Are there individual limit values ​​in the NDA GAT

The US Food and Drug Administration FDA recently published its final guideline "Elemental Impurities in Drug Products", which finalized the draft of July 1, 2016. The guideline provides recommendations for the required documentation metallic impurities (Elemental Impurities, EIs) in accordance with ICH Q3D and the general USP chapters <232> and <233>. The new document applies to manufacturers of pharmaceuticals monographed and non-monographed in the USP. The control of EIs for all finished medicinal products is also addressed in 21 CFR Part 211.

In detail, the guideline deals with the following points:

  • Such as applicants who submit applications for new drugs ("new drug applications" = NDAs) or applications for generics ("abbreviated new drug applications" = ANDAs) for non-monographeddrug should submit to test EIs according to ICH Q3D.
  • As manufacturer of in the USP monographeddrugthat are not marketed under an NDA or ANDA approval, the requirements of the general chapter <232> "Elemental Impurities Limits"and <233>"Elemental Impurities Procedures"the" United States Pharmacopeia "(USP) can correspond.
  • How holders of an NDA or ANDA approval for monographed medicinal products should report CMC changes to the FDA in order to comply with general chapters <232> and <233>.
  • How manufacturers of non-monographed drugs marketed without an NDA or ANDA approval (e.g., non-prescription OTC marketed under an FDA monograph) should control EIs.

The first step after ICH Q3D is to get a Product risk assessment by identifying known and potential sources of EIs (i.e. metals that are deliberately added, metals that may potentially be present in the starting materials used to manufacture the drug, and metals that may potentially migrate into the product from manufacturing or packaging systems ). The second step is (if the risk assessment cannot demonstrate that an EI level is less than 30% of the determined PDE value (Permitted Daily Exposure) in the drug (= control threshold)), to introduce additional controls (for example, integrated as in-process controls or in the specifications of the drug or the starting materials and packaging) to ensure that the amount of EIs complies with the PDE -Value in the medicinal product does not exceed.

The USP also recently introduced new limit values ​​and analytical methods for impurities in its general chapters <232> and <233>. The primary goals are

  • To set limit values ​​for acceptable amounts of EIs in finished medicinal products, and
  • update the methods used to test for EIs in medicinal products and add modern analytical methods.

Since January 1st, 2018 the USP chapters <232> and <233> replace the chapter <231> "Heavy metals". In addition, <232> applies to all drugs with a USP monograph (except for those drugs that are explicitly excluded in <232>). The USP can retain other specific metal limit value tests (e.g. <211> arsenic or zinc in the general packaging chapter on elastomeric closures <381>), which appear in a specific monograph. In addition, USP monographs or general chapters can define EI limit values ​​or report levels that deviate from <232>. If certain limit values ​​are mentioned in a USP monograph or in a general chapter that is referenced in a monograph, these are official limit values ​​that must be observed by manufacturers. However, <232> does not require any routine exams of the drug to ensure compliance with the specifications. Depending on the source of a contamination and the risk that its proportion in the finished drug exceeds the PDE value, alternative approaches can be used to ensure compliance with the specifications (e.g. routine testing of the raw materials and packaging instead of the finished product). In addition, if the risk that the amount of an EI exceeds the PDE value in the drug is reasonably low, it may be permissible not to check every batch of a drug for this EI.

The FDA recommends that manufacturers producing drugs for the American market follow the ICH Q3D recommendations unless the drug is monographed and must meet USP requirements:

  • All new NDAs and ANDAs for medicinal products with an official USP monograph must now follow the requirements for the control of EIs as described in <232> and <233>. NDAs and ANDAs after January 01, 2018 for drugs without an official USP monograph should follow ICH Q3D. Applicants should attach a summary of the risk assessment to each new application that is subject to <232> and <233> or ICH Q3D.
  • Monographed medicinal products on the market that are not NDA or ANDA approved must meet the requirements described in <232> and <233>. Drugs that are not NDA or ANDA approved and do not have an official USP monograph should follow ICH Q3D. Manufacturers should attach the risk assessment to the documentation, which is kept for official review during an inspection at the production site.
  • Changes to NDAs and ANDAs: Changes made to comply with <232> and <233> or to follow the recommendations of ICH Q3D must be documented by the applicant in the next annual report. If a drug that is approved as NDA or ANDA does not meet the requirements of <232> or the recommendations of ICH Q3D, the documentation of a change (to comply with the requirements) in the annual report is not appropriate. These changes, e.g. manufacturing changes to reduce the EI level, should be submitted in accordance with the existing guidance documents for CMC changes after approval. Applicants should attach a summary of the risk assessment to any supplementary application or annual report describing these changes.

If the analytical methods described in the general chapter <233> cannot be used (for example in the case of active ingredients, auxiliary materials, packaging), the USP allows the use of an alternative method in accordance with the "General Notices and Requirements". Each analytical method must meet the validation requirements described in <233>. Alternative methods should be described in detail. If they are used for routine tests, their suitability for this should be verified under actual conditions. In contrast, ICH Q3D does not describe any specific analytical methods for routine testing of materials or to perform a risk assessment, therefore the FDA recommends that manufacturers use the analytical procedures described in <233> or analytical procedures that meet the validation requirements in <233> (in addition to ICH Q2).