Vol 21: Understanding Regulatory Starting Materials for API Drug Substance: What Stage of Development to Define RSMs & Common Questions

March 03, 2023The Pathfinder 27 Min Read

Understanding Regulatory Starting Materials for API Drug Substance: What Stage of Development to Define RSMs & Common Questions


Transitioning chemistry: Regulatory starting materials (RSM) is the point where change control starts. This is also the point where GMP is introduced into the synthesis of a drug substance. Other changes before that cannot affect API or ultimate drug product.

The ICHQ guidelines: The International Conference on Harmonization compiled the informative ICHQ11. This guideline is a globally agreed framework for facilitating CMC changes efficiently and predictably in drug development.

Companies needing guidance can find a lot more information here on establishing drug substance process controls. Depending on specific circumstances, you may find that the ICHQ11 provides a little flexibility in selecting starting materials. The FDA adopts these guidelines.

Based on ICHQ11, sponsors can develop a process understanding of future changes in synthesis and starting materials methods. It offers clarity on all the data required not just for approval but also for substance quality and patient safety.

Regulators expectations: Understanding regulator expectations ensures that your starting material will have the requisite technical and quality elements to allow for commercialization when you submit NDA and BLA. The information in this application is what you would have accrued over time throughout development.

Begin with the end in mind: Start thinking about controls as early as phase two for consistency and verifiable quality and purity levels. Everything up to the point of the regulatory starting material must be subjected to GMP.

Do you have a perfect understanding of the medication that will be served to patients? This is the question that sums up all regulator concerns, questions, and expectations. Start here and compile all data needed to support your synthetic routes.

Apply Good Manufacturing Practices: GMPs are mandatory from the starting material forward in API. Generally, there is little oversight in starting materials, but regulators expect GMPs to extend further back. With a longer synthetic chain, there are fewer chances of impurities in the final Active pharmaceutical ingredient (API). Minimize switching or choosing new suppliers of starting materials for a consistent level of quality

Gather more data: It takes considerable time to develop a package to support a regulatory starting material proposal. The right package should be backed by extensive data. Detail the process, the points where impurities purge, crystallization points, and other elements that address regulator expectations for staring materials.

Understand FDA vs. EMA on the matter: The FDA is flexible in applying ICH guidelines on a case-by-case basis. In Europe, these are more like rules. It is crucial to figure out how you’d fit this approach. For instance, rules will be different for commercially available materials as intermediate versus those that are available as a commodity.

The big question of impurities: Impurities are the biggest concern that underlies issues raised regarding starting material choice for APIS. Find and clarify the points where the contaminants can be purged. Start with a flow diagram of the material, the molecule, and the process and identify purification points, which could be extractions, crystallization, or chromatography.

Specificity helps: The more detailed you are about these materials purge, the better. If you do spike and fate tests and purge studies at that point and track progress throughout purification, that will strengthen your arguments for LBA and NDA. This downstream control process improves your understanding of what kind of controls you need to have on that proposed material and its quality. Downstream.

Perfect upstream process control: Find out what controls the purity of the proposed starting materials. Impurities can range from metal to rogue solvents like benzene and chloroform. Establish a framework for controlling quality and keeping contaminants below the threshold. You can set specs based on data from purge studies and spike tests. In the end, you’ll need to convince FDA or EMA how did this.

Embrace the ICH: The FDA essentially has given you their playbook. The ICH outlines all the things regulators have seen people didn’t do that they should have done. Anyone in the drug business cannot afford not to read these guidelines.


Defining Regulatory Starting Materials for my API drug substance


Regulatory starting materials (RSMs) refer to the raw materials used in the manufacture of pharmaceutical products that are subject to regulation by regulatory bodies such as the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

RSMs are critical components of pharmaceutical manufacturing processes, and their quality and purity are essential for ensuring the safety and efficacy of the final product. RSMs can include active pharmaceutical ingredients (APIs), excipients, solvents, and other materials used in the manufacturing process.

