Plan for Success in Gene and Cell Therapy Manufacturing

Gene and Cell Therapy Planning for Manufacturing Success Early Plasmid DNA: Beginning with the end in mind. WHITEPAPER PRESENTED BY: CONTENTS 3 Introduction: Evolving Landscape of Gene and Cell Therapy 4 Expanded Focus on Chemistry, Manufacturing, and Controls 5 Establishing a Baseline — Be Prepared, Define, and Refine 6 Plasmid DNA Design Considerations 7 Release Specifications — Insights into Overlooked Details 8 The Path Forward and Choosing the Right Partner 10 The Benefits of Partnership 11 Getting Started 12 Conclusion © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 2 Introduction: Evolving Landscape of Gene and Cell Therapy Over the past decade, gene and cell therapy has gone from a clinical concept to a mainstream reality. In 2017 the U.S. Food and Drug Administration (FDA) approved its first gene therapy, and the market has continued to expand. In 2020, the number of gene, cell, and tissue therapy companies globally passed 1,000 for the first time.1 With 510 companies, North America now has almost as many regenerative medicine businesses today as were active worldwide in 2015.2 The proliferation of startups has been accompanied by a surge in interest from Big Pharma companies. From 2017 to 2019, gene, cell, and tissue therapy biotechs were the subject of takeovers worth $44 billion.3 Gene and cell therapies have attracted high interest despite ongoing challenges related to their production. For example, the production and characterization of the viral vectors used to deliver 80% of the gene deliverybased therapeutics in clinical development is expensive, time consuming, and subject to intense regulatory scrutiny of quality.4 The FDA recommends the plasmid DNA (pDNA) used in the production of Adeno Associated Virus (AAV) and lentiviral vectors is derived from qualified banks and undergoes testing to ensure the identity, purity, potency, and safety of the final product.5 As pDNA is used in a variety of gene and cell therapies, including Chimeric Antigen Receptor T-cell (CAR-T) therapies, the evolving need for high quality raw material affects a large portion of the regenerative medicine sector. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 3 In 2020, the number of gene, cell, and tissue therapy companies globally passed 1,000 for the first time. Expanded Focus on Chemistry, Manufacturing, and Controls Gene and cell therapy developers are contending with the implications of the evolving regulatory environment while trying to progress programs as quickly as possible to address unmet needs and secure first-mover advantage in competitive indications. Regulators are facilitating efforts to truncate development timelines through a series of designations that can expedite programs. In the US, the FDA offers a fast track for experimental therapies that treat serious conditions and fill an unmet medical need, as well as a breakthrough therapy designation for prospects that may demonstrate a substantial improvement over available treatments.6 Once candidates with the designations generate supporting clinical data, the FDA may expedite the authorization process using its accelerated approval and priority review pathways, including the Regenerative Medicine Advanced Therapy (RMAT) designation. The European Medicines Agency (EMA) offers comparable benefits, notably through the PRIME scheme it uses to provide drug developers with extra support and accelerated assessments.7 As novel treatments that address major unmet medical needs, gene and cell therapies often qualify for the accelerated pathways provided by the FDA and EMA. The compressed R&D timelines facilitated by the designations have implications for manufacturing, with FDA guidance on the topic acknowledging that companies will continue to learn about and modify their production processes as assets advance through the clinic.5 With some uncertainty inevitable given the speed of R&D, it is critical that gene and cell therapy developers eliminate doubts, and by extension risk, where they can. The selection of a pDNA provider is one area in which companies can recognize benefit through proper preparation. This paper will outline the crucial areas to focus on while selecting a pDNA manufacturer to ensure mutual success. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 4 Regulators are facilitating efforts to truncate development timelines through a series of designations that can expedite programs. Establishing a Baseline — Be Prepared, Define, and Refine It is important first to establish a baseline of requirements. As many gene and cell therapies offer a lifechanging therapeutic option for patients, there is significant pressure to move identified clinical candidates into clinical trials as efficiently as possible. However, some gene and cell therapy companies make the mistake of moving forward before establishing a high-level definition of what their program will look like. A well-organized target product profile (TPP) can provide such a definition by encouraging developers to have the end goal in mind when they begin a program. This will also allow for understanding of future scale requirements and will help avoid the challenges that accompany changes in manufacturing processes. They can support development of a TPP by reviewing six key areas. Making the effort to prepare early on will save valuable time, resources, energy, and money in the long run. The FDA has recognized the value of a TPP, too, using guidance on the topic to state the approach enables sponsors to “streamline their interactions with FDA review staff.”8 Prepare patient profiles Prepare and identify parameters of eligible affected patients Define disease profile Define modality and delivery method for the therapeutic molecule Identify proximity of product to the patient Refine scale and quality requirements for pre-clinical through commercial launch © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 5 Plasmid DNA Design Considerations A TPP is one building block of successful gene and cell therapy programs. Consideration of pDNA construct design is another. The following are key points to review and consider before moving forward to reduce delays, shorten approval time, and realize cost savings. 