An FDA-commissioned study carried out through the National Academies of Sciences, Engineering, and Medicine (NASEM) is helping drive the industry/regulator agenda on advancing innovation in pharmaceutical manufacturing.
In 2020, CDER’s Office of Pharmaceutical Quality (OPQ) engaged NASEM to help FDA look beyond what it has been seeing in its Emerging Technology Program (ETP) towards the manufacturing technologies the agency might expect to review in the next five to ten years, with the aim of assuring that the regulatory framework can support their use.
A series of workshops were convened to solicit input from industry, academic and government experts, and a 120-page report was produced outlining the technical and regulatory challenges and opportunities in enabling the “innovations in pharmaceutical manufacturing on the horizon.”
NASEM and FDA then held a “dissemination” workshop in late October 2021 to bring stakeholder thought leaders together to discuss the report. The workshop was divided into five sessions over two days, addressing in turn: ● advances in manufacturing innovation ● existing mechanisms to enable innovation ● challenges and opportunities ● potential solutions and actions, and ● a path forward.
The four-part story that follows has the NASEM report and discussions as a central reference point as it explores the current industry/regulator dialogue on prominent areas on the innovation agenda, including continuous manufacturing, distributed/point-of-care manufacturing, and digitalization and artificial intelligence (AI).
PART I: The NASEM Study and FDA Reflections
The story opens with a review of the aim and process of the NASEM study, what it covered, the group of experts and organizations involved, and the observations and recommendations that were provided in the report.
The NASEM/FDA workshop began with a summary of the study and the report by Purdue University’s Gintaras Reklaitis, who chaired the study committee. OPQ’s Michael Kopcha then shared his thoughts on the findings of the report and the initiatives his office is engaged in that are addressing the recommendations, including the Emerging Technology Program (ETP) and the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME). Observations were shared at the opening session by members of the NASEM study committee on the study experience and the outcomes of their work.
PART II: The Existing Mechanisms to Enable Innovation
Following the opening remarks, the first workshop session closed with industry perspectives from GSK’s Narendra Bam and Thermo Fisher’s Jessica Settimi on the benefits experienced from innovation and their company’s engagement with FDA’s ETP.
Exploring further the different mechanisms to enable innovation from the regulator and industry perspectives, the second session led off with OPQ’s Larry Lee and Joel Welch explaining how the ETP program was evolving to address the NASEM report recommendations and the pathway forward marked out by the ETP 2.0 roadmap.
Following a review by Biogen’s Rohin Mhatre of existing industry mechanisms to enable innovation in pharmaceutical manufacturing and how Biogen is deploying them, GSK’s Sarah Arden explored the broader opportunities for FDA and global regulatory engagement. Arden had just moved to GSK from FDA, where she was a thought leader in the advanced manufacturing/Pharma 4.0 arena.
PART III: Challenges and Opportunities
The third part of the story builds on the discussion around the “challenges and opportunities” that took place in the third NASEM workshop session.
Resilience’s Tom Ransohoff addressed the challenge of evolving the pharma mindset from one reflecting decades-long development timelines to one receptive to more rapid technology innovation. Echoing that theme, EMA’s Dolores Hernan then pointed to the initiatives going on in the EU to overcome that resistance, which are supported in its strategy papers. These initiatives include EMA’s Innovation Task Force, interface with the Quality and Biologics Working Parties, and collaborations with academic/research institutions and with regulators outside Europe. Â
International Academy of Automation Engineering (IAAE) lead Mike Hourigan echoed industry consultant and former UK MHRA assessor Malcolm Barratt-Johnson on the importance of manpower and education needs in advancing pharma manufacturing and the related initiatives underway through NIIMBL and other organizations – a topic that also drew attention in the engaging panel discussion that followed, which explored the themes raised in the session presentations. Hourigan described the collaborative initiatives IAAE is engaged in with FDA support to develop resources for advancing the use of digital twins and other digital and platform technologies and the adoption of medical product “smart manufacturing.”
