Government/Industry/Academia Collaborative Efforts to De-Risk and Accelerate Manufacturing Innovation Draw Strength from Pandemic Learnings

INTRODUCTION

The US government is continuing to strengthen its collaborative efforts with industry and academia to de-risk and accelerate manufacturing innovation, as the learnings from the pandemic are further digested.

The pandemic experience has thrown an intense spotlight on where the barriers and the opportunities lie – and the high stakes involved – in bringing advanced technology more fully to bear in pharmaceutical manufacturing.

In turn, it has become increasingly clear that stakeholder communication and collaboration at both the domestic and international level is critical to the advancement of the knowledge sharing, platforms, standards, workforce training, and regulatory processes needed to propel innovation forward.

Among the US organizations at the forefront of these collaborative efforts are the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and its companion institutes in the Manufacturing USA network – established in the wake of the Revitalize American Manufacturing and Innovation (RAMI) Act passed by the US Congress in late 2014.

In response to the advanced manufacturing offshoring from the US since around 2000, the act provided funding to support more collaboration between industry, government, and academia in helping the US’s strong technology R&D cross the commercial product manufacturing threshold.

Further significant boosts to the pharma manufacturing innovation efforts have come from the American Pandemic Preparedness Plan, released by the White House’s Office of Science and Technology Policy (OSTP) in September 2021, and the CHIPS and Science Act, signed by President Biden in August 2022.

The five-part IPQ story provides a wealth of insights from key leaders and policy makers on the issues at play and how government, industry, and academia are collaborating through NIIMBL and other organizations to address them in the US and internationally.

PART I: NIIMBL and Its “Going First Together” Mantra

The first part of the story provides an update on NIIMBL’s efforts to accelerate biomanufacturing innovation and develop the needed supporting standards and workforce skills. In focus is a keynote presentation by NIIMBL Director Kelvin Lee at the 2022 PDA Annual Meeting in which he explored how NIIMBL brings together government, industry, and academia to collaborate on de-risking biomanufacturing innovation on a pre-competitive basis. He reviewed the strategic program/workstream approach the institute is taking to tackle overarching issues – focusing attention on the process intensification program, in particular. Also highlighted was NIIMBL’s  200-page case study “N-mAb,” supporting the development and adoption of continuous bioprocesses for monoclonal antibodies.

PART II: US Manufacturing Innovation Leaders Weigh In

The second part moves to the opening plenary session of the 2022 NIIMBL annual meeting, during which a panel of US leaders from organizations involved in supporting biomanufacturing innovation provided their insights on the issues involved and the role that NIIMBL and their respective organizations are playing. Presenting were: ● US Senator Chris Coons ● NIST Director Laurie Locascio ● NIIMBL’s Lee ● White House OSTP Senior Advisor Matthew Hepburn ● CBER Director Peter Marks ● BIO CEO Michelle McMurry-Heath, and ● FDA Principal Deputy Commissioner Janet Woodcock. They reflected on how the pandemic had heightened the importance of the pharma manufacturing innovation dialogue and stakeholder collaboration.

PART III: The Importance of Process and Facility Innovation in Global Health

Part III of the story moves forward to the February 2023 ISPE Facilities of the Future (FOF) Conference where OSTP’s Hepburn provided more insights on the current US government efforts to work with industry on pharmaceutical manufacturing innovation and preparing for future pandemics and other outbreaks. Under discussion by Hepburn were: ● why manufacturing innovation matters and the current OSTP support approach ● the role of public-private partnerships ● pivoting ability and global vaccine delivery ● specific programs, including Manufacturing USA and BARDA Ventures, and ● the need for flexibility/scalability and international harmonization.

Also reviewed is the discussion at an FOF dinner panel of organization thought leaders on whether the global convergence of regulatory processes that took place during the pandemic could continue and the top wishes for improving the pharmaceutical industry by 2030.

A third component of this part of the story is a review of the initiative launched by ISPE in mid-February on “Enabling Global Pharma Innovation.” Included is ISPE’s description of: ● the program goals ● the problem motivating the initiative ● regulatory activities to promote pharmaceutical manufacturing innovation ● learnings from the COVID pandemic ● industry’s innovation efforts, and ● how the program is being organized.

