Articles
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Accelerating Drug Product Development and Approval: Early Development and Evaluation (A. Bak, R. Burlage, N. Greene, P. Nambiar, X. Lu, and A. Templeton)
Industry Perspective – What does Industry Need to Accelerate Drug Product and Process Development? (Chatterjee, B., Steiner, R. & Kaul, G. )
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The “Early Development and Evaluation” session of the NIPTE pathfinding workshop held in January 2023 included a presentation and panel discussion led by Annette Bak, PhD (AstraZeneca) and Allen Templeton, PhD (Merck & Co), followed by small group and open forum discussions.
Dr. Bak and Dr. Templeton, along with Rubi Burlage, PhD (Merck & Co.); Nigel Greene PhD (AstraZeneca); Prabu Nambiar, PhD (Syner-G Biopharma Group); and Xiuling Lu, PhD (University of Connecticut) published an article in Pharmaceutical Research that summarizes the group discussions and perspectives. The complete article is available to subscribers here: Accelerating Drug Product Development and Approval: Early Development and Evaluation | SpringerLink .
The following text highlights some of the conclusions of the workshop session, which are discussed in more detail in the article along with additional topics (Bak, A., Burlage, R., Greene, N. et al. Accelerating Drug Product Development and Approval: Early Development and Evaluation. Pharm Res (2023). https://doi.org/10.1007/s11095-023-03566-1).
What did the group see as the primary barriers to accelerating early drug product development?
Anything new or novel—new modalities, new tailored release profiles, or new manufacturing methods—can differ from more established therapies in the requirements for drug delivery and chemistry, manufacturing, and control (CMC). Traditional modalities benefit from existing experience and knowledge and well-defined methods and control strategies. New modalities, however, face more unknowns, such as product and process-related impurities or interactions with novel excipients. It takes time to address these issues, which can slow down the discovery and development process.
Preclinical development is also facing the need to adopt new technologies in artificial intelligence, automation, and data handling. More data and new computational approaches can help accelerate development but using them is complex. Another challenge is to reduce the use of animals in testing.
What solutions did the workshop participants identify for accelerating CMC development?
Collaboration between academia, industry, and regulatory agencies could facilitate better elucidation of the mechanism of action of novel modalities. A pre-competitive knowledge base could be assembled and used to build preclinical models to identify critical quality attributes. In addition, a pre-competitive analytical toolkit could be developed for novel modalities using what has been learned in traditional modalities.
How can preclinical toxicology studies be modernized and accelerated?
There is high demand for human-relevant drug safety testing for new modalities. One possible alternative to testing in non-human primates is to use organ-on-a-chip or micro-physiological systems. Another potential approach is in-silico testing or machine learning.
How can the regulatory burden be reduced for novel drugs?
FDA has already implemented approaches to accelerating the pathway for critical treatments with designations for Priority Review, for example. Novel therapies do have many unknowns and complexities, but a science- and risk-based approach to CMC development can help. Such approaches should be discussed with FDA prior to filing. Greater collaboration between regulatory agencies and industry is needed to identify solutions to overcome CMC challenges for novel modalities.
For further reading:
Article in Pharmaceutical Research (subscription content): Accelerating Drug Product Development and Approval: Early Development and Evaluation | SpringerLink
Presentation during workshop: Session 1, Early Development and Evaluation
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An “Industry Perspective” session of the NIPTE pathfinding workshop held in January 2023 included a panel discussion hosted by Bikash Chatterjee, President and Chief Science Officer, and Richard Steiner, Senior Manager PCM Business Strategy, both of Pharmatech Associates, a USP Company.
Chatterjee, Steiner, and Goldi Kaul, PhD, Vice-President, External Alternative CMC Development, Boehringer Ingelheim Pharmaceuticals published an article in Pharmaceutical Research that summarizes the group discussions and perspectives regarding the drug product and process development process. The complete article is available here: Industry Perspective – What does Industry Need to Accelerate Drug Product and Process Development? | Pharmaceutical Research (springer.com).
The following text highlights some of the conclusions of the workshop session, which are discussed in more detail in the article along with additional topics (Chatterjee, B., Steiner, R. & Kaul, G. Industry Perspective – What does Industry Need to Accelerate Drug Product and Process Development? Pharm Res (2023). https://doi.org/10.1007/s11095-023-03604-y.
What are some of the barriers to accelerating development, and how can these be overcome?
Advances in technology can accelerate development, yet they may require a shift in regulatory and scientific thinking. New technology areas where adoption can help accelerate development include risk management methods, integrated product and process development, advanced manufacturing technology, and data literacy. Collaboration between industry, academia, and regulatory agencies can be leveraged to promote these new technologies and clarify how they can be adopted.
What do you see as optimal risk management methods?
Risk assessments are key in drug development, and it is necessary to quantify uncertainty to inform decision making. The conventional Frequentist approach uses only current experimental data. Bayesian inference, however, combines current experimental data with past knowledge and expertise to make decisions.
For example, a Bayesian approach to stability testing could incorporate a shorter stability study with a model of stability behavior as evidence in a drug filing. Real-time stability testing would then occur as a parallel activity, rather than prior to filing. Potential approaches include the Accelerated Stability Assessment Program and Physiologically Based Pharmacokinetic Modeling.
Another example of a Bayesian approach is the use of artificial intelligence-based models and surrogate testing frameworks as alternatives to animal testing. The FDA Modernization Act in December 2022 authorized these as possible alternatives, but both industry and FDA are cautious in making changes; criteria for validation need to be further defined.
