Group B – Topics 21-40
Table 21: Raw Materials Procurement Challenges – Lessons from the Pandemic
Facilitators –
Kristin Bennett, Merck & Co., Inc.
Isabelle Lequeux, BioPhorum Operations Group
Scope:
The Pandemic has put a focus on Supply Chains - even before, there were several concerns over
the availability of key raw materials going into cell culture media, key consumables used in Single
Use Systems, and container closure components. The Pandemic has worsened the supply situation
- from initial disruption in supply chains through manufacturing under the pandemic conditions.
Finally, the impact of the preparation for and the production of the vaccine candidates - this has
shock loaded the supply base with important levels of demand for materials and prioritization
schemes which impact supply chain dynamics. The situation has not yet resolved itself into the
new normal level of demand and it will be a while before we do have longer term clarity on the
impact of the Pandemic on global supply chains, especially for key materials; that Planning
Forecast, Demand and Production is more important now than ever and building resilience into
supply chains at a global level across an enterprise (and not just a site level plan) is key to proper
Risk & Business Continuity Management.
Questions for Discussion:
1. How have you been impacted by the Pandemic - in what areas of operations of the supply
chain have you seen be affected as the course of the Pandemic has evolved ?
2. What has the Pandemic made you do different with regards to your supply chain
management practices?
3. What are your major concerns for the future over the next 2–3-year horizon?
What is your long-term approach to building resilience into your global supply chains?
What are your thoughts on the need to collaborate and share best practices as an industry
so that we can make best use of the limited availability of key raw materials and
consumables?
Table 22: Vaccine Potency Assays
Facilitators –
Brian Nunnally, Seqirus, A CSL Company
Jyothy Pillai, Merck & Co., Inc.
Varnika Roy, GlaxoSmithKline
Scope:
Potency is defined as a quantitative measure of biological activity based on the attribute of the
product which can be linked to relevant biological properties. The assay to measure the vaccine
potency is used throughout the vaccine lifecycle to support its research and development and is a
regulatory requirement for the release and stability of clinical materials. Historically, potency
assays based on in vivo models (e.g., challenge with the pathogens after vaccination) have been
used to measure the activity of the product related to its specific ability or capacity to achieve a
defined biological affect. However, the immune response in an animal model may not be predictive
of what will ultimately occur in humans. In addition, with the variability observed in animal
experiments and in conjunction with 3R (Reduction, Refinement and Replacement) policies in
vitro tests should be considered as an alternative to provide biological activity measurement by
relating structural conformity/integrity to functional activity of the antigen and demonstrating
consistency of lot to lot production.
Questions for Discussion:
1. Do you use in vitro relative potency methods for potency release assays vs in vivo?
2. Do you have experiences showing in vitro to in vivo concordance what were the hurdles?
Did you do this in Phase 1 or Phase II?
3. Experience of moving immuno based potency assays to new technologies such as Octet or
Multiplex Bio-plex vs a traditional ELISA- What were the challenges?
4. Do you focus the Potency assay on showing Consistency Lot to Lot vs Mode of Action
demonstration?
5. DP- Drug Product vs Reconstituted Vaccine: Release potency assay on the DP vs
Characterization on the Reconstituted vaccine- What panel would you use?
6. What about replacing an in vivo assay with in vitro for a legacy product? Share any
examples?
7. What kind of comparability studies would be needed to support to a new potency assay?
Are clinical studies always necessary?
Table 23: Adapting CMC Activities for Accelerated Approvals: Challenges and Lessons
Learned, Especially from Pandemics (Stability, Specifications, Analytical Method
Comparability)
Facilitators –
Uma Balasubramanian, Daiichi Sankyo, Inc.
Carol Krantz, Seagen Inc.
Scope:
CMC development activities are often gated by clinical data readouts and can become critical path
if program timelines are compressed. We will discuss strategies for accelerating rate limiting
CMC activities for submission, meeting logistical requirements, and mitigating impact to lifecycle
maintenance. Come prepared to discuss experiences with or ideas for fast-to-market strategies,
perhaps drawing from recent experiences with development of vaccines and neutralizing antibody
therapies for COVID-19.
