Compendial requirements

An entirely different type of contamination arises from the presence of microbiota in a product. As in the case of chemical contamination, compendial requirements for microbiological purity exists. Pharmacopoeial standards vary from country to country, and manufacturers must use the specifications and kill times that meet local requirements. As of this writing, the criteria in the British Pharmacopoeia are more stringent than those estabUshed by the CTFA, which are stricter than those in the United States Pharmacopoeia. In order to meet commonly accepted standards of microbial purity, manufacturing faciUties must be periodically cleaned and all products that can support microbial growth must contain an effective preservative (6). 

In as much as products for the diagnosis and treatment of ocular disease cover the spectrum of practically all dosage forms and, thus, require the same pharmaceutical sciences for their development, in this chapter we discuss the entire scope of considerations involved in the development of ophthalmic products, ranging from regulatory and compendial requirements, through physicochemical, safety, and efficacy considerations, to a discussion of types of dosage forms currently used by the medical practitioner. 

Compendial Requirements of Dissolution Testing—European Pharmacopoeia, Japanese Pharmacopoeia, United States... 

USP recognition of the need to control the in vitro dissolution performance of oral products by some level of compendial requirement was evidenced by the formation of a joint USP-NF panel on physiological availability in 1967. The USP... 

The authors have divided compendial requirements into three different types. For convenience, the Eur. Ph. or USP may be referenced since they have been harmonized and are identical or nearly identical in all requirements. 

The peak has both width (W,) and height (h). The subscript b denotes that the width was measured at the base line. Sometimes the width halfway up the peak (W j) or at 5% of peak height (Wg 05) is used to meet the method or compendial requirements. 

Based on the existence of a pharmaeist-patient-prescriber relationship and the presentation of a valid prescription, pharmacists may compound, in reasonable quantities, drug produets that are commereially available in the marketplaee. For the compounding process, pharmacists shall receive, store, or use drug substanees that have been made in an FDA-approved facility and/or drug components that meet official compendial requirements. If neither of these requirements can be met, pharmacists shall use their professional judgment to proeure alternatives. 

Required documentation—No documentation is required beyond the usual application/compendial requirements. No in vivo bioequivalence documentation is required. 

Notification and updated batch record Stability Application/ compendial requirements plus multipoint dissolution profiles in three other media (e.g., water, 0.1/VHC1, and USP buffer media at pH 4.5 and 6.8) until >80% of drug released or an asymptote is reached Apply some statistical test (f2 test) for comparing dissolution profiles No biostudy... 

Notification of site change Stability Application/ compendial requirements No biostudy... 

Table 4.2. General Compendial Requirements for the Basket and Paddle Apparatus... 

The table shows that without a harmonized monograph, material that is marketed in Europe, Japan, and the United States would require 37 individual tests to be compliant. However with the harmonization draft, industry may comply with compendial requirements in the three regions, with only 12 tests. In some cases, the... 

Excipients used in injectable formulations have to meet several stringent requirements. A positive identification test uniquely applicable to the excipients is required (e.g., infrared spectrophotometry and chromatography). It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or the limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications. Solvents or catalysts used in the excipient production process should be removed to appropriate levels. If naturally derived, excipients should meet endotoxin levels and may require further testing for bovine spongiform encephalopathy (BSE) /... 

When the specification for a compendial excipient differs from the compendial monograph (e.g., additional tests, different analytical methods, or different acceptance criteria) the test results will be accepted from the excipient manufacturer s COA. However, the excipient should still conform to the monograph in an official compendium if there is such a monograph otherwise, justifications must be provided, and labeling needs to be changed to state plainly that the article does not meet the compendial requirement. 

Reconstitution. Times required for reconstitution and the appearance of the constituted solution are also of importance. The nature of the dried material as a result of lyophilization often yields a product that is highly hygroscopic. Reconstitution is often instantaneous on addition of the diluent. For ease of use in a clinical setting, reconstitution times are often less than 2 min. Whatever time is required to resolubilize that material, the constituted solution should be clear and free of any visible particulates or insoluble materials, meeting the compendial requirements such as those outlined within the USP [31]. 

At a minimum, other inactive ingredients used in the product should meet compendial requirements. These include ascorbic acid USP, ether USP, menthol USP, saccharin NF or USP salts of saccharin, and flavors. 

Dissolution document None beyond app. /compendial requirements... 

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. 

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