Excipient efficacy

The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy, in which case additional safety and efficacy data are required. The same qualitative and quantitative composition only applies to the active ingredients. Differences in excipients will be accepted unless there is concern that they may substantially alter the safety or efficacy. The same pharmaceutical form must take into account both the form in which it is presented and the form in which it is administered. Various immediate-release oral forms, which would include tablets, capsules, oral solutions and suspensions, shall be considered the same pharmaceutical form for this purpose. 

The process of formulation for any of the above is generically the same, beginning with some form of product specification and ending with one or more formulations that meet the requirements. Correct choice of additives or excipients is paramount in the provision of efficacy, stability, and safety. For instance, the excipients may be chemically or physically incompatible with the drug or they may exhibit batchwise variability to such an extent that at the extremes of their specification they may cause failure in achieving the desired drug release profile. In addition, some excipients, especially those that are hydroscopic, may be contraindicated if the formulation is to be manufactured in tropical countries. Flence formulators must work in a design space that is multidimensional in nature and virtually impossible to conceptualize. 

The choice of the excipients and their concentration, including their function (e.g., antimicrobial preservatives, antioxidants. ..). In the case of antimicrobial preservatives, data are expected on the preservative efficacy in products on storage, including after reconstitution or dilution and during the period of use. 

Where antioxidants or antimicrobial preservatives are used, the finished product release specification will need to include identification tests and assays for these two types of excipient. The shelf life specification should also include a specification for assay for antimicrobial preservatives. Stability data will be required for both antioxidants and antimicrobial preservatives in the finished product, and in addition the preservative efficacy of the formulated product should be examined over its shelf life and by means of appropriate in-use stability tests. Preservative efficacy data should also be presented at the lower limit of the preservative assay. 

Antioxidants should be used only when it can be shown that their incorporation cannot be avoided by appropriate manufacturing methods or packaging. Their intended performance in the product should be clearly stated—e.g., whether for the benefit of the active ingredient or an excipient. Their efficacy can depend on their nature, their concentration (subject to safety considerations), when they are incorporated in the manufacture of the finished product, the container, and the formulation (particularly their compatibility with other constituents). All of these issues should be addressed. Their activity should also be determined in the finished product under conditions simulating the use of the product. The extent of degradation should be determined with and without the antioxidant. 

Skrabanja et al. [3.6.] do not accept a combination of 12 different excipients e. g. for erythropoetin as the efficacy of each component cannot be proven. The mostly frequently used excipients are listed in five groups ... 

The key objective of our efforts has been to develop a vaginal formulation that optimizes spermicidal and antiviral activity while enhancing spreading and true bioadhesiveness. Utilization of strict design principles for an excipient delivery vehicle, which included substantivity to vaginal mucosa, saline compatibility, compatibility with a wide range of spermicidal and antiviral compounds, low irritation potential, sperm impedance, system stability, and efficacy after stressed storage conditions, resulted in the development of DCE s [11,12,13]. Based on the results from in vitro studies, the DCE vehicle was selected for clinical development. 

Many interactions will directly influence the efficacy of the product, and thus potentially the health and/or treatment of the patient. However, it must be reemphasized that excipient interactions are not always detrimental. Sometimes they can be used to our advantage, particularly in the areas of product manufacture and drug delivery systems (see below). 

Pharmaceutical nonactive excipients have long been applied in a variety of pharmaceutical dosage forms to provide a wide range of functional characteristics that facilitate the optimal delivery of a drug to achieve the desired therapeutic effects. Pharmaceutical excipients are inert materials with no adverse effects on the safety and efficacy of therapeutic products. The Food and Drug Administration (FDA) website (1) provides a database listing all the FDA-approved nonactive pharmaceutical excipients. This provides formulation scientists a useful reference for efficient choices of the suitable excipients for the desired formulations of drug. 

Excipients are additives that are included in a formulation, because they either impart or enhance the stability, delivery, and manufacturability of a drug product. Regardless of the reason for their inclusion, excipients are an integral component of a drug product and therefore need to be safe and well tolerated by patients. For protein drugs, the choice of excipients is particularly important because they can affect both efficacy and immunogenicity of the drug. Hence, protein formulations need to be developed with appropriate selection of excipients that afford suitable stability, safety, and marketability. 

Usually the most difficult aspect of cleaning validation is in determining how to evaluate the efficacy of the cleaning method. Equipment should be sufficiently clean so that the incidental carryover in the first batch after cleaning presents an acceptable risk to excipient quality and performance. Once this determination has been made, it is possible to calculate the maximum amount of residue carried over into the excipient batch. Then a calculation can be made as to how much residue can be left on the equipment surface, assuming the residue is uniform throughout the equipment. 

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