Trends, challenges and priorities

Advancing the cutting-edge science of cell and gene therapies is not without its challenges as the field continues to mature and learn. With many cell and gene therapies under development it is more important than ever to improve understanding of how to develop, control and manufacture these life changing therapies through industry collaboration.

The cell and gene therapy (CGT) sector is advancing rapidly with record breaking increase in funding and an expanding pipeline. Whilst there are still relatively few approved products on the market there are indications that this will increase over the coming years. Some therapies have suffered setbacks due to adverse side effects in patients and these new modalities are under increased scrutiny.

Within this environment, there are many challenges across the CGT lifecycle and the industry is continually developing as expertize and knowledge grow. BioPhorum Cell & Gene Therapy, together with our members, has developed a program of collaboration to address some of these key challenges bringing alignment on various aspects of CGT development and manufacturing to drive standardization across the industry.

biophorum backgrounds cgt 2022 program 54

Included in the program this year is a new workstream which is focused exclusively on RNA and its use as a therapeutic and as a gene editing tool. While previously only found in academic, pre-clinical and early clinical stages – RNA technologies, including mRNA therapeutics, have emerged as a promising drug modality due to their essential biological role in protein expression and potential versatility in manufacturing. RNA is in the global spotlight and is being prioritized due to the Covid-19 pandemic. However, to maintain the current momentum as industry and agencies return to a ‘normal’ cycle of development for a wider range of drugs and therapies, experts in this field need to come together to identify and address challenges unique to the RNA modality.

This year has seen the release of a number of BioPhorum Cell and Gene Therapy publications including recommendations for an approach to potency assay development, specifications for plasmids and gene therapy critical starting materials and other topics supporting validation challenges and environmental health and safety.

In addition to the collaboration workstreams, the Phorum is also building links with other collaborations and standards agencies, such as the Alliance for Regenerative Medicine, the US Pharmacopeia (USP), the Standards Coordinating Body and many others to support and contribute to the development of CGT regulations and standards.

The CGT business is as diverse as the patients it serves and so there are no one-size-fits-all solutions. However, by driving harmonization and alignment in this new industry, the Phorum is promoting the better and faster development of therapies.

Cell & Gene Therapy deliverables 2021 – 2022

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Commercialization - CGT manufacture

Aseptic Process Simulation

A sub-team focusing on the unique challenges of aseptic process simulation (APS) was formed following an initial member benchmarking survey on this topic. A core team was formed from interested members with knowledge and experience of APS relevant to CGT to discuss specific challenges of APS within CGT, such as coverage of process duration and product contact surfaces. The core team aims to draft an article for an initial discussion with the wider interested group and then produce a final article for publication from the entire team. Due to the significant burden on the resources required for CGT APS, the team’s aims are that the publication will help reduce the current drain on resources and save companies time and money in achieving a CGT product launch. The plan for publication is Q3-2022.

Minimize Impact of Testing of on Batch Yield

The final CGT Commercialization sub-team is focusing on options to minimize the impact of in-process and release testing on gene therapy batch yields. The sub-team has identified a list of all assays currently used within routine manufacture and how the volume required is determined. It has ranked this list in order of impact/priority and is working through the assays to identify the specific impacts and potential alternatives that may reduce these – via surveys and calls. The four focus areas are:

  • Bioburden and sterility testing – working towards an article
  • Container closure integrity testing (CCIT) and reserve samples – working towards an article
  • Stability – working towards an article
  • Infectivity and potency – now closed following survey & discussions.
Multi-Product Facility Design

The multi-product facility design sub-team have decided to challenge current paradigms, driven by regulatory expectations for appropriate segregation controls which have driven highly conservative approach’s to facilities designs. The sub-team agreed to proceed by proposing a conceptual layout that better suits industries need for multi-product manufacturing without impact to product quality or patient. They have established a range of conceptual multi-product facility designs from a conventional unidirectional flow with processing in grade B to an unconventional bi-directional flow in grade C. The multi-product manufacturing scenario they have selected is concurrent autologous gene modified ex vivo cell therapy & LVV. The sub-teams ultimate aim to really challenge thinking and push forward with an FMEA to understand the specific risk areas on the most unconventional facility design. Its envisaged that the FMEA high risk areas will determine the feasibility of establishing further engineering or procedural controls that could be employed whilst maintaining product quality and facility control.

