Biotechnology

Quality Assurance and Validation

Kenneth E. Avis, Carmen M. Wagner, Vincent L. Wu, Kenneth E. Avis, Carmen M. Wagner, Vincent L. Wu

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000093582
• Topic: Medicine
• Subtopic: Pharmacology

Biotechnology: Quality Assurance and Validation provides a practical, detailed discussion of what issues Quality Assurance and Quality Control need to identify for effective control in the preparation of biotechnology products. The book presents a series of topics that define some of the unique challenges facing biotechnology companies in producing biopharmaceutical products. The topics selected address quality and validation issues, starting with the cryopreservation of cell lines through the filling and finishing of the product. It includes a validation guide, a clear presentation of how to use filtration effectively, a synoptic view of cleaning procedures, and much more.

1

INTRODUCTION

Kenneth E. Avis

University of Tennessee

Carmen M. Wagner

Wyeth-Lederle Vaccines and Pediatrics

Vincent L. Wu

Integrated Biosystems, Inc.

As biotechnology has moved from research and development to the production and marketing of biopharmaceutical products, greater emphasis on quality assurance (QA) and validation of the processes used has occurred. In fact, many new or improved technologies have been developed. Therefore, the inspiration for this book stemmed from a desire to help meet the need of biopharmaceutical professionals to keep abreast of and have access to a record of some of the developments that have occurred. Incorporating such developments and establishing their reliability are keys to obtaining speedy approval of new products and achieving compliance with current Good Manufacturing Practices (cGMPs) for the processes involved.

Foundational to research and the subsequent development of biopharmaceutical products is the purification, identification, and maintenance of bacterial and mammalian cell lines. At least as critical as proving the identity and purity of chemical molecules for the synthetic development of pharmaceuticals is establishing the reliability of the characteristics of the cells and cell lines for the growth of reproducible cultures in the production of biopharmaceuticals. Since the latter are living, the issues in achieving and maintaining purity and viability are even more challenging. Then, once the quality is known and assured, the validation of the processes developed must ensure reproducibility of the biological process and its outcome.

In most biotechnological systems, the objective is a specific protein or group of proteins. From a QA perspective, the protein(s) must be identifiable, of high purity, and reproducible. Potentially contaminating entities, such as viruses, endotoxins, mycoplasmas, and denatured product must be eliminated or inactivated. Concurrently, analytical methods must be developed to identify and quantitate the active constituent(s) and identify the absence of contaminants. Recent biological and instrumental developments have greatly enhanced analytical capabilities and the ability to validate both the production processes and the test methods. These and many other technological issues associated with the assurance of quality and the validation of the processes required to produce high-quality biopharmaceutical products are presented in this book.

Also of concern is meeting regulatory requirements in a changing technology. Before pharmaceutical and biopharmaceutical products can be made available to the public, they must meet the requirements of the U.S. Food and Drug Administration (FDA), as legislated by the U.S. Congress. Existing FDA requirements for the pharmaceutical industry are not entirely applicable to the biopharmaceutical industry, but those in place are legally enforceable. Efforts to modify the regulations to better meet the needs of both the pharmaceutical and the biopharmaceutical industries have been underway for some time. In 1997, the U.S. Congress passed the Food and Drug Modernization Act, the first significant change in the Federal Food, Drug, and Cosmetic (FD&C) Act in 35 years. Some of the changes specifically affect the biotechnology industry, a result due in part to the efforts of the Biotechnology Industry Organization (BIO). The amended act includes progressive changes, such as implementing a completely electronic submissions program after 5 years, eliminating the Establishment License Application, harmonizing procedures for the FDA Drugs and Biologics Centers, and a move toward eliminating the Center for Biologics Evaluation and Research (CBER) batch certification and monograph requirements for “well-characterized” biotechnology products.

Notably, Statute 830 will expand the FDA’s current program to expedite the filing and approval of new therapies for serious or life-threatening conditions. It will also codify FDA regulations and practices designed to ensure that patients will have access to therapies for serious and life-threatening conditions before they are approved for marketing. This means that an increased number of clinical products for life-threatening conditions will potentially be made available to a larger number of patients sooner.

These sweeping changes are a result of both industry initiative and a recognition of increased confidence in the evolving industry–a strong endorsement of its scientific technology. With the roadblocks to drug approval decreasing, and with the streamlining of the approval process for drug manufacturing changes, there will be increased pressure for manufacturers to keep current with quality and compliance issues for both clinical and marketed products, including increased responsibility to accelerate timely collaborations with regulatory agencies.