PART IV: Charting the Advanced Therapy CMC Pathways

Following the substantial contribution made by A-mAb and A-Vax in bringing a better understanding of how to implement QbD-based principals and CMC best practices into the development of complex biologicals, NIIMBL has been strongly backing similarly informative case studies for continuous manufacturing of mAbs (“N-mAb”) and for cell and gene therapies (“A-Cell” and “A-Gene”). The latter projects, also resulting in 200-plus page documents, were carried out under the direction of the Alliance for Regenerative Medicine (ARM) with NIIMBL support. IPQ also explains the role for NIST-mAb and NIST-CHO  as reference materials supporting and advancing the biotherapeutic development process.

Covered in this part of the story are recent webinars NIIMBL has run addressing its initiatives on big data, process intensification, viral vector manufacturing and analytics, and biomanufacturing readiness levels.

PART V: CBER’s Marks On Taking CGT Development to the Next Level

As the guest speaker at a “Maryland BioNetworking Summit” cosponsored by NIST and the University of Maryland held in February 2023, CBER’s Marks began by reviewing the current state of cell and gene therapy R&D and product approvals. He then discussed some of the barriers to further CGT development and how they can be overcome – focusing on the role that increased global regulatory collaboration needs to play in particular. He concluded his talk by highlighting some of CBER’s current CGT innovation support initiatives. During the Q&A that followed, Marks addressed: ● approving and paying for rare disease therapies ● nonviral vectors ● Phase 0 trials in gene therapy ● standardizing lab processes ● long-term follow-up for gene therapies, and ● price control.

 

A LOOK BACK AT IPQ’S CONTRIBUTION TO THE INNOVATION DIALOGUE

The following is a listing of IPQ’s in-depth stories over the past five years, almost all of which have relevance to the innovation dialogue on which this story is focused. They provide a helpful foundation for understanding the current challenges around assuring that regulatory processes keep pace with advanced manufacturing and help serve the innovation mandate that the pandemic has brought to the fore. The stories are listed in reverse chronological order.

2022

Strengthened European Regulator Support for Advanced Technologies Includes New EMA Quality Innovation Group

● Europe’s Focus on CMC Innovation and Agile Regulation
● Innovation Issues Explored at CASSS CMC Forum in Europe
● MHRA’s “New Era in Regulation”

EMA Toolbox on CMC Flexibilities has been Evolving to Incorporate Industry Input and Learnings from the Pandemic

● EMA Perspective on its Toolbox Guidance and OPEN Initiative
● Industry View on Efficiency Tools and CMC Flexibility Learnings from COVID
● Panel Discussion on Effective Tools for the Future

CBER’s Advanced Technologies Program Growing Stronger with Increased Funding, Expertise, and Collaboration

mRNA-LNP Vaccines Spur Global Dialogue on Nanomaterial Standards and Regulatory Approaches

● Pfizer/BioNTech Lipid Challenges with mRNA-LNP COVID Vaccine
● FDA’s Novel Excipient Review Pilot Program and Nanomaterials Guidance
● USP’s Draft Guideline and Other Efforts on mRNA Vaccine Quality
● The EDQM Nanomedicines Dialogue and WHO on Regulating mRNA Vaccine Quality
● Potency Assays for mRNA-LNP Vaccines

NASEM-Led Study for FDA is Helping Drive Industry/Regulator Agenda on Innovation Needs

● The NASEM Study and FDA Reflections
● Existing Mechanisms to Enable Innovation
● Challenges and Opportunities
● The Path Forward

Pandemic Experience Showcases the Potential for Faster Innovation, More Collaboration, and Workplace and Operations Modernization

● The Evolving Landscape of Pharmaceutical Operations
● Government-Industry Collaboration in This and Future Pandemics
● Reducing the Cost of Vaccine Manufacturing for Broader LMIC Access

Progress in Addressing Impurity Challenges in Focus at USP’s 2022 Peptide/Oligo Workshop

● US and European Regulator Perspective on the CMC Challenges of Oligonucleotides
● USP Standards Development Efforts for Peptides and Oligos
● Peptide and Oligo Analytical, Manufacturing and Raw Material Considerations

Pandemic Experience and Supply-Chain Risk Management Expectations Increase Attention on Excipient GMP Third-Party Auditing

Janet Woodcock and Jeff Baker will Continue to Play Key Manufacturing Innovation Roles in New FDA and NIIMBL Positions

FDA’s KASA and Related PQ/CMC Initiatives on Improving CMC Data Structuring and Sharing Will Help Support ICH M4Q Revision

