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08:20 - 08:30 10 mins
Chairperson's Opening Remarks
08:30 - 09:30 60 mins
Ask the Regulators – Regulatory Breakfast Briefing
  • Arifa Khan - Senior Investigator, FDA/CBER (awaiting final confirmation)
  • Albert Stühler - Deputy Head, Virus Safety, Paul-Ehrlich-Institut

In this hour-long session, delegates will be given the opportunity to pre-submit questions which will then be posed to the regulators and key leaders in the industry. Topics covered historically include:

  • Strategies and considerations for viral safety and raw materials
  • ATMP considerations
  • Cell bank testing and in vitro vs. in vivo assays
  • European clinical trials guidelines and requirements for IMPs from human blood origin
  • Viral safety requirements and orphan drug status
  • Risk assessment and viral safety retroviral safety margin according to ICH Q5A
  • Viral clearance studies and quality standards
  • NGS
09:30 - 10:00 30 mins
Important considerations in successful viral clearance studies
  • Sebastian B. Teitz - Product Manager, Asahi Kasei Bioprocess
10:00 - 10:45 45 mins
Morning Coffee and Poster Tour 1 (3 Posters - 30 Minutes)
10:45 - 11:15 30 mins
Lessons from the CAACB on the Prevention and Control of Adventitious Agent Contamination
  • Paul W. Barone - Director, BioMAN and CAACB, MIT Centre for Biomedical Innovation, USA

Adventitious agent contamination of cell culture-based biomanufacturing operations for the production of protein and monoclonal antibody biotherapeutics are infrequent, but when they do occur, they are very costly, impact manufacturing operations, and can potentially impact patient safety and product supply. To support the biopharmaceutical manufacturing industry the Consortium on Adventitious Agent Contamination (CAACB) at MIT have conducted a number of projects with the goal of identifying best practices in the control and prevention of adventitious agent contamination. These projects include collecting data on industry wide viral contamination experience, collecting data on the effectiveness of media treatment technologies, and identification of industry wide facility segregation approach. This presentation will highlight the key lessons that the CAACB has learned from its current activities.

11:15 - 11:45 30 mins
Harmonization of viral segregation strategy for manufacturing network with multiple facility designs and production scales
  • Bonnie Shum - Engineer II, Global Biologics Manufacturing Sciences and Technology (MSAT), Genentech, a member of the Roche Group

Virus contamination of biologics may arise from contaminated raw materials as well as cross contamination of product intermediates, and risk mitigation such as appropriate viral segregation at manufacturing facilities is essential.  With complex manufacturing networks that consist of multiple facility configurations and production scales, a harmonized viral segregation strategy that accounts for these differences is required to support network flexibility. Pre- and post-viral steps can be challenging to define as viral clearance is a continuum throughout the purification process and reliant on multiple process steps. Given diversity in facility designs and differences in the process step order and viral clearance claims, the development of a network strategy should focus on operational controls, procedural controls, and the demonstration of viral inactivation of cleaning and sanitization.  The presentation will focus on the development of the network-aligned viral segregation strategy at Roche/Genentech to defend viral segregation by the incorporation of regulatory requirements, feedback from across the manufacturing network, and risk-based touch-point analysis.

11:45 - 12:15 30 mins
Late stage viral clearance studies (BLA): study design and experiences made
  • Thomas Preuss - Study Director, Viral Safety Studies, Charles River Biopharmaceutical Services GmbH, Germany

For viral clearance studies for the BLA process the guideline ICHQ5A is obligatory. In contrast to early stage studies the robustness of viral clearance must be demonstrated by different factors, e.g. by adding additional viruses, showing virus distribution, analyzing the impact of aged resin. The presentation will focus on how these requirements are optimized with the viral clearance study design for worldwide acceptance. Analysis of aged resin material, carry over experiments and virus filter performance will be addressed but also untypical results in several most recently performed BLA studies are being presented.

12:15 - 13:30 75 mins
Lunch in the Exhibition Hall and Live Labs
13:30 - 14:00 30 mins
Approach to pre- and post-viral filtration room segregation
  • Serge Monpoeho - Director of Virology, Regeneron Pharmaceuticals

Regeneron has been cited for a lack of physical barrier between pre- and post-viral clearance activities. In response to this regulatory observation, we committed to implementing improvements to further reduce any potential residual risk:

  • Closed System: A functionally closed system for the addition of post viral step in-process solution
  • Temporal Segregation: A dedicated time sequence for assembly of equipment pre- and post-viral activities
  • Process and Personnel Segregation: A dedicated personnel flow path to restrict operators to specific operations to enhance process segregation
  • Material Segregation: The use of dedicated parts for pre- and post-viral clearance operations to further enhance process segregation
  • Environment Segregation: Dedicate specific drains for pre- and post-viral clearance activities
  • Physical Segregation: Due to space constraint, plant retrofitting was not feasible in this particular suite. However, new plant design includes physical segregation of pre- and post-viral clearance activities in downstream.
14:00 - 14:30 30 mins
Alternative Approaches to Viral Segregation in Facility Design and Operation
  • Kavita Ramalingam Iyer - Associate Director, Merck Sharp & Dohme

Viral safety is a key quality in biopharmaceuticals manufacturing. Sufficient virus clearance usually rests on the cumulative effect from different purification steps. A cumulative effect can only be obtained provided that segregation control measures are in place.