As the industry and regulatory bodies worked together to define a well-characterized biopharmaceutical product, so should the effort continue to provide well-characterized manufacturing and QA procedures. The ability of manufacturers to effectively control and analyze the manufacture of biopharmaceutical products is dependent on the effective use of process control and its instrumentation, the development of specific assays for product and process contaminants, and the ability to demonstrate process repeatability through process validation.

This book presents a series of selected topics that define some of the unique challenges facing biotechnology companies in producing biopharmaceutical products. The topics selected address some of the quality and validation issues, starting with the cryopreservation of cell lines through the filling and finishing of the product. Further issues will be addressed in subsequent volumes. We believe you will find this book to be helpful to you in carrying out your responsibilities in biopharmaceutical processing.

CHAPTER CONTENTS

The following summarizes the somewhat divergent but related topics of the next six chapters. These topics were selected because of their timely nature, the current lack of coverage in available reference books, and the availability of highly qualified professionals to write on the topics selected.

Chapter 2, “Cryopreservation: Storage and Documentation Systems,” is written by Frank P. Simione, who is Director of Professional Services and Safety Officer at the American Type Culture Collection (ATCC). Mammalian and microbiological cells are maintained in either private or public collections. The ATCC was established as such a public resource. The importance of the availability of viable, pure, and reliably identified cultures of cells needed for research and production in biotechnology cannot be overemphasized. The author has described how almost all cell lines are preserved for long-term storage by low-temperature freezing (cryopreservation) or by freeze-drying (lyophilization). Mr. Simione takes the reader through the various steps of cell preparation-their identification, preservation, and maintenance of the collection. The inventory and its control is essential in assuring the usefulness of the cells and their availability.

Chapter 3, “Quality Control and Quality Assurance Issues in Biopharmaceutical Processing,” is by Dr. Gary L. Christiansen, a well-known consultant in the field. After reviewing the classical components of pharmaceutical quality control (QC) and QA, the author presents an extensive section on the specific concerns for biotechnology products. He discusses various test methods and requirements, including protein analysis; protein sequencing; peptide mapping; immunoassays; electrophoresis; release testing; and testing for safety, sterility, pyrogen, DNA (deoxyribonucleic acid), mycoplasma, and viruses.

The author then develops process validation concepts and requirements as related to biopharmaceutical processing, the importance of cell line characterization; the need for virus removal or inactivation; the removal of contaminating DNA and nucleic acids; and the removal of other contaminants, such as serum albumin, insulin, and denatured product. The last section of the chapter is an extensive coverage of the expectations of the FDA in an inspection, as identified in several published FDA guidelines. This chapter is an excellent and detailed treatise on QC and QA relative to biopharmaceutical products and their processing. The references include 28 citations, several of which are federal and international documents on regulatory issues.

Chapter 4 is written by Gregory Bobrowicz, an FDA investigator at the time of writing. The author begins “Biotechnology Manufacturing Issues: A Field Investigator’s Perspective” with a brief description of the FDA’s organizational structure, noting that of the five centers adjacent to Washington, D.C. (Rockville, Md.), CBER has primary responsibility for product approval for most biopharmaceuticals. A major portion of the chapter then reviews the topic of FDA concerns, related primarily to the safety of products for human administration. He discusses the occurrence of impurities and how their presence should be controlled, including viruses, mycoplasmas, microorganisms, endotoxins, and the general category of process contaminants. The author also discusses the FDA’s concerns for potency and identity of the product.

In the next section, Mr. Bobrowicz provides a useful discussion of strategies for compliance with FDA requirements. He notes that quite often citations on 483s reflect a complete absence of an attempt at compliance. He also states that firms having good compliance records usually invest heavily in planning, data review, internal audits, managerial involvement, a corporate culture promoting quality, and, finally, an emphasis on investigating all deviations from prescribed limits. The chapter concludes with a comment on why the FDA expects manufacturers to practice adequate controls. This interesting and enlightening chapter concludes with a list of 63 references.

In “Validation of Biopharmaceutical Processes,” written by Drs. Howard L. Levine of BioProcess Technology Consultants and Francisco J. Castillo of Berlex Biosciences, the authors examine the difficult task of validating a biopharmaceutical process. They emphasize the necessity of being sure that the right protein is obtained and maintained throughout the entire process, without introducing contaminating substances such as viruses, endotoxins, foreign proteins, media constituents, and process chemicals. They underscore the importance of validating the process so that it can be controlled and reliably repeated.

