Impurities in bulk drug substances

Category II methods are intended to determine impurities in bulk drug substance, degradation products in finished drug product, or for verification of cleaning processes. These methods are further subdivided into quantitative tests and limit tests. 

Category n — Analytical methods for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These methods include quantitative assays and limit tests. 

The quantitation Limit (QL) is a characteristic of quantitative assays for low levels of compounds in sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. QL is defined as the concentration of related substance in the sample that will give a signal-to-noise ratio of 10 1. The QL of a method is affected by both the detector sensitivity and the accuracy of sample preparation at the low concentration of the impurities. In practice, QL should be lower than the corresponding ICH report limit. 

It also should be noted that FDA may request additional preclinical toxicology studies. This will depend on the degree(s) of difference(s) in the profiles, identities, and the levels of impurities in bulk drug substances produced from the pivotal intermediate made by the various routes of synthesis, and whether the finished drug is intended for short-term or chronic use. 

Because of their therapeutic advantages, the above-discussed oral antidiabetic drugs are more and more frequently used in therapy and are extensively examined by analytical procedures. Especially, the methods for pharmacokinetic studies and for quantification of potential impurities in bulk drug substances are continually being developed. Most favored, in terms of a number of publications, are the HPLC techniques, although TLC methods are also represented. In HPLC, a RP technique with Ci8 columns is more prevalent than the alternative phases. Isolation steps are almost evenly distributed between conventional liquid—liquid extraction and SPE procedures. The UV detection can serve as a reliable tool for determination of most of these antidiabetics. However, new prospects are represented by the MS/MS detection. Sensitive and automated HPLC techniques with column switching are also more and more frequently applied. 

HHS/FDA International Conference on Harmonisation, Guidelines Availability Impurities in New Drug Substances Notice, Federal Register, January 4, 1996 An FDA Perspective on Bulk Pharmaceutical Chemicals, Edmund M. Fry, Pharmaceutical Technology, February 1984, Pages 48-53... 

All compendias [5-7] specify use of a liquid chromatographic method to determine the eight known rocuronium bromide impurities. The chromatographic method corresponds to the chromatographic method used to determine rocuronium in bulk drug substance, as detailed in Section 2.3.1. For the purpose of analyzing impurities, the RS used is the RS of rocuronium that is intended for peak identification, where the identification standard contains impurities of rocuronium bromide and rocuronium bromide itself. 

Characterization of Impurities and Decomposition Products in Bulk Drug Substances... 

T ical percentages of impurity-I in bulk drug substance range from 0.1% to 0.5%, and the t) ical ranges for impurity-II are 0.04-0.12% [14]. 

Section III will detail the process for effectively isolating, purifying, and identifying the impurities and primary degradation products in bulk drug substance and drug product formulations. 

Related compound (B) has the systematic name methyl-( )-(o-chloro-phenyl)-4,5-dihydrothieno[2,3-c]pyridine-6-(7H)-acetate, hydrogen sulfate salt [2], and is a racemic residue formed during the manufacturing process. This compound may appear as a racemic mixture in samples of bulk drug substance as impurities (la) and (lb) [6, 7]. 

The USP [7] provides extensive discussion on impurities in sections 1086 (Impurities in Offical Articles), 466 (Ordinary Impurities), and 467 (Organic Volative Impurities). A total impurity level of 2.0% has been adopted as a general limit for bulk pharmaceuticals [5]. There have been no levels established for the presence of enantiomers in a drug substance/ product. This is primarily because the enantiomers may have similiar pharmacological and toxicological profiles, enantiomers may rapidly interconvert in vitro and/or in vivo, one enantiomer is shown to be pharmacologically inactive, synthesis or isloation of the perferred enantiomer is not practical, and individual enantiomers exhibit different pharmacologic profiles and the racemate produces a superior therapeutic effect relative to either enantiomer alone [8,9]. 

It is prudent to evaluate impurity peaks observed in a supplier s bulk substance and compare them with those observed in the drug product. The extent that the peaks differ may determine the need to obtain further information, including toxicity. Samples of impurities/degradation products methods should be appropriately validated by the ANDA sponsor for their sensitivities and specificities. It also is recommended that the sponsor of an ANDA set up and maintain a stability program for the bulk drug substance. 

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. 

The purpose of this test is to demonstrate that immediate precursors and other known impurities are resolved from the drug substance and do not interfere with any unknown impurities existing in the drug substance bulk. All impurities should also be separated from any TLC-specified impurities. Figure 2 shows a drug substance band separated from all known impurities. The nominal concentration of the compound is determined in the method development phase according to the requirement of LOD and LOQ. 

Since the existing analytical method contained phosphate buffer, method conditions needed to be modified for preparative isolation requiring a volatile mobile phase (0.1% formic acid in methanol). The bulk drug substance lot was purified by preparative HPLC using the modified preparative chromatographic conditions. The component of interest eluted from 5-6 minutes and was collected over multiple runs. The fractions containing the impurity were combined and concentrated by evaporation to give a crude oil. The oil was further purified in a final analytical cleanup to afford 1 mg of sample for NMR analysis. 

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