Organic Impurities Testing: USP plans extensive Revision of General Chapters and Monographs

 Some time ago, the USP launched an initiative to update a number of pharmacopeial monographs and general chapters. In doing so, the organisation takes into account scientific and technological progress in pharmaceutical analytics. In the framework of this initiative, the USP expert panel in charge of "organic impurities in APIs and medicinal products" has been established. Its objectives are the revision of Chapter <1086> "Impurities in Drug Substances and Drug Products" and the creation of a new Chapter <476> "Organic Impurities in Drug Substances and Drug Products". Both chapters are now available as draft documents and can be commented until 31 July 2014.

Further details related to the revision of Chapter <1086> and the creation of the new Chapter <476> which will replace the currently applicable Chapter <466> can be found in a "White Paper" and, more detailed, in a "Stimuli Article". The latter also contains information about a survey carried out last year by the USP under the different stakeholders and users of the pharmacopeia. A large percentage of the interviewees were for the revision of these chapters and for harmonisation with the corresponding ICH guidelines - particularly with ICH Q3A and Q3B.
The revised chapter <1086> reflects the results of the survey. Compared to the previous version, the document includes:

  • References to the ICH guidelines Q3A and Q3B
  • Tables presenting threshold for impurities in APIs and medicinal products that require authorisation regarding new drug applications (NDAs) and abbreviated new drug applications (ANDAs)
  • A decision for the approach regarding the control of organic impurities in APIs/ medicinal products, including OTC products
  • Appendix 1 - definitions
  • Appendix 2 - references and links to ICH guidelines and FDA documents

One can notice that the OTC (over-the-counter) products are included in the scope of this chapter. So far, OTCs have been only partly addressed in FDA monographs. Yet, regarding impurity testing, they haven't been covered - neither in FDA guidance documents, nor in ICH guidelines. Now for the first time, they are the object of a USP's general chapter on impurities. To use thresholds for OTC products, the document states: "Similar principles may be applied to set thresholds and acceptance criteria for degradation products [for OTC products] … Degradation products in these drugs may also need to be reported, identified, and/or qualified." Thresholds should be justified based on historical information such as drug product stability and safety data, as well as the amount of drug substance administered per day.  Higher thresholds may be applied if scientifically justified." These provisions are applicable not only to new OTCs which are still in the development stage, but also to already marketed OTCs. For companies manufacturing these products, this means a considerable additional effort.

The new chapter <476> "Organic Impurities in Drug Substances and Drug Products" describes the formal requirements for controlling impurities. It won't replace Chapter <466> "Ordinary Impurities" but make it superfluous, and with the entry into force of <476> , it will be probably withdrawn. It includes the following sections:

  • Introduction
  • Identification of impurities in APIs and medicinal products
  • Analytical procedures to define impurities and degradation products
  • Reporting impurities and degradation products
  • Setting acceptance criteria for impurities and degradation products
  • Qualification of acceptance criteria for impurities and degradation products

Like Chapter <1086>, Chapter <476> also addresses new medicinal and generic products which are subject to the usual approval procedures (NDA and ANDA), as well as OTC products. The document covers all organic impurities coming from the manufacturing process and/ or degradation of the API/ medicinal product. With the exception of:

  • Impurities arising from excipients
  • Impurities leached from the container-closure system
  • External impurities due to GMP deficiencies
  • Polymorphic forms
  • Impurities arising from residual solvents
  • Elemental impurities

Moreover, the following APIs/ medicinal products are excluded from the scope of this chapter:

  • Veterinary products
  • Biological/ biotechnological products
  • Peptides
  • Oligonucleotides
  • Fermentation products and semisynthetic products derived from them
  • Radiopharmaceuticals
  • Herbal products
  • Crude products of animal or plant origin

This large modernisation project should change many parts of the American pharmacopeia because it includes the revision of many monographs which refer to the general chapters concerned. Yet, the harmonisation with the contents of the ICH guidelines is particularly enjoyable. It is important for the users of the USP-NF to be informed about the new and modified requirements.

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