Scenarios in Regulatory Starting Materials Designation

The designation of Regulatory Starting Materials (RSMs) is guided by guidelines such as ICH Q11. The key factors include the complexity of the synthesis, the step at which the structure of the drug substance is first established, and control strategies for impurities.

Typically, the designation is not based on a fixed number of steps but rather on the complexity and nature of the synthesis process.

The goal is to demonstrate adequate control over the process and the quality of the final drug substance.

Engaging with regulatory authorities early in the process through pre-IND or similar meetings can provide valuable guidance specific to your product and process.

Establishing Regulatory Starting Materials

A Key Consideration in Drug Development

In the intricate journey of drug development, the designation of Regulatory Starting Materials is a pivotal step, often overlooked yet crucial for regulatory compliance and quality assurance.

This article aims to delve into the importance of RSMs, key considerations, and practical examples to guide pharmaceutical companies.

Why RSMs Matter RSMs are the specific substances used in the first step of a drug substance's synthesis where its structure is defined.

Their importance lies in ensuring that the quality of the final drug product is traceable and controllable from these early stages.

Key Considerations in Establishing RSMs

1. Complexity of Synthesis: The more complex the synthesis, the closer to the final drug substance the RSMs are likely to be.
2. Regulatory Guidelines: ICH Q11 provides detailed guidance on the selection of RSMs, focusing on the control of impurities and the synthesis process.
3. Quality Control: Effective quality control measures must be in place from the RSM stage to ensure the integrity of the final product.

Some Case Studies

A Simple Synthesis

1. In a drug where the synthesis is straightforward, the RSM might be an easily sourced, well-characterized compound. Here, the focus is on purity and supply chain reliability.

Complex Case Studies in Establishing Regulatory Starting Materials

1. Biotech Startup with a Novel Synthesis Route: A biotech startup develops a new synthesis route for a known molecule. The route involves a unique catalyst and several intermediates not previously documented. The challenge lies in designating the RSM, as regulatory guidelines are unclear for such novel processes. This scenario requires careful documentation, strong scientific rationale, and proactive engagement with regulatory authorities to determine the appropriate RSM.
2. Repurposing an Existing Compound for a New Indication: A company plans to repurpose an existing compound for a new therapeutic indication. The synthesis process remains unchanged, but the impurity profile differs significantly due to a change in the manufacturing scale. The ambiguity arises in determining if the original RSMs are still appropriate or if new RSMs should be designated to account for the altered impurity profile and manufacturing conditions.
3. Outsourcing Production to a Third Party: A pharmaceutical company outsources the production of a key intermediate to a third-party manufacturer. The third party proposes a slightly modified synthesis route to optimize yield. This change, while seemingly minor, impacts the designation of RSMs. The primary challenge is in ensuring that the modified route doesn't compromise the quality of the final product and that the RSMs are appropriately

Here are some steps for establishing regulatory starting materials

1. Identify the starting materials used in the synthesis of an API.
2. Evaluate the quality and purity of each starting material.
3. Determine the appropriate control strategy for each starting material.
4. Start with a flow diagram of the material, the molecule, and the process.
5. Identify purification points, which could be extractions, crystallization, or chromatography.
6. Specify tests for identity and purity.
7. Provide a justification for how each proposed starting material is appropriate.

Challenging Scenarios in Regulatory Starting Materials Designation

1. Synthesis with Multiple Potential Starting Points: In a complex synthesis involving multiple steps and potential starting points, a company struggles to determine the most appropriate RSM. Each potential RSM has its advantages and drawbacks in terms of cost, availability, and control over impurities. The decision becomes more challenging due to differing interpretations of regulatory guidelines by various global health authorities.
2. Scaling Up from Laboratory to Commercial Production: A pharmaceutical company successfully developed a drug in a laboratory setting with a designated RSM. However, upon scaling up to commercial production, they encounter unexpected variability in the synthesis process. This variability raises questions about whether the initially designated RSM is still appropriate or if a re-evaluation is needed to ensure consistent quality and compliance at a larger scale.
3. Change in Supplier Leading to Variability: A company faces a situation where their regular supplier of the RSM changes the synthesis process slightly due to internal improvements. This alteration, though minor, leads to a slight change in the impurity profile of the RSM, which in turn affects the final drug substance. The company must assess whether this change necessitates a re-designation of the RSM or additional controls in the manufacturing process to maintain product quality.

Timing

Establishing RSMs is a crucial decision in manufacturing, and timing this decision correctly is key for ensuring regulatory compliance and product quality. Consider establishing RSMs:

1. At the Early Stages of Drug Development: Early designation helps in understanding and controlling the synthesis process from the start, impacting the quality of the final drug substance.
2. Before Scaling Up Production: It's important to establish RSMs before transitioning from laboratory-scale to commercial-scale production to ensure consistency and compliance with regulatory standards.
3. When Modifying the Synthesis Process: If there are changes to the synthesis route, either due to optimization or due to a change in suppliers, reassessing RSMs ensures that these modifications don't negatively impact the final product.
4. Before Regulatory Submissions: Having well-defined RSMs is critical for regulatory submissions, as it demonstrates control over the manufacturing process and the quality of the drug substance.
5. When Diversifying Suppliers: If sourcing RSMs from new suppliers, it's necessary to re-evaluate them to ensure they meet the required quality standards and do not introduce variability in the product.

The decision to establish RSMs should be integrated into strategic planning stages, considering both the technical aspects of drug development and the regulatory framework.

