Bulk drug substance

PIC, 1987, Guidelines for the Manufacture of Active Pharmaceutical Ingredients (Bulk Drug Substances) (Document PH 2/87). 

HPLC methods have been widely used for the analysis of OTC in different samples. As described above in the Section 2.3, the HPLC method is described in most of compendia [1,2,4,7] for determination of OTC in bulk drug substances and in some pharmaceutical preparations. The application of HPLC methods for the analysis of antibiotics including oxytetracycline has been recently reviewed by Diaz-Cruz et al. [37] and Lunn [38], A summary of HPLC method for the analysis of OTC is presented in Table 3. 

Except for bulk drug substances, samples can rarely be analyzed directly following simple preparation steps. In many cases, an active ingredient is found in a formulated form or in a physiological fluid or tissue. Likewise, interferences associated with the matrix and the presence of possible degradation products, metabolites, and other closely related compounds mean the target analyte is often highly diluted. Also, an analyte may be difficult to detect. Effective sample preparation steps serve up to three broad purposes (1) eliminate and/or minimize possible interferences, (2) concentrate the sample, and (3) render the analyte of interest into a more easily detectable form. 

Other studies have used quantitative XRPD to evaluate the degree of crystallinity in bulk drug substances, such as calcium gluceptate [36], imipenum [37], cefditoren pivoxil [38], and a Lumaxis analog [39]. 

Local clinical trial may be waived by the licensing authority in the interest of the public good, in which case data from preclinical studies are to be evaluated. TTie approval for import permission is given on Form 45 or 45A, clinical trial on Form 46 and/or 46A, and new bulk drug substance on Form 54a. 

Methods for the quantitation of major components of bulk drug substances or APIs, including preservatives, in finished drug products are classified in Category I. Assay and content uniformity methods fall into this category. These methods demonstrate that the label claim of the drug... 

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. 

Yesilada, A., Tozkoparan, B., Gbkhan, N., Oner, L., and Ertan, M. (1998). Development and validation of a capillary electrophoretic method for the determination of degradation product in naphazoline HCl bulk drug substance. /. Liq. Chromatogr. Related Technol. 21(17), 2575-2588. 

Rao et al. reported a high performance liquid chromatographic method to determine diloxanide furoate and metronidazole in single and in combined dosage forms [41]. A 30 mg equivalent of diloxanide furoate and 25 mg of metronidazole (either as the bulk drug substances or in powdered tablets) was dissolved in methanol, amidopyrine added as the internal standard, and the mixture analyzed by HPLC at room temperature. The analytical column (30 cm x 3.9 mm) consisted of p-Bondapak Cig, with 9 9 1 1 methanol water 0.05 M KH2PO4 0.05 M NaH2P04 as the mobile phase. The flow rate was 1 mL/min), and detection was performed at 254 nm. 

The stability of material stored at elevated temperatures and increased relative humidities was also evaluated. No changes were evident after 3 months of storage at 80°C, or after 3 months of storage at 90% of relative humidity. When kept for 3 months under 2000 lux or 3 days under UV light, the bulk drug substance was unchanged and no degradants were observed. 

The United States Pharmacopoeia describes a spectrophotometric method for the bulk drug substance [4], The method is based on measuring the difference in absorbance at 269 ran and 300 nm for the sample and a reference standard solution ... 

The British Pharmacopoeia on the other hand, recommends the use of a non-aqueous titration method for the bulk drug substance [12], The method calls for the titration of isoxsuprine HCl against 0. 1 M perchloric acid (after dissolving the solid in acetic anhydride), and using 1-naphtho-benzein solution as the indicator. 

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. 

TRS 823, Annex 1 [38] Active pharmaceutical ingredients (bulk drug substances)... 

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. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

The development report has two main sections, one that addresses the dosage form and one that deals with the bulk drug substance The product development scientist compiles the experimental evidence to demonstrate bioequivalency for the first clinical trial lot through those lots that will be used for launch. The report further includes a description of the current process along with a description of the chemical/phys-ical characteristics, purity, related substances, specifications, and stability of the drug substance. 

I Analytical methods for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products. 

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