FDA publish drug development Guidance on Impurities in Drug Substances
This guidance provides revised recommendations on what chemistry, manufacturing, and controls (CMC) information to include regarding the reporting, identification, and qualification of impurities in drug substances produced by chemical synthesis when submitting:
- Original abbreviated new drug applications (ANDAs)
- Drug master files (DMFs) including type II DMFs
- ANDA supplements for changes in the synthesis or processing of a drug substance
The guidance also provides recommendations for establishing acceptance criteria for impurities in drug substances.
The following types of drug substances are not covered in this guidance:
- Biological/biotechnological
- Peptide
- Oligonucleotide
- Radiopharmaceutical
- Fermentation products
- Semisynthetic products derived from fermentation products
- Herbal products
- Crude products of animal or plant origin
Background
In November 1999, FDA published the first version of this guidance. As a result of changes to recommendations on impurities in drug substances for new drug applications (NDAs), which the International Conference on Harmonisation (ICH) included in the guidance for industry on Q3A Impurities in New Drug Substances (Revision 1) (Q3A(R)) in 2003. FDA believes that much of the content of the Q3A(R) guidance applies to ANDAs. See especially sections I through V and the Attachment, Thresholds.
Listing Impurities and Setting Acceptable Criteria for Impuritites in Drug Substance Specifications.
Applicants submitting ANDAs, DMFs, including type II DMFs, and ANDA supplements for changes in the synthesis or processing of a drug substance are required to submit the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance. Submissions should list impurities and set acceptance criteria for those impurities in the drug substance specifications.
Where applicable, the drug substance specification should include a list of the following types of impurities:
- Organic impurities
- Each specified identified impurity
- Each specified unidentified impurity
- Any unspecified impurity with an acceptance criterion of not more than (≤) the
identification threshold in Attachment 1, Q3A(R)
- Total impurities
- Residual solvents
- Inorganic impurities
Setting Acceptance Criteria for Impurities
In establishing impurity acceptance criteria, the first critical consideration is whether an impurity is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified impurity, we recommend that the acceptance criterion be set no higher than the official compendial limit. If a limit for a specified impurity does not exist in the USP, we recommend that you qualify the impurity by comparing it to the observed amounts of the impurity in the reference listed drug product (RLD). In some circumstances, the acceptance criterion may need to be set lower than the qualified level to ensure drug substance quality. For example, if the level of a metabolite impurity is too high, other quality attributes, like potency, could be seriously affected.
Qualification of Impurities
Qualification is the process of acquiring and evaluating data that establish the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing impurity acceptance criteria that includes safety considerations.
An impurity is considered qualified when it meets one or more of the following conditions:
- The observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the reference listed drug product.
- The impurity is a significant metabolite of the drug substance.
- The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature.
- The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies.
Qualification Thresholds
Recommended qualification thresholds based on the maximum daily dose of the drug substance are provided in Q3A(R). When these qualification thresholds are exceeded, we recommend that impurity levels be qualified. In some cases, it may be appropriate to increase or decrease the threshold for qualifying impurities.
Qualification Procedures
- Comparative Analytical Studies, An impurity present in a drug substance covered by an ANDA can be qualified by comparing the analytical profiles of the drug substance with those in the RLD using the same validated, stability-indicating analytical procedure (e.g., comparative HPLC studies).
- Scientific Literature and Significant Metabolites, If the level of the specified identified impurity is adequately justified by the scientific literature, no further qualification is considered necessary.
- Toxicity Studies, Toxicity tests are the least preferred method to qualify impurities. We recommend the tests be used only when impurities cannot be qualified by either of the above procedures. The tests are designed to detect compounds that induce general toxic or genotoxic effects in experimental systems. If performed, such studies should be conducted on the drug product or drug substance containing the impurities to be controlled, although studies using isolated impurities may also be used.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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