Principles of Parenteral Solution Validation: A Practical Lifecycle Approach

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Introduction

Igor Gorsky,    Senior Consultant, ConcordiaValsource LLC., Downingtown, PA, United States

Abstract

This is an Introduction to the book which discusses history and today's status of process validation, as well as structure of this book.

Keywords

Parenteral; Good Manufacturing Practices; Process Validation; Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century; ICH Q8 (Pharmaceutical Development); ICH Q9 (Quality Risk Management); Q10 (Pharmaceutical Quality System); Risk-Based Lifecycle Approach

The term parenteral pertains to those medicinal preparations that are delivered via the route of injection through one or several layers of skin tissue. This word, derived from the Greek words para and etheron, which means outside of the intestine. It is typically referred to those 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 (GMP) of which process validation plays a pivotal, if not the most important role.

To understand simplest physical presentation of the parenteral products subject of process validation topics to be described in this volume 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 from a perspective of uniformity of these products which must confirm to homogeneity specifications of their bulk preparations to be filled and packaged properly in uniform final filled units.

A reader could ask a question why authors are undertaking a discussion on process validation topic for parenteral products when there is already much amount of literature on a subject. What new thoughts and ideas should audience expect from this book? Process validation subject has been a center of attention of regulators and subsequently parenteral industry practitioners for more than 40 years. The subject first was discussed in the mid-1970s, prior to issuance of the FDA compliance program in 1978 (Loftus and Nash, 1984). The program that was issued in 1978 was published before revised cGMP regulations and had a title Drug Product Inspections. Remarkably this 1978 program said the following with regards 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."² Interestingly that subject of process validation has been discussed among practitioners for close to 10 years since this definition was first published. Some examples of these discussions were documented in proceeds of Validation of Manufacturing Process Seminar in Geneva, Switzerland in 1980³ and Validation Seminar held in Dublin, Ireland in 1982.⁴ In the proceeds of Geneva seminar we read the following definition for process validation—"a formal process to demonstrate that a specific product can be reliably manufactured by designed process, while Validation Seminar in Dublin in one of its presentations asked a question of 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 Food and Drug Administration’s Center for Drugs and Biologics and Center for Devices and Radiological Health⁶ Guideline on General Principles of Process Validation went on books in May of 1987 original 1978–1982 definition lost these original concepts of being a life cycle exercise with a sound scientific design of the process and read 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 planned and designed events to succeed would always include this high degree of assurance as in referenced example from a purely statistical manual (Chatterjee, 2003). However in those days pharmaceutical and biopharmaceutical practitioners were not yet given authority by the majority of the management of their organizations to pursue process validation as a continued learning exercise, but rather as a regulatory necessity mainly concentrating on terms establishing documented evidence which meant in their mind a necessary evil of performing three process validation consecutive batches and documenting this event. It should be noted that even than problems and deviations that often occurred while producing these three golden" batches did not alert practitioners, their management or even regulators that there was a problem with an entire concept. Firms were regularly cited by the FDA for lack of robust validated processes while manufacturers were continually having issues when they were introducing new products to the market.

In the 1978 GMPs regulators have embedded 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, which would produce therapeutic materials that would meet their specified attributes. In addition, this section continues that 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 a 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." Therefore suggesting that manufacturers should analyze performance of processes to understand and control batch-to-batch variability. Furthermore cGMP regulations sets requirement on sampling, asserting that they must be representative of produced batch under analysis, This described in section §211.160(b)(3) which says that sampling must meet specifications and statistical quality control criteria as condition of approval and release, as well as section §211.165(d) which continues saying that the batch must meet its predetermined specifications (§211.165(a)). Additionally regulators also point attention of the producers to an appropriate control of components and drug product containers and closures which could add to variability of production outcome. In section §211.84 (b) cGMPs 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 need for changes in specifications or manufacturing or control procedures.⁷ Therefore pharmaceutical products manufacturers would be establishing an ongoing feedback continually evaluating product quality and process performance which is an essential feature of process maintenance and future optimization, improvement, technology transfer, or introduction of new technologies.