As this topic covers many quality aspects of accelerated product development, Table 23 will focus
on control strategy concepts such as specifications setting, stability, and analytical methods. In
parallel, Table 24 will cover topics relating to manufacturing such as site transfers and scale ups,
process and product comparability, and process validation.
Questions for Discussion:
Accelerating submissions:
1. What are strategies for setting DS and DP specifications beyond clinical and manufacturing
experience, with limited lots tested with commercial, validated methods, to enable
sufficient supply chain flexibility?
2. What are strategies for analytical method transfers/validation?
3. How are analytical comparability criteria established for limited pre/post change batches?
4. What strategies can support a harmonized control strategy for simultaneous country
submissions?
5. How can prior knowledge be leveraged?
Logistics:
1. What are the lessons learned from inspections in the times of COVID-19?
2. How might Sponsors better plan for product launches immediately following early
approvals and could communications between regulators and sponsors help?
3. What are the challenges and opportunities of launching from a clinical facility?
4. What are best practices for managing accelerated regulatory reviews, including programs
such as FDA's Real Time Oncology Review, Project Orbis and Quality Assessment Aid?
Lifecycle challenges:
1. How do Sponsors balance global submission requirements if only a subset of countries
agrees to a risk/benefit approach that supports accelerated submission, review, and product
launch?
2. What initial core dossier structure/content would support quicker access to global markets?
3. Have you applied ICH Q12?
Table 24: Adapting CMC Activities for Accelerated Approvals: Challenges and Lessons
Learned, Especially from Pandemics (Site Transfers, Scale Up, Comparability and Process
Validation)
Facilitators –
Markus Goese, F. Hoffmann - La Roche Ltd.
Carol Krantz, Seagen Inc.
Scope:
CMC development activities are often gated by clinical data readouts and can become critical path
if program timelines are compressed. We will discuss strategies for accelerating rate limiting CMC
activities for submission, meeting logistical requirements, and mitigating impact to lifecycle
maintenance. Come prepared to discuss experiences with or ideas for fast-to-market strategies,
perhaps drawing from recent experiences with development of vaccines and neutralizing antibody
therapies for COVID-19.
As this topic covers many quality aspects of accelerated product development, Table 24 will cover
topics relating to manufacturing such as site transfers and scale ups, process and product
comparability, and process validation (PV). In parallel, Table 23 will focus on control strategy
concepts such as specifications setting, stability, and analytical methods.
Questions for Discussion:
1. Accelerating submissions:
a. What approaches can be taken to compress the timing for site transfers and process
validation (e.g. ADCs, mAbs)?
b. What are ways to overcome challenges of limited lots for PV?
c. How can comparability assessments justify provision of site transfer/scale up data
during review and potentially launch with clinical supply?
d. What happens when something goes wrong with manufacturing?
2. Logistics:
a. The DP process is validated but the inputs for the DP PPQ runs are pre-PPQ; can
these DP PPQ batches serve as launch material if their upstream inputs were not
from validation runs?
b. What are lessons learned from inspections during the pandemic?
c. How can Sponsors balance fixed production schedules with pre-license inspections
during accelerated reviews?
d. How might Sponsors better plan for product launches immediately following early
approvals?
e. What are best practices for managing accelerated regulatory reviews, including
pilot programs?
3. Lifecycle challenges:
a. How do Sponsors balance global submission requirements (e.g. different PV data
packages) if only a subset of countries agrees with the risk/benefit?
b. What initial core dossier structure/content would support quicker access to global
markets? Have you applied ICH Q12?
Table 25: Reference Standards for Cell & Gene Therapy Products: Best Practices for
Autologous Therapies
Facilitators –
Kirsten Kramer Jakobsen, Novo Nordisk
Helena Madden, bluebird bio, Inc.
Scope:
Reference standards are a critical component of process control strategies for therapeutic proteins.
Although some international or national standard materials are available for C> products, most
manufacturers are developing their own product-specific internal reference standards for product
development and commercialization. For this unique class of products templated approaches to
reference standards should be feasible for accelerating development. This roundtable will discuss
the challenges in C> standardization and best practices for establishing, characterizing, and
qualifying in-house primary reference material and working reference materials for C>
products.
Questions for Discussion:
1. What are the challenges for C> reference standards you are facing?
2. What are your thoughts on reference standards limited to specific products versus industry-
wide standards for specific product classes?
