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 remain at the forefront of our work.

Speed to First-In-Human

Originally called ‘Speed to clinic’, this team continues to robustly examine our portfolio of work and listen to sponsors when they have reflected on where their companies are most engaged. The team has also maintained its focus on exploring industry perspectives and evaluating the learnings from the Covid-19 experience.

Many Phorum members, representatives and sponsors continue to feel the pressure of significant workloads, juggling priorities, and even pausing some programs. Sharing their experiences and seeing what could be progressed in routine development activities might yield industry-wide benefits.

The team has completed a major benchmarking survey looking at the technical practices of key process/product development activities when manufacturing therapeutic proteins. It also considered the impact of Covid-19 accelerated work programs, whether any changes could be retained as part of sustainable long-term business practices, and the impact of any accelerative actions on the wider development process. We have also submitted an article based on the survey that discusses ‘Accelerated Speed to Clinic Process Development in the Covid-19 era’ to Nature Biotechnology and eagerly await feedback.

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Given the Covid-19 pandemic and its ongoing impact, the team is using pulse surveys to continually reassess members’ experiences of these potential factors to ensure learnings from the group’s membership are captured and used.

The overall message the paper emphasizes is 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

Industry challenge development timelines do the same work in less time can have an impact. This is why the group has been looking at ‘accelerated development’ principles that are increasingly merging with regular development pathways, which have intensified by Covid-19.

Accelerated development is the focus on prior knowledge that falls under the umbrella of the Accelerate CMC Development Workstream, but also feeds into many of our other workstreams in terms of how companies create effective prior knowledge packages.

To meet this prior knowledge need, we have developed and rolled out a tool to capture references to articles or journals cited in filing applications. This will build a repository of prior knowledge to help make future filing applications more robust and justify any of the stories and data they have put forward from an organizational perspective.

The Accelerate CMC Development to Marketing Application Workstream is benefitting from increased sponsor engagement. This will fertilize thinking and may lead to an aligned package of work across many of the technical and tactical workstreams within the Phorum’s program, such as viral clearance, process-related impurities, and cell line development. This could lead to increased sponsor involvement and new coordinated work packages linked to the other workstreams emerging from the Accelerated Development Workstream program. The teams are assessing how this could work alongside the Speed To First-In-Human Workstream.

The team has two key focus areas: Specifications setting and Control strategy with prior knowledge.

In the first area, the team is analyzing the key messages from a survey (conducted with regulatory experts) to review specification-setting strategies and health authority feedback for accelerated assets. The goal is to prepare a ground-breaking position paper that describes the current state and challenges of specifications setting and makes recommendations for the future that advocate specification development strategies for accelerated programs.

In the second, the team is creating a control strategy template, which initially aims to provide an industry-wide ‘platform’ control strategy to help development teams identify the most critical process parameters for upstream and downstream unit operations. It will also offer clear justifications based on broad experience for CMC decisions on parameters that can be characterized and controlled with a low risk of impact on process performance or product quality.

Host Cell Proteins (HCP)

In 2021, the HCP team published a significant paper on High-Risk Host Cell Proteins and an associated database on the BioPhorum website. As a result, we are now recognized as a key player in the HCP community and the team’s work is contributing to the development of higher quality, purer products.

At the recent BEBPA conference, the paper was cited in at least three different presentations. This increased interest shows the huge value created by the paper and the database. Now industry wants the database to be populated with even more information. This demonstrates a real industry need from host cell protein experts with input across disciplines like regulatory, process engineers, toxicologists and immunologists.

This greater interest means that the HCP team has grown to 120+ members and we are looking at bringing in a new meeting structure that will leverage the power that these experts wield in sheer number.

Engagement and collaboration

The Phorum is always looking to stay ahead of the game and react to industry needs. This can be seen when several workstreams changed their names, such as Host Cell Proteins and other Bio-residual Impurities (formerly the HCP Workstream) and Accelerate CMC Development to Marketing Application (formerly the CMC Considerations for Expedited Development Program).

The 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. This creates huge value and brings together highly complex topics under the lens of a ‘bigger picture’ objective. Member company sponsors have always managed the program in a practical and considered way, ensuring commitment remains robust. Still, the recent reviews have created fascinating new missions and a spectacular increase in engagement and the quality of work.

A survey of Phorum members has demonstrated that its work has gone into supporting company Biologics License Applications, including one company’s first successful application in 10 years and another going from DNA to the patient in just eight months. There are likely to be many more valuable examples emerging over the next year.

The Phorum continues to use its large virtual meetings, which are great events that continually feed the program with topics refining their goals and objectives. For example, we recently held BPDG35: Accelerated Development 2022 & beyond June 2022 which was our second large meeting on the subject in the last 12-18 months. The meeting outputs will feed into the existing DG program and influence future topics and team actions to leverage opportunities for speed and efficiency improvements in process development.

Our Small-Scale Models Workstream has now been sunset following the publication of a significant paper on the justification in the use of these models. This makes way for a new workstream focusing on process characterization as the natural next phase of that work. It is currently defining its charter and deliverables and will leverage the learnings from BPDG34: New approaches to process characterization workflows.

As part of that activity, the team is running an exciting six-month trial with our Asian, Japanese and Australian members to accelerate the outputs from the workstream and further enhance our ways of working across the globe. The aim is to build more time-zone and language-friendly calls to build on the Phorum’s engagement and growth and, ultimately, get the most out of the sheer quantity of knowledge and expertise we have within the team. This will support the continuing evolution of the Phorum and the collaboration with new members around the globe.

Two articles highlight the Phorum’s excellence in collaboration and pulling together world-class experts. One is an article to be published in Medicines Innovates on ‘PAT monitoring and control’, the other is on ‘Worst-case conditions for viral clearance’ published in BioProcess International.

