional purity and sterility.¹ This is accomplished by strict adherence to good manufacturing practices, of which process validation plays a pivotal, if not the most important, role.

It should be noted that basic principles employed in the preparation of parenteral products do not vary from those widely used in other sterile or nonsterile liquid preparations. This is important to understand, mainly from a perspective of the uniformity of these products, which must conform to homogeneity specifications for their bulk preparations. That is, they must be filled and packaged properly in uniform final filled units assuring sterility.

Process validation has been at the center of attention of regulators and parenteral industry practitioners for years — more than 40 years to be exact. However, even after introduction of a number of guidances and publication of voluminous literature, blogs, presentations, and other materials on the subject, a considerable number of manufacturers still struggle with establishing effective and efficient process validation programs. This article will look at how process validation evolved to become the primary means of ensuring consistent, high-quality production of parenterals.

The subject was first discussed in the mid-1970s, prior to issuance of the FDA’s compliance program in 1978,² which was published before revised cGMP regulations were adopted and was titled Drug Product Inspections. Interestingly, this 1978 program said the following with regard to process validation: “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 into the production phase. Validation necessarily includes process qualification (the qualification of materials, equipment, systems, buildings, personnel), but it also includes the control of the entire process for repeated batches or runs.”³

The subject of process validation was discussed among practitioners during the 10 years after this definition was first published. Some of these discussions were documented in proceedings of a Validation of Manufacturing Process Seminar in Geneva, Switzerland, in 1980⁴ and a Validation Seminar held in Dublin, Ireland, in 1982.⁵ The proceedings of the Geneva seminar included the following definition for process validation: “a formal process to demonstrate that a specific product can be reliably manufactured by designed process,” while the Dublin seminar, in one of its presentations, asked “how do you ‘establish by systematic means,’ or decide that the process is ‘grounded on a sound scientific basis’?”⁵

It is amazing that five years later, when the FDA’s Center for Drugs and Biologics and Center for Devices and Radiological Health⁶ adopted the Guideline on General Principles of Process Validation in May of 1987, the original 1978 to 1982 definition lost these original concepts of being a life cycle exercise with a sound scientific design of the process, reading simply: “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 attributes.” One could probably read in “high degree of assurance” a reference to the statistical basis of process validation concepts, as statistical examinations into probabilities of success of planned and designed events would always include this “high degree of assurance,” as in the referenced example from a purely statistical manual.⁷ However, in those days most pharmaceutical and biopharmaceutical practitioners were not given authority by their organizations’ management to pursue process validation as a continued learning exercise; rather, it was a regulatory necessity mainly concentrating on the terms “establishing documented evidence,” which meant in their mind a “necessary evil” of performing three process validation consecutive batches and documenting these events. It should be noted that even then, problems and deviations that often occurred while producing these three “golden” batches didn’t alert practitioners, their management, or even regulators to the fact that there was a problem with an entire concept. Firms were regularly cited by the agency for their lack of robust validated processes, while manufacturers were continually having issues when they introduced new products to the market.

As you may remember, in the original cGMPs in 1978, regulators embedded a scientific risk-based life cycle approach into design, qualification, and continued manufacturing of all pharmaceutical products, including parenterals. For instance, section 211.100(a) states that “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.” This requires manufacturers to design a process, including operations and controls, that would produce therapeutic materials that would meet their specified attributes. In addition, this section continues with sampling and testing of in-process materials and drug products requires that control procedures “be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.” This reminds manufacturers that even well-designed processes should include in-process control procedures to assure that the design is on the right path and final product quality is guaranteed.

The following section, 211.110(b), outlines principles for establishment of in-process specifications, affirming that they “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.” This suggests that manufacturers should analyze performance of processes to understand and control batch-to- batch variability. Furthermore, cGMP regulations set requirements on sampling, asserting that they must be representative of the produced batch under analysis. This is described in section 211.160(b)(3), which says that sampling must meet specifications and statistical quality control criteria as a condition of approval and release, as well as section 211.165(d), which states that the batch must meet its predetermined specifications (§ 211.165(a)). Additionally, regulators also point producers to an appropriate control of components and drug product containers and closures, which could add to variability in production outcomes. Section 211.84(b) specifically requires that “representative samples of each shipment of each lot shall be collected for testing or examination,” continuing that “the number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier.”

Finally, section 211.180(e) requires that information and data about product quality and manufacturing experience be periodically evaluated to determine the need for changes in specifications or manufacturing or control procedures.⁸ Therefore, pharmaceutical product manufacturers would establish ongoing feedback that continually evaluates product quality and process performance, an essential feature of process maintenance and future optimization, improvement, technology transfer, or introduction of new technologies.

