This case study highlights the problems that can surface from missing key development activities: little solid-state characterization to understand the physical properties of the API and how it could have an impact on the material's bulk properties, formulation performance (i.e., bioavailability, content uniformity), processability, and stability. What attributes would be required to ensure that the technique is fit for purpose as applied to an early-phase program?

https://www.news-medical.net/whitepaper/20200722/Developing-a-Phase-Appropriate-CMC-Program.aspx. New York We speak to Andrew Lynn, the chief executive at Fluidic Analytics, about the role proteins play in understanding human disease.

If important enough, consider controlling the attribute and adding it to the API specification.

Yet, guidance for early phase CMC support particularly is limited so it is not uncommon to find sponsors that are not taking advantage of the phase-appropriate approach. Only a few decades ago, most drugs were developed from start to finish with well-defined systems of control by large pharma. Before entering into a co-development agreement with a larger pharmaceutical company or selling the company (or the drug) to another company to continue the development, these companies use a development strategy to bring the drug to a certain point within the development cycle. This issue is important, because lower risk classification is associated with less cost for containment of the molecule and more flexible manufacturing options. Some sponsors may focus their efforts on acquiring the funding instead of the development or regulatory drivers. Fifth Floor

Lisa holds a bachelors degree in biochemistry from the University of California at Davis.

articles/phase-appropriate-cmc-activities-facilitate-the-transition-from-early-development-through-commercialization, Phase-Appropriate CMC Activities Facilitate the Transition from Early Development through Commercialization, Approximately six out of 100 molecules make it from the discovery stage to phase III clinical trials (, CMC Considerations for the Transition from Early-to-Late Development, Critical Areas of Risk Consideration for Early- to Late-Phase Transition.

In these instances, the focus may not be on the regulatory requirements, the funding, or long-term developmental requirements, but rather the data and studies required to entice a buyer or partner. To save time, the company decided to move its drug product manufacturing to a new site to accommodate increased scale, with the edict to make it exactly the same as the clinical supplies. Small teams were put in place to monitor transfer and avoid changes. Timing, Funding, Guidance, etc. 4.

When designing an appropriate program a unique combination of drivers, e.g.

2022 MJH Life Sciences and Pharmaceutical Technology. The landscape of drug development has continued to shift over time. Today, this has significantly changed; much early development (Pre-investigational new drug [IND], Phase I, Phase II) work is performed by small- to medium-size companies, many of which are virtual companies. The key raw material suppliers could not meet the initial manufacturing window, because custom excipients were chosen for their phase II. They adopt a development strategy to bring the drug to a certain point within the development cycle (i.e., Phase 2A), then enter into a co-development agreement with a larger pharmaceutical company or sell the company (or the drug) to another company to continue the development. The company itself may need to be willing to accept certain quality responsibilities and their consequences if time is key.

Numerous companies know that they will not have enough funding to support the commercialization of their product. FDA, Analytical Procedures and Methods Validation for Drugs and Biologics, Guidance for Industry (Silver Spring, MD, July 2015). Accepting Appropriate Regulatory CMC Risk, Aligning Pharmaceutical Quality Systems and Product Development, An expert viewpoint on how to avoid surprises in the API manufacturing process, An expert viewpoint on selecting a China-based contract manufacturing organization, An expert viewpoint on selecting the right contract manufacturer for large scale drug production, Chemistry, Manufacturing, and Controls Regulatory Affairs Support, CMC Discussion Topics Around Your Product Development, Design and Implementation of Quality Pharmaceutical Systems, FDA End of Phase II CMC Meeting Preparation, How to understand the impurities in the process of molecule assessment, Identifying and Managing Pharma Contractors and Vendors, Insights into the process of a new drug application, Management and Assessment of the Pharmaceutical Supply Chain, Materialization Characterization and Formulation Development, Meeting Pharmaceutical Regulatory Challenges, Optimizing and Validating Analytical Pharmaceutical Methods, Person-in-plant expertise to support the contract research manufacturer, Pharmaceutical Development and Formulation Considerations, Pharmaceutical Regulatory Submission Preparation and Management, Pharmaceutical Vendor Inspections, Audits and Qualification, Regulatory Considerations Moving from Phase 2 to Phase 3, Seeing the forest for the trees: CMC and Regulatory Affairs, The Process of Bringing a Product to Market, Tips on filing an Investigational New Drug application, Trends in active pharmaceutical ingredient industry, What You Need to Understand About CMC Regulatory Affairs. Under milestone funding, the infusion of additional development funds is tied to reaching a certain milestone, which releases funds to continue development. Intensive remediation was needed to redevelop analytical methods for process development work at a new scale on new equipment. Consider the example of a Phase I API in development. With each phase of the clinical trial the quantity and type of information vital in the CMC sections of an application differs. Lisa Caralli is the Director, Science & Technology, Pharmaceutics at Catalent. News-Medical. The group expected to run a small proof-of-concept study if the phase I was successful and thus made minimal investment in making phase II supplies. Lack of preparation for scale-up activities needed for eventual commercialization can often cause major time delays, increased costs, and a significant amount of rework. These experiments can help generate data on compatibility with these other excipients early on and make the transition between the capsule to tablet smoother. In addition, key analytical testing was not reproducible at larger scales, and the manufacturing process had a lot of variability and in-process controls failures. As a result, smaller companies commonly rely on the expertise of contract laboratories to perform analytical work, act as partners in the development process, and help design the appropriate chemistry, manufacturing, and controls (CMC) analytical activities that will meet their companys specific goals.

