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Validation practices for biotechnology products
Biotechnology Advances, Vol. 15, No. 2, pp. 379-382, 1997 Copyright © 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0734-9750/97 $32.00 + .00
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P I I S 0 7 3 4 - 9 " / 5 0 ( 9 " / ) 0 0 0 0 7 -4
BOOK REVIEW VALIDATION IN BIOPROCESSING Validation Practices for Biotechnology Products J.K. Shillenn, editor, American Society for Testing and Materials, West Conshohocken, 1996 (ix + 152 pages)ISBN 0 8031 2405 8
Validation Practices for Biotechnology Products is a hotchpotch of twelve contributions from a symposium of the same name. The contributions are grouped under (i) facilities and equipment validation; (ii) process validation and planning; and (iii) calibration and change control. Validation is essential to guaranteeing a product's quality and safety. The U.S. Food and Drug Adminstration defines process validation as "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 characteristics." Validation is mandated by the current Good Manufacturing Practices (GMP) regulations that are designed to assure that drugs---final dosage forms as well as bulk products---have the identity, strength, quality, and purity that they are purported or represented to have. GMP compliance and validation are expensive, but failure to comply is often more costly and always criminal. Non-compliance is assumed unless a manufacturer can demonstrate otherwise. GMP regulations and validation requirements cover manufacture, holding, and distribution of drugs; therefore, production processes, equipment and facilities are covered. This book has a more modest scope. Commissioning considerations for pharmaceutical manufacturing facilities are noted, but there is little detail and anyone seeking more information would be thwarted by an absence of literature citations in this section. Commissioning typically refers to facility start-up after construction is complete; however, for a biotechnology facility, commissioning---or at least
379
380
Y. CH1STI
planning for it--begins almost as early as the design stages. Planning is the key. For example, it is easy to establish that a network of containment area drains is correctly connected to the decontamination system, and not to municipal sewer, so long as concrete has not been poured. Later, this simple task becomes a nightmare. From the facility the book moves abruptly to equipment. Validation considerations for liquid nitrogen freezers used in cryogenic preservation of cells are outlined, and next comes validation of sterilizing grade liquid filters. Typically, the 0.2 ~m rated sterilizing filters are qualified to retain Pseudomonas diminuta (ATCC 19146) when challenged at > 107 cells per square centimeter of filter area. Although generally satisfactory, such filters may not retain certain rare microbes: leakage of the mycoplasma Acholeplasma laidlawii and the bacterium Pseudomonas picketii has been observed. Added protection may be gained with 0.1 ~tm rated filters. A separate chapter is devoted to sensitivity considerations in integrity testing of hydrophobic membrane filters for gas sterilization. Such filters are usually tested by the 'forward flow diffusion' method, although visual determination of bubble point continues to be used. The authors propose water breakthrough or intrusion testing as an alternative which supposedly also confirms maintenance of a hydrophobic state. Testing for a hydrophobic state is not usual, and arguments for it remain unconvincing. In "Designing validation into chromatography processes," Gail Sofer provides a brief overview of the relevant factors, but better treatments are available in her books that are not cited. Another paper, detailing experimental work on validation of regeneration operations--clean-in-place and sanitization--for cellulose-based ion-exchange media, suggests alkaline cleaning with 0.5 M sodium hydroxide as being generally satisfactory for a variety of supports. The cleaning theme comes up again later when disinfection is treated. Chemical disinfection is commonly encountered in bioprocessing and, as the book details, the effectiveness of disinfectants needs validating under actual shelf-life and use conditions. The discussion emphasizes selection and validation of disinfecting agents for clean rooms and equipment. Good background material is provided.
