An overview of China's relevant technical review requirements is often drafted based on the standards of developed countries in Europe and America. We have been striving to catch up with advanced regulatory concepts internationally, especially those of the United States. Therefore, a thorough study of FDA's major deficiencies is very helpful in improving the success rate of drug research and registration in China. It is also beneficial for our products to successfully enter international markets, breaking out of Asia and reaching the world. In fact, many large pharmaceutical companies consider the technical requirements of various countries when initiating a research project, which helps their products gain approval in those countries. Below, I will expand on FDA's major deficiencies by analyzing cases or interpreting clauses to help the industry further increase the probability of successful drug registration.
"A new batch needs to be manufactured due to formulation issues (e.g., nitrosamine impurity mitigation or other product stability issues)."
Interpretation: Adjustments to the formulation are necessary due to the detection of nitrosamine impurities or the emergence of other product stability issues. In such cases, if there are significant changes to the formulation, it will involve the production of a new batch, which the FDA classifies as a major deficiency. In China, if a new batch needs to be produced, it is difficult for companies to submit the necessary documentation within four months, so it is essential to avoid the aforementioned issues.
Let me introduce some methods for mitigating nitrosamine impurities. There are three forms of nitrosamine impurity mitigation:
These adjustments may lead to significant changes in the product formulation and may require the production of new batches, which the FDA would classify as major changes. Article 40 of China’s "Drug Registration Management Measures" states that if significant changes occur during the evaluation period of a drug marketing authorization application that may affect the drug's safety, efficacy, and controllability of quality, the applicant must withdraw the original registration application, conduct supplementary research, and reapply.
"Change in specification that would require significant changes to the manufacturing process."
Interpretation: A change in quality standards may necessitate significant modifications to the product manufacturing process. For example, if the European Pharmacopoeia tightens the limit for oxidative degradation impurities of a certain active pharmaceutical ingredient from 0.5% to 0.15%, the company may need to add sodium metabisulfite as an antioxidant in the purification process of that active pharmaceutical ingredient to mitigate the formation of oxidative degradation impurities. This change would be classified as a major change, potentially requiring the production of new batches, which could make it difficult for the company to submit the necessary documentation within four months. Companies are advised to handle such matters with caution.
"Change in or lack of information about the form of the drug substance during drug product manufacturing, which requires the manufacture of a new batch to demonstrate the CQAs are not affected."
Interpretation: For instance, if an active pharmaceutical ingredient (API) belongs to BCS Class IV, it may be formulated into oral tablets using a solid dispersion process to improve its bioavailability. If, during the manufacturing process, the API transforms into a different crystal form, it could affect the product's critical quality attributes (CQAs). In this case, the applicant must develop a quantitative method to detect the amount of crystalline API that may exist in the amorphous API. If the relevant research data are not provided, the applicant may be required to produce new samples to study this aspect, which the FDA would classify as a major deficiency. Researchers are advised to pay attention to crystal form studies when developing amorphous solid dispersion formulations.
"Product quality adversely affected by interaction of API and excipients during manufacturing."
Interpretation: The correct selection of excipients is crucial for formulations, as it can significantly impact both in vivo and in vitro behaviors of the product. In some cases, incompatibility between raw materials and excipients (i.e., adverse interactions between the drug and one or more excipients in the formulation that lead to changes in the physical, chemical, microbiological, or therapeutic properties of the formulation) can result in the rejection of the product. For example, proton pump inhibitor products, such as those from the rabeprazole class, typically require a protective coating on the tablets to prevent direct contact between the active pharmaceutical ingredient (API) and the enteric coating, which can cause degradation of the API.
Let me highlight some scenarios of raw material and excipient incompatibility: such incompatibility can lead to various changes, including alterations in product color or appearance, loss of mechanical properties (such as tablet hardness), changes in dissolution behavior, variations in physical crystal form, reduced efficacy, and increased degradation products. Therefore, researchers should conduct thorough studies on the compatibility of raw materials and excipients during the formulation development phase to avoid issues related to incompatibility.
"For multidose products, failure to provide either antimicrobial effectiveness test results or information to describe and demonstrate validation of a specially designed container-closure system that prevents microbial ingress during the product's in-use period."
Interpretation: For multidose products, such as preservative-free eye drops that do not utilize a special packaging system, if the formulation contains antimicrobial agents but the company fails to provide validation data for the antimicrobial effectiveness studies, the FDA will issue a major deficiency letter. In another scenario, for multidose eye drops where the company does not use an antimicrobial agent in the formulation but instead employs a specially designed container-closure system, such as a bacteriostatic bottle, which prevents microbial ingress during the product's in-use period, the company must provide detailed research and validation data to demonstrate the antimicrobial performance of this specialized packaging. If such relevant research validation data are not provided, the FDA will also issue a major deficiency letter to the company.
With China’s accession to ICH, the regulation of drugs in our country is becoming increasingly internationalized and gradually aligning with international standards. Thoroughly studying the regulatory policies and technical requirements of developed countries such as those in Europe and America is very important for promoting the export of domestic medicines and will also increase the probability of successful product registration to a certain extent. This document interprets some major deficiencies identified by the FDA, hoping to provide assistance and insights to the industry.
FDA: ANDA Submissions Amendments to Abbreviated New Drug Applications Under GDUFA. 202409.
