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Rapid Detection of Bacteria and Viruses in Bioprocess Samples: Justification, Regulation, Requirements and Technologies — How Can Industry Achieve Broad Adoption?

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RAPID DETECTION OF
BACTERIA AND VIRUSES IN
BIOPROCESS SAMPLES:

JUSTIFICATION, REGULATION,
REQUIREMENTS AND TECHNOLOGIES
— HOW CAN INDUSTRY
ACHIEVE BROAD ADOPTION?

CONNECT
COLLABORATE
ACCELERATETM

1

Contents

1.0 2.0 3.0

Executive summary .......................................................................................................................................................................... 6 Introduction ....................................................................................................................................................................................... 8 Current practices ............................................................................................................................................................................10

3.1 Sterility testing ............................................................................................................................................................................. 10 3.2 Mycoplasma testing .................................................................................................................................................................... 11 3.3 Virus testing .................................................................................................................................................................................. 13

Drivers for change...........................................................................................................................................................................15 Overcoming barriers to change ..................................................................................................................................................17

5.1 Technical/operational attributes and impediments.......................................................................................................... 20 5.2 Cost–benefit ratio........................................................................................................................................................................ 21 5.3 Regulatory acceptance............................................................................................................................................................... 21 5.4 Behavioral ...................................................................................................................................................................................... 22 5.5 Summary ........................................................................................................................................................................................ 23

Advocacy for improvement and change....................................................................................................................................24 Conclusions and path forwards ...................................................................................................................................................25

4.0 5.0

6.0 7.0

References ......................................................................................................................................................................................................27 Definitions/glossary .....................................................................................................................................................................................30 Acronyms/abbreviations ............................................................................................................................................................................35 Appendix: Different types of PCR.............................................................................................................................................................36

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List of tables

Table 1: Use and limitation of adventitious virus testing (adapted from ICH Q5A).............................................................................................................................................................................. 14 Table2: Analysis of potential behavioral barriers to the adoption of new technologies ..................................................................................................................................................................... 23

List of figures

Figure 1: Areas of dissatisfaction with current GMP lot release tests........................................................................................................................................................................................................ 17 Figure 2: Impediments to implementing alternative rapid microbiology methods for GMP release testing ............................................................................................................................. 18 Figure 3: Activities to drive regulatory acceptance of alternative rapid microbiology methods..................................................................................................................................................... 19

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Authors

The following member company participants are acknowledged for their efforts and contributions in the production of this document:

AstraZeneca

Jennifer Anderson Rick Lu

Merck & Co., Inc., Kenilworth, NJ, USA

Scott Hooper

Novo Nordisk
Biogen

Cassandra Braxton
Corinna Cavan Pedersen Maria Rathmann Sørensen

  • Chugai Pharma Manufacturing Co., Ltd
  • Pall Biotech

  • Kunihiro Kamata
  • Morven McAlister

Fujifilm Diosynth Biotechnologies

Roche

Williams Nkrumah
Sven Deutschmann Kevin McCarthy

Lonza

Eva Tur Garcia Rita Tommasi

Thermo Fisher Scientific

Michael Brewer

  • Merck
  • BioPhorum

Cristina Barbirato Audrey Chang
Bela Green

Contributor

The team would like to thank the following non-member contributor:

Bioprocessing Technology Institute, Agency for Science, Technology and Research

Andre Choo

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About BioPhorum

The BioPhorum Operations Group’s (BioPhorum’s) mission is to create environments where the global biopharmaceutical industry can collaborate and

accelerate its rate of progress, for the benefit of all.

Since its inception in 2004, BioPhorum has become the open and trusted environment where senior leaders of the biopharmaceutical industry come together to openly share and discuss the emerging trends and challenges facing their industry.

Growing from an end-user group in 2008, BioPhorum now comprises 53 manufacturers and suppliers deploying their top 2,800 leaders and subject matter experts to work in seven focused Phorums, articulating the industry’s

technology roadmap, defining the supply partner practices of the future, and developing and adopting best practices in drug substance, fill finish, process

development and manufacturing IT. In each of these Phorums, BioPhorum facilitators bring leaders together to create future visions, mobilize teams of experts on the opportunities, create partnerships that enable change and provide the quickest route to implementation, so that the industry shares, learns and builds the best solutions together.

