Drug substances analytical testing

A description and the results of all the analytical testing performed on the manufacturer s reference standard lot and qualifying lots to characterize the drug substance should be included. The section should provide information from specific tests regarding the identity, purity, stability, and consistency of manufacture of the drug substance. All test methods should be fully described and the results provided. 

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

The guideline states that the objective of validation is to demonstrate that an analytical method is fit for its purpose and summarizes the characteristics required of tests for identification, control of impurities and assay procedures (Table 13-2). As such, it applies to chiral drug substances as to any other active ingredients. Requirements for other analytical procedures may be added in due course. 

Initial Situation An experimental granulation technique is to be evaluated a sample of tablets of the hrst trial run is sent to the analytical laboratory for the standard batch analysis prescribed for this kind of product, including content uniformity (homogeneity of the drug substance on a tablet-to-tablet basis, see USP Section (905)" ), tablet dissolution, friability (abrassion resistance), hardness, and weight. The last two tests require little time and were therefore done first. (Note Hardness data is either given in [kg-force] or [N], with 1 kg = 9.81 Newton). 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

Specifications refers to a list of tests regarding analytical procedures and appropriate acceptance criteria which are numerical limits, ranges or other criteria provided in an approved application that confirm the quality of the drug substances, drug products, intermediates, raw materials, reagents, and other components. Typically, the specification is a set of numerical values/ranges or characteristics derived from formal/informal... 

TABLE 6 ICH Guidelines Affecting the Analytical Testing of Drug Substances and Drug Products Valid as of November 2005... 

For each dmg substance, the maximum acceptable levels of the various impurities are described in the drug substance monograph or the specification included in the submissions to the regulatory authorities. In this chapter, the ICH Q6A [4] and Q6B [5] definition of specification is used. A specification consists of three parts the test (e.g. moisture content, impurities), references to the analytical procedure (e.g. high-performance liquid chromatography [HPLC], gas chromatography [GC]), and the acceptance criterion (e.g. not more than 0.50%). 

Grimm W. A rational approach to stability testing and analytical development for NCE, drug substance, and drug products marketed product stability testing. In Carstensen JT, Rhodes CT, eds. Drug Stability Principles and Practices, 3rd edn. New York Marcel Dekker, 2000 415-81. 

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. 

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