While the FDA guidance encourages the utilization of a phase-appropriate approach, they lack any specific details of the binding requirements and timing.

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The goal may be to generate the appropriate interest to sell the IP or the company itself, instead of an end goal of commercializing a new drug. DSI, a PLG Company. FDA, INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information, Guidance for Industry, (Rockville, MD, May 2003). Milestone funding. Just a few decades ago, most drugs were developed from beginning to end by large pharmaceutical companies with well-defined systems of control. must then be considered. News-Medical. Hospira Issues Voluntary Recall for One Lot of Propofol Injectable Emulsion, USP, Drug Solutions Podcast: The Current State of Compliance and Validation, PerkinElmer Introduces New Cytometry Management Service, Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug, Including Well-Characterized, Therapeutic, Biotechnology-derived Products, INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information, API Synthesis and Manufacturing, Large Molecule, API Synthesis and Manufacturing, Small Molecule, Specificity (including stress studies as applicable). All rights reserved. First, while the FDA guidances encourage the use of a phase-appropriate approach, they lack specific details of the actual requirements. With competing timelines and resources between itself and other clients in the queues, it is not uncommon, yet, understandable that timelines within a CMO can and do slide. NY 10003-3020, New York San Diego ChicagoLondon Frankfurt Shanghai. Again, FDA gives limited guidance on the expectations. In these instances, development work that may be needed for regulatory approval or studies which would aid in the longer-term development goals are delayed for a later point. Developing a Phase Appropriate CMC Program. Ultimately, funding drives data and the path for CMC requires expertise, knowledge, and agreement. In parallel, Anxious, LLC was making the early phase II supply using their limited bulk API and faced a variety of manufacturing issues, including sticking and poor dose content uniformity. Methods may evolve as the molecule progresses. In this interview, we speak to Dr. David Field about his latest research into anxiety and depression and whether vitamin B6 supplements could help to reduce it. While innovators must position themselves to meet important short-term goals (e.g., IND filings, dosing the first patient, funding, partnering), they must also consider the bigger picture and make risk-based decisions in early development that can facilitate the successful transition to late-phase development. Figure 5:Leverage a partner's integrated global expertise for a seamless early-to-late transition. FDA has a number of guidances which can be utilized to shape the program to meet expectations, including FDAs Current Good Manufacturing Practice for Phase 1 Investigational Drugs Guidance for Industry, and INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information.

FDA and the International Conference for Harmonization (ICH) have several guidances that can be used to design the program to meet expectations, including FDAs Current Good Manufacturing Practice for Phase 1 Investigational Drugs Guidance for Industry (1), Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (2), and INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information (3); and ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (4).

Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments. This site complies with the HONcode standard for trustworthy health information: verify here. 2022. A second reason may revolve around the possible difficulty in implementing a CGMP quality system that allows for differing levels of CGMP compliance throughout the various clinical phases of development. Regulatory agencies in Europe and the U.S. require the CMC section of applications and submissions to have detailed information regarding the drug substance and the formulated product in which the active will be administered. Designing a phase-appropriate CMC strategy can be vital to the success of a small or virtual sponsor. This can often result in conflicts between what development work should be carried out and what has to be completed. These studies were done with limited clinical supplies in a relatively small patient population.

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All rights reserved. Instead of an end goal of commercializing a new drug, the goal may be to generate the appropriate interest to sell the intellectual property or company. Animal models showed some encouraging linear exposure of the drug, and there was a predicted low dose based on the potential efficacious concentrations that were being investigated.

It is crucial to assess the development drivers regarding the program. API. The current synthetic scheme is used to produce 1 kg of material. on this website is designed to support, not to replace the relationship "Developing a Phase Appropriate CMC Program". To mitigate these risks, it is important to characterize every drug lot before use in drug product manufacturing to ensure that drug properties have not changed.