BioPhorum Technology Roadmapping

BioPhorum Technology Roadmapping establishes a dynamic and evolving collaborative technology

management process to accelerate innovation by engaging and aligning industry stakeholders to define future needs, difficult challenges and potential solutions. The Phorum involves biomanufacturers,

supply partners, academia, regional innovation hubs and agencies, serving to communicate the roadmap broadly while monitoring industry progress.

The project through which this paper has been developed is part of a broad portfolio of collaborative

technology implementation projects, mobilized to impact the most critical challenges identified by the first edition of BioPhorum’s BioManufacturing Technology Roadmap https://www.biophorum.com/

phorum/technology-roadmapping/trm-projects-2. This paper is an example of how the Phorum is continuing to deliver tangible results on its mission to accelerate industry innovation.

For more information on the Technology Roadmapping mission and membership, please see

https://www.biophorum.com/phorum/technology-roadmapping/overview/

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1.0

Executive summary

The need for absence of adventitious agents (fungi, viruses, bacteria, including mycoplasma) is inherent to every pharmaceutical manufacturing process, but is of critical concern to the biopharmaceutical industry, where a contamination event can arise from a contaminated cell line, raw materials, cell substrates, equipment, facilities or operators. Biological therapeutics must be demonstrated to be devoid of adventitious agents. This is enforced through extensive selection and testing of cell lines and raw materials, incorporation of dedicated manufacturing steps to remove or inactivate any

adventitious agents, and in-process and final product testing.

The expectations for assurance of microbial safety are clearly stated by global or regional regulatory guidelines and the United States, European and Japanese Pharmacopeias. However, many of these mandatory methods have remained unchanged

for decades and most, if not all, are performed off-line. In the first edition of BioPhorum’s

Biomanufacturing Technology Roadmap it was recognized that in/on/at-line monitoring of biopharmaceutical processes, along with real-time release of the product, are critical to the success of future bioprocessing applications. Therefore, this white paper has been written to address the key factors preventing implementation of alternative rapid microbiology methods (RMM) to assure sterility and absence of adventitious agents, and move the industry from a product release time of weeks towards real-time release.

A focused survey was completed by representative biopharmaceutical end-users, covering a range of job functions. This revealed that the biggest hurdles to adoption of new rapid

methods were regulatory acceptance of these alternative methods, filing a regulatory

change control and the time taken to validate a non-compendial method. Further, there was a consensus that provision of a guidance document that enabled sharing of best validation practices within the industry and included regulatory involvement, would have the greatest impact on widespread industry adoption of new methods.

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Adoption of new technologies to detect adventitious agents for already approved biopharmaceuticals may be viewed as a barrier to change due to the complexity of post-approval change processes and the need to obtain global regulatory acceptance. The additional barriers to change, even for a drug that has not received regulatory approval, are categorized as technical, cost, regulatory and behavioral concerns.

The former three categories also reflect what

should be considered as key attributes prior to implementation of new detection assays, and ways to mitigate these barriers are described. Any new assay should avoid excessive manipulation, not require excessive technical expertise or analysis, minimize the potential for false positive results and must be possible to validate, with the results being easy to interpret without subjective, analyst-based interpretation of the experimental results. Additionally, consideration must be given to the complexities of comparing methods that may have a different output or sensitivities. Ultimately, the objective must be to demonstrate

through appropriate scientific testing and rationale

that the intended method is not inferior to current compendial test methods. Further, the alternative method must enable an unequivocal decision to be made as to whether compliance with the standards

of the monographs would be achieved if the official

methods were used1. therapy medicinal products (ATMPs) or continuous bioprocessing applications), a standardized means of adopting alternative RMM and subsequently gaining regulatory acceptance for the adoption of such methods is clearly warranted. For ATMPs, it is obvious that there is no other solution. ATMPs may potentially have small batch sizes, short shelf lives and/or be produced in a non-current good manufacturing practice (cGMP) facility. In addition,

the benefits of continuous bioprocessing can only

be realized if the current time required to test for adventitious agents can be reduced. In the survey, regulatory acceptance was cited as the main reason for impeding implementation of new methods for the detection of adventitious agents. Meanwhile, the regulatory agencies have encouraged adoption of new technologies to facilitate bioprocessing and the channels that can be used to support end-users are described within this document.

