Trends, challenges and priorities

The ever-increasing need to reduce product development lead times and the opportunities to exploit new technologies in development are two key industry themes that have come to the fore in the last year.

Speed to clinic

We have taken a long, hard look at the portfolio of work, and sponsors have had the time to reflect on where their companies are most engaged. The team has moved forward with the expressed interest in exploring industry perspectives on ‘Speed to clinic’, alternatively known as ‘Speed to first in freezer’ and to evaluate any learnings that may be taken from the Covid-19 pandemic experience. Many of the Phorum’s members, representatives and sponsors have been hit hard by an unprecedented amount of work, juggling priorities, and even pausing certain programs. They are now interested in sharing their experiences and seeing what may be taken forward as part of routine development activities, something that could yield positive industry wide benefits. The group created a charter that drives this pathfinder workstream, and this will grow and evolve as the work develops. They also developed a significant benchmarking survey that was recently released to members. The survey will provide the world’s first industry wide data on what biopharmaceutical organizations have done and are doing regarding process and product development around therapeutic proteins with wide ranging content across various technical areas. The team is also looking at a more holistic perspective of development by evaluating any negative impact accelerative actions have had on downstream events.  Given the Covid-19 pandemic is far from over and members are at different stages of this journey, the team will reassess members experiences on these potential factors through pulse surveys throughout the upcoming 12—18 months to ensure learnings across the whole membership are continually captured and may be capitalized on.

biophorum post images development group 191

The group has been invited to submit a journal paper and plan to use the opportunity to start the discourse of a potential new practice paradigm which is hoped will ultimately positively influence regulatory pathways. The overall message will emphasize that it is possible to make safe and efficacious products quicker than what is currently accepted, which will benefit everyone, including patients, the industry, and all associated stakeholders.

Accelerating CMC Development to Marketing Application

The industry faces an ongoing challenge to accelerate development timelines – to do the same work (and sometimes more) in less time but this can have knock-on effects. To address this, the group has been looking at the principles applied to ‘accelerated development’ that are increasingly merging with regular development pathways (compounded by the Covid-19 situation). Increased sponsor engagement is being seen at a technical level within the Accelerate CMC Development to Marketing Application workstream. This will fertilize thinking and may create an aligned package of work across many of the technical and tactical workstreams within BioPhorum’s Development Group’s program, such as viral clearance, process-related impurities (currently included within the scope of the Host Cell Proteins workstream) and Cell Line Development. This could lead to more sponsors attending and more coordinated work packages linked to the other workstreams emerging from the Accelerated Development workstream program. The teams are currently assessing how this could work alongside the Speed to Clinic / Speed to First in Freezer pathfinder workstream.

The team currently has two key focus areas: (i) Specifications setting and (ii) Control Strategy with Prior Knowledge. Regarding the former, the team is extracting key messages from a survey conducted (in partnership with regulatory experts) to review specification setting strategies (and health authority feedback) for accelerated assets. The goal is to prepare a boundary pushing position paper that describes the current state and challenges regarding specifications setting and poses recommendations for the future – advocating specification development strategies for accelerated programs. Additionally, the team is creating a control strategy template. The initial aim of which is to provide an industry wide ‘platform’ control strategy to help development teams identify the most critical process parameters for both upstream and downstream unit operations. It will also provide clear justifications based on broad experience for CMC decisions on parameters that can be characterized, as well as controlled with a low risk of impact on process performance or product quality.

In-Silico Strategies

Coming to the combination of speed and technology, one emerging topic from members is In-silico Strategies. This creates computer models that can be used to predict or replace experiments (using machine learning, AI, etc.) and helps scientists to design more efficient studies using previous knowledge, such as an understanding of the biological effect of molecules in the body. This promises the exciting prospect of performing fewer physical experiments, and saving money while increasing the focus, speed, and efficiency of development. The team need to determine out how to collaborate effectively whilst navigating the challenges of intellectual property and is a nascent topic for the industry.

Host Cell Proteins – increased scope

Process-related impurities is of enormous interest to sponsors and we have been looking to see how this mission could fit into the existing program. Host Cell Proteins has been identified as the best fit – we have expanded the workstream and developed a process for including discussions on this topic without disrupting its current plan of work. Through 2021 the HCP team have published an incredibly useful paper on high-risk host cell proteins along with a data base which is available on the BioPhorum website. The team are so active in the area of HCPs that the sponsor community are now considering if the process related impurities topic is deserving of its own dedicated workstream.