1. Sequence verification and traceability: Companies that fail to fully consider this point can struggle to maintain sequence integrity over time and suffer costly production delays. A good solution is to have a plan for the electronic sequence file and related data to ensure the reference material needed matches the provided sequence. 2. Design elements a. GOI [Gene of Interest]: As the gene that is introduced to counteract a disease, the parameters of the GOI are important. Reducing non-essential sequences and identifying interactions between the GOI and the bacterial system support long-term success. Additionally, retention of ITRs or LTRs (inverted or long terminal repeats) is critical and must be demonstrated by restriction digest analysis, and ideally, by sequencing. Confirming stability of the ITRs early on will ensure better packaging of the viral payload. b. ORI [Origin of Replication]: ORI affects plasmid yield and residual host impurities. Lower copies per gram of bacterial mass translate into increased representation of residual host impurities. Downstream actions can reduce impurities, but at the cost of lower plasmid yield. c. Selection Marker [Antibiotic Resistance]: Specific markers are needed to select the plasmidcontaining strain. Ampicillin-resistance cassettes have served, and in some cases still serve, that purpose but they create the risk of residual beta lactams. Switching to a kanamycin or sucrose selection cassette early can prevent having to make this change later on. 3. Standardization: Consider if the plasmid backbone has been used in the clinic previously. If so, this can help expedite the review/approval process by referencing existing documentation and data. Also, consider how much you’ve altered or changed your plasmid during development. Using the same manufacturing service provider and processes for R&D and clinical production will help ensure consistency. 4. Nomenclature: The lack of a name or different names throughout the lifespan can cause confusion and impact project initiation for clinical plasmid manufacturing. Companies can mitigate those risks by asking themselves what the construct is named, what it will be labeled when it is dispensed and vialed, and whether the nomenclature has been retained over the entire lifespan of the construct. Consider that the name of your plasmid will become visible to multiple parties within your supply chain, and that deidentification of your disease target may be important for confidentiality. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 6 Release Specifications — Insights into Overlooked Details Release specifications are also an important area to consider, and there are many potential setbacks if this step is missed. 1. Critical Quality Attributes (CQA): FDA defines a CQA as a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.9 In the context of gene and cell therapies, there are multiple factors to consider. Over the course of time, Aldevron has identified the below methodologies as standard release testing. a. Performance i. DNA homogeneity: Densitometry analysis of Ethidium Bromide stained AGE shows the supercoiled content of the construct. ii. Concentration and ABS 260/280 ratio purity: UV spectrophotometry shows the plasmid DNA purity and concentration. b. Safety i. Endotoxin: Kinetic Chromogenic LAL quickly screens for endotoxins that can cause adverse reactions. ii. Sterility: USP <71> or BacT Alert show if microbes are present. c. Process host residuals i. DNA: Quantitative PCR confirms residual host DNA. ii. RNA: SYBR Gold stained agarose gel electrophoresis confirms host RNA. iii. Protein: Micro BCA confirms host protein. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 7 2. Qualification and Validation: An important discussion on assay validation will be needed between your internal quality control and assurance team(s), and/or consultants, as well as regulators on what may be required for your particular product. a. Qualification: Assay qualification ensures methods behave as intended, thereby enabling their use for release testing of products and information gathering. b. Validation: A robust validation program encompasses process, cleaning, equipment, computer, and method validation. Analytical method validation confirms that a given method works as intended and enables companies to satisfy regulatory requirements. Most assays require validating by the time a therapy reaches phase 3 development. Equipment and process validations are essential since they confirm that the application and the instrumentation are “fit for purpose,” and computer validations ensure the integrity, security, and retention of information through conformance to 21 CFR Part 11 expectations. Finally, cleaning validation confirms that the total allowable maximum carryover values (TAMC) are appropriate to mitigate any cross-contamination risks. Most validation studies typically take 12 to 16 weeks. 3. Stability Long-Term Studies: Stability testing is frequently overlooked. Establishing a stability program early on for both your Master Cell Bank and purified plasmid DNA will help ensure you have accounted for sufficient material in the manufacturing step and will affect your final dispensing during the manufacturing process. The FDA has provided guidance related to stability programs.10 Stability studies should be conducted to ensure an acceptable shelf life of your plasmid over time. Each potential combination of vial, buffer, concentration, and the specific construct itself may affect the long term stability of the plasmid such as homogeneity or other characteristics. 