3. What are your thoughts on best practices for development of reference materials for C>
programs and autologous therapies?
4. What materials are used as reference standards during the different phases of product
development?
5. How are you envisioning bridging to a new reference material during product
development? What statistical assessments are performed to justify difference between
PRS and WRS?
6. What are the challenges and strategies for assigning potency for bioassay reference
standards? What type of testing and acceptance criteria do you apply to prevent potency
drift during product lifecycle?
7. Are there any unique considerations for evaluating stability of C> reference
standards? How are acceptance criteria established?
Table 26: Harmonization of Global Regulatory Submission Writing to Enable Acceleration
Facilitators –
Shannon Holmes, Biogen
Minh Luu, Genentech, a Member of the Roche Group
Scope:
There has been a recent shift in submission practices where the timeline gaps between regulatory
submissions to major regions (e.g., FDA/EMA/PMDA) vs. other regions have narrowed. This has
been enabled by accelerated regulatory pathways and a recognition of the need to get potential
access to life-saving therapies globally. While faster, broader access is a positive benefit, there
are practical implications in trying to gain approval in multiple countries as the same time. This
roundtable will discuss and share best practices on how to author global Module 3 submission
content to enable accelerated submissions to multiple regions. Topics to be discussed include:
development of “core” dossiers, balancing customization to various HA requirements vs.
minimizing differences in submissions, reacting to developing/changing regulations, lifecycle
management approaches, and experiences using reliance pathways. Also, we may discuss how
ICH Q12 and KASA (Knowledge-aided Assessment and Structured Applications) may facilitate
or complicate the preparation of global dossiers for accelerated programs.
Questions for Discussion:
1. Are companies creating one global dossier or multiple versions that can be tailored to
most major regions?
a. Are templates prepared and agreed upon ahead of time?
b. Does parallel authoring occur between regions?
2. What core manufacturing and testing content can be authored to meet most regional
expectations (e.g., critical parameters only, key manufacturing steps, etc.)?
3. What Q12 aspects might be binding in different regions?
4. What challenges have companies faced in different regions (e.g., chromatogram
requirements, compendia differences, development data expectations, registering
information typically provided during inspection, protocol challenges [e.g., reference
standard/WCB regional expectations])?
5. Do companies develop a strategy beforehand regarding which details to omit in
anticipation of a query vs. what to include in anticipation of having to push back on
other items? Is a risk assessment/risk register used for making these strategic decisions?
Table 27: Best Practices for Working with CMOs for De-centralized Manufacturing
Facilitators –
Bharat Dixit, ClearB Therapeutics
Erin Tulip Bioverativ, a Sanofi Company
Scope:
Centralized manufacturing has been the dominant model for large-scale production since the
Industrial Revolution. In contrast de-centralized manufacturing (DCM) also referred to as
‘redistributed’ manufacturing relies on leveraging manufacturing capacity across several
geographic regions, providing local and responsive manufacturing, typically customized to the end
user. The DCM concept is especially attractive for certain modalities/products such as cell and
gene therapy (CGTs), primarily to overcome challenges associated with long-term storage and
long-distance shipping.
CMOs (Contract Manufacturing Organizations) with established platform processes along with
comprehensive knowledge of the scientific, technical, and local regulatory requirements and
presence in various geographical locations can bring unique capability and capacity. DCM
approach also allows utilization of multiple CMOs having unique expertise in distinct unit
operations such as initial processing, fill-finish etc.
In addition to several advantages, DCM, also poses challenges such as overall quality control,
batch-batch reproducibility and integration/handover of information from one site to other, local
regulations, batch sizes and cost as a result of running and managing multiple sites.
In this round table, we plan to discuss key advantages, disadvantages, challenges and individual
experience when working with CMOs for DCM
Questions for Discussion:
1. Are there some technologies more suitable for DCM than others?
2. Experience working with/ implantation of new technologies/equipment’s
3. Dos and Don’ts when working with CMOs for DCM (keeping CMOs name anonymous)
4. Additional complexity encountered when using multiple CMOs for the same product and
best practices for meeting these challenges.
