ANDAs impurities in drug substances - Pharmanet

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Draft-Not for Implementation7778798081828384858687888990919293949596979899100101102103104105106107108109110111the impurity profile of the drug substance, and possible degradation products. Thisdiscussion may include only those impurities that may reasonably be expected based onknowledge of the chemical reactions and conditions involved.In addition, the DMF holder or the ANDA applicant should summarize the laboratorystudies conducted to detect impurities in the drug substance. This summary shouldinclude test results of materials manufactured during the development process and batchesfrom the proposed commercial process, as well as results of intentional degradationstudies used to identify potential impurities that arise during storage. Assessment of theproposed commercial process may be deferred until the first batch is produced formarketing. The impurity profile of the drug substance lots intended for marketing shouldbe compared with those used in development and any differences discussed.The studies (e.g., NMR, IR, and MS) conducted to characterize the structure of actualimpurities present in the drug substance at or above an apparent level of 0.1 percent (e.g.,calculated using the response factor of the drug substance) should be described. Note thatall recurring impurities at or above an apparent level of 0.1 percent (see section IV) inbatches manufactured by the proposed commercial process should be identified.Degradation products observed in stability studies at recommended storage conditionsshould be similarly identified. When identification of an impurity is not feasible, asummary of the laboratory studies demonstrating the unsuccessful effort should beincluded in the DMF or application. Where attempts have been made to identify impuritiesbelow the 0.1 percent level, it is useful to also report the results of these studies.Identification of impurities below apparent levels of 0.1 percent is generally not considerednecessary. However, identification should be attempted for those potential impurities thatare expected to be unusually potent, producing toxic or pharmacologic effects at a levellower than 0.1 percent. In all cases, impurities should be qualified as described later in thisguidance. Although it is common practice to round analytical results of between 0.05 and0.09 percent to the nearest number (i.e., 0.1 percent), for the purpose of this guidance,such values should not be rounded to 0.1 percent in determining whether to identify theimpurities.B. Inorganic ImpuritiesInorganic impurities are normally detected and quantitated using pharmacopoeial or otherappropriate procedures. Carry-over of catalysts to the drug substance should be evaluatedduring development. The need for inclusion or exclusion of inorganic impurities in thedrug substance specifications should be discussed. Acceptance criteria should be based onpharmacopeial standards or known safety data.J:\!GUIDANC\2452DFT.WPDJuly 21, 19984
Draft-Not for Implementation112113114115116117118119120C. Residual SolventsThe control of residues of solvents used in the manufacturing process for the drugsubstance should be discussed. Any solvents that may appear in the drug substance shouldbe quantified using analytical procedures with an appropriate level of sensitivity.Pharmacopoeial or other appropriate procedures should be used. Acceptance criteriashould be based on pharmacopeial standards or known safety data taking intoconsideration dose, duration of treatment, and route of administration. Particularattention should be given to quantitation of toxic solvents used in the manufacturingprocess as described in the ICH guidance Q3C Impurities: Residual Solvents.121IV.ANALYTICAL PROCEDURES122123124125126127128129130131132133134135136The DMF or abbreviated application should include documented evidence that the analyticalprocedures are validated and suitable for the detection and quantitation of impurities. Differencesin the analytical procedures used during development and proposed for the commercial productshould be discussed in the DMF or abbreviated application.Organic impurity levels can be measured by a variety of techniques, including those that comparean analytical response for an impurity to that of an appropriate reference standard or to theresponse of the drug substance itself. Reference standards used in the analytical procedures forcontrol of impurities should be evaluated and characterized according to their intended uses. It isconsidered acceptable to use the drug substance to estimate the levels of impurities when theresponse factors of the drug substance and impurities are close. In cases where the responsefactors are not close, this practice may still be acceptable, provided a correction factor is appliedor the impurities are, in fact, being overestimated. Analytical procedures used to estimateidentified or unidentified impurities are often based on analytical assumptions (e.g., equivalentdetector response). These assumptions should be discussed in the DMF submission or abbreviatedapplication.137138139140141142143V. REPORTING IMPURITY CONTENT OF BATCHESAnalytical results should be provided for all batches of the drug substance used for stabilitytesting, as well as for batches representative of the proposed commercial process. The content ofindividual impurities, both identified and unidentified, and total impurities observed in thesebatches of the drug substance should be reported with the analytical procedures indicated. Atabulation (e.g., spreadsheet) of the data is recommended. Impurities should be designated bycode number or by an appropriate descriptor, for example, name or retention time. Levels ofJ:\!GUIDANC\2452DFT.WPDJuly 21, 19985
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