● The Advancing Knowledge-aided Assessment Component of KASA
● Bringing Biologics into the KASA System
● The Progress of FDA’s PQ/CMC Initiative
● The Goals of Accumulus Synergy in CMC Data IT and Regulatory Communication
● The Drivers for Revising ICH M4Q and Evolving the CMC Regulatory Process

Key GMP Focal Points in Europe Include Guidance Revisions, New Vet Regulations, and Adaptive Assessment/Inspection Approaches

● Update on EMA GMP-related Activities
● MHRA Innovation Pathway and Proposal for Point-of-Care Regulatory Framework
● Insights from Europe and ICMRA Regarding Onsite Inspection Alternatives

 

2021

USP and Ph. Eur. Initiatives in the Biologics Arena Continue to Bear Fruit; FDA Joins the Pharmacopeias in Upgrading Particulate Guidance

● Update on USP’s Evolving Role and Current Initiatives In the Biologics Arena
● European Pharmacopoeia and FDA Join USP in Focusing on Particulate Control

COVID Vaccine Industry Project Leaders Are Sharing Insights on How the Daunting CMC Challenges Were Addressed

● Implementing the Pfizer/BioNTech mRNA Vaccine Development Plan
● New Digitalized Facility as Springboard for Moderna’s mRNA Vaccine
● Oxford University/AZ Partnership for Global Adenovirus Vaccine Access
● J&J’s Experience in Handling the Supply Chain Challenges
● Novavax’s Approach to Assuring Comparability for its Protein-based Vaccine
● Inter-Company Panels at DIA and ISPE Meetings on Vaccine Experience

Biomanufacturer Raw Material Control on Regulatory Front Burner as Analytical Power and Formulation Challenges Intensify

● Biotech Regulator Vantage Point on Raw Material Control
● The Added Challenges of Materials Management for CGTs
● Biomanufacturer Use and Control of Polysorbates

Manufacturing, Impurities, and Characterization Methods Are Key Regulatory Focal Points for Peptides and Oligonucleotides

● Recent CMC/Regulatory Challenges of Oligonucleotide Drugs
● Comparability Challenges in Crossing Over to Generics
● Comparing Peptide and Oligonucleotide CMC Issues
● Starting Material Specifications for Oligonucleotides

A Confluence of Forces Is Now Spurring Combination Product Regulatory Reform in Europe

● EU Pharma Strategy Roadmap, Comments from Industry, and Related Agency Strategies
● Culture/Structure/Process Change and Global Alignment
● HPRA CEO Lorraine Nolan on HPRA and EMA Strategy
● EMA’s Zaïde Frias and NB/Industry Perspectives on EU Regulatory Transformation

Pandemic Urgencies Highlight Constraints in Manufacturing Change Regulatory Paradigm and Where Adjustments Are Needed

● Industry Quality Leaders on the Global PAC Regulatory Problem and Solutions
● Evolving the Quality Regulatory Paradigm at the Global Level

Regulators Are Exploring with Industry How to Strengthen Quality Risk Management Practices, with Revision of ICH Q9 a Key Focal Point

● ICH Q9 Revision Lead O’Donnell on the Evolution of QRM
● FDA’s Rick Friedman on Advancing Aseptic Processing through QRM
● Industry/Academia Thought Leaders on the Evolving QRM/KM Relationship

Regulators Share Pandemic’s CMC Impact at CASSS Japan Forum; Guidance Output Continues Apace in Q1 2021

● EMA Perspective
● FDA CBER Perspective
● FDA CDER Perspective
● Panel Discussion Among US, Europe, and Japan Regulators

Academia/Industry Collaboration Intensifies on Addressing the Pressing Needs in Biopharma Workforce Development

● NIIMBL’s Engagement with Academia on Workforce Development Needs
● ISPE Workforce of the Future Traction at UMBC and UC Davis
● Keck Institute’s Behrens on Biopharma Talent Needs and KGI/Industry Partnering
● Xavier’s Phillips on Sharable Quality and Regulatory Science Curriculum
● CASSS Panel on Opening Up Biopharma Career Pathways
● European and Global Workforce Development Collaborations

Latest Improvements in FDA’s Inactive Ingredient Database Include Change Log and Use of Maximum Daily Exposure

Recent Technology and Partnership Advances Made Possible Precision and Speed of Vaccine Response to Pandemic, NIAID’s Graham Stresses at CASSS WCBP Conference

