Bringing a new therapeutic to market is a complex and multifaceted process culminating in submission and approval of a new drug application (NDA). Within the NDA, the chemistry, manufacturing, and controls (CMC) section plays a pivotal role in demonstrating drug quality, safety, and efficacy. In this blog, we demystify the CMC section of NDA preparation, providing insights and guidance for navigating this intricate landscape. 

The influence of CMC on the NDA process 

Identification of a promising molecule is just the start of a long journey to product approval. CMC is a critical component in the development strategy for an asset, and the FDA’s expectations regarding a sponsor’s level of CMC product and process knowledge increases as a molecule advances to market. By the time of NDA submission, a sponsor should be able to demonstrate that the clinical materials used in pivotal trials are representative of the proposed commercial processes and product. 

The CMC component of an NDA provides detailed information on the investigational drug’s composition, manufacturing processes, quality controls, and stability. It ensures that the product is produced consistently and controlled in accordance with the quality standards suitable for its intended use. Regulatory authorities scrutinize the CMC section to assess whether the sponsor can reliably manufacture the drug on a commercial scale while maintaining strict product quality and integrity. 

Key components of the CMC section 

The CMC section of an NDA contains detailed information on the following aspects of the investigational drug: 

• Drug substance or active pharmaceutical ingredient (API). This includes information about the physical and chemical properties of the API, including molecular structure, purity, and potency, and the reference standards or materials used in analytical testing. It describes the synthetic route, raw materials, reagents, and solvents used, along with the control strategies employed to ensure consistency. It also provides detail on the identification and quantification of potential impurities, including degradants and residual solvents, and offers evidence demonstrating that the manufacturing process produces API of consistent quality.

• Drug product (finished dosage form). The includes an explanation of the rationale for the chosen formulation, including excipient selection and compatibility studies. It also includes a detailed description of the manufacturing steps, equipment used, in-process controls, and critical process parameters, as well as any container closure systems. The sponsor should elaborate on the defined acceptance criteria and test methods for ensuring quality and consistency of the finished dosage form. For sterile products, details on sterility assurance and microbial limits are needed.

• Analytical methods. In addition to validation data for the analytical methods used to test the API and drug product to demonstrate accuracy, precision, specificity, and robustness, the sponsor should provide results from multiple batches to show consistency and compliance with specifications.

• Compliance with good manufacturing practices (GMP). This includes details on the manufacturing sites, including GMP certifications and inspection history, and the quality management system. 

CMC processes that require early and ongoing work throughout product development and into approved product stewardship include:  

• Product process validation. Validation involves detailed documentation of every step of the production process, from raw material sourcing to final product packaging in good manufacturing practice (GMP) compliant facilities. The objective is to demonstrate that the manufacturing process consistently produces a product that meets all predefined specifications. Validation reports are to be included in a marketing application.

• Stability studies. These studies are used to establish shelf life and are designed to assess how the quality of the drug product changes or varies over time under the influence of environmental factors such as temperature, humidity, and light exposure. Stability studies are initiated to support clinical trial material and continue to support the intended final formulation in the NDA and after approval.

• Batch testing. This is the final step in ensuring product consistency and quality. Each batch of drug product undergoes rigorous testing to confirm conformity with all predefined specifications prior to release for distribution. This testing includes assessments of potency, purity, dissolution, and sterility, where applicable, among other parameters. Detailed documentation and reporting of batch testing results are essential components of NDA submission. Following approval, release testing continues on every lot of drug product prior to release into the market. 

Navigating the hurdles  

Three common challenges associated with CMC are: 

1. Scaling up manufacturing processes. Differences between small-scale and commercial-scale manufacturing can impact product quality. Performing scale-up studies can help in the development and validation of manufacturing processes at commercial-scale, with adjustment of control strategies as needed.
2. Managing impurities. Identifying and controlling impurities, especially genotoxic impurities, is critical to drug safety. The key is to develop sensitive analytical methods and to implement robust purification processes to minimize impurity levels.
3. Complying with global regulations. Regulatory requirements may vary across regions, creating complexity. Harmonizing CMC documentation according to ICH guidelines and then tailoring submissions to specific regional requirements can help streamline the process. 

Strategies for successful CMC preparation 

Cross-functional collaboration and early communication with regulators are essential for successful CMC preparation. Engaging teams from nonclinical, clinical, manufacturing, quality, and regulatory affairs at the outset helps ensure alignment.  

Managing risk is critical. Begin by conducting a thorough risk assessment to identify and mitigate potential issues in manufacturing and control. Take it a step further by implementing quality by design (QbD) principles to identify critical quality attributes (CQAs) and critical process parameters (CPPs) to enhance understanding and control over the manufacturing process. 

Utilize opportunities for pre-submission meetings with regulatory agencies to discuss CMC issues and obtain feedback. If any questions or deficiencies are raised during the submission and review process, be prepared to respond promptly and effectively.  

Early planning for positive downstream impact  

Bringing a new product to market is a highly orchestrated process that involves rigorous scientific evaluation, comprehensive documentation, and regulatory scrutiny. The CMC section of the NDA is central to this endeavor, not only facilitating regulatory approval but also laying the foundation for successful commercial manufacturing. With early, integrated planning and a commitment to quality, sponsors can provide regulatory agencies with a deep understanding of how a drug is conceived, manufactured, and controlled, ensuring approval and delivery of safe, effective, and consistent medications.  

For support developing the CMC section for a new drug product, contact us.