Ultimately, it appears that, for the biopharmaceutical industry to achieve broad adoption of new technologies for the rapid detection of bacteria, fungi and viruses, the barrier does not lie with technical solutions. Rather, to overcome the regulatory

hurdles, whether perceived or real, it would benefit

regulatory and industry stakeholders to align on a potential validation strategy that could cross different product types and production sites, such that a single consolidated validation package is possible. The outcome of this white paper will set forth the foundation for this next step.
However, to facilitate resolution of current drug shortages or to assure patient safety for rapidly

emerging fields in biotechnology (such as advanced

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2.0

Introduction

Biological therapeutics used for the prevention and treatment of human disease may be produced from a variety of cells of eukaryotic or prokaryotic origin, including human, non-human mammalian (e.g. hamster), avian, insect, fungi, yeast and bacteria². Adventitious agent safety is a

The ICH Q5A guideline serves as the primary regulatory guideline for viral safety in biologic manufacturing processes based on animal and human cell cultures. The safety assurance is achieved through the application of a robust and effective virus testing program, which adopts a three-tiered approach8:

major concern during the manufacturing of biopharmaceuticals. In the Guidance for Industry

Characterization and Qualification of Cell Substrates

and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications,

the FDA defines an ‘adventitious agent’ as:

“A microorganism (including bacteria, fungi, mycoplasma/spiroplasma, mycobacteria, rickettsia, viruses, protozoa, parasites, transmissible spongiform encephalopathy (TSE) agent) that is inadvertently introduced into the production of a biological product.”

•••

Selecting and testing of cell lines and other raw materials

Assessing capacity for viral clearance and inactivation by a manufacturing process

In-process and/or final product virus testing.

A viral safety test panel for contaminants in biologics currently includes electron microscopy (EM), assays for retroviruses, and detection of virus in cell culture and animal host systems. In vitro virus detection has been accomplished using multiple cell lines to which the sample is applied and subsequently observed for cytopathic effect (CPE), hemagglutination (HA) or hemadsorption (HAD) during the 14–28 days of incubation. In vivo assays involve

inoculation of specific animal species and subsequent

observation for mortality, and the testing of tissue for the presence of hemagglutinins. These assays have been considered necessary to detect new or emerging viruses and to complement narrowly focused virus-

specific assays such as polymerase chain reaction (PCR)

that came into routine use later (e.g. Rodent Parvovirus, MMV or Calicivirus 2117 detection). The use of multiple and distinct cell lines and animal hosts stems from the knowledge that viruses can have a limited host range (i.e. infect certain species but not others), or exhibit tropisms

for specific cell types or tissues (e.g. proliferate in kidney epithelial cells but not in fibroblasts). Certain host systems

may be more permissive for virus replication and therefore more likely to show CPE in vitro or mortality in vivo. Animal

hosts were included to detect agents that are difficult to

propagate in vitro, or are non-cytopathic or cause immunemediated disease (e.g. Lymphocytic Choriomeningitis Virus (LCMV))9.
An adventitious agent contamination event can arise from a contaminated cell line source or during production (e.g. cell substrates, raw materials, equipment, facilities and/ or operators). Although contamination of bioreactors and biologic therapeutics is rare, several manufacturers have reported such incidents in biotechnology manufacturing

processes or final products in the past decades, and the

consequences can be catastrophic3, 4. This paper will focus on adventitious agent detection with special attention to virus and bacteria (including mycoplasma) agents that are of concern in all biological manufacturing bioprocesses.

Several examples of bioprocess contamination by adventitious agents have been documented over

the years, implicating Bacillus cereus, Paenibacillus

curdlanolyticus, Leptospira licerasiae, Mouse Minute Virus

(MMV), Epizootic Hemorrhagic Disease Virus (EHDV), Reovirus 2 (REO-2), Cache Valley Virus (CVV), and Calicivirus 21175, 6, 7. Therefore, regulatory agencies worldwide mandate testing for adventitious agents in each lot/batch of material in adherence with cGMP.

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Similarly, there are mandatory quality control (QC) methods that must be incorporated to assure the

cell banks, cell cultures, cell culture harvest and final

product is devoid of bacteria (including mycoplasma).