Engagement and collaboration

In 2020 and 2021, several workstreams changed their names; the HCP Workstream renamed itself Host Cell Proteins and other Bio-residual Impurities, the CMC Considerations for Expedited Development Program became Accelerate CMC Development to Marketing Application, and Formulation reflects the scope better as Formulation and Drug Product Development. This deeper engagement of sponsors on accelerated development mirrors their increasing involvement with the program on industry priorities and how clarity within the program is constantly being revisited, bringing together highly complex topics into a ‘bigger picture objective’. The member company sponsors have always managed the program in a practical and considered way, ensuring commitment remains robust, but the latest review is bringing forward fascinating new missions and a spectacular increase in engagement and quality of work. A survey of workstream members has demonstrated that the work the teams have been doing has gone into supporting several company BLA applications (biologics license application), including one company’s first successful application in ten years and another going from DNA to patient in just eight months. There are likely to be many more valuable examples such as this emerging in the forthcoming year.

The Phorum continues to have exceptional participation at virtual meetings, now seen as a ‘seeding ground’ for the various workstreams in terms of ideas, and a way of ‘super charging’ the team, its goals and objectives. These virtual meetings are encouraging higher numbers of participants to engage from member companies to promote even more questions and discussions.  The group is looking forward to broad engagement at BPDG33 ‘Accelerated Development: 2021 and beyond’ in November, which will take place over three days and include focused daily meetings on speed to clinic, accelerated development, and a sponsor’s only day for reflection on the previous day’s learnings and coordination of broader plans for the future.  This year recognizes the fertile ground for discussion in many of the topic areas identified and has seen a considerable growth in the number of members, participants, and sub-teams within the workstreams who are keen to collaborate and progress these deliverables. Looking forward, the challenge for the remainder of 2021 and into 2022 will be how best to support the engagement and enthusiasm in these exciting areas.

Development Group deliverables 2021

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Milestones

Viral Clearance

The workstream continues to track the adoption of recommendations from its ‘Retrospective evaluation of low-pH viral inactivation and viral filtration data from multiple company collaboration’ and ‘Retrospective valuation of cycled resin viral clearance studies – A multiple company collaboration’ papers. It does this via an annual survey to understand outcomes to drive future collaboration with regulators and influence potential future changes in testing standards.

During 2021/22, several additional topics are underway or planned. The team have completed a benchmarking survey on modular viral clearance for IND filings and are currently sharing and reviewing case studies to identify successful filing approaches.

AEX Subteam

The team are also working towards ‘A multicompany collaboration on AEX chromatography’ publication to support future modular claims. The team has also provided feedback into the ongoing ICH Q5a revision and a panel representative attended a workstream call to provide an update on the revision’s workplan and outline of topics.

Future topics include management of process changes and impact on viral clearance studies and Triton X100 alternatives. 2022 will see the team working with external partners to support the transition of industry best practice into global standards.

Formulation and Drug Product Development

Clinical in-use

A commentary entitled ‘An intercompany perspective on biopharmaceutical dose administration, compatibility and in-use stability studies’ has been accepted by J Pharm Sci. It was published online in October. This publication addresses regulatory strategy, clinical site and patient considerations including blinding, masking, placebo approaches, setup, execution, reporting, clinical and in-use stability testing. A presentation will be drafted based on this for a BioPhorum webinar in the first instance followed by external meetings in 2022.

High concentration formulation publication

A benchmarking survey on stability challenges with high-concentration formulations has been completed and the output from this will form the basis of a publication currently being drafted to provide an industrial perspective on prediction of viscosity and stability compared to practical experience of developing high concentration formulations.

The participants have continued to enjoy lively discussions on many live ‘Ask BioPhorum’ questions. These topics provide a quick check of current practice within the industry for in-the-moment challenges such as backfill pressure when adding diluent to lyophiles, inherent protein particle consideration for SC dosing, target fill volume filling machine variability etc.

CSTD

The CSTD (closed system transfer devices) sub-team publication was published as a commentary by Journal of Pharmaceutical Sciences  in February 2020. A presentation  based on the publication for use at external meetings has been prepared.

