Trends, challenges and priorities

As 2021 draws to a close, BioPhorum Drug Substance  members have been challenging their thinking to ensure the program remains focused on priorities for the industry that can only be solved by the collective attention of the members. From this work, the following trends are prominent:

Speed to market

Speed to market remains a strategic priority for the industry. One of the key lessons learned from the Covid-19 pandemic has been that it is possible to accelerate development, technology transfer and commercialisation to enable new medicines to reach patients faster. This can only be achieved by making trade-offs between speed and efficiency in the development process, and hence requires the industry to increase the rate of improvement post-launch and enhance the ability to solve operational issues as they arise.

Faster adaptability of lifecycle management:

A recent survey of BioPhorum Drug Substance members identified the need for better internal connections to facilitate improvements between R&D, Operations and Regulatory Affairs. By exploring the extent to which the adaptability of the product lifecycle management process is impacting improvement across the industry, the following typical challenges were highlighted:

  • Product life cycle management (from discovery to post patent loss – market withdrawal or transfer to third party) is not working effectively.
  • The resource requirements for filing maintenance detracts too much from continuing product/process development improvement.
  • The factors (including regulatory constraints and variable regulatory requirements) that are limiting our rate of improvement have not been collectively identified and characterized.
  • Further work is required to explore opportunities in both the short and longer term to increase improvement in the rates of innovation, process simplification and problem solving to address these challenges.

Growing emergent markets:

Another significant trend is growth in emerging markets, such as China, with an associated expansion in manufacturing capability and regulatory interaction. As a consequence, taking a strategic perspective on second sourcing of raw materials will become critical to enable future innovation and maintain security of supply. The Raw Materials workstream within Drug Substance has recognized this challenge by publishing an industry proposal for a simplified registration process of complex and innovative raw materials in Europe and is developing technical pilots in order to enable our members to take an industry-leading position on managing this trend.

Security of supply

One of the ongoing consequences of the pandemic is the continued disruption to the supply chain. This is resulting in component shortages and is associated with the risk of interruptions in the supply of medicines for patients. Solutions range from short term actions to mitigate risk and maintain agility to longer term initiatives to harmonize the design of components and take a proactive approach with regulators to enable acceleration of post approval change controls.

Drug Substance deliverables 2021

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Milestones

Closed Systems

This team’s main focus is to develop the closed systems playbook, a transformational document for the industry that will provide guidance on how to fully embrace closed systems and make the paradigm shift to building facilities that utilize Controlled Not Classified (CNC) environments. Implementation of closed systems in a CNC environment has significant savings in terms of capital and operational costs of new facilities, and reduced lead times to build them, while reducing regulatory risk. It is anticipated that this will be delivered by the end of the year.

The team continues to look at the closed systems aspects of viral segregation, with the focus on what will it take to realise future facility design and can we truly operate a ballroom facility. Quantitative and Qualitative risk assessment approaches will be utilised.

The team is developing a guidance of how key concepts within the new draft of Annex One can be successfully implemented within low bioburden drug substance facilities. The focus is initially closed systems, however the project may expand to a working group across all drug substance workstreams.

Lastly, the team is considering creating a new sub-team to focus on closure validation, a key aspect of utilizing closed systems in CNC.

Mult-Product Facility

This team is developing a risk assessment to understand the steps required to reuse Protein A resin in clinical manufacturing. The team have also formed a collaboration with a research team in The Science Foundation Ireland Research Centre for Pharmaceuticals  who are developing a lab based study program on Protein A resin reuse.

Making and Moving Operational Cell Banks

Moving the site of manufacture for commercial cell banks (microbial or mammalian), renewing working cell banks for commercial products, or making minor changes to cell banking processes are becoming more onerous from a regulatory perspective, and do not have a consistent harmonized approach even within a single regulatory body.

This workstream is producing a paper to make suggestions to regulatory authorities and propose minimum filing requirements with the following features:

  • One clear and consistent approach, based around a number of change scenarios to establish an industry-harmonized, science-based approach to the safe management of making and moving operational cell banks for commercial products
  • Application of scientific-based criteria to the characterization and comparability approach for changes to cell banks. The relative risk for a product should determine the amount of data that is reasonable for comparability.

SUS Joint Leadership Team (Value Realization Program)

The SUS Joint Leadership Team is accountable for the realization of value from the Single-Use Systems (SUS) Workstream’s deliverables. In partnership with BioPhorum Supply Partner, a rolling five-year plan will be developed focusing on mitigation of inbound supply chain risks through improved forecasting and demand planning, standardization of testing and design of SUS components, and the evaluation of alternative sterilization techniques. Additions to the SUS program will be included to reflect the issues and priorities of member companies.

