Drug substance recommendation

The FDA guidance document on impurities in drug substances recommends that individual impurities greater than 0.1% should be fully characterized and quantified by a validated analytical method. In addition, the USP permits up to 2% of ordinary nontoxic impurities in APIs. Such impurities may include residual starting materials, intermediates, reagents, by-products, degradation products, catalysts, heavy metals, electrolytes, filtering aids, and residual solvents. 

Data to demonstrate the stability characteristics of both the drug substance and the drug product must be collected. Studies using three different batches of both substance and product in their respective containers/packaging must be conducted. Real-time data should be collected under conditions of temperature and relative humidity in line with the recommended storage. Conditions in different world climatic zones must be taken into consideration for cases where normal environmental... 

A pharmacopeia is a collection of recommended specifications and other information for therapeutic products, including drug substances (active ingredients), excipients, dosage forms (also called preparations), and other articles. One function of a pharmacopeia is to provide a uniform and public basis on... 

Unlike the straightforward methods for solubility, dissolution, and gastric stability, the BCS guidance recommends several methods to determine the permeability class membership of a drug substance (Table 28.1). 

Hancock et al.63 reported a comprehensive review of a wide variety of pharmaceutical powders. Investigation of electrostatic properties of the drug substance or drug-excipient mixtures during preformulation has been recommended.64 Such studies may be particularly relevant for dry powder inhalation systems. 

Since solubility and permeability are the two most important factors influencing oral absorption of drugs, the following biopharmaceutical classification system (BCS) for drug substances, based on the work by Amidon et al.,67 has been recommended by the FDA 68... 

Long-term testing Stability studies under the recommended storage condition for the retest period or shelf life proposed (or approved) are performed with several drug substance batches in the stipulate packaging. In the general case, the storage condition is at a temperature of 25°C and 60% relative humidity. 

The tests for microbial limits and recommendations for microbial quality criteria of raw materials, excipients, drug substances, and pharmaceutical products have been established in pharmacopoeial compendia for over 30 years. These tests are listed in the USP 24 Chapter (61) Microbial Limits Tests and in the Ph. Eur. 3rd ed.. Biological Tests 2.6.12 and 2.6.13, Microbial Contamination of Products Not Required to Comply with the Test for Sterility (total viable count, tests for specified microorganisms) and the JP XIII 30 Microbial Limit Test. 

For drug substances, a retest date is generally determined. The period up to the retest date is a period during which the material is known to adhere to its specification, for example, for assay or degradants. The retest date may be assigned on the basis of real-time stability data obtained at the recommended storage conditions or on the basis of accelerated stability data obtained under more stressful conditions. 

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. 

For the assay of drug substance or finished drug product, it is normally recommended to have a range of 80-120% of the nominal concentration. 

As recommended by the ICH, the usual range for the potency assay of a drug substance or a drug product should be 20% of the target or nominal concentration and 30% for a content uniformity assay. At least five concentration levels should be used. Under normal circumstances, linearity is achieved when the coefficient of determination (r2) is >0.997. The slope, residual sum of squares, and... 

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