VALIDATIONIN BIOPROCESSING
Only one paper deals with a fermentation process per se, detailing validation specifics for a recombinant E. coli-based production. Of especial significance is how, through planning and coordination, validation data from pilot-scale batches can be used to guide and speed the production-scale validation. Characterization and quality assurance of recombinant protein therapeutics continues to draw attention even though many sensitive and effective methods are now available for assessing specific quality attributes. In "A new methodology for quality control testing of biological and recombinant products," Zaslavsky and Chaiko propose protein partitioning in aqueous two-phase systems as a measure of 'quality.' The partition coefficient is indeed sensitive to molecular properties of proteins, but not sufficiently for it's use as a reliable index of therapeutic quality. HPLC and other chromatographic methods are more sensitive because they rely on a large number of partitioning steps rather than the single equilibrium stage of the proposed approach. Yet greater sensitivity to molecular characteristics is seen in various types of electrophoreses. In my view, aqueous two-phase partitioning is useful mainly in protein recovery, and only in combination with other purification operations. Moving to the issue of computers in bioprocessing, their validation is not so straightforward and it is less widely understood. As the book emphasizes, a system definition (what it must do) and identification of critical functions are the underpinnings of rational validation. A modular approach to validation is recommended in which component parts are qualified prior to qualification of the integrated system. On other relevant issues, the book presents an overview of development, documentation, and management of GMP procedures, but the discussion in this section does not reflect the specific terminology employed in the biopharmaceutical industry: apparently the author is more in tune with the ISO quality assurance approaches. The final paper focuses on managing the ongoing calibration and change control program in a facility. Continual, timely, and documented calibration in accordance with established procedures, assures that a process remains within specifications. A change control program, on the other hand, guards
381
382
Y. CHISTI
against ill-conceived, undocumented changes that may affect the validation status or the process performance. Despite a wide-ranging and critical impact of GMPs on bioprocessing (including food processing), graduating biochemical engineers are rarely aware of the regulations or their implications. Few educators have the relevant training or industrial experience; therefore, the literature on GMPs and validation issues must bear an added educational burden. But tutoring to the novice is not what this book is about: validation principles are not covered; the treatment is not comprehensive enough; and most papers do not give the necessary background within their specialized topics. Nevertheless, quality assurance, regulatory compliance, and validation departments of biopharmaceutical producers, as well as consultants and institutional libraries, should find the book useful.
Yusuf Chisti Department of Chemical Engineering University of Waterloo Waterloo, Ontario Canada N2L 3G1
~.i~,i i .~:' ~.;~. ELSEVIER
P I I S 0 7 3 4 - 9 " / 5 0 ( 9 " / ) 0 0 0 0 7 -4
BOOK REVIEW VALIDATION IN BIOPROCESSING Validation Practices for Biotechnology Products J.K. Shillenn, editor, American Society for Testing and Materials, West Conshohocken, 1996 (ix + 152 pages)ISBN 0 8031 2405 8
Validation Practices for Biotechnology Products is a hotchpotch of twelve contributions from a symposium of the same name. The contributions are grouped under (i) facilities and equipment validation; (ii) process validation and planning; and (iii) calibration and change control. Validation is essential to guaranteeing a product's quality and safety. The U.S. Food and Drug Adminstration defines process validation as "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 characteristics." Validation is mandated by the current Good Manufacturing Practices (GMP) regulations that are designed to assure that drugs---final dosage forms as well as bulk products---have the identity, strength, quality, and purity that they are purported or represented to have. GMP compliance and validation are expensive, but failure to comply is often more costly and always criminal. Non-compliance is assumed unless a manufacturer can demonstrate otherwise. GMP regulations and validation requirements cover manufacture, holding, and distribution of drugs; therefore, production processes, equipment and facilities are covered. This book has a more modest scope. Commissioning considerations for pharmaceutical manufacturing facilities are noted, but there is little detail and anyone seeking more information would be thwarted by an absence of literature citations in this section. Commissioning typically refers to facility start-up after construction is complete; however, for a biotechnology facility, commissioning---or at least
379
380
Y. CH1STI
