Reference-Standard Material Qualification - Pharmaceutical Technology

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Reference-Standard Material Qualification
The author reviews the types of reference-standard materials used in drug-product manufacturing, discusses current regulatory requirements, and outlines a reference-standard qualification program.


Pharmaceutical Technology
Volume 33, Issue 4, pp. 66-73

Storage and impurity detection

Impurities classified as organic (process and drug related), inorganic, or residual solvents (4) can be introduced during the manufacturing process for the drug substance, drug product, or excipient and/or through storage of the material. Impurities should be controlled throughout the manufacturing process. Impurities that are process-related should be kept to a minimum to avoid degradation and unwanted pharmacological effects. Compounds that are susceptible to hydrolysis, for example, should be thoroughly dried to remove moisture and then stored in a desiccator. Reference standards that contain a high percentage of organic volatile impurities may experience purity changes over time as the solvents evaporate. Impurities within acetone, a Class 3 solvent, for example, are permissible up to 5000 ppm or 0.5%, according to USP and ICH guidelines (5). The amount of acetone present may change during storage because of its volatility and therefore may alter the reference standard's purity.

Another reason to limit impurities is demonstrated in the following scenario. Consider a reference standard that is 90% pure. The remaining 10% of impurities have to be identified and monitored through the life of the material. More analytical tests must be performed, and the probability of the purity changing during the review period increases. Then consider a reference standard with a purity of 99.9%, which has less need for additional characterization and potential degradation. Such a product can be monitored more effectively. In addition, this type of standard reduces the degree of systematic and random error from the combined analytical tests.

If the reference standard is in a salt form, the amount of salt present must be determined so that the purity can be corrected for content. Applying the molecular weight to the correction will not account for residual salt that may be produced during synthesis. If possible, it is recommended the reference standard be in a salt-free state to reduce the characterization tests required.

Organic impurities. Determination of organic impurities is the most challenging aspect of developing a suitable analytical method because these impurities are unique to the parent compound and because various degradation pathways can lead to various impurities. Actual and potential organic impurities that arise during synthesis, purification, and storage must be identified and quantitated. The synthesis of the reference standard should be evaluated to predict and identify potential impurities from raw materials. Potential degradation product also can occur as a result of storage. Short-term (forced degradation) and long-term (evaluation under accelerated conditions) stress testing, therefore, should be evaluated during development. The design of the long-term stress test depends on the intended storage condition.

The quantity of organic impurities present can be determined with high-performance liquid chromatography (HPLC) and ultra-violet (UV) detection. Degradation products and compounds related to the product can be evaluated by the area percent or from the relative response of the standard being used. The technique used to obtain this data will depend on the amount of impurities and related compounds present and the decomposition pathway of the reference-standard material.

To consider the impact on the purity evaluation using area percent versus relative response factor, the following scenario may be considered. If analysis shows an impurity at 0.05% and the relative response factor of the impurity is half of the standard (i.e., the amount of impurity present shows a 50% detector response compared with the equivalent amount of standard), then there could be 0.1% of actual impurity. This level may be insufficient to affect overall purity results. If there was 1% impurity based on area percent present, however, then there would be 2% of actual impurity that could affect overall purity.

The approach to determining the relative-response factor for each impurity is a more accurate process, but potential pitfalls should be considered. The relative-response factor approach requires additional development because the component needs to be isolated and the relative response factor must be determined. In addition, as the reference standard ages, new unknown impurities may be detected. The relative-response factor of these new impurities must be determined, and the method updated if the new unknown is significant enough to alter the purity. Much of this information may be ascertained during the development of the drug substance.

Impurities that arise from raw materials, synthesis, purification, and storage require careful consideration because they may not produce detector responses that are related to the reference-standard material. Quantitation by area percent would not be appropriate in such cases. Rather, the impurities must be isolated and identified so that an appropriate reference standard can be used, or a relative response factor determined. For example, if the reference-standard material is a salt, then the cation response would not be equivalent to the reference standard. In such instances, a specific reference standard is required for the cation, and a separate analytical method for quantitation may be needed.

Inorganic impurities. Inorganic impurities such as metals and noncombustible materials are typically evaluated using compendial procedures. If inorganic impurities are proven to be less than the reporting threshold at initial characterization, then further analysis is not required.

Residual solvents. The potential for residual solvents should be evaluated during development of the drug substance and can be estimated by reviewing the synthesis pathway. USP General Chapter <467> Residual Solvents details a generic procedure for this evaluation. Residual solvents, however, may be specific to the manufacturing process and require a specific test procedure. An additional specific test procedure may be required if the USP procedure is not suitable for the reference standard being evaluated, or if the solvents used during synthesis are not included in USP <467>. If residual solvents (previously referred to as organic volatile impurities, or OVIs, by USP) are proven to be less than the reporting threshold at initial characterization, further analysis is generally not required at subsequent intervals. If the amount of residual solvents present affects the purity, however, they should be evaluated at each requalification interval.


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