Environmental, Health and Safety, and Biosafety

The EHS and biosafety team focuses on the safety of personnel when working with CGT processes at scale. This encompasses those in Research and Development (R&D) as well as those in traditional manufacturing roles. The term personnel includes support functions (quality assurance, site safety, engineering, etc.), as well as personnel who may require access to site, e.g. emergency responders and local physicians. It does not include patient safety.

Cell Risk Assessment

The current team is focused on the development and manufacturing stages, up to and including the supply of materials for clinical trials. Following the publication of the Environmental health and biosafety risk assessment framework for commercial-scale cell and gene therapy manufacturing and template, a Cells Risk Assessment sub-team was formed. The team has published the first in a series of case studies where the risk assessment is applied to real-world examples to stress-test the risk assessment, offer future improvements and provide a resource pack for the EHS worker.

This first paper, called Risk assessment of cells used in early development, explores early generation of cell banks. The focus is now the tech transfer from R&D/early development into a GMP manufacturing environment and how that affects the risk mitigations needed.

CGT EHS Resources

The EHS Resources sub-team has a long term goal of forming a dynamic website that contains resources for the EHS professional. The current focus of the team is safety data sheets. The current format is well suited to chemicals but is less appropriate for CGT products and intermediates. The team is sharing its experiences of the use and content of safety data sheets, and will publish a consensus template sheet with text to help the user early in 2022.

High Level Analytics

Potency

Following publication of their article, Challenges for potency assay development for in vivo and ex vivo gene therapies GTs) and the matrix approach in September 2021, the Potency sub-team continues to promote adoption a matrix approach to overcome some of the key challenges for potency assay development for in vivo and ex vivo GTs by showcasing their paper at industry conferences.

Approaches to Improve Methods

Clinical dose determination of AAV requires exact quantification and relies on accurate analytical measurements of vector genome copies for rAAV titration. Following survey findings (June 2020), dPCR may offer improvements in precision and accuracy over traditional qPCR platforms. To more robustly inform industry of the potential benefits of dPCR to measure vector genome copies, the Approaches to Improve Methods sub-team will collaborate on a platform comparison study initating October 2021 referring to a common protocol developed by the team. Following the study, the team will collate and present the study data in a future  paper.

Phase-Appropriate Approach to Assay Validation

Members of the Phase-Appropriate Approach to Assay Validation sub-team are developing an initial general paper that is aimed at promoting alignment on a common and compliant, phase-appropriate approach to assay validation relevant for CQAs of the most prevalent CGT modalities that will help promote a more efficient pathway towards each stage of filling.

Next-Generation Sequencing

Next-generation sequencing (NGS) has revolutionized genomic research, although its adoption in the manufacture of therapies has been slow. Challenges to its adoption arise from a lack of current regulatory guidance on the use of NGS for CGT applications and difficulties when validating a GMP-compliant method. This difficulty also stems from the complexity of implementing an NGS workflow that requires end-toend validation of wet-laboratory assays, automation and sequencing instrumentation and the supporting software analysis pipeline. A core team of members of the Next Generation Sequencing sub-team are drawing on their collective experience to develop an introductory paper that will illustrate NGS workflows suitable for identity testing (viral vector identity). The paper content will be enriched by regularly engaging with the interested wider group for a series of discussion sessions / Q&A.

Empty/Full Capsids

A new, dedicated sub-team was established by High Level Analytics members in August 2021 in response to growing interest to increase understanding of empty/full capsids testing strategy. The Empty / Full Capsids sub-team are initially developing a comprehensive benchmarking survey that will consider vector agnostic, general questions focussed on gaining an understanding of how industry defines empty and partially full capsids as well as AAV and LVV dedicated sections which will explore vector – specific testing strategies. The survey outcome will determine the team’s next steps. Finally testing strategies for other process-related impurities (e.g. host cell DNA and plasmid DNA) as well as replication competent testing are being progressed via monthly workstream calls and benchmarking surveys.

Raw Materials – Sourcing, Quality And Volume

Plasmid Release Specifications

The  subteam has written an industry consultation paper that proposes a platform approach for testing the critical starting materials; plasmid E. coli master cell banks and plasmid DNA used in the manufacture of CGTs. The information collected in response to the consultation will be used to generate consensus. Work in this area will continue in the form of industry outreach, through presenting at conferences, open-access webinars, and promotion of the article through social media outlets.