planning for it--begins almost as early as the design stages. Planning is the key. For example, it is easy to establish that a network of containment area drains is correctly connected to the decontamination system, and not to municipal sewer, so long as concrete has not been poured. Later, this simple task becomes a nightmare. From the facility the book moves abruptly to equipment. Validation considerations for liquid nitrogen freezers used in cryogenic preservation of cells are outlined, and next comes validation of sterilizing grade liquid filters. Typically, the 0.2 ~m rated sterilizing filters are qualified to retain Pseudomonas diminuta (ATCC 19146) when challenged at > 107 cells per square centimeter of filter area. Although generally satisfactory, such filters may not retain certain rare microbes: leakage of the mycoplasma Acholeplasma laidlawii and the bacterium Pseudomonas picketii has been observed. Added protection may be gained with 0.1 ~tm rated filters. A separate chapter is devoted to sensitivity considerations in integrity testing of hydrophobic membrane filters for gas sterilization. Such filters are usually tested by the 'forward flow diffusion' method, although visual determination of bubble point continues to be used. The authors propose water breakthrough or intrusion testing as an alternative which supposedly also confirms maintenance of a hydrophobic state. Testing for a hydrophobic state is not usual, and arguments for it remain unconvincing. In "Designing validation into chromatography processes," Gail Sofer provides a brief overview of the relevant factors, but better treatments are available in her books that are not cited. Another paper, detailing experimental work on validation of regeneration operations--clean-in-place and sanitization--for cellulose-based ion-exchange media, suggests alkaline cleaning with 0.5 M sodium hydroxide as being generally satisfactory for a variety of supports. The cleaning theme comes up again later when disinfection is treated. Chemical disinfection is commonly encountered in bioprocessing and, as the book details, the effectiveness of disinfectants needs validating under actual shelf-life and use conditions. The discussion emphasizes selection and validation of disinfecting agents for clean rooms and equipment. Good background material is provided.
VALIDATIONIN BIOPROCESSING
Only one paper deals with a fermentation process per se, detailing validation specifics for a recombinant E. coli-based production. Of especial significance is how, through planning and coordination, validation data from pilot-scale batches can be used to guide and speed the production-scale validation. Characterization and quality assurance of recombinant protein therapeutics continues to draw attention even though many sensitive and effective methods are now available for assessing specific quality attributes. In "A new methodology for quality control testing of biological and recombinant products," Zaslavsky and Chaiko propose protein partitioning in aqueous two-phase systems as a measure of 'quality.' The partition coefficient is indeed sensitive to molecular properties of proteins, but not sufficiently for it's use as a reliable index of therapeutic quality. HPLC and other chromatographic methods are more sensitive because they rely on a large number of partitioning steps rather than the single equilibrium stage of the proposed approach. Yet greater sensitivity to molecular characteristics is seen in various types of electrophoreses. In my view, aqueous two-phase partitioning is useful mainly in protein recovery, and only in combination with other purification operations. Moving to the issue of computers in bioprocessing, their validation is not so straightforward and it is less widely understood. As the book emphasizes, a system definition (what it must do) and identification of critical functions are the underpinnings of rational validation. A modular approach to validation is recommended in which component parts are qualified prior to qualification of the integrated system. On other relevant issues, the book presents an overview of development, documentation, and management of GMP procedures, but the discussion in this section does not reflect the specific terminology employed in the biopharmaceutical industry: apparently the author is more in tune with the ISO quality assurance approaches. The final paper focuses on managing the ongoing calibration and change control program in a facility. Continual, timely, and documented calibration in accordance with established procedures, assures that a process remains within specifications. A change control program, on the other hand, guards
381
382
Y. CHISTI
against ill-conceived, undocumented changes that may affect the validation status or the process performance. Despite a wide-ranging and critical impact of GMPs on bioprocessing (including food processing), graduating biochemical engineers are rarely aware of the regulations or their implications. Few educators have the relevant training or industrial experience; therefore, the literature on GMPs and validation issues must bear an added educational burden. But tutoring to the novice is not what this book is about: validation principles are not covered; the treatment is not comprehensive enough; and most papers do not give the necessary background within their specialized topics. Nevertheless, quality assurance, regulatory compliance, and validation departments of biopharmaceutical producers, as well as consultants and institutional libraries, should find the book useful.
Yusuf Chisti Department of Chemical Engineering University of Waterloo Waterloo, Ontario Canada N2L 3G1