Storage and Transport

The workstream is developing the content and principles for its best practice guide on the use of stability data to minimize temperature excursions during shipping. By following this guidance, many companies will significantly reduce the number of unnecessary temperature excursions they have to raise during shipping. This will have significant benefits in reducing the time and costs associated with the churn of non-value-added investigations and reduced regulatory scrutiny. There are also associated gains to be made by not over-engineering thermal protection systems.

A high-level roadmap is also being developed for ‘end-to-end temperature control management best practice’. This is a framework for industry that explains all the ‘pillars’ needed for temperature control management.

The impact of the pandemic has limited the ability of the team to progress these as we had wished, however progress does continue forward.

Post Approval Strategy

The workstream has continued with its national and regional model of activities.

In 2021, the Brazil sub-team concluded its activities with the definition of the impact of the changes to the regulations on post-approval changes and stability requirements on internal processes so that full value is realized across our member organizations.

The Colombia sub-team through its relationships with the medicines agency (INVIMA) and local industry groups (AFIDRO and ANDI ) has contributed to the decision from INVIMA to revise their post-approval change regulation, which will in the same a-way as it did to Brazil, save years to the implementation of post-approval changes in one of the other big markets in South America.

During 2021, the Russia sub-team revised the paper on the implementation of the Russian Pharmacopeia, so that it fits more with the change in the regulatory environment of the region. It has also continued to share knowledge and experience of the new EAEU (Eurasian Economic Union) regulatory framework. Key learnings will be captured in a poster that can be shared internally in our member organizations to ensure that their learnings are available to all.

The China sub-team after its review of the 45 new regulations last year, is sharing insights and best practices for their implementation. Key learnings will be captured in a poster that can be shared internally in our member organizations to ensure that their learnings are available to all.

The South Korea team shared with the rest of industry and regulatory agencies the challenges associated with post-approval changes in the country and the region, through a presentation at the PDA Asia Pac conference in Oct 2021.

A new team was created in 2021 to promote the implementation of ICH Q12 and Post-Approval Change Management Protocols in the LATAM countries. The team is in ideation phase.

Raw Materials Program

.The Raw Materials Program is charged with bringing raw materials under control with a view to:

  • Driving predictable raw material performance
  • Optimizing the raw material testing regime to reduce duplication and speed to raw material release.
  • Enhancing raw material flexibility to support dual sourcing.

To this end manufacturers and suppliers are working to define a five-year plan and jointly leading a series of workstreams and initiatives to tackle immediate challenges including Media Fingerprinting and Raw Material Equivalence.

Media Fingerprinting – the team will be writing best practice guidance to achieve a simpler, more accurate ID testing for media and other non-compendial materials making it easier to qualify across suppliers
Nitrosamines – the team plans to publish lessons learnt from live benchmarking discussions considering the implications of the recent FDA and EMEA guidelines and plans for implementation
Raw Materials Change Notification – the team are finishing a guidance paper which identifies the relevant change areas, for raw materials and the type of changes which the biopharmaceutical industry needs to be informed about. It will include the required information, in terms of supporting data and documentation, to support notification of changes.
Raw Material Equivalence – the team is working in conjunction with the Regulatory Governance team to develop an industry proposal for the registration of raw materials. The proposal will be tested against viral filters

Human Performance Community of Practice

Applying the power of human performance documentation for successful outcomes

  • Do your colleagues struggle with a never-ending cycle of document revisions while, with every document update, the rate of process deviations stays steady?
  • Does your organization use a ‘one-size-fits-all’ approach to document design where training relies on reading and understanding text to meet a compliance requirement?
  • Do you know what training method works for operators, so they perform the process competently while keeping deviations to a minimum?

This paper reimagines how documents are to be used in the biopharmaceutical industry. Instead of a reactive approach to audit findings and deviations with frequent SOP updates that can result in many longwinded documents and past-due training, we describe how documents should be written and designed based on how they are to be used, and that different documents serve different purposes when training and working. This paper is in the final draft stages and should be published in Q4 2021

Microbial Control

LER

The low recovery of endotoxin in undiluted drug products and in-process samples has been a topic of great concern with the FDA. The paper compares recovery of different endotoxins sourced from reference standard endotoxin (RSE) and control standard endotoxin (CSE) which use purified lipopolysaccharide, as well as naturally occurring endotoxins (NOE). By assessing spiked sample recoveries for endotoxin masking using various vendor reagents in sample buffer preparations, this study was designed to evaluate the “classic” excipient buffer combinations that are known to affect the endotoxin recovery with the traditional USP LAL reagents. Another factor in this study was to evaluate how NOEs sourced/prepared from different microorganism species and if the growth preparation method in a high or low nutrient affects the endotoxin recovery of NOEs.

Design Harmonization

The workstream is in the very early stages of developing an industry best practice guide to creating a single design authority for single-use systems and technologies. It is planned to be published during 2022.
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