The Formulation workstream has re-chartered and subsequently been renamed as the Formulation and Drug Product Development workstream to better reflect its scope. New topics include: challenges of ultra high concentration formulation and delivery, process performance qualification (PPQ) perspectives for drug product formulation and experience of stage two validation, quality by design (QbD) principles in formulation development and formulation challenges experienced with new modalities based on therapeutic proteins.

The CSTD subteam met recently to discuss experiences from regulatory authorities on use of the BioPhorum published risk based approach. The team will consult with the BioPhorum CMC Regulatory workstream regarding compatibility approaches.

A benchmarking survey on the challenges of ultra high concentration formulation and delivery has been drafted and is under discussion within the workstream.

Novel surfactant collaboration

A live ‘Ask BioPhorum’ on evaluating novel surfactants to replace polysorbate sparked interest in working together with an excipient company to advance a novel surfactant. A subteam is working to define the scope and the criteria that a novel surfactant would need to fulfil. This will be presented to the sponsors for buy in to co-develop a novel surfactant.

Host Cell Protein and other Bio-Residual Process-Related Impurities

HCP – Clinical Risk Assessment

The Clinical Risk Assessment sub-team mobilized in late 2020. The purpose of the team is to develop a risk-assessment template which can be used to assess HCPs by the industry. The team has recruited toxicologists and immunologists to assist drafting the tool and provide the clinical perspective. A Literature review and a gap analysis of published tools is in progress.

HCP Characterization and Risk Assessment Process

A survey on this topic was produced in Jan 2021, however the review only commenced in Sep 2021 as other activities took precedence. The purpose of this survey is to gather preliminary information from across the biopharmaceutical industry on the characterization and risk assessment of HCP using mass spectrometry. The overall aim is to map the process companies use to identify and assess the safety risks presented by Host Cell Proteins.

Other bio-residual Impurities

The team expanded the focus of the group into other bio-residual impurities in mid-2020 but the main focus will remain on HCPs with a further paper on ‘HCP risk assessment’ planned for 2021. The main objective is to improve industry knowledge on the impacts of residual impurities with a view to understanding the risk associated during process development.

USP General Chapter <1132> Expert Panel Update

Industry expert and HCP participant Ying Zhang (Pfizer) presented an update on behalf of the USP Host Cell Protein Expert Panel (as presented at the recent Bioprocessing Summit) to the HCP workstream on ‘Best Practices for Identification and Quantitation of Host Cell Protein Impurities in Biological Products using Mass Spectrometry’ . The USP expert panel includes seven active HCP workstream participants and was established in March 2020. The purpose of this Expert Panel is to write a new general chapter on best practices for identification, characterization, and quantitation of Host Cell Protein (HCP) impurities in biological products using mass spectrometry (MS).

Cell Line Development

Cell line development challenges can negatively impact product supply, safety and manufacturability and lead to an increased cost of goods and extended project timelines. This workstream would like to generate and implement best practices and standards for understanding, monitoring, predicting, and controlling process variability to help member companies start to address these challenges.

The workstream have captured all the lessons learnt from the accelerated timelines in response to the Covid-19 pandemic, and discussed and agreed the advantages and disadvantages of the various strategies trialled to expedite timelines. During a charter refresh conducted in September 2021, the team voted overwhelmingly to move on from this topic. However a core number of participants were interested in continuing to explore accelerated cell line development and to accommodate this a sub team was mobilized and has commenced discussions on next steps.

The new topic for the remainder of 2021 is the use of targeted integration in cell line development to develop protein therapeutics. Benchmarking surveys and case studies have been proposed to greater understand ‘Who is using this technology?’ and to knowledge share and discuss the challenges and benefits associated with targeted integration.

Forced Degradation Studies

Kevin L. Carrick, Director of Science and Standards in Biologics for the USP updated the participants on the new biopharmaceutical stability chapter in September. A more detailed presentation is being sought.

Use of forced degradation in comparability studies has been explored using a series of case studies from participating companies including Pfizer and Janssen and others are planned. The team will draft a benchmarking survey to compare approaches to using forced degredation studies for comparability studies.

Qualification of Small-Scale Models (SSM) – Upstream and Downstream

The workstream have shared several interesting case studies on ‘The use of SSM in continuous processing’.