Table 28: Scaling Out: What Is It? What Are the Requirements
Facilitators –
Ekta Mahajan, Genentech, A Member of the Roche Group
Veena Warikoo, F. Hoffmann-La Roche AG
Scope:
This table will discuss opportunities and challenges associated with scaling out for small/large
molecules, high/low volume production and product development stage. The traditional
manufacturing promoted starting with small scale and scaling up to accommodate larger
production demand. However, with globalization and numerous individualized therapies, will
traditional manufacturing concept continue or would trends shift towards scaling out. The
participants will discuss opportunities for scaling out or scaling up, enabling factors for scaling
out, scenarios unfriendly for scaling out and regulatory and validation considerations.
Questions for Discussion:
1. Decision of scaling up vs. scaling out
a. Challenges
b. Opportunities, e.g. Individualized therapies
2. Impact of automation and adoption of SU: Enable scaling out?
3. Benefits of scaling out on other activities
a. Does it enable automation of supply chain?
b. Provide flexibility with global production, decentralized facilities, manage demand
volatility
c. Enable multi-product facilities, multiple modalities
d. Easier regulatory path for facility extension, commissioning, change management,
family approach for validation
4. Scenarios where scale out is not feasible or cost effective
Table 29: Analytics for Accelerated Products: Challenges and Opportunities
Facilitators –
Carl Miller, Seagen Inc.
Christopher Yu, Genentech, a Member of the Roche Group
Scope:
With the commitment to deliver future medicines to patients faster and in more cost-effective
manners, biopharmaceutical industry and regulatory bodies around the world continue to advance
the strategies and approaches for accelerated approvals. From product and process characterization
and identification of critical quality attributes, to establishing appropriate methods and control
strategies for commercial manufacturing, advanced analytics is of critical importance to
accelerated development. What are key considerations in analytics to better support faster and
shortened process development? With Breakthrough and Priority Medicines programs in place,
what has been our experience supporting accelerated submissions? What are the specific advice
from health authorities in the area of analytics from such reviews?
This roundtable discussion will include technical and regulatory considerations in analytics for
accelerated clinical development and market authorization applications. Challenges experienced
as well as opportunities within the analytics area will be the focus of the sharing and collaborative
learning.
Questions for Discussion:
1. Platform or prior knowledge – how far can we go in leveraging what we know from other
products?
2. New technologies and their applications – What are opportunities and potential hurdles?
3. Critical Quality Attributes (CQAs) – How do we decide what to test in less time?
4. Control strategy and specifications, reference standard and shelf life – How are these
elements satisfied while working with (limited) clinical and process knowledge?
5. Method development, validation and transfer – How do we best navigate the various stages
of the method life cycle?
Table 30: Emerging Analytical Technologies to Get to Market Faster
Facilitators –
David Cetlin, Cygnus Technologies
Sonali Garg, AstraZeneca
Kimberly Wolfram, Biogen
Scope:
As the pharmaceutical industry moves into the cyber-physical era, sometimes referred to as
Industry 4.0, it will be imperative to harmonize expectations when developing advanced
manufacturing technologies to accelerate their successful adoption and maturity. Even though
many industries are already realizing the benefits of APC, intelligent control concepts are not yet
widely adopted in biotech, with very few published applications. Most bio-pharmaceutical plants
still operate in a very manual mode without the data infrastructure required for real-time process
modeling (from a data synchronization and aggregation standpoint). Even when the data
infrastructure is sufficient, questions regarding regulatory impact, global acceptance, intended use,
risk versus benefit, cost and model maintenance frequency may lead to strong headwinds to
adoption of the technology. (Romero-Torres, 2018).
New modalities and technologies enable the development of analytical technologies as these can
greatly improve product understanding and gain better control of the manufacturing process and
product quality. Some of the recent emerging technologies and strategies for product
characterization, release and stability include novel and advanced analytical instruments (mass
spectrometry, NGS), sensitive and more specific methods, process analytical technology (PAT),
implementation of high throughput (HTP) methods and greater use of automation.
This roundtable aims to discuss the challenges involved in the development and possible solutions
which our industry is adapting to ensure the introduction of the novel technologies.
Questions for Discussion:
1. Do you have experience in submitting or submitting and gaining approval for emerging
analytical technologies? If so, what was your experience, challenges, and learning?
2. What is the status in your company and where do you see the further applications of Multi-
Attribute Method (MAM) going forward?
3. What are some of the new analytical technologies you have been using to support Cell &
Gene Therapy?
