Designing a CMC Development Plan for Combination Products: A Small Biotech Challenge

Combination products are an increasingly important area of drug development that offer many potential benefits, such as enhanced efficacy, targeted delivery, and synergistic effects. However, the development and regulatory approval of combination products can be complex and challenging, particularly for small biotech companies with limited resources and expertise in this area. In this blog article, we will explore the key considerations for designing a CMC (chemistry, manufacturing, and controls) development plan for combination products from a small biotech perspective. We will also discuss some of the challenges that small biotech companies may face during the development and regulatory approval process for combination products and provide guidance on overcoming these challenges. Whether you are a small biotech company developing a combination product or a regulatory professional seeking to understand the regulatory landscape for these products better, this article will provide valuable insights into this exciting and rapidly evolving area of drug development.

What are Combination Products?

Combination products, which combine two or more different types of medical products (drugs, devices, or biologics) in a single entity, are increasingly becoming an essential category of medical products in the pharmaceutical industry. Developing combination products is a complex process requiring close collaboration between disciplines, including regulatory affairs, quality assurance, manufacturing, and clinical research. This article will guide how to design a CMC (chemistry, manufacturing, and controls) development plan for combination products from a small biotech perspective and highlight some of the challenges that may be encountered during this process.

• Define the Combination Product

The first step in designing a CMC development plan for a combination product is to define the product itself. This includes identifying the active pharmaceutical ingredients (APIs), the medical device components, and any other excipients or materials used in the product. It is also essential to consider the intended use of the combination product, as this will influence the design of the CMC development plan.

• Conduct a Risk Assessment

Once the combination product has been defined, a risk assessment should be conducted to identify potential hazards and risks associated with the product’s development and manufacturing. This assessment should consider all product lifecycle aspects, including design, manufacturing, packaging, storage, and use. The risk assessment should also consider any regulatory requirements and standards for the product.

• Develop a Quality Target Product Profile (QTPP)

The QTPP is a key element in designing a CMC development plan for combination products. The QTPP defines the desired quality attributes of the combination product and provides a roadmap for the development process. The QTPP should consider the intended use of the product, the desired safety and efficacy profile, and any other relevant factors.

• Develop a Control Strategy

The control strategy outlines the critical quality attributes (CQAs) that must be controlled to ensure the quality, safety, and efficacy of the combination product. The control strategy should be based on a thorough understanding of the product’s manufacturing process and should include measures to ensure consistency and reproducibility.

• Conduct Product Development Studies

Product development studies should be conducted to support the CMC development plan. These studies should include formulation development, process development, and analytical development. The goal of these studies is to optimize the product’s performance and ensure that it meets the desired quality attributes outlined in the QTPP.

• Conduct Manufacturing Process Validation

Manufacturing process validation is a critical component of the CMC development plan. This process involves demonstrating that the manufacturing process can consistently produce a product that meets the desired quality attributes. Validation should be conducted using a risk-based approach, and should include process performance qualification (PPQ) studies.

The Challenges

Developing a CMC development plan for combination products can be challenging, especially for small biotech companies. Some of the common challenges include:

• Limited Resources

Small biotech companies often have limited resources, making it difficult to conduct the necessary product development studies and validation activities.

• Regulatory Complexity

Combination products are subject to complex regulatory requirements, which can be challenging for small biotech companies to navigate.

• Technical Complexity

Combination products are inherently complex, as they involve the integration of multiple different products. This complexity can make it challenging to develop and validate manufacturing processes.

Some example questions that arise when developing a combination product

Here are some example questions that can arise when developing a combination product:

1. What is the appropriate regulatory pathway for my combination product? Should I seek approval as a drug-device combination product or a biologic-device combination product?
2. How do I ensure that the individual components of my combination product are compatible and do not interact negatively?
3. How do I determine the appropriate dosage of each component in the combination product to ensure safety and efficacy?
4. How do I design appropriate clinical trials to assess the safety and efficacy of my combination product?
5. How do I ensure that my manufacturing process is consistent and reproducible, and that I can meet the required quality standards for my combination product?
6. How do I ensure that my combination product will be reimbursed by payers, and that it will be cost-effective for patients?
7. How do I protect my intellectual property when developing a combination product that may involve multiple components and technologies?

These are just a few examples of the questions that can arise when developing a combination product. The specific questions will depend on the nature of the product, the intended use, and the regulatory requirements in the relevant jurisdictions. It is important for developers of combination products to seek expert advice and guidance early in the development process to ensure that they are addressing all relevant issues and are well-positioned for regulatory approval and commercial success.

Examples of recently approved Combination Products

There have been several combination products recently approved by regulatory agencies around the world. Here are a few examples:

1. Breztri Aerosphere: This is a combination product consisting of three drugs (budesonide, glycopyrronium, and formoterol fumarate) in a single inhaler. It was approved by the FDA in 2020 for the maintenance treatment of chronic obstructive pulmonary disease (COPD).
2. Veklury: This is a combination product of the drug remdesivir and a lipid nanoparticle carrier. It was approved by the FDA in 2020 for the treatment of COVID-19.
3. Phesgo: This is a combination product consisting of the drugs pertuzumab and trastuzumab, which are used to treat breast cancer. It was approved by the FDA in 2020 for use in certain patients with HER2-positive breast cancer.
4. Symdeko: This is a combination product consisting of two drugs (ivacaftor and tezacaftor) in a single tablet. It was approved by the FDA in 2018 for the treatment of cystic fibrosis.
5. Duzallo: This is a combination product consisting of two drugs (lesinurad and allopurinol) in a single tablet. It was approved by the FDA in 2017 for the treatment of gout.
   

