CMC Strategy Forum Europe 2020

The EFPIA MQEG Biomanufacturing sub-team has published a number of position papers and is currently progressing industry consensus activities on other key topics. Updates will be given on the progress of recent position papers relating to certain key topics such as drug device combination products, antibody drug conjugates and polysorbates. A subsequent session comprising of presentations followed by a panel discussion will be dedicated to AAV: Current Status, Manufacturing Challenges and Opportunities. The number of clinical studies in which adeno-associated viral (AAV) vectors are used for in vivo gene transfer is steadily increasing. Excellent safety profile and high transduction efficiency for numerous target tissues speak for AAV vectors in in vivo gene therapy in diseases such as coagulation disorders, hereditary blindness and neurodegenerative diseases. Gene therapies are predicted to have a similar increase kinetics as has been the case for monoclonal antibodies since the beginning of the 1980s. However, there are still a number of hurdles to be overcome in the field of manufacturing and control before a similar market penetration as for monoclonal antibodies can be envisaged. Especially the complexity of manufacturing and analytics restrict a broad application of the technology. The current main problem for gene therapy with AAV is the low yields and small manufacturing scales. Depending on the selected manufacturing technology (suspension/adherent cell culture, flatware/fixed bed, etc.), the manufacturing units may have to be significantly multiplied for larger numbers of patients, which can only be limited by significantly intensifying the process. This is also currently being pursued for the production of monoclonal antibodies. This satellite symposium will use case studies of successful AAV-based therapies to familiarize participants with the basic therapeutic mechanisms but also shed light on manufacturing-related challenges and opportunities in particular whilst also giving an overview of the regulatory challenges of AAV therapeutics.

Polysorbates (PS) are the most common surfactants in biopharmaceutical products and used to stabilize proteins against various (interfacial) stresses during the product life-cycle. Commercially available PS are complex mixtures with a large structural heterogeneity and variable composition. Additionally, PS may degrade in the therapeutic protein formulation by oxidation or hydrolysis (chemical or enzymatically driven) forming multiple degradants which even may precipitate out and form subvisible and visible particles. This complexity poses challenges during different stages of product development. Within the European Federation of Pharmaceutical Industries and Associations (EFPIA) a group of 23 experts from 16 pharmaceutical companies started to exchange scientific and technical information on the use and characterization of polysorbate in biopharmaceutical products. They worked out a survey with 137 questions to benchmark the handling, analysis, degradation, control strategies, and regulatory aspects of polysorbate. Preliminary results of this survey will be presented.

Antibody drug conjugates unite the specificity and long circulation time of an antibody with the toxicity of a chemical cytostatic drug using smart linkers to reduce systemic toxicity and increase therapeutic index. This combination of a large biological molecule and a small synthetic molecule creates an inherent increase in complexity. Multiple production processes are required to produce the naked antibody, the drug and the linker, followed by conjugation of aforementioned entities to form the final antibody drug conjugate. The connected processes further increase the number of points of control, resulting in necessity of additional specifications and an increased load of analytical characterization. By combining scientific understanding of the production processes with risk-based approaches, quality should be demonstrated at those points where control is required and redundant comparability studies, specifications or product characterization avoided. Over the product development lifecycle, this will allow process qualification to focus on those areas affected by a change and prevent redundant studies. The structure of a module 3 global technical dossier for an ADC needs to reflect each of the production processes and the combined overall approach to quality. Historically, regulatory authorities have provided varied expectations on its structure. An overview is provided of essential information to be included showing that multiple approaches work as long as adequate cross-referencing is included. This talk outlines the content of a white paper soon to be published by a workstream under the Biomanufacturing Working Group by EFPIA.