4. What is the value proposition being shared with your company or agency regarding
emerging technology?
Table 31: New Modalities and Technologies (other than CGTP)
Facilitators –
Candyce Lebeduik, Merck & Co., Inc.
Cindy Wu, Merck & Co., Inc.
Scope:
Drug development has expanded tremendously from small molecules to complex biological
modalities, and this trend has accelerated with a greater diversity in the types and applications of
new modalities and new technologies. The conjugated drugs in anti-body drug conjugates (ADCs)
have been small molecules, but there is a wide variety of new types of conjugated modalities under
investigation. The growth represents a challenge for pharmaceutical industry as well as global
regulatory authorities while the regulations will need to adapt to the everchanging landscape.
This round table will serve as an interactive forum to discuss current challenges, learnings and best
practices across industry and regulators.
Questions for Discussion:
1. Types of new modalities and technologies
a. Innovative antibody therapeutics
b. New developments in preventive biological products
c. Multifunctional modalities
d. Emerging technologies
2. What are the main challenges for new modalities and technologies?
a. Lack of specific regulatory guidance and no clear legislative pathway
b. Registration classification dependent requirements
c. Designation of starting materials and intermediates
d. Comparability and characterization
e. Process related impurities and product related impurities
f. Potency and stability
3. Any best practices and lessons learned from industry and regulators
a. Antibody drug conjugates (ADC)
4. Considerations for global drug development in US, EU, China, Japan and other markets
a. Harmonized regulatory requirements
b. Science and risk-based approach
Table 32: Visible and Sub-visible Particles: Practical Experiences in Manufacturing
Support and Quality Control
Facilitators –
George Bou-Assaf, Biogen
Jan Olaf Stracke, F. Hoffmann - La Roche Ltd.
Scope:
Sub-visible and visible particulates need to be controlled in parenteral products to ensure patient
safety. USP <1> and EP <7.0> provide guidance to visible particles in parenteral products.
Furthermore, recent USP Chapter <790> and monograph <1790> specify conditions and clarify
requirements of “essentially free from particulates” introducing AQL concept. However, there are
many common challenges in industry practices and testing, such as setting practical acceptance
criteria, analyst training/qualification, characterization of observed visible particles and adequate
corrective action.
With regard to subvisible particle testing, low volume DP presentations (for example AAV
products or dosage forms for intra-vitreal administration with fill volumes as low as e.g. 0.25 mL)
are gaining importance in the industry. New testing strategies and technologies are required to deal
with these challenges.
This round table will serve as an interactive forum to discuss current issues and learnings across
industry and regulators.
Questions for Discussion:
1. Visible particle Testing/Training
a. What types and sizes of defects are included in visible particle training sets?
b. How to differentiate inherent particles versus foreign particles?
c. Which methods are applied for characterization and determination of particle identity?
d. Can visible particle standards (NIST) be used to enhance training toolkit?
e. Manual or automated visual inspection? Advantages (and maybe limitations) of
automated visual inspection instruments over manual inspection?
2. Visible particle acceptance criteria
a. What does “essentially or practically free of visible particles” mean?
b. What level of particulates is acceptable?
c. How are particles qualified in particulate prone products, i.e. which data are needed to
support/justify?
3. Subvisible particle considerations for low-volume products
a. What different strategies are each of the companies adopting?
b. Beyond light obscuration, what are other techniques are companies looking into?
Acceptable by regulatory agencies?
c. What other considerations need to be taken into account?
Table 33: Multi-Attribute Method - Challenges in Using MAM for QC of Therapeutic
Proteins
Facilitators –
Zhiqi Hao, Genentech, a Member of the Roche Group
Chongfeng Xu, Biogen
Scope:
Multi-attribute method (MAM), a liquid chromatography-mass spectrometry (LC-MS) based
peptide map method, consists of a targeted quantitation function and a non-targeted feature known
as new peak detection (NPD). The targeted function provides relative quantitation of multiple
PQAs in a single analysis, while NPD is a data processing approach performing differential
analysis of LC-MS chromatograms, which can be used to detect unexpected peaks in clinical
batches compared to reference standard.
