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RRTs may be provided in monographs for informational purposes (to aid in peak assignment). Unless specific requirements are included in a monograph, USP General Chapter ‹621› allows that “there are no acceptance criteria applied to RRTs.”
No. RRTs may be provided in monographs for informational purposes (to aid in peak assignment); however, these values are not conclusive and should not be used as the sole means to establish the impurities that may be present in a material. Other impurities, degradation products, and/or formulation components may produce chromatographic peaks having the same or similar RRTs to those of specified impurities / specified degradation products in the test procedure. It is incumbent upon a manufacturer to characterize, by appropriate means, the impurity profile of their drug substance / drug product to establish the impurities and degradation products that may be present before routinely accepting peak assignments based on an RRT match.
The Organic Impurities tests and acceptance criteria in drug substance and drug product monographs generally reflect those of FDA-approved products and have historically been developed from sponsor submission(s). USP does not determine the acceptance criteria; rather, they are determined during the drug approval process and ultimately approved by the FDA. In some cases, USP’s in-house laboratories have developed and/or validated analytical procedures to propose improvements to USP monographs. For a given monograph, the Briefing section of the Pharmacopeial Forum (PF) proposal that introduced a new or revised Organic Impurities test or acceptance criterion may provide additional details as to the source(s) of this information.
The impurity profile presented in a monograph is based on available information representing one or more articles of commerce. The impurity profile in the monograph may not be applicable to all approved products due to differing synthetic routes and/or drug product formulations. Ultimately, it is incumbent upon each manufacturer to characterize the impurity profile of their own product.
As described in applicable guidance, which include, but are not limited to, FDA’s Guidance for Industry, Q3A Impurities in New Drug Substances, June 2008, ICH, Revision 2; FDA’s Guidance for Industry, Q3B(R2) Impurities in New Drug Products, August 2006, ICH, Revision 3; and USP General Chapter ‹1086› Impurities in Drug Substances and Drug Products, the characterization of a product’s impurity profile refers to the process of establishing the impurities and degradation products (both actual and potential) that are most likely to arise during the synthesis, purification, and storage of a drug substance and additionally during the manufacturing and storage of a drug product. These impurities and degradation products may be identified, as is required when their content exceeds the applicable identification threshold established by the regulatory authority, but they may also include unidentified impurities and unidentified degradation products. Differing synthetic routes and the unique chemical environments of different drug product formulations mean that impurity profiles may differ for different manufacturers’ products.
The methods used to characterize an impurity profile include, but are not limited to, a sound scientific appraisal of the chemical reactions involved in the synthesis of the drug substance and the impurities associated with raw materials, stability studies, forced degradation studies, and knowledge of degradation pathways. Analytical techniques capable of providing structural information may be employed to establish the identity of detected impurities, when appropriate. These techniques include, but are not limited to, ultraviolet (UV) spectroscopy, infrared (IR) spectroscopy, mass spectroscopy (MS), and nuclear magnetic resonance (NMR) spectroscopy. Chromatographic relative retention times (RRTs) provided in some USP Organic Impurities tests are not conclusive and, therefore, cannot be used as the sole means to establish the identity of an impurity.
