Drug substances specifications

TABLE I Impurity Results from Three Validation Batches Using the New Suppliers Drug Substance. Specifications Are <0.1%... 

A summary report, including protocols and results, should be provided for the validation studies of each critical process or factor that affects the drug substance specifications for ... 

Regarding production of bulk drug substances, specifications for contaminants should be established for all solvents used in the process. A comparison should be performed between the manufacturer s Certificate of Analysis and the submitted specifications, and any discrepancies should be justified. A full description for the route of synthesis should be given, as this is important for the testing and control of impurities and process solvent residues. The FDA expects that, at the time of submission, it will be determined if the drug substance exists in a multiple solid state form (racemic mixture stereoisomer) and whether this affects the dissolution and bioavailability of the drug product. 

Regarding laboratory controls, a review of laboratory notebooks and chromatograms should be done to check the reliability and authenticity of the supporting data in the methods development and testing of the clinical, bio, and stability batches. Reference standards used should be certified as standards. The FDA expects that, for bulk substances, the suitability of reference standards should be more extensive than that of bulk drug substance specifications. A comparison of analytical methods and specifications for lots of drug substance used in clinical batches and biobatches should be performed to see if any deletions or revisions to any specifications occurred. 

Inorganic impurities are normally detected and quantified using pharmacopoeia or other appropriate procedures. Carryover of catalysts to a new drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in a new drug substance specification should be discussed. Acceptance criteria should be based on pharmacopoeial standards or known safety data. 

The specification for a new drug substance should include a list of impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities that are likely to occur in the commercial product. The selection of impurities in a new drug substance specification should be based on the impurities fotmd in batches manufactured by the proposed commercial process. Those individual impurities with specific acceptance criteria included in the specification for a new drug substance are referred to as specified impurities in this guidance. Specified impurities can be identified or unidentified. 

Unspecified impurity An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification. 

Information on impurities, including their structure, acceptance limits, and control, is to be briefly described. For control of a drug substance, specifications (including justifications) and analytical procedures (including validation information) used for testing are to be summarized. Data on reference standards or reference materials used for drug substance testing are to be provided. Information on batches and the results of batch analyses are to be described. 

The most frequent use of NMR spectroscopy in drug substance specifications is as an identity test H, X or multinuclear spectroscopy may be used as impropriate. A possible advantage of multinuclear NMR is the increased specificity afforded by the wider spectral width and the ability to distinguish the active ingredient from compounds not containing the observed heteroatom. NMR may offer greater structural specificity than other spectroscopic techniques, and it has therefore been used in identity tests for more complex molecules such as peptides and proteins as well as heparins. Another use of NMR in specifications has been to confirm that the drug substance is present in the correct polymorphic form (see below). 

The IND contains information regarding the drug s composition and synthesis and lists all specifications that have been set for the drug substance. Specifications are set for many tests, which may include trace metals. All subsequent batches of the drug that will be used in clinical studies must meet these specifications before their release. The IND contains information regarding animal toxicology study data and protocols for clinical trails. The IND clinical study protocol for a new drug candidate consists of three clinical phases (Table 2). 

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