Modernizing Organic and Elemental Impurities Standards

Through its continued effort to harmonize and update pharmaceutical standards, the US Pharmacopeial Convention (USP) is revising and modernizing its chapters on elemental and organic impurities in pharmaceutical development and manufacturing.  To gain some insight on these changes and how they may affect the industry, Pharmaceutical Technology spoke with Kahkashan Zaidi, principal scientific liaison, USP, and Antonio Hernandez-Cardoso, senior scientific liaison, USP, about these updated United States Pharmacopeia (USP) chapters.

To hear more about elemental impurities standards, attend USP’s upcoming presentation, “Pharmaceutical Impurities,” to be held on Thursday, May 18, 2017 at 10:30 am to 12 pm, as part of the Drug Manufacturing track at CPhI North America 2017.

Elemental impurities

PharmTech: What prompted the updates to the elemental impurities chapters?

Hernandez-Cardoso and Zaidi (USP): No specific event triggered the revision of the elemental impurities standards. USP engages in continuous evaluation and revision of all its standards in order to maintain scientific and public health relevance.

In addition to coordinating efforts in this area with FDA and the industry, USP worked closely with the International Council for Harmonization (ICH) to ensure alignment of its standards for elemental impurities with the ICH Q3D Guideline for Elemental Impurities.

PharmTech: What are the key points of USP <232> and <233> that drug manufacturers should be aware of?

Hernandez-Cardoso and Zaidi (USP): There are some key considerations for manufacturers regarding compliance with General Chapters <232> and <233>. USP chapter <232> requirements are for drug products. This chapter is aligned with ICH Q3D in all respects but one: total parenteral nutrition products. Those are within scope for Q3D, but out of the scope of General Chapter <232>.  

One thing for manufacturers to keep in mind is that General Chapter <233> does not restrict them to use only the ICP technique (Inductive Coupled Plasma). This chapter is very flexible and offers guidance on validation requirements for several alternative procedures to test for elemental impurities.

PharmTech: How is USP keeping USP <232> and <233> harmonized with ICH requirements and FDA expectations?

Hernandez-Cardoso and Zaidi (USP): USP’s toxicology experts worked closely with the ICH Q3D toxicologists to achieve a consistent outcome. USP revised the content in General Chapter <232> after this collaboration to ensure alignment across both documents.  USP’s Elemental Impurities Expert Panel and Chemical Analysis Expert Committee added additional elements and corresponding limits in General Chapter <232> based on the collaboration with the ICH Q3D. 

Organic impurities

PharmTech: In addition to the chapters on elemental impurities, USP updated chapters on organic impurities. Why does USP feel it is necessary to modernize organic impurities testing?

Hernandez-Cardoso and Zaidi (USP): USP continuously reviews and modernizes its quality standards to incorporate new technologies, testing methods, and procedures, as well as to reflect the best practices in industry and to keep the standards in the USP–National Formulary (NF) relevant to users.

In 2013, USP’s Expert Panel on Modernization of Organic Impurities Testing in Drug Substances and Drug Products decided to revise USP General Chapter <1086> to be in line with current regulatory thinking on over-the-counter (OTC) and generic products regarding organic impurities testing. Also, recommendations from a stakeholder survey indicated that the use of terminology and principles established in ICH Q3A and Q3B guidelines should be reflected in any effort to modernize chapters.

The Expert Panel was also tasked with evaluating the advantages and disadvantages of moving relevant text from the current General Chapter <1086> to a new General Chapter below <1000>. General Chapters numbered above <1000> are informative while General Chapters below <1000> contain mandatory requirements.  

PharmTech: What changes is USP making to USP <1086> and what should drug manufacturers know about the upcoming <476> chapter?

Hernandez-Cardoso and Zaidi (USP): Based on the input received from the stakeholder survey and from a workshop co-sponsored with FDA on organic impurities in OTC products, the Expert Panel decided to update <1086> to reflect the terminology and principles of ICH Q3A and Q3B. The intention is to add some statements and applicable information to keep them aligned for existing and legacy products.

Regarding <476>, the Expert Panel decided to create a companion mandatory chapter including acceptance criteria aligned with the organic impurities thresholds established in the ICH guidelines. The proposal (similar to the current approach in the European Pharmacopoeia) is to incorporate cross references in monographs to address unspecified and total impurities, on a case-by-case basis, based on maximum daily doses (MDD), as outlined in ICH Q3A and Q3B.

The final piece of information to be synchronized will be the General Notices. Once the final text in <1086> and <476> is approved, the current text in General Notices will be revised accordingly.

PharmTech: When will these changes to impurities testing and requirements be implemented?

Hernandez-Cardoso and Zaidi (USP): The work on revising these General Chapters is ongoing. The first step was to address the comments received when the chapters were open for public comments and to make the relevant changes.

New versions of <476> and <1086> will be published in Pharmacopeial Forum (PF) for another round of public comments. Some of the changes being considered are the inclusion of cross references in monographs, better coordination with the Expert Committee on OTCs to synchronize implementation activities, incorporating decisions taken with FDA on terms used (“Disregard Limits” vs “Reporting Thresholds”, for example), and the possibility of a delayed implementation date for compliance.

CPhI North America Presentation

PharmTech: What will participants learn at your CPhI North America session?

Hernandez-Cardoso and Zaidi (USP): Participants will learn about the work being conducted at USP through Expert Committees and Expert Panels to modernize General Chapters <486> and <1086> (related to organic impurities). They will also learn of any updates to General Chapters <232> and <233> (elemental impurities), particularly as related to the upcoming official date for compliance (January 2018).