4. Quality Technical Agreement (QTA): A QTA defines both specific quality parameters for a project and the party responsible for the execution of those parameters. The level of detail may vary depending on the project’s developmental stage, so ensure each party is aware and able to deliver on expectations. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 8 The Path Forward And Choosing The Right Partner The need to assess pDNA design, release specifications, and other complex considerations expeditiously — and the magnitude of problems that can arise from a failure to do so — drives many gene and cell therapy companies to search for an experienced partner that can help them make the right decisions. Yet, the effectiveness of that collaborative approach is tied to the choice of partner. That is one decision gene and cell therapy companies need to make on their own, but the following framework can help identify the right partner. The Ability to Expand The needs of a gene and cell therapy program will have to scale with regard to quality and capacity. To avoid bottlenecks, therapeutic developers need to know that their partner has the capacity to grow with them — and flexibility to adapt to potential process changes — as they move through the clinic and onto the market. Working with a partner that falls short of that standard can force therapeutic developers to transition to a new collaborator mid-program. Such switches are complicated and can cause delays. Aldevron has responded to an anticipated increase in the needs of its clients by committing to more than double the size of its GMP facility. When complete, the facility will have more than 50 production suites containing single-use bioreactors. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 9 Supply Chain Capability A company may decide to eschew partnering altogether and instead establish its own manufacturing and supply infrastructure. Companies that take that insourced approach free themselves of the challenge of managing multiple partners, but also expose themselves to another set of highly specialized problems. Insourcing forces companies to take on major tasks such as creating a quality management system, building a cGMP facility, and hiring, training, and retaining appropriate talent. Many companies decide the downsides associated with those tasks outweigh the challenges of partnering, leading them to outsource pDNA production and other activities. Companies that are open to outsourcing can mitigate the downsides by choosing a partner that makes interactions as seamless and easy as possible. In doing so, companies access expertise and capabilities that will advance in line with their needs and innovation in the wider sector while mitigating risk of taking this on themselves. Contract Considerations Contract considerations often take longer to execute than expected, meaning there is value in incorporating them into earlier stages of the partner selection process. While not essential, many companies see benefits to entering into master service agreements (MSAs) with their chosen partner. A MSA allows the involved parties to negotiate future contracts and statements of work more quickly because they can rely on the foundation of the terms within the master agreement for future business. Having this type of agreement already in place saves time, as the same terms only need to be negotiated once, and helps to establish a rapport between the organizations. Freedom to Operate and Licensing Considerations Gene and cell therapy companies often need to negotiate licensing or royalty terms related to cell lines, specific constructs, or manufacturing processes. There is value in considering the implications of such agreements early in development. Failure to do so can lead companies to commit to terms that they later deem to be onerous, leaving them with a choice between continuing with the materials that may be financially burdensome or trying to find an alternative late in development. Considering the full spectrum of available options early can free companies from financial commitments altogether by enabling them to identify and potentially select royaltyfree materials. Aldevron provides immediate access to royalty-free lentiviral plasmids that consistently generate functional viral vectors. The pALD-Lenti system has been used in clinical trials and remains royalty-free even once a product comes to market. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 10 The Benefits of Partnership Aldevron is a leader in advancing biological science. Our custom manufacturing services have provided scientists across the globe with the essential components to accelerate research for groundbreaking science and breakthrough discoveries. It is Aldevron’s mission to provide products and services that make meaningful contributions to biological science worldwide. We seek to be the partner of choice for producing high-quality plasmid DNA, mRNA, and other biologicals in support of our clients’ comprehensive objectives. When partnering with us, you gain access to our years of industry experience, strong scientific expertise, and preclinical, clinical, and commercial capabilities. Industry Experience With over 22 years of experience and more than 2,500 clinical lots manufactured, we have a proven track record for success. From biologics contract services to comprehensive off-the-shelf solutions, we supply what you need when you need it, with expert support. We offer a long history of industry expertise and serve as your trusted advisors. Quality and Flexibility Aldevron offers two different service levels, GMP-Source® (GMP-S) and cGMP, to support requirements