Excipient specification

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

The manufacturer and user should mutually agree upon the excipient specifications. The manufacturer must have the facility and process capability to consistently meet the mutually agreed upon specifications of the excipient(s). Subcontracting or significant changes to a supplier s audited process that could affect the physical, chemical, or functionality of the excipient in a final dosage form should be immediately communicated or pre-approved as mutually agreed upon between customer and supplier. 

Discussion of excipient specifications and release parameters. Note any special requirements that are not typical compendial requirements (e.g., particle size). Include comparative evaluation for multiple sources. 

Excipient manufacturers are now supplying excipients specifically geared toward manufacture of ODTs. One of them is spray-dried mannitol. The properties of this excipient suitable for ODTs include good compressibility at low hardness and fast disintegration, desirable properties for the manufacture of ODTs. The two brands commercially available include Pharmaburst by SPI Pharma and Pearlitol by Roquette. The hope is that it will stimulate the development of ODTs in house for pharmaceutical companies not traditionally involved with manufacture of ODTs. 

Table I Food Chemicals Codex and Japanese Pharmaceutical Excipients specifications for myristic acid.

Guidance is provided on process validation, in-process specifications, and action limits. The concept of the use of internal action limits is described, to control the consistency of the process at less critical stages. Data obtained during development and validation runs should provide the basis for provisional action limits to be set for the manufacturing process. Approaches to the testing of raw materials, components, and excipient specifications are described. 

Many excipients are extracted from or purified by the use of organic solvents. These solvents are normally removed by drying the moist excipient In view of the varying and sometimes unknown toxicity of solvents, it is important that excipient specifications include tests and limits for residues of solvents and other reactants. 

As many excipients are capable of stabilizing proteins under different conditions, it is unlikely that the stabilization effect is excipient-specific. It is widely believed that the stabilizing mechanism of excipients involves the preferential exclusion of the added excipient from the protein in aqueous solution and during freeze-thawing [192]. Briefly, a protein in an aqueous environment is in dynamic equilibrium between the native and the denatured (unfolded) forms. As the exclusion of excipient from the unfolded form is greater than that from the native form, the equilibrium will shift toward increasing concentration of the native form. Thus, the unfolding of protein in the presence of excipient is a thermodynamically... 

The US. Pharmacopeia (USP XXII) or National Formula (NFXVII) (20) also provide a similar description however, the peroxide value is not defined (Table 9). These specifications are also given in the Handbook of Pharmaceutical Excipients (HPE), pubhshed jointiy by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (21), which defines lecithins both from plants and eggs. The Merck Index (22) specifies a slightiy lower acid value. The Japanese Monograph (ISCI-II) (23) specifies a slightiy lower acetone-insoluble matter and a lower heavy-metal content. 

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). 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

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. 

Non-specific absolute assay methods, e.g. volumetric titration, can be applied to avoid the establishment of a reference substance. This is only appropriate, however, when the monograph describes a separation test for related substances. This approach is certainly valid for the determination of the content of pharmaceutical raw materials but less acceptable for the assay of content of pharmaceutical preparations where the employment of specific assay methods is recommended (ICH Guideline 1994) to take account of decomposition of the active ingredient during the shelf life of the product and to avoid possible interference from excipients. 

In many products it seems highly probable that there exists a narrow range of optimum moisture contents that should be maintained. More specifically, the effect of moisture on MCC-containing tablets has been the subject of an investigation that demonstrates the sensitivity of this important excipient to moisture content [10]. These researchers found that differences exist in both the cohesive nature and the moisture content to two commercial brands of MCC. A very useful report on the equilibrium moisture content of some 30 excipients has been compiled by a collaborative group of workers from several pharmaceutical companies and appears in the Handbook of Pharmaceutical Excipients [11,12],... 

In addition to the information relating to excipients in the development pharmaceutics guidelines there are two guidelines that specifically address excipients in pharmaceutical products—3AQ9a (adopted February 1994) and EMEA/CVMP/004/98 Final (adopted February 1999). These expand on the information in the development pharmaceutics guidelines. 

Excipients should be listed in the composition using their Ph Eur name (or one from another national pharmacopeia from an EEA member state), the International Nonproprietary Name, or an exact scientific designation, other than for materials such as preservatives or coloring agents which can be identified by an E-number. Third country pharmacopeial names may be acceptable. Coloring matter is subject to the provisions of specific legislation in the EEA. 

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. 

For nonpharmacopeial materials a full specification should be included in the application. This should include appropriate tests and requirements for physical characteristics, identification, relevant purity tests, and performance-related tests. Characteristics likely to influence bioavailability of the finished product should be controlled. Routine tests and specifications should be described. Methods should be validated. The material should be fully characterized, with full data on the chemistry concerned and including consideration of the safety of the excipient. Any relevant European Directive requirements or other international specifications should be met, but additional requirements might apply depending on the intended use of the product—e.g., for materials to be used in sterile products. 

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. 

The formulation of this type of product usually employs a small number of ingredients and sometimes only the active ingredient. Particle size and particle size distribution, rugosity, and particle charge should be considered for all ingredients, and the specific grade of excipients should be stated. The excipients should be sourced from a single supplier (with data to demonstrate the suitability of different batches of material), but if multiple sources are used, additional data will be required to establish the suitability of different batches from each supplier. 

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