Organic impurities in medicines targeted by proposed USP standards

Stakeholder input sought on modernized standards

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The U.S. Pharmacopeial Convention (USP) has proposed new and revised standards for organic impurities in drug substances and drug products—one of the critical quality attributes that has the potential to affect drug safety and efficacy.

“These proposed changes regarding organic impurities are part USP’s ongoing efforts to develop modernized standards that align with current scientific thinking and regulatory guidance, while also continuing to address industry’s focus on medicine quality,” said Ron Piervincenzi, Ph.D., chief executive officer of USP.

Organic impurities include process impurities and degradation products in drug substances as well as degradation products found in drug products.

Drafts of the new and revised standards appear in the May–June 2014 issue of Pharmacopeial Forum (PF)—USP’s free-access, online publication for posting proposed changes to currently official public standards. The publication of the drafts initiates a 90-day public comment period ending on July 31, 2014. All interested parties from industry, academia, regulatory agencies and other stakeholder groups are strongly encouraged to comment. “Stakeholder input is critical to the development of quality standards for medicines that protect public health and also reflect sound modern science,” said Piervincenzi.

The two drafts that appear in PF are revisions to General Chapter <1086> Impurities in Drug Substances and Drug Products and the proposal of new General Chapter <476> Organic Impurities in Drug Substances and Drug Products. While stakeholder input to the proposed changes are expected to trigger subsequent revisions, the chapters—once official—will be included in USP’s compendia of monograph and general chapter standards, U.S. Pharmacopeia—National Formulary (USP–NF).

A stimuli article also appears in the May–June PF issue, detailing the rationale behind these proposals. This includes details of a June 2013 survey conducted to garner feedback on USP’s modernization initiative overall and stakeholder input on current USP standards related to organic impurities. The stimuli article also addresses the scope of chapters <1086> and <476> and a strategy for their implementation.

USP’s Organic Impurities in Drug Substances and Drug Products Expert Panel recommended the changes proposed in PF. Established in 2011 under a different name and with the initial charge of recommending revisions to <1086>, the advisory Panel was formed the same year that USP and the U.S. Food and Drug Administration (FDA) co-sponsored a workshop to explore over-the-counter (OTC) medicine quality. A key challenge that USP and FDA identified during the workshop was the large number of OTC product monographs associated with single or multiple drug substances and how to develop and modernize standards for such a large group of ever-changing products.

With the modernization of USP monographs underway, the scope of the Panel’s work was later expanded and the development of new General Chapter <476> was added as a priority. For medicines marketed in the U.S., drug substances and drug products covered by proposed General Chapter <476> can generally be placed in one of two categories: (1) those covered by FDA approvals (e.g., most New Drug Application [NDA], Abbreviated New Drug Application [ANDA] and Biologic License Application [BLA] products) and (2) those not requiring FDA pre-approval for marketing (e.g., products covered by the FDA OTC monograph system).

The proposed changes to General Chapter <1086> are intended to align it with current scientific and regulatory standards. They also include new definitions, threshold tables and a decision tree for use when impurities associated with drug substances and drug products need to be addressed or reported.  Based on stakeholder input from the June 2013 survey, both chapters <1086> and <476> are aligned with the regulatory approaches and scientific concepts of International Conference on Harmonization (ICH) Q3A and Q3B guidelines for impurities.

Also noted in the stimuli article is that General Chapter <476> is not intended to replace General Chapter <466> Ordinary Impurities. USP’s ongoing effort to modernize monographs in USP–NF includes the elimination of references to General Chapter <466>, a process independent from the revision of <1086> and the creation of <476>. Over time, General Chapter <466> will become obsolete and will be omitted from USP–NF. New monographs are expected to refer to General Chapter <476>, as appropriate.

To view General Chapters <1086> and <476> and the associated stimuli article, go to:

For more information, contact [email protected].