Excipient Functionality testing

Pharmaceutical excipients are increasingly considered important quality attributes of a drug product. They have an effect not only on product manufacturability, but also on product stability. The physical characterization of excipients has received the most attention, as discussed earlier. Excipient functionality testing and multisource excipient equivalence have been reviewed in the literature.21 However, chemical impurity profiles of excipients have not, in general, received similar attention. 

The conference endorsed the goals of the pharmacopeias to improve and harmonize standards for existing excipients, to focus on testing methods, and address specifications after test methods had been agreed upon, and to develop functionality tests, including particle size, siuface area, and density. 

Tableting process, since being introduced in the early 1840s, has witnessed numerous changes in the form of stringent regulatory requirements for the excipients and product stability. Increasing regulatory pressure on purity, safety, and standardization of the excipients has catalyzed the formation of an international body, the International Pharmaceutical Excipients Council (IPEC) (13). IPEC is a tripartite council with representation from the United States, Europe, and Japan, and has made serious efforts to harmonize requirements for purity and functionality testing of excipients (14).

It is important to assure consistency from lot-to-lot for the desired functionality. While the compendial monograph focuses on chemical characteristics and demonstrates the safety of the raw material, some excipients require functionality tests to assess their performance in the finished drug product. These tests reflect the physical... 

TABLE 9.4 Typical Function of Some Excipients and Their Functionality Testing... 

Mohan G. 2005. Functionality testing of excipients and their impact on formulation development. Am. Pharm. Rev. 8(6) 64-67. 

The Handbook of Pharmaceutical Excipients [1] contains some details of functional tests carried out on a wide range of excipients. The excipients all have phar-macopeial monographs, but it is important to understand that compliance with a monograph does not indicate equivalence between different grades or suppliers. 

One of the difficulties that beset the product developer is the lack of meaningful tests by which excipients (including direct compression diluents) can be assessed. This has led to the development of the so-called functionality tests. Some functionality tests that have been suggested (e.g., particle size, surface area) are in fact physical test methods being carried out under closely defined conditions. The relation of such a test to the actual function of the excipient needs to be established. After this link has been made, a more suitable title for these tests might be functionality-related tests. ... 

Brittain, H.G. Functionality testing of excipient materials. Pharm. Technol. 1993, 9 (9), 72-73. 

As can be seen from the table, the excipients all have pharmacopoeial monographs, but it is important to understand that compliance with a monograph does not indicate equivalence between different grades or suppliers. The monographs confirm the chemical identity and purity of the excipients but do not measure the performance of the materials as diluents. To establish the equivalency of excipients obtained from different sources, it is necessary to perform some kind of functionality testing. The Handbook of Pharmaceutical Excipients, a joint publication between the Pharmaceutical Press and the American Pharmaceutical Association, contains some details of functional tests carried out on a wide range of excipients, but the onus on establishing equivalency of excipients still remains with the user. 

This aromatic alcohol has been an effective preservative and still is used in several ophthalmic products. Over the years it has proved to be a relatively safe preservative for ophthalmic products [138] and has produced minimal effects in various tests [99,136,139]. In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20-30 minutes at a pH of 5, it will decompose about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions. 

Where there is a Ph Eur or national pharmacopeial specification for the excipient, this should be applied. Third country pharmacopeial specifications may also be acceptable. Routine tests and specifications should be stated. Function-related specifications should be included. 

In general, it is preferable to choose excipients and processes for IR dosage forms that do not result in a formulation that requires a particular pH to function well. In the general population, the pH in the stomach is quite variable (see the subsection Choice of Dissolution Test Conditions for Quality Control ) and there is no guarantee that the dosage form will be exposed to acid, so dosage forms that require acid to facilitate release are unlikely to perform robustly in the clinical practice setting. 

Reduce product cost due to improved functionality (56) and fewer test requirements compared with individual excipients (32). 

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