Who regulates the approval of Combination Products

The regulation of combination products is a complex process that involves multiple regulatory agencies around the world. In the United States, combination products are regulated by the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA). The specific regulatory center that oversees a particular combination product depends on the primary mode of action of the product.

In Europe, combination products are regulated by the European Medicines Agency (EMA) and the European Commission. The EMA has a dedicated division, the Committee for Medicinal Products for Human Use (CHMP), that is responsible for evaluating and approving medicinal products, including combination products. In addition, there is a separate regulatory body called the European Medicines Agency’s Committee for Advanced Therapies (CAT), which is responsible for the regulation of certain combination products that contain gene therapies, cell therapies, or tissue-engineered products.

In other regions worldwide, such as Japan and Canada, combination products are regulated by similar agencies that oversee drug, device, and biological products. The specific regulatory pathway for approval of a combination product varies depending on the specific product and the regulations in the country or region where it is being developed and marketed.

More about the specific regulatory center that oversees a particular combination product and how it depends on the primary mode of action of the product.

The specific regulatory center that oversees a particular combination product in the United States depends on the primary mode of action of the product. The FDA uses a “primary mode of action” approach to determine which center will have primary jurisdiction over a combination product.

If the combination product’s primary mode of action is that of a drug, then the FDA’s Center for Drug Evaluation and Research (CDER) will be the primary regulatory center responsible for reviewing and approving the product. Examples of combination products with a drug mode of action include a combination of two or more drugs, such as a fixed-dose combination product or a combination product that enhances the efficacy of a drug by targeting a specific mechanism of action.

If the combination product’s primary mode of action is that of a device, then the FDA’s Center for Devices and Radiological Health (CDRH) will be the primary regulatory center responsible for reviewing and approving the product. Examples of combination products with a device mode of action include a combination of a drug and a medical device, such as a drug-eluting stent or an inhaler with an integrated drug delivery system.

If the combination product’s primary mode of action is a biologic, then the FDA’s Center for Biologics Evaluation and Research (CBER) will be the primary regulatory center responsible for reviewing and approving the product. Examples of combination products with a biologic mode of action include a combination of two or more biologics, such as a combination of monoclonal antibodies or a combination of cell therapy and gene therapy.

Some specific examples of modes of action for combination products include:

• Enhanced efficacy: A combination product that enhances the efficacy of a drug by targeting a specific mechanism of action. For example, a combination of a chemotherapy drug and a targeted therapy drug that works by blocking a specific receptor on cancer cells.
• Targeted delivery: A combination product that delivers a drug to a specific site in the body or organ. For example, a combination of a drug and a medical device designed to deliver the drug to a specific area in the lung.
• Synergistic effects: A combination product that works by combining two or more drugs that have synergistic effects. For example, a combination of two antibiotics that work together to combat a bacterial infection.

Overall, the specific regulatory center that oversees a combination product will depend on the primary mode of action of the product, as well as other factors such as its intended use and other features of the product.

The Guidance for Combination Products

There are several guidance available for combination products, which provide regulatory and scientific advice for the development, approval, and post-approval of these products. Here are a few examples:

1. FDA Guidance for Industry and FDA Staff: “Current Good Manufacturing Practice Requirements for Combination Products” – This guidance provides recommendations for complying with the current good manufacturing practice (CGMP) requirements for combination products, including the manufacturing, testing, and quality control of these products.
2. FDA Guidance for Industry: “Considerations for the Assessment of Safety and Efficacy of Combination Products” – This guidance provides recommendations for the assessment of safety and efficacy of combination products, including the clinical trial design and endpoints, as well as considerations for the use of biomarkers and patient-reported outcomes.
3. FDA Guidance for Industry and FDA Staff: “Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program” – This guidance provides recommendations for submitting a request for feedback or a meeting for medical device submissions, including combination products.
4. EMA Guideline on the Investigation of Drug Interactions – This guidance provides recommendations for the investigation of drug interactions, including drug interactions between the components of a combination product.
5. EMA Guideline on the Clinical Development of Fixed Combination Medicinal Products – This guidance provides recommendations for the clinical development of fixed combination medicinal products, including combination products that contain two or more active substances.

These are just a few examples of the guidance available for combination products. The specific guidance documents that apply to a particular combination product will depend on the product’s characteristics, mode of action, and regulatory jurisdiction. It is important for developers of combination products to consult with regulatory authorities early in the development process to ensure that they are following the appropriate guidance documents and meeting regulatory requirements.

Conclusion

In conclusion, the development and regulatory approval of combination products can be a complex and challenging process, especially for small biotech companies. However, with careful planning and execution, small biotech companies can successfully navigate the regulatory landscape and bring innovative combination products to market. By following the appropriate guidance documents and engaging with regulatory authorities early in the development process, companies can ensure that they are meeting regulatory requirements and addressing potential issues before they become obstacles to approval. In addition, collaborations and partnerships with other companies or academic institutions can provide access to specialized expertise and resources that can be invaluable in developing combination products. Ultimately, the successful development and approval of combination products will require a combination of scientific, regulatory, and business expertise, as well as a willingness to adapt and collaborate in a rapidly evolving landscape.

Designing a CMC development plan for combination products is a complex process that requires a multidisciplinary approach. Small biotech companies face unique challenges in this process, including limited resources, regulatory complexity, and technical complexity. However, with careful planning and execution, small biotech companies can successfully develop and commercialize combination products that meet the needs of patients and healthcare providers.