API quality research is not only a technical discussion but also a core issue concerning the safety and efficacy of medications. In modern pharmaceutical research, it is crucial to fully understand the properties and characteristics of APIs, ensure consistency and stability in the manufacturing process, and improve the quality and reliability of medications. During API quality research, many challenges arise: how to handle issues when they occur, which guidelines to follow, and how to deal with supplementary data requests.
Medicilon’s Cloud Lecture Hall invites Jianmei Wang from the Process Department to provide a comprehensive and in-depth analysis of API quality research from multiple perspectives. Jianmei will address potential issues in API quality research and explain how to effectively handle them one by one.
01 How should the deuteration ratio of deuterated drugs be studied? Are there any relevant guidelines that can be referenced? What are the CDE's requirements for the study of the deuteration ratio?
Jianmei Wang: The deuteration ratio is the percentage of D atoms at the modification sites of deuterated drugs. Currently, widely used methods include quantitative ^1H NMR spectroscopy and LCMS. In the LCMS method, chromatographic data is obtained using the selected ion-monitoring mode, which measures the peak areas of each deuterated compound. The peak areas can be corrected based on the natural isotope distribution provided by Chemdraw software. The relative content of each deuterium isotope is then directly calculated from the corrected peak areas, allowing for the determination of the drug’s deuteration ratio.
The calculation of deuteration ratio can be performed according to recommended industry standards or formulas found in relevant literature. Currently, there are no specific guidelines available for reference.
CDE does not have specific regulations for deuteration ratio studies, so it is necessary to determine based on the drug itself what level of deuteration ratio is safe and effective. During IND application, multiple batch testing results can be referenced to establish a reasonable limit.
02 Simply relying on conventional strong wash conditions may not always remove polymer impurities effectively. Are there any guidelines in this regard?
Jianmei Wang: In quality research work, it is important to constantly monitor CDE’s training and regulatory requirements. For example, in supplementary data requests, CDE may provide some prompts, such as reference formulations and end-of-shelf-life samples of self-prepared formulations. During the compounding process, it is common to observe that the amount of polymers produced (within 18 hours) is significantly higher than the polymer content in the final product at the end of its shelf life. This is related to reaction principles and may involve the formation of L-type and M-type polymers. In response to this situation, the compounding solution can have a certain effect on enriching polymers.
03 How should skip testing be arranged?
Jianmei Wang: Each year, 10% of the batches or 3 batches per year (whichever is more frequent) should be tested. Testing is required for newly produced batches and samples retained within product shelf life. If fewer than 3 batches are produced within a year, testing of all batches is necessary.
04 Do raw materials for drug applications need to undergo assessment for nitrosamine impurities?
Jianmei Wang: Yes, assessment of nitrosamine impurities is an essential part of drug IND applications. Even if the IND application is successful, regulatory reviewers may request a risk assessment. If there is a risk of nitrosamine presence identified during the assessment, confirmatory testing will be required. If confirmatory testing results show no detection of nitrosamine impurities (below 10% of the limit), standards may not need to be established. However, if the content exceeds 10%, attention is needed to determine if it is below the 30% threshold. Establishing standards would then involve skip testing or routine testing.
The exceptions are as follows:
In the drug application process, for products where the API itself poses significant mutagenic/carcinogenic risk and products defined under ICH S9 as causing late-stage cancer, control is conducted according to standards such as Q3A/Q3B.
05 How can residual solvents be appropriately relaxed?
Jianmei Wang: Under certain circumstances, such as short-term (e.g., 30 days or less) or topical use, higher levels of residual solvents may be acceptable. It is important to justify the rationale for these solvent levels based on different circumstances.
Here’s a simple example of an IND application: According to ICH Q3C (R9) guidance, the limit for n-heptane is 0.5% for a dosage of 10g. For XXX, with a maximum clinical daily dose of 200mg, the acceptable limit for n-heptane is set at 25%. Considering the product’s manufacturing process and multiple batch testing results, the limit for n-heptane is established at 1.0%.
06 How to set impurity limits for starting materials and intermediates?
Jianmei Wang: If the testing results of starting materials and intermediate impurities meet their respective quality control limits, they can be controlled according to those limits. If they do not meet the limits, validation through methods like spiking studies is needed to demonstrate that under certain limits, the API quality can still meet regulatory requirements under current manufacturing conditions.
07 Should all impurities in validation be screened to determine if they cause mutations?
Jianmei Wang: In the early stages of new drug development, it is common practice to screen starting materials, intermediates, the API, and API-related impurities. For drugs intended for market application and generics, thorough research is recommended, aiming to assess as much as possible before establishing limits. Subsequently, validation and multiple batch testing are conducted based on these assessments. Based on the testing results, decisions are made regarding the necessity of setting standards.
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