Viral segregation control measures implemented by industry often do not commensurate with the associated risk they seek to mitigate. Consequentially this may lead to complex facility design with disproportionate control measures. In addition to impacting speed of valuable medicines to patients, the approach has detrimental impact on capital and operating costs as well as making facilities less flexible and adaptable – counter to the direction the industry needs to take. Factors to this scenario include influence of historical internal practices, company procedures and guidance, perceived risk of regulatory approval and sub optimal health agency guidance documents. There is consensus within industry and health agency that where technology has improved with regards to protecting the product from contamination, regulations control measures have not moved in step.

Following the principles of Risk Management approaches as espoused in EU GMP Annex 2 and ICH guidance, the BPOG Closed systems team proposes methods to facility segregation that are alternative to conventionally applied methods of physical barriers and engineering controls (e.g. walls and dedicated AHU’s).  These alternative methods include use of closed systems along with procedural and temporal controls, as determined by the risk assessment of the process. The acceptability of these methods will be demonstrated via case studies.

The presentation will also elaborate on how these measures can lead to an expansion of interpretation and application of the current health agency regulations pertaining to Viral Safety.  Consequently, this would bring them inline with current technological advancements and understanding.

The benefit of this approach is a risk based method that allows organisations to simplify future facility design, ensuring high quality product enters the market in a timely manner and upholding patient safety.

Key Objectives

  • Share Risk based approaches aligned with regulatory guidance, and their use for a rational, simplified facility design
  • Identification of key areas for implementing contamination prevention measures
  • Discuss use of system closure as a means for viral segregation purposes, reducing footprint and complexity compared with traditional approaches such as physical separation by walls.
14:30 - 15:00 30 mins
Characteristics of virus assay systems for viral clearance studies: the use of PCR and / or infectivity methods
  • Maria Farcet - Manager, Global Pathogen Safety, Shire, Austria
  • Regulatory requirements/expectations – infectivity may be preferred, but PCR sometimes necessary
  • Virus models with low/no infectivity, or complex infectivity assays (e.g. HEV, B19V)
  • Combined mode of virus reduction: Ab-mediated NF enhancement, removal and inactivation during column chromatography
  • Points to consider with PCR
  • Virus stock preparations: nucleic acid content, infectivity vs. PCR titres
  • Method design: what is / is not detected?
  • Multi-spiked study runs: a possibility?
15:00 - 15:30 30 mins
Considerations for biosafety testing of viral vectors and vaccines
  • Richard Adair - Virology and Technical Support Manager, SGS Virology
15:30 - 16:15 45 mins
Afternoon Coffee and Poster Tour Two (3 x Posters 30 Mins)
16:15 - 16:45 30 mins
Continuous low pH viral inactivation for mAb production processes
  • Laura David - Research Associate, Bayer/INVITE GmbH, Germany

As continuous processing using disposable equipment is gaining more and more importance, the application of continuous viral clearance within this new process environment needs to be evaluated. Continuous low pH viral inactivation was developed and implemented into the MoBiDiK PRO demonstration plant. In order to transfer the defined and tight residence time distribution from batch to continuous processing, the coiled flow inverter (CFI) was implemented. It allows robust operation while using disposable equipment in a compact design. Current achievements and future challenges will be discussed.

16:45 - 17:15 30 mins
Regulatory overview: Perspectives and outlooks
  • Drive in industry to move from batch to continuous manufacturing
  • Viral safety considerations and the opinion of the regulators on this
  • How should viral testing and clearance/inactivation technologies be applied in a continuous setting?
  • How and when should continuous culture be tested for adventitious agents when it runs for longer periods of time than batch cultures?
  • How should commonly utilized viral clearance unit operations, such as low pH viral inactivation or viral filtration, be incorporated into CP operations to ensure viral clearance according to guidance (ICH, 1999, 2005)?
  • How should a representative scale model be designed and implemented for viral clearance/inactivation spiking studies with the increased productivity and product load that CP operations entail?
17:15 - 17:20 5 mins
End of BPI 2018