The acceptance criteria in monographs reflect those of FDA-approved products, including for some product approvals that predate ICH quality guidelines. Differences in acceptance criteria content and format may reflect historical differences in regulatory approaches and/or variations in product-specific approvals. Unless otherwise indicated, a limit for Total impurities in a drug product monograph represents the sum of all specified and unspecified impurities above the reporting threshold. The term impurities in this context refers to any component of the drug product that is not the drug substance or an excipient of the drug product and includes all synthetic process related impurities and degradation products. Unless otherwise indicated, a limit for Total degradation products in a drug product monograph represents the sum of all specified and unspecified degradation products above the reporting threshold. The term degradation product refers to an impurity resulting from a chemical change in the drug substance brought about during manufacturing and/or storage of the drug substance or drug product. Both USP General Chapter ‹476› Control of Organic Impurities in Drug Substances and Drug Products and USP General Chapter ‹1086› Impurities in Drug Substances and Drug Products state that “the preferred terms applicable to organic impurities procedures are ‘impurity’ and ‘total impurities’ in the drug substance monographs and ‘degradation product’ and ‘total degradation products’ in the drug product monographs.” (Emphasis added)
Process impurities that are controlled in the drug substance and that are not degradation products may be authorized by the manufacturer’s responsible regulatory authority for exclusion from a drug product’s Total degradation products result, with appropriate justification. According to the FDA’s Guidance for Industry, Q3B(R2) Impurities in New Drug Products, August 2006, ICH, Revision 3, manufacturers may provide a rationale to their regulatory authority “for exclusion of those impurities that are not degradation products (e.g., process impurities from the drug substance and impurities arising from excipients).”
Manufacturers of FDA-approved products whose specifications differ from those in the monograph, such that their product would not comply with the standard, are encouraged to request a revision to the monograph as described in USP Guideline for Submitting Requests for Revision to USP–NF. According to USP General Notices and Requirements, section 3.10. Applicability of Standards, “any official article is expected to meet the compendial standards if tested, and any official article actually tested as directed in the relevant monograph must meet such standards to demonstrate compliance.”
Manufacturers with products under review by FDA still awaiting approval, whose product specifications differ from those in the monograph, such that their product would not comply with the standard, should consider submitting a pending request for revision as described in the Pending Monograph Guideline.
Any questions about what to or how to report information on your drug substance COA should be directed to the responsible regulatory authority. One potentially applicable guidance document, FDA’s Draft Guidance1, Postapproval Changes to Drug Substances, September 2018, states: “Impurities that are listed in the compendium but cannot be formed in the manufacturing process do not need to be included in the specification; however, a footnote should be added to the specification and COA for the final drug substance that states that the impurity cannot be formed. If compendial impurities are controlled upstream or as unknown impurities in the drug substance, a footnote should also be added to the specification and COA of the final drug substance.” Manufacturers who desire to change the information currently being reported on a drug substance COA associated with an approved product, may need to file an appropriate supplement to their product registration with the responsible regulatory authority.
1 This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.
The purpose of the table in the System suitability section included in some O.I. tests is to provide relative retention times, as information that could aid in peak assignment, for all compounds of interest (when this information is available to USP). These compounds might include specified impurities or specified degradation products; counterion(s) of the active pharmaceutical ingredients; compounds used for system suitability checks; internal standards; and identified impurities with no specified acceptance criteria (e.g., synthetic process impurities in some drug product monographs).
Because this is supplemental information, which is not essential for regulatory compliance, no acceptance criteria (or RRFs, if applicable) are associated with these compounds beyond the acceptance criteria / RRFs associated with unspecified impurities or unspecified degradation products, as applicable. Users of the standard are responsible for their application of this supplemental information. If a manufacturer determines that RRFs are necessary for the accurate quantitation of any impurity, the manufacturer may need to file an appropriate supplement to their product registration with the responsible regulatory authority to support any changes impacting an approved product specification, including but not limited to the conversion of an unspecified to a specified impurity or to a specified degradation product.
Several USP General Chapters address important concepts related to the control of organic impurities and facilitate a better understanding of how to navigate the organic impurities information provided in USP monographs. Notable among these are USP General Chapter ‹476› Control of Organic Impurities in Drug Substances and Drug Products and USP General Chapter ‹1086› Impurities in Drug Substances and Drug Products. Additional resources, in the form of regulatory guidance documents, are available on the U.S. Food and Drug Administration’s (FDA’s) website, Guidances (Drugs), as well as sections of the Agency’s CDER Manual of Policies & Procedures | MAPP which may be relevant. Quality Guidelines issued by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) provide another valuable source of information. Individuals seeking additional, in-depth learning opportunities should explore the variety of offerings available through the USP Education website.