In August of 2002, the FDA embarked on the significant new initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century, to enhance and modernize the regulation of pharmaceutical manufacturing and product quality — to bring a 21^st-century focus to this critical FDA responsibility.¹⁰ This initiative was significant for many reasons, including that process validation would be playing a much more prominent role than formal data gathering. It was hoped it would help manufacturers to establish sustainable cultures based on:

• understanding of risks to manufacturing processes, as well as
• building of knowledge bases about their products and processes.

Specifically, the Final Report for this initiative informed industry that “FDA has also taken steps to clarify” its “approach to process validation, which was a subject of the 1996 proposal.” The FDA further stated that it had published a revised compliance policy guide (CPG) titled Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08, Sec.490.100) and that it intended to further address the validation aspects of the CGMPs by updating the 1987 Guideline on Process Validation, as announced on March 12, 2004. In this new draft guidance, the agency aspires to “address the relationship between modern quality systems and manufacturing science advances to the conduct of process validation.”⁹

While the FDA hoped its draft guidance would be released in 2005, it took an additional three years for the draft guidance to be published and then three more years for the final draft to be issued. Meanwhile, the FDA, along with the European Medicinal Agency and the Ministry of Health of Japan, in a spirit of globalization, introduced the International Congress for Harmonization (ICH), which prescribed concepts similar to those described in cGMPs for the 21^st century initiative and issued drafts of three pivotal guidances, which became pillars of the risk-based life cycle approach to process validation. These, of course, were ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System). These three guidances represent the pillars upon which the concepts of the process validation continuum are built. They are based on scientific design, well understood statistically driven scientific measurement systems, risk-based analysis, and continued knowledge monitoring, understanding, and feedback.

References/Notes:

1. Pharmaceutical Process Scale-Up, edited by Michael Levin, Igor Gorsky, Parenteral Drug Scale Up, Marcel Dekker, NY 2005
2. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash, Marcel Dekker, NY 1984
3. Food and Drug Administration Compliance Program No. 7356.002. Compliance programs are updated yearly and published in the FDA Compliance Program Guidance Manual, available from National Technical Information Service (NTIS), U.S. Dept. of Commerce, 5285 Port Royal Road, Springfield, VA (information as of 1984).
4. European Organization for Quality Control, Section of Quality Control in the Pharmaceutical and Cosmetic Industries and Swiss Association for Pharmaceutical Quality, 4th European Seminar on Quality Control in the Pharmaceutical and Cosmetic Industries, Validation of Pharmaceutical processes, September 25/26, 1980, University of Geneva Reports.
5. Convention for the Mutual Recognition of Inspections with Respect of the Manufacture of Pharmaceutical Products, Validation, A Seminar held in Dublin, 14 and 17 June, 1982.
6. These are three separate centers now: The Center for Drug Evaluation and Research (CDER), The Center for Biologics Evaluation and Research (CBER), and Center for Medical Devices and Radiological Health (CDRH).
7. Shoutir Kishore Chatterjee, Statistical Thought: A Perspective and History, Oxford University Press, Oxford, United Kingdom 2003, page 82.
8. Grace E. McNally, Senior Policy Advisor U.S. Food and Drug Administration, Center for Drug Evaluation and Research Office of Compliance Division of Manufacturing and Product Quality, Process Validation A Lifecycle Approach Presentation, FDA-PDA Annual Conference, San Antonio, May 6 2011
9. Pharmaceutical CGMPs For The 21st Century — A Risk-Based Approach Final Report, Department of Health and Human Services U.S Food and Drug Administration, September 2004

About The Author:

Igor Gorsky has been a pharmaceutical industry professional for over 30 years. He held multiple positions with increasing responsibility at Alpharma, Wyeth, and Shire. He worked in production, quality assurance, technical services, and validation, including as associate director of global pharmaceutical technology at Shire. He is currently principal consultant at ValSource. He is leading the PDA Water Interest Group and a PDA Task Force for revision of PDA TR 29: Points to Consider for Cleaning Validation. In addition, he is a member of ASTM E55 and one of the authors of ASTM E3106 and E3207. He has a BS in mechanical/electrical engineering technology from Rochester Institute of Technology.

About The Book:

Principals of Parenteral Solution Validation, A Practical Lifecycle Approach (Academic Press, Nov. 2019) presents readers with practical methods of implementation of process validation programs for parenteral preparations, presenting them with real solutions and logical pragmatic methods for cultivating validation cultures within their organizations. The book should be especially useful in an age of globalization to assist practitioners from all over the world in an assembly of a scientific knowledge building blocks that would help them to design, qualify, manufacture and maintain robust products and processes providing patients with safe, pure and effective parenteral products. In addition to providing an overview of a lifecycle of the parenteral product processes — including discussions about process design, process qualification, and process maintenance — also touches upon subjects that help specifically for aseptic process manufacturing, such as the use of statistics, aseptic process simulations, post aseptic sterilization and others.