Composite drug substance method

Composite Drug Substance Method of a Basic Drug... 

Composite Drug Substance Method for a Basic Drug Substance... 

For drug substances and drug products, applications for enantiomers and racemates should include a stereochemically specific identity test and/or a stereochemically selective assay. The choice of control tests should be based on the method of manufacture and stability characteristics and, in the case of the finished product, its composition. 

Molecules which exhibit optical activity are molecules which have a handedness in their structure. They are chiral . Chemists often have reasons to obtain chemical pure aliquots of particular molecules. Since the chirality of molecules can influence biological effect in pharmaceuticals, the chiral purity of a drug substance can pose a challenge both in terms of obtaining the molecules and in assaying the chiral purity by instrumental methods. While diastereomers can have different physical properties including solubility, enantiomers have the same physical properties and the same chemical composition. How then to separate optically active molecules ... 

Where the specific impnrity is unavailable or is too costly, the use of composite or degraded samples is possible. This approach involves the nse of a dirty sample of a drug substance or the creation of a mixture of impurities through the in situ forced degradation method. Both of these approaches are best nsed for qualitative uses. In each of these mixtures, the impurities are present in unknown quantities. The real benefit of this type of impnrity standard is the low cost and the ability to unequivocally identify the peak loci of the impurities. When these mixtures are used in conjunction with a compendial standard and a well-developed set of relative response factors the resnlts will meet most analytical needs. 

According to the ICH guideline, revalidation of a CE method is necessary in case of a major change, e.g., in the synthesis of the drug substances, in the composition of the finished product, or in the analytical procedure [ICH Q2 (Rl)]. ... 

For purposes of this part, such patents consist of drug substance (ingredient) patents, drug product (formulation and composition) patents, and method of use patents. 

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. 

Confirm formulation composition, including, but not limited to, drug substance content, drug substance stability, excipient levels, water, and residual solvents, using appropriately characterized methods. 

This part of an application contains a precise description of the composition, methods of manufacture, specifications, and control procedures for the drug substance and the drug product. It also includes an environmental impact analysis statement for the manufacturing process and for the ultimate use of the drug. (Refer to the Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application and 21 CFR 314.50(d)(1), which set forth specific data requirements for this section.)... 

Regarding the components of bulk fermentation processes, the strain of the organism used to manufacture the drug substance for the clinical study should be compared with the strain to be used in commercial production. Strain identification includes microbiological, cultural, and biochemical characteristics. A comparison of the media composition and method of sterilization, sterilization parameters, and the pH of the medium after sterilization should be done. All fermentation stages, parameters, and conditions should be described in detail (i.e., temperature, pH) and documented. 

Chiral separations can be considered as a special subset of HPLC. The FDA suggests that for drugs developed as a single enantiomer, the stereoisomeric composition should be evaluated in terms of identity and purity [6]. The undesired enantiomer should be treated as a structurally related impurity, and its level should be assessed by an enantioselective means. The interpretation is that methods should be in place that resolve the drug substance from its enantiomer and should have the ability to quantitate the enantiomer at the 0.1% level. Chiral separations can be performed in reversed phase, normal phase, and polar organic phase modes. Chiral stationary phases (CSP) range from small bonded synthetic selectors to large biopolymers. The classes of CSP that are most commonly utilized in the pharmaceutical industry include Pirkle type, crown ether, protein, polysaccharide, and antibiotic phases [7]. 

As with the bulk drug substance, spedfications for both enantiopure and racemic chiral drug products should include both a stereochemically spedfic identity test and stereochemically selective assay method. The analytical method to be used should not be arbitrarily chosen to be the same as for the bulk drug but should be chosen on the basis of the composition, method of manufacture, and stability characteristics of the formulation. 

Verification or revalidation should be performed when relevant, for example, when there are changes in the process for synthesis of the drug substance changes in the composition of the finished product changes in the analytical procedure when analytical methods are transferred from one laboratory to another or when major pieces of equipment instruments change. 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

Characterization in the solid-state and compendial methods has been discussed already. Quantitative tests to characterize drug substance and drug product composition require that significant consideration be given to method development. Methods such as thin layer chromatography, gas chromatography, HPLC, supercritical fluid chromatography, and capillary electrophoresis... 

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