In addition the team have prepared and begun the review of a general benchmarking survey and have drafted a follow-up survey which focusses on specific unit operations related to upstream and downstream processes.

Bioassay

The participants are looking at the challenges of monitoring reference sample stability in the early phase and have completed a benchmarking survey which is under discussion to share approaches.

WCBBA Automation of cell based bioassays presentation

The  workstream will present the results of a discussion and benchmarking survey on the automation of cell-based potency assays at the forthcoming WCBBA meeting. The survey and talks will focus on a number of topics including: handling of cells, transitioning from manual to automated assays and validation approaches when assays are both manual and automated.

Accelerate CMC Development to Marketing Application

The workstream is looking to develop industry positions/recommendations on how to effectively expedite CMC development activities to support global licensing of accelerated assets; leveraging prior industry knowledge and knowledge developed within the program of work along with key learnings gained from Covid-19 accelerated development pathways.

There are currently two key focus areas being driven by separate sub teams: Specifications Setting and Control Strategy Template and Prior Knowledge.

Specifications setting: working in partnership with CMC Regulatory SMEs

The sub team developed a detailed survey to support a potential ‘boundary pushing’ white paper advocating specification development strategies for accelerated programs. The survey covers two main areas:

  • Company approaches to specification setting in the accelerated development space
  • The Health Authority feedback on the strategies used by member companies

The team are mid way through review of the survey results and are reflecting on the key messages and how these can feed into the intended position paper.

Control strategy template and prior knowledge

The subteam has built a consensus classification of critical upstream and downstream process parameters with justification of excluding certain parameters from consideration in development of accelerated control strategies. This was discussed at the BPDG31 meeting and has been instrumental in informing the creation of a control strategy template which is now being drafted. The intent is to provide an industry wide ‘platform’ control strategy to help development teams identify the most critical process parameter and to provide clear justifications based on broad experience for CMC decisions on parameters that can be characterized as well controlled with a low risk for impact on process performance or product quality.

They have also prepared a list of ‘prior knowledge’ applications for prioritization, looking at specific unit operations but also other activities e.g. mechanistic modelling. The proposal is to ultimately prepare prior knowledge data sets (where appropriate) and guidance on how individual companies can create effective prior knowledge packages. A thorough review of this is on-going, as well as discussions on how this will be an effective tool in a practical setting.

CMC Regulatory

This workstream continues to provide a safe environment for CMC Regulatory professionals to collectively address regulatory topics, to share knowledge and best practices with the ultimate aim of improving industry license application processes, experiences and success rates. Since November 2020, the team has completed a charter refresh, offering and prioritizing a number of key topics of focus for 2021/22.

Comparability is a hot topic in the CMC Regulatory area. The team have compiled a short survey to understand the main comparability challenges that companies are facing, where there are gaps and need for an aligned approach. The results of this survey will be used to better define the problem statement and scope of the topic. The team would also like to approach the topic from a lifecycle management point of view in gaining insights to member companies experiences of feedback from different Health Authorities for major changes. The team are keen to tease out the requirements from different regulators in relation to comparability and ways to justify avoiding clinical bridging. A key message in terms of overall approach to the topic is that the focus should be on strategies and level of endorsements of strategies in the comparability space.

Regulations in China and/or emerging markets

The team concluded discussions on the main points identified for CTA (clinical trial applcation) applications in China and agreed to expand the topic to emerging markets as a standing ‘hot topic’ agenda item to share ‘real-time learnings.

Specifications setting

Working in partnership with Accelerate CMC Development SMEs, a subteam have developed a detailed survey to support a potential ‘boundary pushing’ white paper advocating specification development strategies for accelerated programs. The survey covers two main areas: Company approaches to specification setting in the accelerated development space, and the Health Authority feedback on the strategies used by member companies. The sub team is towards the end of its review of the survey results and is reflecting on the key messages and how these can feed into the intended position paper. Feedback was sought at the BPDG33 event.

Established Conditions for Process (ICHQ12 implementation)

A complex topic, there has been much off-line discussion (and a live survey) to establish how to approach this area. A sub-team was set up and started by gathering inputs from all companies on experience to date and interpretation of the literature and FDA pilot program. The team has also provided preliminary feedback to the cross-phorum ILM/RTR initiative. The subteam have agreed that the majority of companies are still working out how to use established conditions for process. There is very little, if any, experience beyond the pilots and the practical benefits are still being understood. This subteam will reconvene when there is more experience and understanding in this area.

