Excipients approved

Where an unusual excipient is chosen, or where an established excipient is chosen for a dosage form that results in its administration by a novel route of administration, then additional data will need to form part of the application. In effect, a novel excipient will need to be supported by data similar to those required for a new drug, with full supporting data including composition, function, and safety. Novel excipients include the components of the matrix in prolonged release products, new propellants, and new permeability enhancers. The exception to this need for extensive supporting data would be for a material already approved for food use and administered by the oral route or a material already approved for cosmetic use with a topical route of administration. In all cases the quality of the excipients has to be described adequately and shown to be satisfactory (which will depend on its role). 

Neumega is the tradename given to the IL-ll-based product approved for the prevention of thrombocytopenia. The product is produced in engineered E. coli cells and is presented as a purified product in freeze-dried format. Excipients include phosphate buffer salts and glycine. It is reconstituted (with water for injections) to a concentration of 5 mg ml-1 before s.c. administration. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Neorecormon (tradename, also known as epoetin beta) is a recombinant human EPO first approved for medical use in the EU in 1997. It is indicated for the treatment of anaemia associated with various medical conditions, most commonly chronic renal failure and cancer patients receiving chemotherapy. Neorecormon is produced by recombinant DNA technology in a CHO cell line and is manufactured as outlined in Figure 10.5. It is presented in lyophilized format at various strengths (500-10 000 IU/vial) and contains phosphate buffer, sodium chloride, calcium chloride, urea, polysorbate and various amino acids as excipients. 

Information on existing or new excipients can be described and provided to the FDA in an NDA directly. Alternatively, the manufacturers of excipients may prepare and submit type IV Drug Master Files (DMF) to support the use of an excipient in one or more NDAs. The DMFs are discussed in FDA s regulations under 21 CFR Section 314.420 and the FDA-issued Guidance for Drug Master Files (8). When authorized by the DMF submitter (i.e., the excipient manufacturer) and cross-referenced by an NDA submitter, the FDA reviews the DMF to make determinations on the safety, manufacture, and quality of the excipient use in the new drug that is the subject of the then pending NDA. The DMF becomes active when reviewed in conjunction with the review and approval of an NDA. 

The FDA guidance on IVIVC development and validation defines a number of circumstances where an IVIVC can be used to justify a biowaiver request in support of (1) level 3 process changes, (2) complete removal or replacement of non-release-controlling excipients, (3) level 3 changes in release-controlling excipients, (4) approval of lower strengths, and (5) approval of new strengths. Additionally, use of the IVIVC to justify biorelevant dissolution specifications is cited as the optimal approach. 

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 ... 

List the common excipients used and also the regulatory requirements for approving excipients. 

N9 is currently the only approved spermicide in the U.S., and formulators must take this into strategic account. However, in the design of new polymer vehicles, the use of an approved spermicide is a logical choice for product introduction. However, compatibility of such excipients is an important consideration in the formulation of new chemical spermicides. 

Formulation of dry powders for inhalation must rely on a very short list of excipients to fulfill the customary roles of diluent, stabilizer, solubilizer, processing aid, and property modifier (e.g., flow enhancer). In the United States, only a few materials are approved for use in inhalation products, and of those (e.g., propellants, surfactants) many are of little help in dry powder formulation. 

Filgrastim is a recombinant human G-CSF (produced in E. coli), approved for chemotherapy-induced neutropenia since 1991. Although the 18.8 kDa recombinant product is not glycosylated and contains an additional N-terminal methionine residue (due to expression in E. coli), it displays biological activity indistinguishable from native G-CSF. The product is presented in freeze-dried format and contains buffer elements as well as sorbitol and Tween as excipients. 

EMEA Comparative table of current and proposed specifications. Batch analysis data on two production batches for all tests in the new specification. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the excipient complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable. Minor change type IB requires approval... 

The FDA has proved to be responsive to criticism, probably more so than many other federal agencies. To give one example, in 1989 it took roughly 33 months for a market approval letter to be issued from the date of request 10 years later this dropped to 13 months. Issues still remain, however. No new drug excipients had been approved in over 20 years because no manufacturer was willing to spend the money on the extensive toxicity testing required without commercial exclusivity or protection. 

Compendia that describe excipients used for various formulations such as parent-erals, vaginal formulations, and antibiotics are offered in a number of publications (7-9). The FDA publishes on its internet site, www.fda.gov, the downloadable Inactive Ingredient Database. The components of proprietary inactive ingredients are not always included. All inactive ingredients that are present in currently approved final dosage form in drug products are listed. Whenever included, one may need to search for such data under individual component entries. 

The inactive ingredients are updated quarterly, by the fifth working day of April, July, October, and January. To search for the excipient, one can enter any portion of the name of an excipient, of at least three characters. Search results are displayed alphabetically, sorted first by ingredient, then by the route of administration and dosage form. Routes of administration and dosage forms are derived from current approved labeling. Refer to the IIG query search results column headers for data field definitions. 

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