Endonucleases

This subteam aims to resolve technical issues and identify opportunities for improvement of endonucleases standards and specifications. A gap analysis of current standards has identified an opportunity to include an endonuclease best practice and/or specific validated standard to cover specific testing methods. The team aims to develop an industry stimulus article to propose a common, standardized approach for testing of endonucleases where they are used as a raw material in CGT product manufacturing.

Transfection Reagents

The subteam has identified common issues with transfection reagents with issues identified include certificate of analysis (CoA), drug master file, testing and quality biomanufacturing issues. Working with suppliers the team aims to develop improved alignment and a best practice, standardized approach to provide aligned benefits to both parties.

Leukopaks

The subteam aims to fully understand the challenges of the industry pain points with Leukopaks from the initial collection, processing through to the end-user.

A detailed survey has been completed with focus areas including the tests needed to characterize leukopaks, patient data required by different processes, transportation of leukopaks and managing relationships and standardisation with the cell collection centres. The team are currently analyzing the results data to identify key themes. Initial areas of concern include processing centre standardisation, transportation and tracking, testing, quality, and variability in the supply of leukopaks.

Supply Issues

This subteam’s aim is to look at the technical and quality supply issues within CGT raw materials. It is not focused on the long-range planning, forecast, and delivery of raw materials unless it is specifically CGT aligned and not covered within BioPhorum Supply Partner.

The team are developing a survey to send to GMP Single-Use material manufacturers. Areas of interest include:- regulatory, baseline understanding, direct supplier, quality, supplier second and third tier, HSE and technical. This will be a cross phorum effort aligned with BioPhorum Supply Partner and contacting around 20 suppliers. The benefit will be to uncover any cross-industry pinch points the team can work through and appraise for the advantage of all.

Regulatory Strategy

A function of this workstream is to provide regulatory support to the CGT technical teams and provides a forum where members share regulatory intelligence; track and stay aware of new guidance/industry standards and as well as activities that may be in progress by other external groups. During regular workstream calls, members consider and provide regulatory feedback to member questions received via Ask BioPhorum as well as offering regulatory input to CGT technical sub-teams when this would be valued to accelerate sub-team progress. By sharing knowlege and experiences, individual learnings may benefit all. Furthermore, whenever new CGT guidance is published, members will consider opportunities to review and discuss guidance to be aligned on interpretation and provide comments where possible. This is evidenced by the formation of two separate review groups so far this year, who have returned commentary on draft FDA and EMA guidance during respective consultation periods with a new review group forming in October 2021 to review “Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial” published by FDA for public consultation (September 2021).

Comparability

Demonstrating comparability presents some unique challenges for CGT developers owing to, for example, fast-tracked chemistry, manufacturing and controls (CMC) development, limited patient clinical data, batches and number of batches, and commercialization may require process transfer. Furthermore, regulatory guidelines on CGT product comparability across regions are vague, leading to a diversity of practice. CMC changes are expected and inevitable, particularly during early development, and this cross – workstream  subteam is aiming to document regulatory requirements as well as to provide recommendations on key considerations to help guide an appropriate rigor for comparability studies that is comensurate with timing of where change may ocur during product life cycle. A future article is planned and targeted for publication in 2022.

Multi-Product Facility Design

Collaborating with commercialization members, the Multi-Product Facility Design sub-team have developed a range of trial concept facility designs assuming a base-case multi-product scenario of autologous ex-vivo gene modified cell therapy and viral vector required for resultant drug product.

Working outside of the project environment, the team is able to consider disruptive conceptual layouts that challenge current thinking on cleanroom classifications, segregation and flows. By considering the key risks and presenting potential controls, the team hopes to stimulate further conversation amongst industry and regulators to advance multi-product design to better meet current and future needs.

The team is exploring opportunities to further develop initial designs by potential cross-working with engineering partner member companies and linking where appropriate with the Standard Facility Design Workstream ( BioPhorum Technology Roadmapping).
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RNA as a therapeutic and gene-editing tool

RNA CQAs and Assays

An analytical focused sub-team prioritizing challenges around CQAs and Assays for RNA products. This sub-team has identified 2 specific lists of challenges/activities to be discussed, focusing on CQAs and on Assays. These are documented within their charter, although their first priority has been to map the existing landscape of literature and guidance relating to RNA analytics to help prioritize the challenges to address by identifying existing gaps in knowledge. This ‘mapping the landscape’ activity has created a growing list (currently 26) of documents as a reference that will help members in RNA analytical challenges. 

