Modernizing Pharmaceutical Manufacturing: FDA View Janet Woodcock M.D. Director, Center for Drug Evaluation and Research US FDA
Agenda • Key points • Current status of pharmaceutical manufacturing • Potential advantages of modernization • Barriers to implementation • Horizon scan: Scientific, economic, sociopolitical factors that will drive change • What will be the pace of change?
Key Points • Current pharmaceutical manufacturing processes result in multiple problems, including time to build and qualify new facilities, time and cost of scaleup, repeated need for off-line laboratory testing steps, and inability to utilize modern process control methodologies • Technologies to transition to continuous processes exist • Tradition, perception of risk (including regulatory risks), initial investment and sunk costs limit uptake • There is not a business case for every product • Changes in drug development (rapid clinical development, small target populations) and new demands (drugs for victims of terrorism, war, natural disasters; need for supply redundancy) will require more agility and flexibility in manufacture
Key Points • FDA will continue to support innovation and research: regulation should not be a barrier • Current methods produce fit-for-purpose drugs. • Specifications should be clinically relevant, not based on what can be achieved, e.g., content uniformity • Use of continuous manufacturing will not be a method to shut out generic or biosimilar competition—regulatory authorities will pay attention to this
• Terminology
Current Status • Vast majority of small molecule manufacturing done with sequential unit operations interspersed with wet laboratory testing and final sampling and release • Biologicals often use continuous methods for culture with sequential unit operations downstream • Much experimentation and effort underway in both spaces • FDA has approved four drugs using continuous methods for FDF; more expected • Continuous API submissions expected from both innovator and generic sectors • Biopharmaceutical manufacturing: evolutionary vs. revolutionary
Potential Advantages: small molecule FDFs • Faster scale-up with fewer surprises
• No accident that several of the FDF submissions to FDA were for breakthrough therapies—short clinical development programs put pressure on manufacturing process • FDA not infrequently encounters situations where manufacture at commercial scale is a rate-limiting step
• Much smaller footprint: current prolonged timeframes to build and qualify new facilities and get acceptance from multiple regulators • Less environmental impact • Less use of solvents, waste • Cleaning • Worker safety
Potential Advantages: small molecule FDFs • Ability to respond faster to increasing demand—shortages • Health care system is outraged over shortage situations—compromise clinical care • Very slow response capability if a dominant manufacturer stops manufacture
• Potential for regional manufacturing hubs • Current FDF’s are ”world travelers” • Long, convoluted supply chains put products at risk: natural disasters, war, etc
• Possibility of novel dosage forms • Must we use excipients? Do we have to have tablets or capsules? • API could be printed, sprayed, injected, and so forth
Potential Advantages: API • Obviously different considerations apply • Smaller footprint • Less environmental impact • New chemistries: highly exothermic, extreme temperatures • Considerations of demand and volume of production needed • Continuous polymer synthesis for peptides and oligonucleotides to improve yield and purity is being explored
Potential Advantages: Biologicals • Decrease use/cost of media; reduce footprint • Reduce/eliminate costly, time-consuming cleaning operations between campaigns • Integration of downstream steps reduce time, costs • Use of multi-attribute methods to replace conventional QC and release tests • Rapid screening of performance space over many conditions; automated experimentation • Conduct development studies at commercial scale • Novel containers for biological products
Overall Advantages • Scale production unit to demand; small, modular, flexible manufacturing methods where appropriate • Opportunity to use modern process control methods: Model based control strategy using process models for in-process control and product release • Automated feedback controls • Continuous monitoring of critical parameters • Elimination of end-process sampling and testing
• Opportunity for disruptive innovation in manufacturing methods • Only limited by your imagination!
Barriers to Implementation • Perceived risk • These technologies, although not new, are new to pharmaceutical manufacturing • Viewed as less risky to stick with tried-and-true approaches for innovators (need to get asset to market) and generics (low profit margin) • Manufacturing not view as key competitive advantage for innovators
• Perceived regulatory problems • US FDA and many other regulators are on board • However, still not clear how inspectorates, other regulators will respond • Need for regulatory acceptance, and varying regulatory requirements, in many regions continues to be a problem
Barriers to Implementation • Cost • Large investment in current facilities • Implementing complex new technology requires larger up-front investment • Specific and somewhat different personnel required; if expertise lacking, success much less probable • Likely will be used for new products or highly successful existing drugs with expanding markets; not useful immediately in all cases
• Tradition, bureaucracy • Large firms have well-established procedures and departments • Departure from norms also an innovation
FDA Activities • Emerging technology team—to ease path of innovation • Collaborations within Federal government, with industry, academia and consortia (e.g., NIIMBL) • Grants to academia • In-house laboratory capability—Center of Excellence in Manufacturing Science and Innovation established in OPQ, CDER • Understand unique challenges in downstream bioprocessing, especially related to viral clearance • Explore validation of advanced analytical platforms such as multi-attribute methods • Explore process modeling and simulation in regulatory risk assessment
Policy Advances • ICH has accepted FDA’s proposal for new guideline development for continuous manufacturing • USP has established an expert committee on CM to identify potential opportunities for standards • ASTM published E2968 Standard Guide for Application of Continuous Processing in the pharmaceutical industry
Horizon Scan: What Factors Will Drive Change? • Science of drug discovery and development • Unprecedented understanding of molecular basis of disease with consequence of disease subsets with specific drug targets • Knowledge about pathogenesis of rare and orphan diseases • Consequence: very small patient populations, rapid drug development with highly successful interventions and demand for rapid availability • This will likely intensify over time
• Cost pressures • Pharmaceutical costs in US not sustainable • Worldwide: how to make/keep medicines affordable?
Horizon Scan: What Factors Will Drive Innovation? • Emergencies • Warfare, pandemics, bioterrorism, natural disasters, transportation disruptions • Immediate needs for huge surge in supply; alternate sourcing • Currently in US—stockpiles of certain drugs as FDF • Both US public health and military authorities interested in agile, flexible, transportable manufacturing on-demand • Probably technologically feasible right now, from API • API manufacture will require much more work
• Call to decrease supply chain length; regional manufacturing
Factors That Will Drive Change • Recognition of reliable drug supply as national security issue and pharmaceutical/biopharmaceuticals as important high-tech manufacturing sectors • Opportunities for innovation • Miniature manufacturing platforms for mobility • Small, modular manufacturing platforms for low volume products
Pace of Change • Factors • • • • •
Non-traditional manufacturers, e.g., NGOs, other non-profits, consortia Rapidly developing countries with high needs and many well-trained scientists Perceived need for emergencies Interest of non-pharmaceutical innovators Price pressures on pharmaceuticals
• Regulators unlikely to be rate-limiting factor • Technology not a limiting factor • Is this “pre-competitive” technology, at least for innovators? Collaboration could rapidly advance the field
Summary • Methods of pharmaceutical/biopharmaceutical manufacturing likely to change dramatically over next ??? years • Evolution of science and technology will drive need for new methods • Technology is available and used in other sectors • Regulators on board • Some have envisioned ”pharmacy on demand”: perhaps patient’s medicines/doses deposited on film—no tablets, individualized therapy. Probably far in the future but not out of reach of current technology, just impractical at present. • All of this in the service of patients and better health!