The methods for determination of sterility of the final

product are described in United States Pharmacopeia (USP) <71> and European Pharmacopoeia (Ph. Eur.) 2.6.1, while testing for mycoplasma in cell banks, cell cultures and harvests is reported in USP <63> and Ph. Eur. 2.6.7. These are based on conventional growthbased techniques (with the exception of the indicator cell-based mycoplasma detection method10, 11, 12). Both the sterility and mycoplasma methods are described in detail in section 3 (Current practices) of this paper. These methods assume that any contaminating microorganisms

are able to grow under the test conditions specified, with

the incubation period ranging from 14 days for sterility testing to 28 days for mycoplasma testing. It is noted that both the USP and Ph. Eur. now include provisions for the
Therefore, this paper has been written to summarize the following key areas for consideration by the end-user for adoption of new methods:

1. Key barriers to implementing alternative RMM in the biopharmaceutical industry

To gauge industry opinion, participants from 11 biomanufacturing organizations (representing quality assurance (QA), QC, manufacturing and process development) completed a focused survey to understand current practices used for adventitious agent and sterility testing, as well as identify the roadblocks to implementation.

The key barriers identified from the survey can be broadly classified into four main categories:

technical, cost, regulatory and behavioral. The

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  • Religion's Evolutionary Landscape

    Religion's Evolutionary Landscape

    BEHAVIORAL AND BRAIN SCIENCES (2004) 27, 713–770 Printed in the United States of America Religion’s evolutionary landscape: Counterintuition, commitment, compassion, communion Scott Atran CNRS–Institut Jean Nicod, 75007 Paris, France; and Institute for Social Research–University of Michigan, Ann Arbor, MI 48106-1248 [email protected] http://www.institutnicod.org Ara Norenzayan Department of Psychology, University of British Columbia, Vancouver, British Columbia V6T 1Z4 Canada [email protected] www.psych.ubc.ca/~ara Abstract: Religion is not an evolutionary adaptation per se, but a recurring cultural by-product of the complex evolutionary landscape that sets cognitive, emotional, and material conditions for ordinary human interactions. Religion exploits only ordinary cognitive processes to passionately display costly devotion to counterintuitive worlds governed by supernatural agents. The conceptual founda- tions of religion are intuitively given by task-specific panhuman cognitive domains, including folkmechanics, folkbiology, and folkpsy- chology. Core religious beliefs minimally violate ordinary notions about how the world is, with all of its inescapable problems, thus en- abling people to imagine minimally impossible supernatural worlds that solve existential problems, including death and deception. Here the focus is on folkpsychology and agency. A key feature of the supernatural agent concepts common to all religions is the triggering of an “Innate Releasing Mechanism,” or “agency detector,” whose proper (naturally selected) domain encompasses animate objects rele- vant to hominid survival – such as predators, protectors, and prey – but which actually extends to moving dots on computer screens, voices in wind, and faces on clouds. Folkpsychology also crucially involves metarepresentation, which makes deception possible and threatens any social order.
  • A Psycho-Historical Theory of the Identification of Living and Social

    A Psycho-Historical Theory of the Identification of Living and Social

    Biol Philos (2015) 30:359–382 DOI 10.1007/s10539-014-9447-x Agent tracking: a psycho-historical theory of the identification of living and social agents Nicolas J. Bullot Received: 26 June 2013 / Accepted: 16 April 2014 / Published online: 29 April 2014 Ó The Author(s) 2014. This article is published with open access at Springerlink.com Abstract To explain agent-identification behaviours, universalist theories in the biological and cognitive sciences have posited mental mechanisms thought to be universal to all humans, such as agent detection and face recognition mechanisms. These universalist theories have paid little attention to how particular sociocultural or historical contexts interact with the psychobiological processes of agent-identi- fication. In contrast to universalist theories, contextualist theories appeal to partic- ular historical and sociocultural contexts for explaining agent-identification. Contextualist theories tend to adopt idiographic methods aimed at recording the heterogeneity of human behaviours across history, space, and cultures. Defenders of the universalist approach tend to criticise idiographic methods because such methods can lead to relativism or may lack generality. To overcome explanatory limitations of proposals that adopt either universalist or contextualist approaches in isolation, I propose a philosophical model that integrates contributions from both traditions: the psycho-historical theory of agent-identification. This theory investi- gates how the tracking processes that humans use for identifying agents interact with the unique socio-historical contexts that support agent-identification practices. In integrating hypotheses about the history of agents with psychological and epis- temological principles regarding agent-identification, the theory can generate novel hypotheses regarding the distinction between recognition-based, heuristic-based, and explanation-based agent-identification.