The sub-team has also reviewed in-depth a WHO guidance to stimulate further discussion around RNA analytical challenges and generate further topic ideas; and the sub-team has also performed a journal article review to further expand awareness of the challenges to be addressed by the team.  This sub-team is now working towards its next deliverable of creating a CQA & Assays table detailing the what, why, where, when and how for RNA product attributes, which will eventually form the basis of an article for publication.

CDMOs and CROs supporting RNA production/ manufacturing

Upon defining the sub-team charter and action list the team progressed their first activity of identifying transfer considerations that are unique to RNA products which could result in delays to a product transfer between a developer/sponsor and a contract organization. The team are now converting this into a set of slides that companies will be able to use as a checklist during an NPI meeting to highlight and pre-empt potential issues unique to RNA products. 

The team also intend to include specific examples, where possible, for each identified aspects.  Following this, they will leverage that activity to help generate a questionnaire detailing questions / requirements sponsor/developer companies would have to help select the best CDMO/CTO to support their RNA product manufacture & testing. Additionally, the questionnaire will also include questions from the CDMO/CTO organization perspective for the Sponsor/developer, to ensure the product has the suitable development and background for a smooth transfer (provide clear indication of requirements).

Scale-up Challenges for RNA Drug Substance and RNA Drug Product Manufacturing

Following establishing a sub-team charter and list of scale-up challenges for RNA manufacture, the team have initially focused on creating a series of mRNA manufacture process flows (mRNA/LNP DP) to establish a common frame of reference for ongoing team discussions. In addition to providing a tool to facilitate future discussion and remove the ‘it-depends on the process’ comment when discussing scale-up challenges, the process flows will be a useful educational resource for members new to mRNA manufacture.  The team has also added descriptive text for all the key process steps and are now in the process of converting this content into a short article with the aim to publish this content on the BioPhorum website before progressing in-depth discussions on the list of scale up challenges identified.

Validation

Validation Templates

The subteam are working towards generating CGT specific templates for validation activities. The currently available templates can often be unsuitable for CGT products as they tend to be based on general biologics, which is at a different level of maturity to CGT. This can often result in additional work for the CGT user who may be required to complete irrelevant sections or provide unnecessary justifications as to why sections are incomplete. The team will generate usable templates specific for CGT products, with clear instructions that can be easily adaptable for use. The team are currently working towards generating a process performance master plan (PPQMP) template and plan to prepare templates for risk assessment, comparability and development activities.

Viral Clearance

A sub-team focusing on the unique challenges and possible options for viral clearance within CGT; taking into consideration that the introduction of a viral vector is often a key component of for a CGT product. The team are working towards a paper that will highlight the challenges, map the current regulatory landscape and propose potential solutions associated with viral clearance in this field. The principal focus of the publication will be on gene therapies, however, unique consideration will be given will be given to viral clearance (or lack of) for cell therapies also. The team have also completed a survey around viral clearance studies prior to Phase I/II & inclusion in IND submissions for AAV product.

CGT Method Validation controls

In developing gene therapy products using a transfection process, the only major change from product to product may be the gene of interest plasmid used. However, there is a requirement to conduct process characterization specifically for each product. This newly formed subteam will investigate if process characterization data can be leveraged across multiple products to accelerate validation timelines. The team will establish if a platform approach is possible for CGT and define what constitutes a robust platform process. The goal of the team is to generate an article detailing regulatory requirements, challenges and potential solutions for CGT process characterization and platform approaches. They will also detail a ‘best-practice’ approach to leverage process characterization data with a view to accelerating validation and generate a mock-case study to demonstrate this.

Small batch sizes and limited material can often mean securing sufficient reference standard quantities for CGT can prove challenging. As a result, validation of analytical methods can be difficult when proper controls are unavailable, particularly within an accelerated program. Lack of CGT specific guidance and standards around this topic further adds to the challenges for CGT products. The subteam will look to address the challenges associated validating an analytical method with limited available reference standards and will focus on analytical methods for releasing viral vectors in cell therapies and gene therapies. They will target a delivery of a paper detailing current guidance, challenges and solutions and present a mock study/risk-based approach to validating analytical methods when reference standards are scarce. In addition, the team will seek to contribute to standard development in this area, with a view to establish a working relationship with standard bodies/agencies in order to contribute to a CGT specific standard.

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