Process validation continues to be a topic of much debate and con-fusion for bio pharmaceutical manufacturers. It is usually perceived as a regulatory requirement and good business practice, since it can prevent failed batches when based on science and risk assessments. This book provides insights into the key aspects and current practices of process validation.

Chapter 1 addresses some of the current process validation concerns. In Chapter 2, the use of a risk assessment method (failure modes and effect analysis [FMEA]) is presented as a means to prioritize process parameters for further process characterization prior to validation. FMEA provides a logical approach that can aid in establishing critical parameters and ensure process robustness. Specific examples on the use of FMEA will aid readers to establish this method in their own organizations.

Process characterization is a prerequisite for process validation. In Chapter 3, a description of how to carry out thorough and consistent process characterization is presented. “Precharacterization” studies, which are used to help define the scope of the actual experimental characterization work, are also discussed. The discussions on timing of process characterization, needed resources, and a stepwise approach provide valuable insights. The importance of scale-down in process characterization is also addressed.

Accurately scaling down to mimic manufacturing processes is essential in several aspects of process validation. Chapter 4 provides further guidance and strategies for scaling down unit operations, including chromatography, chemical modification reactions, ultrafiltration, and microfiltration. In addition to general scale-down principles and parameters, the authors address specific problems and present some examples.

Prior to establishing a process that can be validated, it is essential to consider potential risks from adventitious agents, which include viruses, bacteria, fungi, mycoplasma, and transmissible spongiform encephalopathies. The potential sources of these agents and testing programs for them are described in Chapter 5. Examples of contamination events in biopharmaceutical manufacturing are presented. Bioburden assessment and sterility issues are also addressed, and a summary table describes adventitious agents, rec-ommended tests, and stages at which to perform testing.

In Chapter 6, the life span of both chromatography and filtration media is addressed. There are discussions on the various factors that influence life span, along with experimental approaches for validation. The use of small-scale models for validation is discussed. The application of concurrent validation to provide life span data, an approach gaining more acceptance lately, is also discussed in this chapter.

Chapter 7 begins with an overview of filtration validation and a discussion of validation that can be performed in scaled-down studies as well as those aspects that require manufacturing scale. Next is a section on the validation of sterilizing-grade filters. Subsequent sections address validation of filters used for clarification and virus removal filters. Details of tangential-flow filter validation are presented. Also included are descriptions of specific validation issues in clarification of bacterial cell harvest and lysate clarification, mammalian cell clarification, and protein concentration and diafiltration. Cleaning validation for reusable membranes is also discussed.

It has been said that without assays, you have nothing. In Chap-ter 8, analytical test methods are discussed with a special focus on well-characterized biological and biotechnological products. Appropriate methods for testing raw materials and in-process samples during the various manufacturing steps are addressed. The authors also discuss Process Analytical Technology (PAT), which is being driven by the FDA as a means to better control processes. Another section of this chapter presents methods used for product characterization, release, and stability testing. Also included are the ever-problematic potency assay and strategies for choosing a quality control testing scheme. Other topics discussed are the use of assays for demonstrating comparability, assay validation, dealing with out-of-specification (OOS) results, and assay revalidation.
In Chapter 9, the reader is provided with a regulatory perspec-tive on facility design and validation issues. Written by two ex-FDAers, this chapter provides details on the regulatory requirements and the information that should be provided in a license application. Also presented are the requirements for cell inoculum suites and areas intended for fermentation/harvest, purification, and bulk filtration. In addition, support areas, such as those used for preparation of media and buffers, and the use of closed systems to reduce environmental classifications are discussed. There are extensive sections on utilities, cleaning, and environmental monitoring. Multiproduct facility issues are addressed. In the section on facility inspections, the authors provide insight into the current focus of inspections.

Chapter 10 discusses the importance of taking a risk-based approach toward computerized system compliance and how it adds value to the product and process that is commensurate with cost. It is concluded that a sound computer system validation (CSV) program encourages the introduction of new and exciting technolo-gies with the ultimate promise of safer, more effective, and more affordable medicines.

In Chapters 11, 12, 13, and 14, many of the concepts described in the previous chapters are illustrated with case studies. First, we learn in Chapter 11 about process optimization and characterization studies for the purification of an E. coli-expressed protein product. Chapter 12 also addresses purification validation — in this case, for a therapeutic monoclonal antibody that is expressed and secreted by Chinese hamster ovary (CHO) cells. In Chapter 13, a matrix approach for process validation of a multivalent bacterial vaccine is described. Chapter 14 describes viral clearance validation studies for a product produced in a human cell line.
We hope this book will provide the reader with valuable insights into the current trends in process validation. Over the years, the biotechnology industry has advanced and we are now addressing concepts such as comparability and matrix approaches to validation. By sharing their knowledge, the authors have contributed to the biopharmaceutical industry’s enhanced application of science- and risk-based approaches to process validation.


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