IV: The Path Forward
The second day of the NASEM/FDA workshop included sessions focused on “solutions and actions” and “a path forward.” Perspectives were offered by OPQ’s Adam Fisher and Tom O’Connor, NIIMBL’s Kelvin Lee, Rutgers University’s Fernando Muzzio, and Duke-Margolis Center for Health Policy’s Gillian Sanders Schmidler and Stephen Colvill.
Fisher focused heavily on the FRAME initiative – explaining its current focus on developing the regulatory framework to support end-to-end continuous manufacturing, distributed and point-of-care (POC) manufacturing, and artificial intelligence, in particular, as the initiative shifts from the foundation and planning phases into the implementation phase. O’Connor followed with insights on how FDA’s collaborative research and training programs were informing application assessments, and policy, workforce and guidance development. Included in Part IV is an update provided by O’Connor at the IFPAC June 2022 conference on FRAME’s outreach activities. These include a series of papers that are nearing release on distributed and POC manufacturing and AI, intended to further stakeholder engagement on the regulatory issues involved.
Lee provided his insights on: ● how business risk concerns, along with a fragmented global regulatory environment, are creating resistance to implementing manufacturing innovations, and ● the need for stakeholders to join with FDA in overcoming the hurdles and assuring that the needed resources are in place. Muzzio discussed Rutgers collaborative work on continuous direct compression and the support it has gotten from FDA in creating a “knowledge base for CDC.” An effort is now underway with USP to develop a “Knowledge Center for Pharmaceutical Continuous Manufacturing,” intended to facilitate PCM adoption. The Duke-Margolis experts added their ideas on the opportunities for strengthening biopharma innovation and supply chain resilience, including funding to develop “Centers of Excellence.”
The panel discussion that concluded the workshop focused on how the key issues in advanced manufacturing implementation could be addressed. A summary by the workshop committee of those discussions is included.
A LOOK BACK AT IPQ’S CONTRIBUTION TO THE INNOVATION DIALOGUE
2022
â—Ź The Evolving Landscape of Pharmaceutical Operations
â—Ź Government-Industry Collaboration in This and Future Pandemics
â—Ź Reducing the Cost of Vaccine Manufacturing for Broader LMIC Access
Progress in Addressing Impurity Challenges in Focus at USP’s 2022 Peptide/Oligo Workshop
â—Ź US and European Regulator Perspective on the CMC Challenges of Oligonucleotides
â—Ź USP Standards Development Efforts for Peptides and Oligos
â—Ź Peptide and Oligo Analytical, Manufacturing and Raw Material Considerations
â—Ź The Advancing Knowledge-aided Assessment Component of KASA
â—Ź Bringing Biologics into the KASA System
● The Progress of FDA’s PQ/CMC Initiative
â—Ź The Goals of Accumulus Synergy in CMC Data IT and Regulatory Communication
â—Ź The Drivers for Revising ICH M4Q and Evolving the CMC Regulatory Process
â—Ź Update on EMA GMP-related Activities
â—Ź MHRA Innovation Pathway and Proposal for Point-of-Care Regulatory Framework
â—Ź Insights from Europe and ICMRA Regarding Onsite Inspection Alternatives
2021
● Update on USP’s Evolving Role and Current Initiatives In the Biologics Arena
â—Ź European Pharmacopoeia and FDA Join USP in Focusing on Particulate Control
â—Ź Implementing the Pfizer/BioNTech mRNA Vaccine Development Plan
● New Digitalized Facility as Springboard for Moderna’s mRNA Vaccine
â—Ź 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
â—Ź Inter-Company Panels at DIA and ISPE Meetings on Vaccine Experience
â—Ź Biotech Regulator Vantage Point on Raw Material Control
â—Ź The Added Challenges of Materials Management for CGTs
â—Ź Biomanufacturer Use and Control of Polysorbates
â—Ź Recent CMC/Regulatory Challenges of Oligonucleotide Drugs
â—Ź Comparability Challenges in Crossing Over to Generics
â—Ź Comparing Peptide and Oligonucleotide CMC Issues