Other Things to Consider

The top concerns when establishing RSMs include:

1. Complexity of Synthesis: Understanding the complexity of the synthesis pathway is crucial to determining appropriate RSMs.
2. Control of Impurities: RSMs must be selected considering their impact on the impurity profile of the final product.
3. Regulatory Compliance: Ensuring that the chosen RSMs comply with relevant regulatory guidelines like ICH Q11.
4. Supply Chain Reliability: The availability and consistency of the RSM supply are essential for uninterrupted production.
5. Impact on Quality and Safety: RSMs should not adversely affect the quality and safety of the final drug product.

These concerns highlight the need for a strategic approach to RSM selection, balancing scientific, regulatory, and practical considerations.

Understanding the Selection of Drug Substance Starting Materials

In their comprehensive article, Illing, Timko, and Billett explore the critical process of selecting starting materials for drug substance synthesis. This selection, integral to drug development, is governed by a regulatory framework emphasizing the point at which regulatory change control and current good manufacturing practices (CGMPs) are introduced.

Key Highlights:

1. Regulatory Framework: The article reviews guidelines from major regulatory bodies like the US FDA, EMEA in the EU, and Japan's MHLW, alongside ICH guidelines.
2. Starting Material Definition: It's described as a substance significantly incorporated into the drug's structure and can be a raw material, intermediate, or the drug substance itself. The selection is influenced by factors like chemical properties, commercial availability, and impurity profiles.
3. FDA and EMEA Guidelines: Criteria for starting materials include structural importance, commercial availability, well-defined properties, and commonly known procurement procedures. The EMEA emphasizes detailed characterization and control of materials.
4. Design Space and Risk Management: ICH Q8 and Q9 introduce concepts like design space and quality risk management, emphasizing a science-based approach to manufacturing control.
5. Process, Analytical, and Change Control: The selection process involves balancing process control (ensuring the integrity of the starting material), analytical control (monitoring impurities and quality), and change control (managing modifications in the starting material or process).

Conclusion

Selecting starting materials for drug synthesis is a nuanced process requiring a balance between regulatory compliance and efficient manufacturing. This involves a thorough understanding of process controls, analytical techniques, and adaptive change management to ensure patient safety and product quality.

References

1. D. Jacobson-Kram and T. McGovern, 'Toxicological Overview of Impurities in Pharmaceutical Products," Advanced Drug Delivery Reviews 59 (1), 38–42, 2007.

2. ICH Q8 Pharmaceutical Development (Geneva, Switzerland, May 2006).

3. ICH Q9 Quality Risk Management (Geneva, Switzerland, June, 2006).

4. FDA, Guidance for Industry: BACPAC I: Intermediates in Drug Substance Synthesis; Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation, Feb. 2001, withdrawn, Fed. Regist. Notice June 1, 2006.

5. FDA, Guidance for Industry: Drug Substance: Chemistry, Manufacturing, and Controls Information, Jan. 2004, withdrawn Fed. Regist. Notice June 1, 2006.

6. ICH Q7 Good Manufacturing Guide For Active Pharmaceutical Ingredients, (Geneva, Switzerland, Aug. 2001).

7. FDA, Guidance for Industry: Guidance for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (Rockville, MD, Feb. 1987).

8. FDA, Guidance for Industry: Changes to an Approved NDA or ANDA, Rev. 1 (Rockville, MD, Apr. 2004).

9. EMEA Committee for Proprietary Medicinal Products, Guidance on the Chemistry of New Active Substances, CPMP/QWP/130/96, Rev 1 (London, England, Dec. 17, 2003).

10. EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Part II, Basic Requirements for Active Substances used as Starting Materials (Brussels, Belgium, Oct. 2005).

11. EDQM Division Certification of Substances, Public Document PA/PH/Exp. CEP/T (06) 35, "Certification of Suitability of Monographs of the European Pharmacopoeia. How Can the Content of the Applications for a Certificate of Suitability for Chemical Purity Be Improved? The Top 10 Deficiencies found in applications" (Strasbourg, France, Dec. 2006).

12. MHLW, Pharmaceutical and Food Safety Bureau, Guidelines on Mentions in Manufacturing / Marketing Approval Application Dossiers for Pharmaceuticals and Others Based on Revised Pharmaceutical Affairs Law, PFSB/ELD 020001 (Tokyo, Japan, Feb. 10, 2005).

13. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach, Final Report (Rockville, MD, Sept. 2004).

14. ICH Q3A R2 Impurities in New Drug Substances (Geneva, Switzerland, June 2006).

15. ICH Q3C Impurities: Residual Solvents (Geneva, Switzerland, Dec. 1997, and ICH Q3C Tables and Lists, Rev. 3, Nov. 2005).

16. ICH Q6A Specifications: Test Procedures and Acceptance Criteria For New Drug Substances and New Drug Products: Chemical Substances (Geneva, Switzerland, Oct. 1999).

17. L. Muller et al., "A Rationale for Determining, Testing, and Controlling Specific Impurities in Pharmaceuticals That Possess Genotoxicity," Regulatory Toxicology & Pharmacology 44, 198–211 (2006).

18. EMEA Committee for Medicinal Products for Human Use, Guideline on the Limits of Genotoxic Impurities, CPMP/SWP/5199 (London, England, June 28, 2006).

19. Code of Federal Regulations, Title 21, Food and Drugs, Volume 3, Chapter 1, Subpart B: Food Additive Safety, Section 170.39: Threshold of Regulation for Substances Used in Food-Contact Articles (General Services Administration, Revised Apr. 1, 2007).