In the pharmaceutical industry, RSMs are subject to strict quality control measures, including testing and certification, to ensure that they meet the required standards for purity, potency, and quality. The use of RSMs that do not meet these standards can lead to serious adverse effects and may result in regulatory action against the manufacturer.

The regulatory requirements for RSMs vary depending on the jurisdiction and the type of product being manufactured. However, in general, RSMs must be sourced from qualified suppliers, meet established purity and quality standards, and be accompanied by appropriate documentation, including certificates of analysis and regulatory filings. To define regulatory starting materials (RSMs) for your active pharmaceutical ingredient (API) drug substance, you should follow the regulatory guidelines and requirements of the applicable regulatory authorities, such as the FDA, EMA, or other relevant agencies.


The following are some general steps you can take to define RSMs for your API drug substance:


  • Identify the starting materials used in the synthesis of your API. This includes all raw materials and intermediates used in the manufacturing process.

  • Evaluate the quality and purity of each starting material. You should assess the critical quality attributes (CQAs) of each starting material, such as identity, impurity profile, potency, and stability.

  • Determine the appropriate control strategy for each starting material. This includes setting specifications and acceptance criteria, establishing analytical methods for testing, and identifying potential impurities or contaminants that could impact the quality of the API.

  • Conduct a risk assessment to evaluate potential risks associated with the use of each starting material. This should include an assessment of the potential impact on patient safety and the potential for the starting material to impact the quality of the API.

  • Document all of the above information in a regulatory filing or application, such as a New Drug Application (NDA) or Marketing Authorization Application (MAA), as required by the relevant regulatory authority.

It is important to note that the specific requirements for defining RSMs will depend on the regulatory guidelines and requirements in your specific jurisdiction. It is recommended that you consult with regulatory experts or seek guidance from the applicable regulatory authorities to ensure you meet all requirements.


What Stage of Development do I need to define my RSMs


It is important to define your regulatory starting materials (RSMs) as early as possible in the drug development process. This is because RSMs can have a significant impact on the quality, safety, and efficacy of your final drug product, and defining them early can help ensure that your development program is aligned with regulatory expectations.

Typically, RSMs are defined during the early stages of drug development, such as during the preclinical or early clinical stages. At this point, you should have identified the chemical structure of your API and the intended route of synthesis. You should also have a good understanding of the potential impurities or contaminants that may be present in your starting materials and the impact that they may have on the quality of the final product.

Defining RSMs early in the development process allows you to establish appropriate control strategies, set specifications and acceptance criteria, and identify any potential risks associated with the use of specific starting materials. This can help you to minimize the risk of regulatory issues or product quality problems later in development.

However, it is also important to note that RSMs may need to be re-evaluated or refined throughout the development process as additional information becomes available. For example, changes to the synthetic route or changes to the intended use of the drug product may require a re-evaluation of the RSMs.


Common questions that come up when determining regulatory starting materials


There are several common questions that may arise when determining regulatory starting materials (RSMs) for your active pharmaceutical ingredient (API) drug substance. Some of the most common questions include:

  • What is the chemical structure of the API, and what starting materials are required for its synthesis?
  • What are the critical quality attributes (CQAs) of the RSMs, such as purity, identity, and potency?
  • What are the acceptable levels of impurities or contaminants in the RSMs?
  • What analytical methods are required to test the RSMs for their CQAs and impurities?
  • How will the RSMs be controlled during manufacturing to ensure consistent quality?
  • What are the potential risks associated with the use of specific RSMs, and how will these risks be mitigated?
  • Are there any regulatory guidelines or requirements that need to be followed when defining RSMs?
  • How will changes to the RSMs or manufacturing process be managed and communicated to regulatory authorities?

Answering these questions is essential for defining RSMs and ensuring that the resulting API drug substance meets regulatory requirements for safety, efficacy, and quality. It is recommended that you work closely with regulatory experts and consult relevant regulatory guidelines to ensure that all critical questions are addressed.


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