Established Conditions for Analytical methods

Dialogue initiated with the IQ Consortium (IQC) for potential collaboration on a decision tree. The IQC is currently focussing on small molecules however, the intention is for the Q12 Working Group to reach out to BioPhorum to collaborate on demonstrating how Q12 tools can impact analytical lifecycle management, support implementation across industry and Health Authorities (see page 17 of July IQC paper linked below:)

IQC paper

In-Silico Strategies

The ultimate goal of the team is to recognize how in-silico simulations can be implemented to optimize and predict wet-laboratory experimentation to bring new medicines to the market more quickly, reduce development lead times, e.g. remove the need for cell culture cycles (four weeks) and, ultimately, have an integrated control strategy.

The team continue to focus on model validation with the objectives of identifying model application and how to validate a high impact model for release testing and how to qualify a medium/low impact model depending on the model’s intended use. The team also intend to identify the different types of models and the calibration requirements prior to validation (e.g. empirical vs. mechanistic).

The team have generated agreed definitions relating to mechanistic, empirical and hybrid in-silico models and are progressing the development of (i) a model maturity workflow (end to end including scientific models and relevant stage gates to regulatory models) and (ii) a decision tree to identify impact level depending on a model’s intended use.

For 2022 the team will start a new topic: How to build a good model. The goal to produce a ‘Go to guide’ on how to build a good model and share examples of best practices for developing models that can help accelerate process development.

PAT Monitoring and Control

Systematic Assessment of PAT subteam

To help the industry move from concept to regulatory approval using new process analytical technologies (PAT) in the best way, the team plans to publish a summary of the results of a benchmarking survey of business drivers for PAT. A paper on the systematic assessment of PAT applications for biologics has been prepared for publication and will help companies understand which technologies are deployed in each phase and the business drivers during the development and manufacturing lifecycle.

Applied Automation

This focus group evolved into a workstream after consolidating initial learnings from a 2020 focus group on two specific vendors equipment. The team remain very keen to hear from vendors in relation to these systems and as such, are in the process of sanctioning some form of interactions with the vendors to share these challenges, and also gain some feedback.

In late 2020/early 2021, the team agreed an update to the project charter where the initial focus was to develop an end-to-end workflow of the development process, including data flow. As a means of achieving this goal, the team are currently implementing a simple database tool in order for the workstream community to understand who the SMEs are within the workstream for the various technologies and data handling systems in the automation space. The longer-term plan for the database, is to make this evolve into a more tangible tool for the team so they can perform a systematic and quantitative assessment of where automation is adding or has the potential to add most value – again, another objective in the teams charter. This will result into the team shaping end-to-end workflows, understanding the main integration challenges that are experienced and identifying how to solve them.

A smaller number of the Applied Automation team and Cell line Development team have met to discuss the Beacon Technology. This ad-hoc call was to understand common challenges with the technology and there were some great inputs to discussions. The group learnt  that there is a community user group available to join via the supplier of the technology and this was flagged as a good opportunity to discuss the technology further.

Speed to Clinic (Pathfinder)

Due to the COVID-19 pandemic, biopharmaceutical companies are under unprecedented pressure to provide efficacious preventative and therapeutic treatments, at speed. Traditionally, this can take several years and given the need for much faster delivery, many companies have made substantial changes to their development processes. However, to date, there is no consolidated industry data on what changes have been made, what impact they have and whether these are sustainable business practices. A benchmarking survey to address this gap was issued to  Speed to Clinic pathfinder group members in September 2021 and initial results were presented at the BPDG33 meeting in early November 2021. Concomitantly the first draft of a journal paper has been developed which is hoped to be published in Q1 of 2022.

Analytics

The next topic that the team wish to focus on is ‘Peptide mapping as an ID test – where to draw the line?’ A benchmarking survey is being designed in order to cover this topic. The objective is to use the data gathered to gain insights to company strategies and technical applications of peptide mapping and the experiences contributing to these. The team are keen to identify areas where improvements can be made by determining how and where other companies are achieving higher performance levels. Obtaining regulatory insights that companies have experienced in relation to peptide mapping is also of high interest to the workstream. The survey was issued in October 2021.

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