â—Ź Starting Material Specifications for Oligonucleotides
A Confluence of Forces Is Now Spurring Combination Product Regulatory Reform in Europe
â—Ź EU Pharma Strategy Roadmap, Comments from Industry, and Related Agency Strategies
â—Ź Culture/Structure/Process Change and Global Alignment
â—Ź HPRA CEO Lorraine Nolan on HPRA and EMA Strategy
● EMA’s Zaïde Frias and NB/Industry Perspectives on EU Regulatory Transformation
â—Ź Industry Quality Leaders on the Global PAC Regulatory Problem and Solutions
â—Ź Evolving the Quality Regulatory Paradigm at the Global Level
● ICH Q9 Revision Lead O’Donnell on the Evolution of QRM
● FDA’s Rick Friedman on Advancing Aseptic Processing through QRM
â—Ź Industry/Academia Thought Leaders on the Evolving QRM/KM Relationship
â—Ź EMA Perspective
â—Ź FDA CBER Perspective
â—Ź FDA CDER Perspective
â—Ź Panel Discussion Among US, Europe, and Japan Regulators
● NIIMBL’s Engagement with Academia on Workforce Development Needs
â—Ź 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
â—Ź CASSS Panel on Opening Up Biopharma Career Pathways
â—Ź European and Global Workforce Development Collaborations
Pandemic Intensifies USP’s Focus on Supply Chain Vulnerabilities and Vaccine Development
2020
Pandemic Spurs Deepening of Pharmacopoeia/Regulator/Industry Communication Channels
â—Ź EDQM Pandemic Actions Continue Apace in Fall 2020
â—Ź Pharmacopeia, Regulator and Industry Expert Panel Explores Pandemic and Nitrosamine Communications
â—Ź Second Panel Focuses on Pandemic Organizational Impacts and Key Learnings
â—Ź EDQM and Ph. Eur. Evolution Addressed by Leaders Keitel and Vielle
COVID-19 Vaccine Urgency Throws Spotlight on Next-Gen Sequencing as Key Facilitator
â—Ź Adventitious Agent Testing in Focus at CASSS CMC Forum Europe
â—Ź Sanofi Pasteur and Ghent University Experience with NGS
â—Ź A Decade of Regulator/Industry Collaboration on NGS
â—Ź Stakeholder Engagement Begins on ICH Q5A Revision
â—Ź Effort to Reduce Animal Testing for Vaccines Includes Global Health Fund Support for NGS
Attention Heightens on Creating an Independent Regulatory Pathway for Introducing Novel Excipients
● FDA’S Novel Excipient Program Proposal and Stakeholder Comments
â—Ź IPEC/IQ Thought Leaders on the Novel Excipient Drivers
â—Ź Subcutaneous Biotherapeutics, Pediatrics, and Delayed Release
â—Ź USP Initiatives Supporting Novel Excipient Development
â—Ź Assessing and Managing Excipient Risks
2019
CBER Reviewers Are Working with Sponsors in Exploring CMC Flexibility for Cell and Gene Therapies
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
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 Guidance Revisions by FDA and PIC/S Deepen Industry’s DI Resource Pool
UK MHRA’s “No Deal” Brexit Preparations Include Role for “Responsible Person – Import”
2018
IPEC Digesting Implications of China’s Ending of Separate Excipient Approval Process
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
Pharma is Exploring How to Maximize ICH Q12 Value in Practice; Q12 EWG Encourages Feedback
Expanding Field of Advanced Therapies Puts Pressure on FDA’s Review Staff to Keep Pace
2017
Contracting Relationships and Quality Agreements Are High on FDA’s Inspection Radar Screen
FDA’s Office of Pharmaceutical Quality Advances Review/Inspection Integration
European Pharmacopoeia Has Turned Up the Heat on ICH Q3D Implementation and Biotherapeutics
Janssen Highlights Value of Academic Collaboration in Move to Continuous Manufacturing
Vertex Sheds Light on Continuous Manufacturing Approval and Post-Approval Challenges
Continuous Manufacturing is Driving More Focus on Excipient Fitness for Purpose
CDER Offering More Concrete Advice on Continuous Manufacturing as Experience Grows
FDA’s Broad-Based Effort to “Modernize” Combination Product Regulatory Process in Full Swing
Strengthening Biotherapeutic Regulation Worldwide Will Remain a High Priority for WHO in 2017
Combination Product Regulatory Improvements Remain High on Pharma’s 2017 Wish List
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