With several recent FDA approvals and a strong drug pipeline, gene therapy is coming of age. With this comes the requirement to ensure that there are robust manufacturing processes in place in order to scale with demand and to make these therapies readily accessible to those who need them. However, current manufacturing processes for gene therapies have often been developed with limited scalability in mind and large shifts in technology have to take place to enable industrialization. This also has to be done while keeping costs in mind. Here, we will present the challenges and solutions to scale up process steps required to develop manufacture iCELLis bioreactor process for scalable production, purification and analytics of AAV viral vector. After implementation of a large-scale of the entire process, we offer the client scalability and speed to the market

Scientific literature shows that, recombinant AAV vectors derived from human- versus insect cell manufacturing platforms exhibit significant different potency. The causes for these differences seem currently not entirely clear. It is reasonable to conclude that we do not yet know certain important quality attributes of the rAAV products. This lack of knowledge is especially critical in case of manufacturing changes and scale-up activities during development of the manufacturing process because comparability of the resulting rAAV material has to be ensured. Thus, with respect to a future Marketing Authorization Application it is important to apply a state-of-the-art characterization panel in order to have the best possible picture of the manufactured rAAV material.

ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management” reached Step 4 during the last ICH meeting in Singapore in November 2019. Q5A(R2) “Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin” was endorsed by the ICH Assembly in June 2019 and EWG are advancing work on the concept paper. Q2(R2)/Q14 “Analytical Procedure Development and Revision of Q2(R1) Analytical Validation” and Q13 “Continuous Manufacturing of Drug Substances and Drug Products” are anticipated to sign-off on Step 1 in May and June 2020, respectively. This session will provide updates for these guidelines and concept papers through a series of discussions and case studies with industry and regulators to illustrate the mindset of the Expert Working Groups, before the next ICH meeting in Vancouver, BC, Canada in May 2020.

The guideline, ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, is intended to work with ICH Q8 to Q11 Guidelines and will provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. The guideline has been under development since 2014 and in November 2019 it was finalized by the Expert Working Group. In EU, the guideline and its annexes were published at the EMA webpage on 4. March 2020. The Q12 guideline was thereby implemented in EU. An implementation note was published on the EMA webpage together with the guideline. Full implementation of all elements of Q12 is not possible at this stage as some parts are not considered compatible with the existing EU legal framework on variations. This presentation will give a short introduction to ICH Q12 and give and the implementation in EU will be illustrated. In addition, the presentation will give a short update on the revision of ICH Q5A and share information on the on-going work in ICH Quality Discussion Group (QDG)

The ICH Q12 Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management and its Annexes reached Step 4 of the ICH Process at the ICH meeting in Singapore on 21 November 2019. This new Guideline provides a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. One essential concept of ICH Q12 is that sponsor propose, and regulators agree to Established Conditions (EC’s) for manufacturing processes. ECs are legally binding information considered necessary to assure product quality. ICH Q12 on January 27th, 2020 CASSS sponsored a Sharing Science Solutions workshop on the identification of Established Conditions in support of ICH Q12 implementation. Run in parallel with the CASSS CMC Strategy Forum North America meeting in Washington DC, this workshop invited industry participants and FDA to share ideas and progress toward the implementation of ICH Q12 with a focus on the identification EC’s and their proposed reporting categories. Over 50 attendees participated in the workshop, representing over 20 companies (large and small), FDA (CBER, CDER), and PEI. Three industry case studies were presented, followed by a panel discussion and a working session where workshop participants identified EC’s for a cation-exchange chromatography case study using Traditional/Minimal, Enhanced, and Performance-based approaches. This talk will provide a summary of that workshop.

Continuous Manufacturing is the future standard for solid oral dosage forms. The greater process understanding, and control is redefining how drugs are produced. The faster, more precise and reliable manufacturing approach is enabling accelerated development. The case study reviews how continuous manufacturing supports accelerated development programs in a globalized context. The format will allow for interactive Q&A.

The new ICH Q14 guideline is proposed to harmonise the scientific approaches to analytical procedure development and provide the principles relating to the dossier description. The new guideline will include elements of enhanced development for analytical procedures, which may contribute to more robust methods. This guideline is intended to improve regulatory communication between industry and regulators and facilitate more efficient, sound scientific and risk-based approval as well as post-approval change management of analytical procedures. The guidance will complement existing and in-draft ICH guidance. The revision of ICH Q2 will provide a general framework for validation of different analytical techniques for analysis of products in the scope of ICH Q6A and Q6B. This will include validation principles for spectroscopic or spectrometric techniques (NIR, Raman, NMR, MS etc.,) some of which often require multivariate statistical analyses. Validation principles for techniques for analysis of biological products are also covered. This presentation will give an update on progress with these two guidelines, explain the current structure and content and introduce some of the key concepts.