The authors have organized Chapter 5 by first discussing cell banks, the testing of specimens to be assured of freedom from contaminants and validation for cell integrity. They then discuss the operational qualification (OQ) of equipment, such as fermentors, incubators, media preparation equipment, sterilizers, biosafety hoods, chromatography systems, and filtration equipment. The fermentation or cell culture process is a critical one that must be run aseptically in a defined and controlled manner and must be validated repeatedly to produce the anticipated harvest of the product. The authors move from this topic to that of validation of downstream processing–the process of product purification. Downstream processing usually involves chromatography to purify the product and tangential flow filtration to concentrate the macromolecules.

In a discussion of the performance qualification (PQ) of downstream processes, the authors describe rigorous testing procedures to demonstrate the reproducibility of the process. Since biological processes typically introduce or fail to remove various contaminants, they must be subsequently inactivated or eliminated. Therefore, under the heading of clearance studies, the authors discuss the purification processes utilized and the testing required to ensure that purification has appropriately eliminated or removed such contaminants as DNA, host cell proteins, pyrogens, and viruses. The authors conclude the chapter with a discussion of tangential flow filtration and its validation–a very significant process in the purification of biopharmaceutical products. At the end of the chapter, the authors provide a very valuable list of 93 literature references from the field.

Chapter 6 is an in-depth examination of the topic of filtration to remove viruses from biological fluids. It was written by Dr. Hazel Aranha-Creado, a senior staff scientist at Pall Corporation. The first five sections of the chapter present a brief but classical review of background information concerning viruses–their sources and detection–along with methods of viral clearance and the regulatory approach to viral clearance. Since the issue of viral contamination is critical with respect to the safety of biological products, and viruses are potential contaminants in most biological products of human and animal origin, the processes must be designed and validated to give a high level of assurance that any viruses present have been eliminated by the processing conditions.

The author then discusses methodologies for virus removal from liquids by filtration, emphasizing both direct flow and tangential flow filtration. The various types of polymers used for the filter membranes are also presented. Since full dependence is placed on filters to effect virus removal, their integrity throughout their use in the process must be assured. Therefore, the author provides details of the testing available for determining filter integrity. The chapter concludes with an impressive list of 102 literature references.

Chapter 7, the final chapter in this volume, is a survey of the concepts and processes for cleaning equipment used in biopharmaceutical processing and the validation of cleaning processes. Jon Voss, president of KMI Systems, and Robert O’Brien, manager of validation at Biopure Corporation, have joined together to prepare their very important and practical chapter. The chapter is divided into two sections: The first section presents the concepts and methods for cleaning equipment after being used for biological processes, including their special cleaning requirements, while the second section presents the validation of cleaning processes. Both manual and automated clean-in-place (CIP) processes are covered in a helpful and practical manner in this quick-reference chapter.

It is believed that this book will find a welcome niche in biopharmaceutical processing technology as a reference tool because of the useful information it contains and the quality of its presentations. There is much to be learned concerning the relatively new field of biopharmaceutical processing. This book fills a significant number of gaps in the knowledge base for this specialty.

2

CRYOPRESERVATION: STORAGE AND DOCUMENTATION SYSTEMS

Frank P. Simione

American Type Culture Collection

The long-term preservation of biological specimens and associated data assists in ensuring reproducibility and comparability in biomedical research. There are two major goals in preserving living cells and organisms: maintain the specimens viable and unchanged for a long period of time and avoid contamination. Serial subculturing carries with it the risk of genetic change and exposure to unwanted contaminants. The cell culture literature contains numerous references to work performed with cells that were unknowingly contaminated, the most classic instance being that of HeLa contamination (Lavappa 1978; Nelson-Rees et al. 1981). This problem continues, and more and more sophisticated means of characterization have led to the discovery of other mixed or misidentified cell populations.

Low-temperature preservation by freezing and storage at cryogenic temperatures is the most effective means of maintaining cells and organisms unchanged for later use. Although the principles of low-temperature preservation are widely applied, the practices differ depending on the intended use of the stabilized cells. Effective preservation regimens start with the characterization and identification of the material to be preserved, since low-temperature preservation of cells is not a panacea, and one cannot expect to recover from the process better quality specimens than were present prior to preservation (Stevenson 1963).

The parameters for cryopreserving a living cell or organism are...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Foreword
• Author Biographies
• 1. Introduction
• 2. Cryopreservation: Storage and Documentation Systems
• 3. Quality Control and Quality Assurance Issues in Biopharmaceutical Processing
• 4. Biotechnology Manufacturing Issues: A Field Investigator’s Perspective
• 5. Validation of Biopharmaceutical Processes
• 6. Ensuring Virological Safety of Biologicais: Virus Removal from Biological Fluids by Filtration
• 7. Cleaning and Validation of Cleaning in Biopharmaceutical Processing: A Survey
• Index
• Drug Manufacturing Technology SeriesKey-Concept Cross-Reference Index for Sterile Dosage Forms