Pandemic Intensifies USP’s Focus on Supply Chain Vulnerabilities and Vaccine Development

 

2020

Pandemic Spurs Deepening of Pharmacopoeia/Regulator/Industry Communication Channels

● EDQM Pandemic Actions Continue Apace in Fall 2020
● Pharmacopeia, Regulator and Industry Expert Panel Explores Pandemic and Nitrosamine Communications
● Second Panel Focuses on Pandemic Organizational Impacts and Key Learnings
● EDQM and Ph. Eur. Evolution Addressed by Leaders Keitel and Vielle

COVID Vaccine Global Distribution Challenges Explored by Bio Supply Management Alliance (BSMA) Panel of European Experts

Pandemic Stresses Increase FDA Attention on Risk Management Plans for Drug Shortage Prevention and Mitigation

USP’s Global Efforts to Strengthen Standards and Accelerate Innovation for Biologics Include ICH Engagement

CBER Director Marks Traverses the Complex COVID-19 Vaccine/Therapy Regulatory Landscape at FDLI’s Annual Conference

Stronger Unapproved Stem-Cell Enforcement Accompanies FDA Center for Biologics’ Cell and Gene Therapy Advancement Efforts

Design-Based Development Paradigm for Cell/Gene Therapies Will Significantly Reduce Costs, Timelines and Regulatory Concerns, AGT CEO Galvin Maintains

Synthesis and Analysis Advancements Are Unleashing the Potential of Peptides and Oligos, Spurring CMC Regulatory Dialogue

USP Convention Meets Virtually in May 2020 to Review Upcoming Priorities, with Both 200-Year Legacy and Current Pandemic in Focus

COVID-19 Vaccine Urgency Throws Spotlight on Next-Gen Sequencing as Key Facilitator

● Adventitious Agent Testing in Focus at CASSS CMC Forum Europe
● Sanofi Pasteur and Ghent University Experience with NGS
● A Decade of Regulator/Industry Collaboration on NGS
● Stakeholder Engagement Begins on ICH Q5A Revision
● Effort to Reduce Animal Testing for Vaccines Includes Global Health Fund Support for NGS

NIIMBL Progress Includes Partnership with Biophorum on Buffer Mixing and Global Health Fund with Gates Foundation

Top FDA Drug Compliance Concerns during 2019 Included OTCs, Supply Chain Information Flow, Compounding, and Genotoxic Impurities

Existing Accelerated CMC, Advanced Manufacturing, and Inspection Initiatives are Supporting Regulators in Pandemic Response, FDA’s Cruse Explains in Recent Field Office Updates

Attention Heightens on Creating an Independent Regulatory Pathway for Introducing Novel Excipients

● FDA’S Novel Excipient Program Proposal and Stakeholder Comments
● IPEC/IQ Thought Leaders on the Novel Excipient Drivers
● Subcutaneous Biotherapeutics, Pediatrics, and Delayed Release
● USP Initiatives Supporting Novel Excipient Development
● Assessing and Managing Excipient Risks

US/EU MRA Implementation, US Congressional Hearings, and Industry Surveys Shed Light on Global GMP Inspection Challenges and Collaboration Opportunities

 

2019

International Mutual Inspection Recognition Expands with ASEAN Accrediting Philippines Using PIC/S Criteria

CDRH Case for Quality Voluntary Improvement Pilot Collaboration Shows Impressive Results for Device Manufacturers

FDA and Industry Quality Metrics Initiatives Are Paving the Way to Manufacturing and Regulatory Advancements

Industry Experience with Autologous Cell Therapies Underscores Need for Upfront Planning on Integrating Facility Design, Operations, and Supply Lines

The Processing and Formulation Complexities of Therapeutic Biologics Compel Heightened Focus on Excipient Needs

USP Views Early Broad Stakeholder Engagement as Essential in Developing Performance-Based Standards for Biologics

CBER Advice on CGT Process and Facility Management Includes Early Consideration of Engineering and Capacity Needs

Preparing for CMC Changes is Difficult but Pivotal to Accelerating CGT Development, Industry Experts Are Stressing

CBER Reviewers Are Working with Sponsors in Exploring CMC Flexibility for Cell and Gene Therapies

CBER and CDER Directors Offer Insights on Overcoming Hurdles to Biomanufacturing Innovation at NIIMBL Annual Meeting

Regulators and Industry Are Probing More Deeply into the Complexities of Preservative Usage

