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

RAPID DETECTION OF BACTERIA AND VIRUSES IN BIOPROCESS SAMPLES: JUSTIFICATION, REGULATION, REQUIREMENTS AND TECHNOLOGIES — HOW CAN INDUSTRY ACHIEVE BROAD ADOPTION? CONNECT COLLABORATE ACCELERATETM 1Contents 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 <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 2List 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 <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 3Authors 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 <ul style="display: flex;"><li style="flex:1">Chugai Pharma Manufacturing Co., Ltd </li><li style="flex:1">Pall Biotech </li></ul><ul style="display: flex;"><li style="flex:1">Kunihiro Kamata </li><li style="flex:1">Morven McAlister </li></ul>Fujifilm Diosynth Biotechnologies Roche Williams Nkrumah Sven Deutschmann Kevin McCarthy Lonza Eva Tur Garcia Rita Tommasi Thermo Fisher Scientific Michael Brewer <ul style="display: flex;"><li style="flex:1">Merck </li><li style="flex:1">BioPhorum </li></ul>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 <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 4About 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 <a href="/goto?url=https://www.biophorum.com/phorum/technology-roadmapping/trm-projects-2" target="_blank">https://www.biophorum.com/ </a><a href="/goto?url=https://www.biophorum.com/phorum/technology-roadmapping/trm-projects-2" target="_blank">phorum/technology-roadmapping/trm-projects-2</a>. 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 <a href="/goto?url=https://www.biophorum.com/phorum/technology-roadmapping/overview/ " target="_blank">https://www.biophorum.com/phorum/technology-roadmapping/overview/ </a><ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 51.0 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. <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 6Adoption 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 <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 72.0 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. <ul style="display: flex;"><li style="flex:1">©BioPhorum Operations Group Ltd </li><li style="flex:1">|</li><li style="flex:1">October 2019 </li></ul>Rapid detection of bacteria and viruses 8Similarly, 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

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

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