for clinical and commercial products. These service levels include additional the requisite in comparison to offerings intended for preclinical applications. GMP-S is a cost-effective and time saving alternative to cGMP, which often serves as an ideal solution for early-phase clinical trial materials. Our cGMP service provides the highest quality oversight, and process control, and can support any application. Devotion to Regulatory and Quality Requirements The production of gene and cell therapies is subject to specific regulatory requirements in the U.S., European Union, and other territories. The FDA lists almost 30 gene and cell therapy guidance documents with a number focused specifically on CMC.11 The EMA has published an even longer list of documents detailing its position on advanced therapy medicinal products, such as gene and cell therapies.12 These regulations are continually being added to and revised. At Aldevron, we are well versed in the intricacies of these global regulations and, as a specialist in the field, committed to staying up to date as agencies revise their positions. The Ability for a Long-Term Partnership and Ongoing Support Aldevron has a firmly established foundational system in place to support you and your team as they develop and scale. Our state-of-the-art facility is equipped with the most advanced technology and supports multiple commercial products. We will soon have finished expanding our cGMP and GMP-Source® plasmid capacity 10-fold. Our facility supports clients with requirements for gene editing, gene therapy, and gene modified cell therapy applications. As a potential partner, we bring 20+ years of experience and strong technical expertise to support any and all pDNA manufacturing requirements. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 11 Getting Started Getting started with Aldevron is easy. From start to finish, our Aldevron team members show their commitment to the success of our clients through consistency, flexibility to needs and schedules, and true knowledge about the demands of the biotech world. In an effort to ensure we deliver the highest quality, fundamental biologics needed, we have added an efficient and easy process for clients to engage us as partners. By adding a streamlined front-end business process, we activate a quick-to-manufacture workflow, ensuring the project starts properly and ends successfully with strong communication throughout. Information and Material Transfer Technical Review Project Launch Statement of Work Execution Discovery © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 12 Conclusion There are many important considerations to take into account before choosing a manufacturer to produce your plasmids. Seeking a partner with the expertise and ability to scale up and out, in addition to asking the right questions upfront will not only save time and money now, but it will also help enable breakthroughs to reach patients awaiting these potentially transformational approaches and a better quality of life. At Aldevron, our success as a business feeds a higher ambition—to serve. In all we do, we support our partners in their discovery and to the millions of people who benefit from those discoveries. For more than 22 years, Aldevron has been manufacturing the highest quality, fundamental biologics that scientists have, and are using to rid the world of disease. And we are just getting started. Partner with us to enable your next breakthrough. References 1. ARM Global Regenerative Medicine & Advanced Therapy Sector Report H1 2020. http://alliancerm.org/ wp-content/uploads/2020/08/ARM_1H-Report_-FINAL.pdf. 2. 2015 Annual Data Report on gene and cellular therapies. https://alliancerm.org/wp-content/ uploads/2018/04/ARM_Annual_Report_2015_Web_Version_FINAL.pdf. 3. Advancing Gene, Cell, & Tissue-Based Therapies. https://alliancerm.org/sector-report/2019-annualreport/. 4. Lehmicke, M. Manufacturing Cures: Infrastructure Challenges Facing Cell And Gene Therapy Developers. https://invivo.pharmaintelligence.informa.com/IV124277/Manufacturing-Cures-InfrastructureChallenges-Facing-Cell-And-Gene-Therapy-Developers (2019). 5. Center for Biologics Evaluation & Research. CMC Information for Human Gene Therapy IND Applications. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/chemistrymanufacturing-and-control-cmc-information-human-gene-therapy-investigational-new-drug (2020). 6. Office of the Commissioner. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapyaccelerated-approval-priority-review (2019). 7. Agency, E. M. PRIME: priority medicines. (2018). 8. Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool. https://www.fda.gov/media/72566/download. 9. Q8(R2) Pharmaceutical Development. https://www.fda.gov/media/71535/download. 10.Q1A(R2) Stability Testing of New Drug Substances and Products. https://www.fda.gov/media/71707/ download. 11. Center for Biologics Evaluation & Research. Cellular and Gene Therapy Guidances. https://www.fda.gov/ vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances (2020). 12.Anonymous. Guidelines relevant for advanced therapy medicinal products. https://www.ema.europa. eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relevant-advancedtherapy-medicinal-products (2018). Aldevron serves the biotechnology industry with custom production of nucleic acids, and proteins. Thousands of clients use Aldevronproduced plasmids, mRNA and gene editing enzymes for projects ranging from preclinical to clinical trials to commercial applications. Aldevron specializes in GMP manufacturing and is the creator of the GMPSource® service offering to support viral vectors for early phase studies. © 2019 Questex Content Marketing. All rights reserved. All registered trademarks are property of their respective owners. GENE AND CELL THERAPY: PLANNING FOR MANUFACTURING SUCCESS EARLY 13