In August of 2002 FDA embarked on the a 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 21st century focus to this critical FDA responsibility.⁸ This initiative was significant for many reasons. Process Validation would be playing a much more prominent role than formal data gathering. It would hopefully 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 Final Report for this initiative informed industry that FDA has also taken steps to clarify its our approach to process validation, which was a subject of the 1996 proposal. FDA further stated that they have published a revised compliance policy guide (CPG) entitled Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08, Sec.490.100) and that they 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 they aspire to address the relationship between modern quality systems and manufacturing science advances to the conduct of process validation.⁹ They hoped for this draft guidance to be released in 2005. However it took additional three years for new draft guidance to be published and then three more years for the final draft to be issued. Meanwhile, FDA, along with European Medicinal Agency and Ministry of Health of Japan in a spirit of globalization introduced International Congress for Harmonization (ICH) which in fact followed similar concepts described in cGMPs for 21st Century initiative and issued drafts three pivotal guidances which became pillars of Risk-Based Lifecycle Approach for Process Validation. These of course were ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System). These three guidances include main concepts of Process Validation Continuum based on scientific design, well understood statistically driven measurement system, risk-based analysis and continued knowledge understanding and feedback. However even after introduction of a number of guidances, publishing of voluminous literature, blogs, presentations, and other materials on a subject considerable number of manufacturers seem to fail establishing effective and efficient process validation programs.

Therefore the goal of this book is to present 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. This 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.

This book in addition to overview of a life cycle of the parenteral product processes which include discussions about process design, process qualification, and process maintenance will also touch upon subjects that help specifically for aseptic process manufacturing such as use of statistics, aseptic process simulations, post aseptic sterilization, and others.

We divided our book into three sections to help better understanding of the subject and to assure logical flow of information. First four chapters describe enablers of Process Validation for Parenteral Products, analyses’ tools and review of essential simultaneous activities such as cleaning validation.

These chapters include:

Chapter 1: Process Validation: Design and Planning.

Chapter 2: Aseptic Process Validation: Aseptic Process Simulation Design.

Chapter 3: Quality Risk Management of Parenteral Process Validation, Part 1: Fundamentals.

Chapter 4: Equipment Cleaning Process.

Chapter 5: Quality Risk Management of Parenteral Process Validation Part 2: A Risk-Based Quality Management System.

After reading these chapters our reader is introduced to actual Process Validation activities which include three stages:

Chapter 6: Use of Statistics in Process Validation.

Chapter 7: Process Validation Stage 1: Parenteral Process Design.

Chapter 8: Process Validation Stage 2: Parenteral Process Performance Qualification.

The final, third section of the book deals with practical aspects of aseptic manufacturing as well as practical activities that are performed during parenteral production. Prospective reader will be introduced to case studies and practical examples in this section. These chapters are:

Chapter 9: Process Validation Stage 3: Continued Process Verification.

Chapter 10: Preuse/Poststerilization Integrity Testing of Sterilizing Grade Filter.

Chapter 11: Environmental Monitoring.

Chapter 12: Isolators.

Chapter 13: Post Aseptic Fill Sterilization and Lethal Treatment.

Our ultimate goal is to present parenteral drug manufacturers with a volume that helps in their implementation of comprehensive process validation programs and hopefully becomes go to reference on this essential subject. We welcome the reader to proceed into a world of parenteral processes validation.

References

1. Chatterjee SK. Statistical Thought: A Perspective and History Oxford: Oxford University Press; 2003.

2. Loftus BT, Nash RA. Pharmaceutcal Process Validation New York: Marcel Dekker; 1984.

Further Reading

1. Barker, R. (1982). Convention for the Mutual Recognition of Inspections with Respect of the Manufacture of Pharmaceutical Products, Validation. Validation Convention, (p. 24). Dublin.

2. European Organization for Quality Control, S. o.. Validation of Pharmaceutical Processes Geneva: University of Geneva Reports;