Excipient standards, drug

Analytical methods and specifications must be established and validated so as to define and control the quality and purity of the raw materials, intermediates and the finished product. For many standard chemical raw materials, the development of specifications will not be necessary as they are already published in US and European pharmacopoeia (for example, standards for water, organic solvents and various excipients). The ultimate objective of these activities is to be able to manufacture the drugs required for clinical trials in accordance with good manufacturing practice (GMP). 

Another excipient used in feed additive premixes is a diluent used to dilute or standardize activity. Diluents are similar in composition to grain carriers, except the particle size is generally smaller. No attempt is made to absorb the active drug to the individual particles of the diluents. If a liquid is used it is mainly for dust control. A diluent is considered for use when the level of the active ingredient components in the premix approaches or exceeds 50% of the product or when two or more active components vary greatly from one another in density [13]. Examples of diluent materials are ground limestone, sodium sulfate, kaolin, corn cob flour, and ground oyster shells. 

The extent of homogeneous mixing of pharmaceutical components such as active drug and excipients has been studied by near-IR spectroscopy. In an application note from NIRSystems, Inc. [47], principal component analysis and spectral matching techniques were used to develop a near-IR technique/algorithm for determination of an optimal mixture based upon spectral comparison with a standard mixture. One advantage of this technique is the use of second-derivative spectroscopy techniques to remove any slight baseline differences due to particle size variations. 

Tablet excipient interactions are occasionally observed when evaluating a drug product for purity. Since there are many excipients in a typical pharmaceutical tablet, known bands need to be identified to make it easier to evaluate for degradation products. Unfortunately, occasionally an inert excipient may react with a derivatizing agent used in TLC making this entity appear as a band that now needs to be identified. In Fig. 13.33, a placebo tablet, an extracted tablet, a handmade tablet blend of all components, and the drug substance standard are all applied to the same HPTLC plate and developed. These results alert the analyst to any excipients that may interfere in the evaluation of the tablet for purity. In this case, the only bands observed in the tablet blend and extracted tablet are the same bands seen in the tablet blend.

If an excipient had been observed, it would need to be identified. In Fig. 13.34, the drug substance standard is applied on lane 1 next to the extracted tablet. The remaining lanes labeled 2-12 are individual excipients in this particular tablet. Only one excipient, number 6, appears and it does in fact have the same R value as the band observed in the tablet. This confirmatory test is commonly used to identify interfering excipients. Now this band can be labeled appropriately, rather than mistakenly labeled as a degradant or impurity. 

At present, despite the advantages offered by the buccal delivery route, such as the bypass of intestinal and hepatic first-pass metabolism for systemic delivery, very few pharmaceutical products employ this route of administration. The reasons that contribute to this situation include (1) high costs associated with development, (2) lack of standardized tests to identify drug candidates suitability for this route, (3) the limited understanding of the impact of metabolism and/or transporters found in the oral cavity mucosa on buccal delivery, and (4) the relatively small number of reports describing the usefulness and safety of excipients/permeation enhancers in humans [82, 83], Therefore, the... 

The FDA maintains a database of approved excipients Drug Information Electronic Orange Book, http //www.fda.gov/cder/ob/default.htm). Standards and tests for regulatory acceptable excipients are included in the US Pharmacopoeia and National Formulary. Two such tests, dissolution and stability, are included in Exhibit 5.12 for reference. For new excipients to be included in a drug formulation, they have to satisfy one of the following criteria ... 

Provide standard pharmacopoeial methods for the assay of unformulated drugs and excipients and some formulated drugs, e.g. those that lack a strong chromophore. 

NDA applicants are required to submit a list of all excipients (as well as other drug components), used in the manufacture of a proposed new drug. Additionally, the applicant must provide sufficient information to establish that the use of each excipient is safe for its intended use, at its intended quantity. This information includes safety data, a statement of the composition, specifications, and any analytical methods used for the excipient. When a USP/NF monograph exists for an excipient, the applicant may state that the excipient in the drug will comply with the standards in the monograph instead of providing composition, specification, and analytical method information. The required safety information includes... 

In the absence of existing human exposure data or other review of the excipient, FDA recommends in its guidance on Pharmaceutical Excipients (2) that the excipient be evaluated using a battery of standard nonclinical tests (7). Which tests are appropriate depends upon the likely patient exposure given the intended use of the drug if approved. Table 1 provides a summary of the necessary tests. This test paradigm will likely be considered as setting the standard for data requirements for any new excipients, whether or not approved by the FDA in an NDA or ANDA, or reviewed by some future alternative review/approval mechanism. 

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