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

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.  

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.


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 and the three that will follow in the series are 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.


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


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


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


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


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


Faster Inspection Follow-Up, Global Workload, Draw CDER Compliance Office Attention as 2018 Approaches

Contracting Relationships and Quality Agreements Are High on FDA’s Inspection Radar Screen

Europe is Assessing Challenges of Implementing Combination Product Regulatory Changes; Attention on CPs Increasing Globally

FDA’s Office of Pharmaceutical Quality Advances Review/Inspection Integration

Quality System Transformation Needed for Next-Gen Product Acceleration, Johnson & Johnson’s Sallans Tells ISPE/FDA/PQRI Conference

Tension Between Quality Regulatory Paradigm and Pharma’s Innovation, Acceleration and Harmonization Imperatives in Spotlight

European Pharmacopoeia Has Turned Up the Heat on ICH Q3D Implementation and Biotherapeutics

Biopharma Is Working with Analytics Providers and Government Agencies to Further Multi-Attribute Method Use in QC

Janssen Highlights Value of Academic Collaboration in Move to Continuous Manufacturing

Global Excipient and Drug Manufacturers Weigh Implications of China’s New Excipient Dossier and “Bundling Review” Requirements

New and Generic Drug User Fees, 21st Century Cures Act, Fuel FDA Regulatory Process and Culture Changes for Combination Products

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

International Regulatory Initiatives Guide Agencies Down Info-Sharing/Reliance/Recognition Pathway; ICMRA Targets Initiative Coordination

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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