Pharmacopeia requirements

The British Pharmacopoeia specifies a biological assay for the sodium salt of rifamycia SV [14897-39-3]. It also specifies a spectrophotometric assay for rifampicia (201). The United States Pharmacopeia requires an hplc assay for rifampin (202). 

As discussed above, testing to conform to pharmacopeia requirements may not be sufficient to assure excipient quality in the manufacture of low-dose formulations. Often, excipients make the bulk of the dosage form and if a dry blending and direct compression is utilized, the functional properties of excipients become even more critical compared to a granulation process. Typical functional properties to be tested for excipients include the following ... 

Pharmacopeias require that hard capsules be tested in the same apparatus as tablets even though they have very different physical properties. Filled capsules contain entrapped air, and most formulations will float on water. Devices are required to ensure that they sink, and these can influence the results obtained. Gelatin and hypromellose are adhesive materials and tend to block wire meshes that form part of the standard equipment. The way in which capsules disintegrate and dissolve is dependent upon several factors such... 

This makes it impossible to follow the European Pharmacopeia requirements for the number of containers to be tested (10% or 4, whichever is the greater), without preparing extra vials of the product specifically for the test, which is economically unrealistic and also imposes an additional radiation burden on to the operators. There are also problems with the volume of the product available for testing. The European Pharmacopeia states that if the quantity in the container is between 4 and 20 ml, which is common for technetium products, 2 ml should be used for each culture medium being tested. If followed strictly, this would mean a large reduction in the volume of material available for patient use. 

Radiochemical Purity. The European Pharmacopeia requires thin-layer chromatography (TLC) (distance 10-15 cm) for the identification of impurities using methylethylke-tone (MEK) as solvent. The radioactivity corresponding to Tc-HSA must not be less than 95% (Council of Europe 2005). 

The JnitedSfates Pharmacopeia (76) specifications for sodium monofluorophosphate require a minimum of 12.1% fluoride as PO F (theoretical 13.2%) and a maximum of 1.2% fluoride ion reflecting unreacted sodium fluoride. Analysis for PO F is by difference between total fluoride ia the product less fluoride ion as determined by a specific ion electrode. The oral LD q of sodium monofluorophosphate ia rats is 888 mg/kg. 

The US. Pharmacopeia (USP) specification for phenol includes (/) purity is to be no less than 98 wt %, (2) clear solubiUty of 1 part of phenol in 15 parts of water, (2) a congealing temperature to be not lower than 39°C, and (4) a content of nonvolatiles of no more than 0.05 wt %. Commercially, phenol specifications far exceed the USP requirement. Typical commercial phenol specifications are Hsted in Table 5. Higher purity material is required for some apphcations. 

Specifications. Table 10 shows the tests required to satisfy the demands of the Pharmacopeias of the United States, Europe, and Japan... 

Surgical sutures are sterile, flexible strands used to close wounds or to tie off tubular structures such as blood vessels. Made of natural or synthetic fiber and usually attached to a needle, they are available ia monofilament or multifilament forms. Sutures are classified by the United States Pharmacopeia (USP) (1) as either absorbable or nonabsorbable. The USP also categorizes sutures according to size (diameter) and Hsts certain performance requirements. Sutures are regulated by the Food and Dmg Administration (FDA) as medical devices under the Food, Dmg, and Cosmetics (FDC) Act of 1938, the Medical Device Act of 1976, and the Medical Device Reporting regulation of 1995. 

Benzoic acid is available in industrial and technical grades, and in grades meeting the specifications of the United States Pharmacopeia (18), the Pood Chemicals Codex (19), or the British Pharmacopeia (20). Typical specifications are Hsted in Table 5. Analytical methods required for testing to meet the specifications listed in regulatory texts are described in those texts. 

Calcium carbonate is one of the most versatile mineral fillers (qv) and is consumed in a wide range of products including paper (qv), paint (qv), plastics, mbber, textiles (qv), caulks, sealants (qv), and printing inks (qv). High purity grades of both natural and precipitated calcium carbonate meet the requirements of the Food Chemicals Codex and the United States Pharmacopeia and are used in dentifrices (qv), cosmetics (qv), foods, and pharmaceuticals (qv). 

Food and pharmaceutical grades of calcium carbonate are covered by the Food Chemicals Codex (7) and the United States Pharmacopeia (8) and subject to U.S. Food and Dmg Administration Good Manufacturing Practices (9). Both purity requirements and test methods are available (7,8). Calcium carbonate is listed in the U.S. Code of Federal Regulation as a food additive, and is authorized for use in both paper and plastic food contact appHcations. 

Water for injection (WFI) is the most widely used solvent for parenteral preparations. The USP requirements for WFI and purified water have been recently updated to replace the traditional wet and colorimetric analytical methods with the more modern and cost-effective methods of conductivity and total organic carbon. Water for injection must be prepared and stored in a manner to ensure purity and freedom from pyrogens. The most common means of obtaining WFI is by the distillation of deionized water. This is the only method of preparation permitted by the European Pharmacopoeia (EP). In contrast, the USP and the Japanese Pharmacopeias also permit reverse osmosis to be used. The USP has also recently broadened its definition of source water to include not only the U.S. Environmental Protection Agency National Primary Drinking Water Standards, but also comparable regulations of the European Union or Japan. 

Where there are existing pharmacopeial specifications for active ingredients in the Ph Eur or the pharmacopeia of a member state, these will be expected to apply. Other pharmacopeial specifications or in-house specifications may be used in other cases. The same is true for excipients where harmonized specifications are mentioned. Particular quality requirements related to a particular application are discussed, e.g., particle size control requirements. 

All bioassays are comparative in nature, requiring parallel assay of a standard preparation against which the sample will be compared. Internationally accepted standard preparations of most biopharmaceuticals are available from organizations such as the World Health Organization (WHO) or the United States Pharmacopeia. 

USP/NF Reagents that meet the purity requirements of the U.S. Pharmacopeia (USP) and the National Formulary (NF). Generally of interest to the pharmaceutical profession, these specifications may not be adequate for reagent use. 

Figure 7 The sinker required in the Japanese Pharmacopeia. (Courtesy of VanKel, a member of the Varian, Inc. Life Science Business, Cary, North Carolina, U.S.A.)...

All FDA-approved drugs products must meet the quality requirements described in the U.S. Pharmacopeia (USP) (1,2). If a drug product is to be manufactured elsewhere in the world but marketed in the United States, compliance with existing USP-NF monographs is crucial. Non-compliance may result in the FDA blocking entry of the product into the U.S. market or removing the product from the market. For other markets compliance with USP standards is not binding. For... 

Currently, the Japanese Pharmacopoeia (JP) is the only pharmacopeia that requires a specific sinker device for all capsule formulations. The USP recommends a few turns of a nonreac-tive material wire when the dosage form tends to float (12) (see Chapter 2 for illustrations of the Japanese and USP sinkers). Because sinkers can significantly influence the dissolution... 

Articulating the three concepts for harmonization was particularly important. Prospective and retrospective clarify the distinction between work required to avoid conflict when establishing standards for pharmacopeial articles for which standards do not exist, or where few standards exist among the pharmacopeias, from work required to reconcile differences among well-established standards for articles that may have been in the pharmacopeias for considerable time. Prospective harmonization was inaugurated for biotechnology-derived products. Retrospective harmonization focused on pharmaceutical excipients and analytical tests and methods. Forward harmonization expresses a philosophy and environment for harmonization consistent with advances in pharmaceutical analysis. 

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