MAM has been discussed with FDA’s Emerging Technology Team, which works with drug
developers to facilitate the adoption and implementation of novel technologies. It is suggested
that MAM could be used as a replacement for at least several conventional QC methods, including
hydrophilic interaction liquid chromatography for glycan profiling, ion exchange chromatography
for charge variant analysis, reduced capillary electrophoresis-sodium dodecyl sulfate for clipped
variant analysis, and identity test as well. There has been broad interest in the implementation of
MAM for QC testing of therapeutic proteins in the biopharmaceutical industry.
This roundtable focuses on the scientific and regulatory considerations and challenges when
implementing MAM for QC of therapeutic proteins.
Questions for Discussion:
This roundtable will begin with an introduction by participants on the current status of MAM in
their organizations. The following are topics for discussion:
1. Method development
a. Targeted MS: Precision, Robustness, etc.
b. New Peak Detection: false positive detections, thresholds and fold changes that
constitute a new species
2. Method validation
a. System suitability
b. Operating MAM in QC lab
3. Setting product release specifications: MAM vs conventional method
4. Regulatory considerations
a. Risks assessment of using MAM to replace conventional QC method
b. Best practices for incorporating MAM data and information in regulatory
submissions
5. New and unique MAM applications, and MS in QC beyond MAM.
Table 34: Structure Function Studies of Non-standard mAb and Protein Therapeutics
Facilitators –
Peter Day, Genentech, a Member of the Roche Group
Jyothy Pillai, Merck & Co., Inc.
Scope:
In recent years, structure-function roundtable discussions have focused largely on approaches for
standard monoclonal antibodies (mAbs). However, protein therapeutics, non-standard mAbs,
fusion proteins, and protein scaffolds, are becoming increasingly common. For the non-mAb
protein therapeutics mentioned, the novel structures and targets can lead to challenges in defining
the Quality Target Product Profile and therefore make it difficult to identify critical quality
attributes. In this roundtable session, we will focus on approaches to the structure-function
relationship of non-mAb protein therapeutics, what can be leveraged from extensive knowledge
of mAbs and what new approaches are needed.
Questions for Discussion
1. What, if any, novel analytical tools are being used to investigate the structure-function
relationship of non-mAb protein therapeutics?
2. What are the challenges associated with designing potency assays that accurately reflect
the MoA of multi-faceted protein therapeutics?
3. Is knowledge gained from structure-function studies of standard mAbs largely applicable
to non-standard mAbs and other protein therapeutics?
4. To what level do you include structure-function considerations in your developability
assessment of non-mAb protein therapeutics?
5. For established commercial products/biosimilars, are there lessons learned,
improvements, or different approaches to structure-function that can inform efforts on
newer molecules?
Table 35: Gene Editing Pharmaceutical Characterization and Control Strategies
Facilitators –
Jennifer Chadwick, BioAnalytix
Michael Molony, Sangamo Therapeutics
Scope:
While the principles of control strategy for gene editing biotherapeutics are similar to other
parenterals, there are unique challenges with this new class of modalities. Control of raw materials,
critical ancillary reagents, analytical reference standard, stability testing, supply chain and making
manufacturing changes create opportunities to design and implement distinctive approaches for
gene editing therapies. For gene editing products, a templated approach for a control strategy
should be possible to accelerate development. In this roundtable we will discuss the phase
appropriate controls for production, process development decisions, release testing and
distribution of gene editing products.
Questions for Discussion:
1. What are the key assays you utilize for pre-IND characterization of drug substance/drug
product used for gene editing? What assays are most informative for making process
development decisions? Have your characterization assays evolved during clinical
development stages? Why and how?
2. What are the unique aspects of raw materials to evaluate and control for gene editing
products? What are the key considerations/concerns about intermediates/critical
ancillary materials for development of ex vivo (transformed cell) therapies? What
difference are there for in-vivo (gene editor molecule introduced by vector) therapies?
3. What are the unique aspects of progression of control strategy for gene editing products
through clinical development for ex-vivo vs in-vivo editor delivery? What are the
process control aspects? Formulation and administration control aspects?
4. Envisioning a templated approach to manufacturing and testing, similar to the A-mAb
approach -can this be done for gene editing therapies? What elements from A-mAb
would be most applicable to gene editing therapies?
5. Reference Material: what are you using and how do you choose/make decisions on
your reference standard(s)?
