Understanding Regulatory Submissions and the Role of Regulatory CMC Project Management

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Understanding Regulatory Submissions and the Role of Regulatory CMC Project Management

What is regulatory CMC? An individual in a regulatory affairs CMC role provides the strategy and knowledge needed to ensure that CMC practices are carried out in accordance with the requirements of regulatory bodies, such as the FDA (US Food and Drug Administration) and EMA (European Medicines Agency). CMC regulatory is pivotal in ensuring that drugs and treatments being manufactured are safe, effective, and of high quality for patients.

CMC roles are present in all stages of the drug lifecycle from development and manufacturing to licensing and marketing. At each stage, CMC professionals provide knowledge, understanding, and interpretation of regulations so that the drug has the best chance of being approved. Regulatory in CMC principally involves authoring and compiling regulatory submissions and interacting directly with personnel at regulatory bodies through Strategy.

Regulatory Submissions for a medicinal drug product includes documentation or data submitted to a regulatory authority for review, included in an application (NDA/BLA), or in response to a question during the review of the healthcare product. The submission outcome determines whether a drug can proceed beyond clinical trials into commercialization.

Regulatory submission complexities have always been a matter of concern for smaller emerging biotechs. But even more so recently. Submissions requirements are increasingly stringent, and the applications involve a significant amount of documentation and data. Here is everything you should know about regulatory submissions.

Types of regulatory submissions

  • Clinical trial applications (INDs, CTAs)
  • CMC Information Amendments
  • Marketing applications (NDAs, BLAs, MAAs)
  • Responses to agency inquiries during the review
  • Applications for modifications of submissions
  • Availing contract services
  • Post-approval commitment submissions

The format can be paper, electronic, or both, but of course lately, the agencies are encouraging the use of the eCTD format. The complexity or amount of information involved vary by type of submission. Comprehensive submissions maximize the probability of a favorable regulatory review.

Regulatory Submission Challenges

Country specific requirements: Managing different country-specific stipulations for submissions such as those for the United States and Europe can be challenging. Manufacturers must track global regulations for changes or differences that could affect submission requirements.

Lack of regulatory strategies: Manufacturers should define the appropriate strategy upfront and conduct pre-submission meetings with the agencies for guidance and clarity on needed data. A sound regulatory strategy is premised on the target market, competitive landscape, an unmet medical need, opportunity for first-in-market, and initial target indication.

Inconsistent data: The FDA and other agencies reveal that companies often fail to adequately describe their product context. Multiple subject matter experts may also author different sections of the submission, leading to an inconsistent storyline.

Limited submission experience: Companies face difficulties hiring and retaining experts to manage submissions. Further, business strategy changes such as expedition or new combination products can result in skills gaps in the submission teams.

Regulatory Submissions Best Practices (We focus on the Chemistry, Manufacturing, and Controls (CMC) here)

You will need comprehensive information on the CMC section of an IND, especially for late-phase clinical trials. Plan for detailed and well-audited applications, supplements, and amendments by collecting data throughout the development process.

Develop a refined regulatory strategy with your defined approaches on formulation development and quality-based manufacturing. Implement quality assurance and regulatory compliance frameworks for drugs and biologics early on. Also, ensure to:

  • Brush up on the regulatory requirements for each subsequent submission. Requirements evolve over time!
  • Define the appropriate regulatory strategy with approval in mind and conduct pre-submission meetings with the agencies for guidance and agreement.
  • Build a comprehensive, cohesive, and data-backed storyline for the product
  • Define how you'll manage the multitude of documents needed in the submission is critical; use predefined templates for consistency.

How to Streamline Regulatory Submissions

Investigational New Drug, Preparation, and Submission

Consult with seasoned SMEs and/or regulatory experts on product data evaluation. In line with your regulatory strategy, build clarity, precision, and consistency across all documents that are to be included in the applications.

New Drug Application Submission (NDA) 505(b)(1)

New Active Ingredients (APIs) that have not previously been approved. This type of submission requires extensive clinical and nonclinical studies to prove a product's safety and efficacy.

Seek to optimize the organization, quality, and comprehensiveness of your NDA applications. Ensure to include all data and interpretation of compliance data. Audit requirements must be met, and CTD applications must meet stipulations.

New Drug Application Submission (NDA) 505(b)(2)

The  505(b)(2) product contains similar active ingredients to an approved drug. The CMC information required is similar to that of the NDA505(b)(1) except that the data partly relies on the FDA's findings of safety and efficacy related to a previously approved product. In-depth knowledge of filing requirements and the use of acceptable approaches in drug development can help your case. Drugs with new indications, changes in dosage form, strength, formulation, dosing regimen, or route of administration. New combination products, Prodrugs of an existing drug, and in some cases, drugs with new active ingredients where the FDA has express permission to rely on data not developed by the NDA applicant.

Biologic License Application Submission (BLA)

BLAs are for biological products, while NDAs are for small molecule drugs. BLAs should include all information about the product that was obtained over the development process. The submission should demonstrate the biologic's safety, potency, and purity.

Include adequate data in the application, such as synthesis data and interpretation to guarantee product approval. Strive for compliance regulations and FDA audit requirements for biologics and ensure eCTD submissions meet specifications. The BLA is regulated under 21 CFR 600 – 680.

Abbreviated New Drug Application Submissions (ANDA) 505(j)

Start by gathering the relevant ANDA information that can help guarantee a comprehensive application. Compile adequate data on how the product performs in the same way as the innovator drug. Attach supplemental details on drug chemistry, manufacturing and controls, and other needed information.   

Complex Generic Product Submissions

Complex generic products are identical to a brand name drug except that they have a complex active ingredient, new formulation, complex route of delivery, or new drug-device combinations. Application requirements are identical to ANDA submissions.

Submission Project Management

An experienced and competent project manager can be the key difference between successful and unsuccessful regulatory submissions. At DSI;

We have regulatory submission experience: We bring a broad knowledge of Agency regulations and expectations on direct experience. We interact with the FDA project managers and reviewers daily as the focal point of contact for our clients.

We can help with your regulatory strategy: We offer regulatory and product guidance to our clients and serve as project coordinators. We guide on optimal practices for efficient and compliant applications.

We can improve your document controls: We coordinate submission authoring, reviews, strategy discussions, and publishing and life-cycle application maintenance activities for cohesive and consistent product storylines.

We support the entire submission process: We can also accompany the sponsors into agency meetings (FDA and EMA scientific meetings) and in teleconferences participation.

We gladly welcome your questions on how our strategic approaches can help you succeed in your regulatory submissions. Contact us at 855-805-8402.