The value of the Bayesian approach has been shown in accelerated regulatory approval programs, and there is potential to apply similar thinking to drug development more broadly. This newer but also proven approach can create a more rapid and lower-cost development path.
How can product and process development be better integrated?
The Bayesian approach could be used to develop models based on existing data that could be used as a product starting point. Product development could move forward with less stability and toxicology data, in parallel to ongoing testing. FDA’s biowaiver process for BCS 1 API molecules for immediate release generic drug products is based on this concept.
The concept of formulation by design considers commercial-scale manufacturing variables during the product design stage, which simplifies process development. One example is considering processability when selecting excipients. Another application is delaying selection of final dosage form until Phase 2.
Applying these concepts could shorten time to market.
How can advanced manufacturing technology facilitate development?
Pharmaceutical continuous manufacturing (PCM) is one example of advanced manufacturing technology that can both reduce development risks and shorten time to market. PCM simplifies process development because it does not require scale up from development to commercial scale. Greater control of the process and real-time testing eliminate many conventional quality issues. Experiments can also be performed faster than in a batch process.
What is the importance of data literacy?
Advanced manufacturing technologies and Bayesian principles of development require data acquisition, analysis, and management using Industry 4.0 tools. Artificial intelligence, machine learning, and digital twins are examples of tools for which a higher level of data literacy is needed. A clear regulatory framework for these approaches is also crucial.
What are the next steps?
Clear expectations from FDA are crucial to making industry comfortable with adopting new technologies and tools. FDA’s Emergency Use Authorization (EUA) program demonstrated the benefit of a Bayesian approach to drug development and approval and proved the ability to manage risk without compromising efficacy and safety. Applying these concepts in a broader context could speed the drug development process.
For further reading:
Article in Pharmaceutical Research (open access): Industry Perspective – What does Industry Need to Accelerate Drug Product and Process Development? | Pharmaceutical Research (springer.com).
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A NIPTE Pathfinding workshop session identified limitations in the current drug development methods and discussed how new technologies could be a solution.
A “Product Formulation and Process Development” session was held at the NIPTE pathfinding workshop in January 2023. Workshop leaders, Dr. Mauricio Futran, industry consultant with Pharmaceutical Engineering Solutions, LLC; Dr. Fernando J. Muzzio, Distinguished Professor at Rutgers, the State University of New Jersey; and Bikash Chatterjee, President and Chief Science Officer, Pharmatech Associates-a USP Company, subsequently published an article in Pharmaceutical Research exploring this topic. The complete article is available here: Accelerating Process Development and Product Formulation. The following text highlights some of the conclusions of the workshop session, which are discussed in more detail in the article (Futran, M., Muzzio, F. & Chatterjee, B. Accelerating Process Development and Product Formulation. Pharm Res (2024).)
What are some of the barriers to accelerating development, and how can these be overcome?
Conventional development approaches and some aspects of the regulatory paradigm associated with approval and post-approval changes limit acceleration of development, scale-up, tech transfer, validation, and commercialization. Advanced manufacturing techniques, such as continuous processing using process analytical technology (PAT) for real-time process characterization, have been demonstrated to enhance process understanding and enable simultaneous product and process development. In addition, these techniques allow faster process optimization, closed-loop process control, and real-time quality control.
Another ongoing challenge is that although these new manufacturing technologies, modeling and prediction tools, and new excipients are available, they are not widely known. This lack of awareness and experience is a barrier to wider adoption. Precompetitive collaborations could enhance adoption of innovative methods for the whole industry. These groups could, for example, develop models, systems, and databases, as well as work with regulators to understand what is needed for acceptability. Greater involvement of contract development and manufacturing organizations in these collaborative efforts could further promote innovation.
How does continuous processing accelerate development?
The traditional method of drug substance and drug product manufacturing is batch processing: raw materials are put into the processing unit (e.g., a reactor) for a set time, and then the product is taken from the unit and it is emptied in preparation for the next batch. In continuous processing, the raw materials are continuously fed to the operation, and the product is continuously removed. In the continuous approach, experiments can be run more quickly and more data can be collected, because the variables can be changed and data and samples collected while the process is running continually.
Successful use of this method to rapidly explore a design space for product formulation and process parameters has been demonstrated by the C-SOPS consortium at Rutgers in the development of the continuous process for Janssen’s Prezista, which was the first FDA-approved oral solid-dosage drug product converted from batch processing to continuous processing. Similar approaches can be used with injectable drug products, biologic drug substances and drug products, and continuous flow chemistry for API production.
What is adaptive process development?
In today’s typical process development method, initial versions of a drug formulation and its manufacturing process are chosen before the clinical trial phase. In adaptive process development, formulation and product and process development would continue during Phase I clinical trials, and changes could be made based on the trial results. This approach could possibly be combined with adaptive clinical trials, leading to increased clinical success as well as better optimized products.
What changes are needed in the regulatory framework to facilitate development?
Regulators, especially the US FDA, already support greater use of advanced manufacturing methods and a science- and risk-based quantitative approach based on engineering controls. For example, FDA’s recently established Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative is intended to support adoption of advanced manufacturing technologies. However, regulations need to continue to evolve to use engineering controls rather than procedural controls for processes using advanced manufacturing methods. The framework for post-approval changes, including requirements for stability testing, must also evolve. Greater coordination between regulators, industry, and academia could facilitate industry progress.
For further reading:
Article in Pharmaceutical Research: https://doi.org/10.1007/s11095-024-03708-z
Presentation during workshop: insert link to Futran and Eastgate presentation Futran_Eastgate_Product+Formulation+and+Process+Development_Day1.pdf (squarespace.com)