6. What is the basis of establishing analytical comparability early in development? How
would one demonstrate analytical comparability of gene editing products when major
changes to the manufacturing process or the product itself occur during later phases of
clinical development?
7. What are the unique characterization and control challenges with gene editing products
that you are facing? What are the corresponding regulatory challenges?
a. What are the issues for ex-vivo vs. in-vivo potency assay development and release
assay specification setting?
b. What are the challenges of each type of gene editing technology (TALENs, ZFPs,
or CRISPR/Cas-9) with regards to characterization and why? Advantages and
disadvantages?
c. What is the role of NGS/WGS (whole genome sequencing—in vivo)/WES (whole
exome sequencing—ex vivo) in gene editing therapies? What are the advantages /
disadvantages of short vs. long read sequencing technologies for this modality?
What are the challenges of this technology? What role does bioinformatics play
and are these types of platforms able to be validated?
d. How do you statistically quantify the efficiency of gene editing?
8. How do you address the safety risks in your control strategy?
e. What are the challenges with proving editing fidelity of the genome modifications
as it relates to safety?
f. How do you address insertional mutagenesis, oncolytic activity, off-target
genotoxicity at unintended sites, and/or immunogenicity?
g. Pharmacokinetics and biodistribution?
h. Tumorogenicity?
i. Genetic stability of insert?
Table 36: Practical Considerations for Implementing ICH Q14 for Each Drug Modality –
Old and New
Facilitators –
Christof Finkler, F. Hoffmann - La Roche AG
Jinhui Zhang, CDER, FDA
Scope:
Analytical procedures are necessary to help develop products and monitor the manufacturing
process, measure critical quality attributes and to help ensure the quality of final products. These
analytical procedures can be modified or improved throughout the product lifecycle because of
continual improvement activities. This round table is intended to encourage discussion on practical
consideration for implementation of ICH Q14 with respect to chemical modalities, analytical
methods and control strategies.
A new guidance, ICH Q14 Analytical Procedure Development, is in development and its current
status is step 1. The guideline will provide an opportunity to present the outcome of Analytical
Procedure Development in both traditional and enhanced approaches (i.e., QbD models) and to
facilitate identifying and then selecting operating conditions for methods. The guidance may also
assist sponsors with information about model updates and re-validation experiments that reduce
the regulatory burden of post-approval changes (PAC) with the goal to enable more efficient,
scientifically sound and risk-based change management procedures.
Questions for Discussion:
1. How will Q14 be related to Q2 (R1) revision, and what will be the benefit if Q14 and
Q2(R2) are combined?
2. How to align different aspects of AQbD (Analytical quality by design) /MLCM (Method
lifecycle management) that are already present with Q14?
3. How will this new guidance apply to analytical methods for new modalities lack of prior
knowledge?
4. How will Q14 be related to Q13, in terms of development of procedures for Real Time
Release Testing (RTRT), validation of multivariate procedures, and application of process
analytical tools (PAT)?
5. How will Q14 facilitate implementation of method improvements and novel technologies?
6. How are the requirements different if it is an entirely new type of test (i.e. no prior product
specification) vs replacing an existing test for the product attribute?
7. What type of regulatory flexibility is the industry expecting for different modalities?
Table 37: Challenges in Meeting Global Pharmacopoeia Requirements – Strategies to
Harmonize
Facilitators –
Markus Blümel, Novartis Pharma AG
Tami Wu, Seagen Inc.
Scope:
Compliance with requirements published by pharmacopoeias around the world is a legal and
regulatory requirement for companies operating globally. The test methods, monographs and
general chapters published by pharmacopoeias affect the entire lifecycle of a
product. During development and late-phase clinical trials each company must establish an
appropriate standard of quality to ensure that drug substance and drug product consistently meet
the defined quality profile. The compendial compliance is required when a drug is submitted to
regulatory agencies to gain marketing approval. There is merit to ensure compendial compliance
already during the development stage, to ensure a smooth product launch and commercialization.
Challenges arise, when regulatory expectations and processes differ between different regions, e.g.
with regards to acceptance criteria or analytical approaches used to evaluate the material and/or
product. Once a drug product is licensed, the manufacturer must comply with their approved
registration and with applicable monographs and associated general chapters, along with other
applicable content in the pharmacopoeias.