The dynamic nature of our industry shows there is fertile ground for discussion in many of the above topic areas and more. We have also seen considerable growth in the number of members, participants, and sub-teams within the workstreams that are keen to collaborate and progress these deliverables.

The challenge for the remainder of 2022 and into 2023 will be how best to support the engagement and enthusiasm in these exciting areas.

Development Group deliverables November 2021 to November 2022

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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

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.

High concentration formulation publication

A benchmarking survey on stability challenges with high-concentration formulations has been completed and the output from this will forms the basis of a publication providing an industrial perspective on prediction of viscosity and stability compared to practical experience of developing high concentration formulations. The publication has been submitted as a commentary to J Pharms Sci and reviewer comments are currently being addressed.

A presentation based on this publication was presented at BPDG36 in October 2022

Formulation and drug product development Live Ask BioPhorum sessions

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 FDA/EMA requirements related to drug-device combinations, prediction of real time stability based on abbreviated storage under accelerated conditions, conatc material risk assessment, recent pharmacy manual requests from HAs, Extending shelf life with research stability data, CCI, formulation change from GLP tox material to clinical trial material, process characterization strategy for injectable drug products, formulation changes during pivotal trials, interpretation of ICHQ1B photostability. use of pneumatic tube system transportation, Donnan effect and excipient concentration for labels, SC compatibility and in-use stability with syringe and needle, impact of fill volume increase on shelf life, .

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

Novel surfactant co-development 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 of technical experts has defined a scope and plan to select and progress a suitable surfactant. This was presented to the sponsors for buy in to co-develop a novel surfactant.

Platform formulation in early-phase development

This benchmarking survey covers all biologic protein modalities in Phase 1/2a. It covers the rationale for a platform formulation at a strategic level followed by; platform formulation use for candidate selection, platform composition & presentation, assessing platform fit, IP for platform formulations and evolution of your formulation from early phase platform to product specific. The survey is currently being worked up for discussion.

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

Clinical Risk Assessment

Since team mobilization early 2021, the team have recruited toxicologists and immunologists to assist and advise from a clinical perspective. Literature review and gap analysis of risk assessment templates inclusive of member company risk assessment approaches has been completed. The team are currently in the process of writing a white paper to provide industry with a resource to be able to evaluate the impact of the individual HCPs identified in specific processes for target publication in Biotechnology and Bioengineering in Q4 2023.

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 was to gather preliminary information from across the biopharmaceutical industry on the characterization and risk assessment of HCP using mass spectrometry. The results have allowed mapping of the process member companies use to identify and assess the safety risks presented by Host Cell Proteins.

Product & Process Related Impurities

Since team mobilization late 2022, the expanded team’s focus point is to improve industry knowledge on the impacts of residual impurities exclusive of HCPs (which will remain the main focus of HCP workstream & RA Sub team) with a view to understanding the associated risks during the product development stages. Topic discussions and ranking has taken place where priority has been agreed to establish a list of common process impurities prior to moving into the control strategy surrounding the impurities.

Enzymatic Activity Assay

Review completed Jan – May 2022, survey was to share knowledge into how, why and when enzymatic activity assays are preformed throughout the industry.

Use, monitoring & Reduction of HCPs during Process Development through to technology transfer

Benchmarking survey generation currently in progress- expected live end Q4 2022.

Database Admin

Team mobilized late 2022, following on from the “High Risk” HCP publication and the generation of the HCP Database. Main focus point of the team is to carry on with the research, generation and verification of data for the main database to allow completion of the CHO cell line. Moving forwards the team will work to expand and develop the database further by the addition of further cell lines eg, e-coli and mammalian.

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). Additional updates are expected by end Q4 2022.

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

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, Janssen and GSK. The participants have also enjoyed some structured discussion sessions on the use of forced degradation studies (FDS) in the decision making process for lack of similarity in bioassay assays and impact.

Use of FDS for formal comparability assessments

A subteam is currently drafting a manuscript on “An industry perspective on approaches to forced degradation studies in support of formal comparability studies for biologics.” Forced degradation studies (FDS) may be used as part of comparability assessments to support demonstration that pre-change and post-change materials are comparable following manufacturing process changes evaluate the impact of manufacturing process changes on the safety and efficacy of a biologic drug. There is not much detailed guidance regarding the design and interpretation of forced degradation studies in analytical comparability assessments and as a result there is a degree of uncertainty in when to execute and how to and interpret these studies .

The workstream conducted an intercompany collaboration exercise, which included a benchmarking survey and group discussions around the use of forced degradation for comparability exercises of protein based biotherapeutics. The results provide insights into the design of forced degradation studies, analytical characterization and testing strategies, evaluation/assessment criteria, and considerations for non-platform modalities. This article discusses the outcomes of the survey across 18 companies and provides industry perspective, experience, and insight into the practicalities of using FDS for comparability.

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 workstream has had many detailed discussion session on aspects of approaches and control strategy for implementation of ready to use (RtU) cells in bioassays. This has lead to a manuscript being drafted for BioTechniques that will cover considerations for expansion of cell types for banking, RtU cell banking establishment and size, logistics for how RtU cells are made and frozen, release strategy qualification vs validation, when to introduce them, switching strategy and lifecycle management with RTU cells.

Automation of cell based bioassays presentation

The workstream revisited a benchmarking survey on the automation of cell-based potency assays to understand how automation is progressed in the last four years. The survey covered 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.

Process Characterization

The Process Characterization workstream have identified four key knowledge areas to address. Before initiating the more technically detailed knowledge areas, the team recognized the need to ensure that common terminology should be utilized by workstream members to avoid ambiguity, company specific synonyms and align with regulatory definitions for specific terms where applicable. 139 terms were identified and defined.
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