KASA and PQ/CMC Initiatives Gain Momentum in FDA’s Effort to Strengthen Quality Review Process

EMA’s Draft Guideline on Drug-Device Combinations Sheds Needed Light on Expectations for Device Assessment

IPEC Continues to Encourage China to Align with Global Science-Based Excipient Standards

MHRA Inspectors are Advocating Data Mapping as a Key First Step on the Data Integrity Pilgrimage

Data Integrity Compliance Experts Are Urging Industry to Apply Regulator Perspective and Learnings in Refining Data Systems and Auditing

The Role of Quality Culture in Data Integrity Is Getting More Attention as Regulator and Industry DI Guidances Evolve

Data Integrity Guidance Revisions by FDA and PIC/S Deepen Industry’s DI Resource Pool

Cell and Gene Therapy Initiatives Prominent on Biomanufacturing Agenda of U.S. National Institute of Standards and Technology

FDA’s Focus Has Sharpened on Water Systems in the Wake of Nonsterile Product Microbial Contamination

Pharmacopoeia/Industry/Agency Global Dialogue on Compendial Compliance and Harmonization Continues, with Medicine Availability at Stake

FDA Investigators Will Focus on Simple GMP Lapses when Inspecting Complex Biotech Systems, Former Compliance Official Cosgrove is Advising

Gates Foundation’s Expanded Commitment to Global Medicines Encompasses CMC/Regulatory Problem Solving

CDER’s Office of Pharmaceutical Quality is Opening New Regulatory Pathways to Span Its Broad Responsibilities and Global Reach

Technology Roadmapping Leads NIIMBL Project Expansion Across Biopharmaceutical Manufacturing/Analytics/Workforce Landscape

UK MHRA’s “No Deal” Brexit Preparations Include Role for “Responsible Person – Import”

Retiring FDA Office of Generic Drugs Director Uhl Cautions Industry That Haste Makes Waste in Application Approval Timelines

 

2018

Emergency Preparations Draw Heightened Industry and Regulator Attention as Natural and Man-Made Disasters Proliferate

CBER’s Compliance Office Absorbing Impact of Cell/Gene Therapy Wave in its Pre-Market and Surveillance Operations

FDA’s BLA Review Sheds Light on Evolution of Biotherapeutic Product Analytical Methods and Their Regulation

Foreign Inventory Completion, Faster Inspection Follow-up Among CDER Compliance Office 2018 Achievements; API, OTC Process Findings Spotlighted

Refined Training, Project Selection, and Membership Processes Strengthen ICH’s Global Harmonization Efforts

IPEC Digesting Implications of China’s Ending of Separate Excipient Approval Process

Diverging Regional Excipient Regulations Are Creating Problems For Excipient Manufacture, Distribution and Use Globally

Novel Excipients, DMFs, and Atypical Actives Among Pressing Issues on IPEC-Americas’ Front Burner

Role of Established Conditions Drawing Attention in Global Dialogue on ICH Q12’S Potential

Experience with In Vitro Fertilization Clinics Raises Strong Warnings on Cell Culture/Processing Air Purification

CMC Priorities of EFPIA’s European Biopharmaceutical Enterprises Include ADCs, Drug/Device Combos and Statistics

Pharma is Exploring How to Maximize ICH Q12 Value in Practice; Q12 EWG Encourages Feedback

Understanding Drug/Device Terminology Differences is Critical to Combination Product Control and Regulatory Communications, Industry Experts are Stressing

FDA Inspection Findings Provide Additional Insight on CGMP Expectations for Combination Product Manufacturers

Improving Communications on Drug/Device Combination Product Quality and Performance is an Increasing Priority in the US and Europe

Opening Panel at CASSS 2018 WCBP Conference Assesses FDA’s 2017 CMC Regulatory Experience with Biotherapeutics and Key Challenges Going Forward

Expanding Field of Advanced Therapies Puts Pressure on FDA’s Review Staff to Keep Pace

Facility and Excipient Information Shortfalls Identified by FDA As Among Key Contributors to ANDA Review Delays; GDUFA II Driving Expanded Guidance

NIST is at Intersection of Industry/Government/Academia Efforts to Support the “Ecosystem” Needed for Cell/Gene Therapy Advancement

Industry/Regulator Communication is Linchpin in Addressing Cell/Gene Therapy CMC Challenges, Experts on Both Sides Are Affirming

 

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