Many pharmacopoeias support initiatives for harmonization, to establish consistent, global
pharmacopoeia standards. This roundtable session will provide opportunity for participants to
discuss challenges, share perspectives and successful experience on how to meet health authority
expectations to comply with pharmacopoeia requirements, and deliver quality medicines that
extend and improve the lives of patients worldwide.
Questions for Discussion:
No questions included at this time.
Table 38: Core Analytical ICH Topics & Their Impact ICH Q6, Q2/14
Facilitators –
Mary Beth Pelletier, Biogen
Janeen Skutnik-Wilkinson, Biogen
Scope:
Current thinking has evolved significantly since ICH Q6 & Q2 were first developed. In order to
adjust to the changes in science and technology ICH Q2 is being revised, ICH Q6 is proposed for
revision and ICH Q14 has been adopted as a new topic for development. We are in a unique
position where there is still time to influence the development and outcome of these guidances.
This roundtable is intended to discuss the impact of these changes and gather broad input on the
revisions that can be shared with ICH.
Questions for Discussion:
1. What key aspects would people like to see in the revision of ICH Q6?
2. How can the revisions of Q6/ Q2/Q14 facilitate accelerated product development and
lifecycle management?
3. How can Q6 be modified to apply to newer modalities?
4. Modernization: As part of a comprehensive approach what alternate justifications to define
specification criteria beyond statistical analysis of manufacturing batches for clinical
studies could be used?
5. ICH Q14 discusses the importance of prior knowledge, has your company been using prior
knowledge in the development and lifecycle of analytical methods
a. Have you successfully leveraged the concept of platform analytical procedures to
reduce scientific and regulatory burden in a risk based manner?
6. How has change management for analytical methods evolved overtime? And how have
you incorporated QRM into this process?
7. What incentives does industry need to implement Q14?
8. How do we balance science & risk based approach with the desire for specificity in some
markets? (the “we are harmonised but request additional specifics and differences”)
9. Applicability/non applicability of standards for gene therapy and how are you navigating?
Table 39: Status of Vaccine Therapies for COVID-19
Facilitators –
Chiara Indiani, Merck & Co., Inc.
Candyce Lebeduik, Merck & Co., Inc.
Brian Nunnally, Seqirus, A CSL Company
Scope:
COVID-19 has created an unprecedented (I do hate that term and it is overused, but relevant here!)
challenge for vaccine manufacturers. However, we have seen amazing new opportunities which
were unimaginable only one year ago. As of the writing of this abstract, Pfizer and Moderna have
been able to secure Emergency Use Authorization in the United States for their mRNA-based
vaccines, launching their products to the public in record speed. Many other companies are
following closely behind and will contribute to solving this overwhelming public health crisis.
This roundtable will focus on the current status of use for the COVID-19 vaccines and what the
future holds, as best as we can tell. We will discuss what we have learned because of this and how
we can apply those lessons to a brighter future yet to come.
Questions for Discussion:
1. What is the current status of the COVID-19 vaccines? What vaccines are imminent?
2. What have we learned from this experience? What is temporal and what will be long
lasting?
3. What about other platforms other than mRNA?
4. Now that we have these vaccines – what comes next? How will post-approval changes
and customer input alter the landscape?
Table 40: Status of Biotherapeutic Therapies for COVID-19
Facilitators –
Tura Camilli, Amgen Inc.
Sameer Parbatani, Merck & Co., Inc.
Daniel Peng, Merck & Co., Inc.
Scope:
The SARS-Cov2 pandemic has brought the need for therapies to be developed at unprecedented
speed, challenging both Industry and regulators to partner in developing strategies to address these
new challenges.
Points of discussions will include an assessment of the therapeutic SARS-Cov2 landscape, a
discussion of the technical, operational, and regulatory hurdles in development of these therapies,
and a conversation around the needs and challenges ahead.
Questions for Discussions:
1. What do companies and regulators perceive as the greatest technical hurdles to rapid
development?
2. What have been strategies to mitigate impact to existing manufacturing network operations
and ensure continued supply?
3. What are some of the challenges associated with Global submissions?
4. What are some lessons learned from the development of these therapeutics to other
emerging infectious viral diseases?
5. As the pandemic evolves, what are the foreseen needs and challenges ahead?