Drug quality assessments.
The acquisition of suitable methods begins with preparation of a list of synthetic intermediates, by-products and degradation products, based on data available in the literature. Samples of the compounds are obtained from drug manufacturers, chemical suppliers or synthesized in house. Pharmacopeial and other methods, if available, are evaluated in the laboratory to determine if the related compounds are resolved from the drug and from each other. If not, methods to achieve this resolution are developed. The use of related compounds to define the conditions for resolution raises the probability that other related compounds, not on hand during the method development, will be resolved from the drug. Related compounds can also be used as system suitability standards and to assess the extent of error introduced by quantitation of related compounds against the drug as a standard. Adjustments for differences in detector response can be made if necessary.
An example of these activities is afforded by P.M. Lacroix's work on Diltiazem, a coronary vasodilator. At the time New Drug Submissions were being received by the directorate, there were no monographs for Diltiazem in the US or British pharmacopeias, and there were no reports in the literature documenting resolution of the drug from its related compounds. Eight related compounds were cataloged from a survey of the synthetic and degradation processes, and samples obtained from manufacturers. An HPLC method was developed to resolve the related compounds from the drug and from each other. The minimum quantiflable amount of the related compounds was about 0.1%, using the drug as a standard. The method was adapted for assay of Diltiazem in drug raw material and tablet products and used as the basis for evaluating Diltiazem raw materials imported into Canada.
The Diltiazem methods were accepted by the United States Pharmacopeia (USP) as the basis of the Diltiazem Hydrochloride and Diltiazem Tablet monographs which are to become official standards on January 1, 1990. The USP is recognized under the Food and Drugs Act as a legal standard in Canada. It is an important avenue to visible public standards for pharmaceuticals.
Salbutamol, a bronchodilator, has been available for years in tablet, metered dose inhaler and other formulations. Recently, in anticipation of New Drug Submissions from several manufacturers, N. Beaulieu developed HPLC methods for the determination of Salbutamol and related compounds in drug raw material and formulations and the mean drug content per unit dose delivered by metered dose inhalers. These and other methods were used to evaluate an inhaler product in New Drug Submission status. It was quickly shown that the drug raw material proposed for the inhaler was of acceptable quality. However, in determining the mean unit dose delivered by the inhaler, the drug was found to contain about 10% of unknown purities. The level of impurities was substantially greater in drug delivered through the metering valve, as compared to drug obtained by opening the pressurized container. Two of the impurities gave FT-IR and mass spectra consistent with butylated hydroxytoluene, a common anti-oxidant, and 2,2'-methylene bis(4-ethyl-6-t-butylphenol), a compound similar to known rubber additives. The latter may have been leached from the valve assembly.
The inhaler formulation was evaluated by T.D. Cyr with BP Apparatus A for "Pressurised Inhalations: Disposition of the Emitted dose." Apparatus A is a two-chamber device for separation of larger and smaller particles in the emitted stream, larger particles being trapped in the first chamber. For the product under evaluation, it was judged that the percentage of small particles was too low for effective delivery of the drug to the lungs.
The deficiencies in this product were uncovered before a Notice of Compliance was issued by the directorate and hence before it was available to the Canadian public. Standards based in part on the findings noted above were set by the Bureau of Human Prescription Drugs. The manufacturer has met these standards and the product, now available to the public, offers consumers a quality alternative to other inhaler formulations.
Most drug raw materials submitted to the directorate for use in Canada are of acceptable quality. This is no doubt due, at least in part, to the well known laboratory evaluation activities of the Drugs Directorate. It is worthwhile to have assurance that this will continue to be the case, considering that the cost per Canadian is about a nickel a year. Ask an asthma sufferer if he thinks he got his money's worth from the salbutamol work!
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|Author:||Lovering, Edward G.|
|Publication:||Canadian Chemical News|
|Date:||Nov 1, 1989|
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