Active ingredients/substances

Part 111 Documentation on the Active Ingredient (Substance) of the Pharmaceutical Preparation... 

Brief report on the manufacturing process of the active ingredient (substance)... 

The document is expected to provide evidence of the scientific claims with respect to the chemical composition, especicilly the purity and declared fluctuations in the active ingredient (substance). 

Capsaicin, an active ingredient in red pepper, is well known for its ability to release and deplete substance P in sensory C fibers. However, this action is not specific for substance P, as neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin also are released. 

The quality of a drug substance is controlled by its specification. An internationally harmonized guideline on specifications and tests for chemical substances as active ingredients and in drug products makes reference to chiral compounds. This has recently been finalized and is discussed in Section 13.5.2. 

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

The guideline states that the objective of validation is to demonstrate that an analytical method is fit for its purpose and summarizes the characteristics required of tests for identification, control of impurities and assay procedures (Table 13-2). As such, it applies to chiral drug substances as to any other active ingredients. Requirements for other analytical procedures may be added in due course. 

A uV-Diethyl-m-toluamide (DEET) is the active ingredient in many insect-repellent preparations. Plow might you synthesize this substance from m-bromotoluene ... 

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 active ingredients in a shampoo play three fundamental roles. Some allow water to wash away the substances that make hair dirty. Others adhere to hair to impart a desirable feel and texture. The rest are emulsifiers that keep the mixture from separating into its components. To accomplish these effects, ingredients combine two types of interactions a strong attraction to water (hydrophilic) and an aversion to water (hydrophobic). It may seem that these properties are incompatible, but shampoos contain molecules that are designed to be simultaneously hydrophilic and hydrophobic. One example is sodium lauryl sulfate, our inset molecule. The ionic head of the molecule is hydrophilic, so it interacts attractively with water. The hydrocarbon tail is hydrophobic, so it interacts attractively with grease and dirt. Molecules of the shampoo associate with hydrophobic dirt particles to form hydrophilic clumps that dissolve in water and wash away. 

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. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

End-use formulations should be used as the test substance. If an active ingredient is marketed in two commercial formulations, then both should be used in the study, since there may be differences in residue levels and dissipation rates, e.g., a wettable powder versus a liquid formulation. The best solution would be plots located at the same site for a side-by-side comparison. This should only be necessary at one of the sites. However, each formulation should be represented in the study unless a strong case can be made for a worst-case scenario. 

Tracer materials are defined as any product included in the test substance that can be recovered analytically for determining the drift from the application. This may be the active ingredient in an actual tank mix, or it may be a material added to the tank mix for subsequent detection. The selection of an appropriate tracer for assessing deposition rates in the field is critical to the success of a field study. Tracer materials such as low-level active ingredient products, colored dyes, fluorescent dyes, metallic salts, rare earth elements and radioactive isotopes have been used with varying degrees of success in the field. An appropriate tracer should have the following characteristics ... 

Active ingredient tracers or test substances can be quantified using gas chromatography (GC) and high-performance liquid chromatography (HPLC) analyses. 

The receipt of the test substance should be documented upon arrival at the test site. The name of the product, manufacturer, active ingredient concentration, expiration date, storage location, storage requirements, lot or batch number, the amount received, the condition at receipt, and whether the material is an emulsifiable concentrate (EC), fiowable, powder or otherwise should be noted in the research notebook. In addition, one should note the purchase date, the shipment date, and the carrier of the product. 

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