Good Manufacturing Practices

Good manufacturing practice (GMP) is that part of QA that is aimed at ensuring that radiopharmaceuticals are consistently manufactured or prepared and handled in hospitals to a quality appropriate to their intended use (Kristensen 1979 Nordic Council on Medicines 1989). It is concerned -with both manufacture or preparation in hospitals, and quality control (QC). The principles and guidelines of GMP for medicinal products have been laid do-wn in Council Directive 91/356/EEC, presented in volume IV of the European Regulations (European Economic Community 1997). 

QC is that part of GMP that is concerned with analytical testing, documentation, and evaluation to ensure that the quality of the radiopharmaceutical complies with the relevant standard (European Pharmacopeia [Ph. Eur.], (Council of Europe 2005). 

Surveillance is part of a QA program, designed to monitor quality of the radiopharmaceuticals as closely as possible. Drug defects and adverse reactions should be recorded and reported to national and/or international centers. All instances of unexpected biodistribution of radiopharmaceuticals in patients should be reviewed in order to detect whether any changes could have taken place in the quality of the radiopharmaceutical. If possible, the radiochemical purity of such a radiopharmaceutical should be determined. 

GMP is not product specific. It concerns how a quality system on the manufacturing of a certain kind of pharmaceutical should be set up (constructed), and what then in practice should be done to reach and maintain the construction quality in order to produce a product of satisfactory quality. 

The QC performed by the manufacturer of a ready-for-use product or a kit or the eventually performed QC in the hospital are not sufficient to ensure that the right quality is maintained. 

The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction, and purification), this rationale should be established on a case-by-case basis. Table 9 gives guidance on the point at which the API starting material is normally introduced into the process. 

From this point on, appropriate good manufacturing practice (GMP) as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that step as critical. 

Chemical manufacturing Production of the API Introduction of the Production of Isolation and Physical processing 

API derived from animal Collection of organ, fluid, or Cutting, mixing. Introduction of the API Isolation and Physical processing 

All equipment should be designed and constructed in a manner that prevents the retention of moisture (unless it is designed to deliberately stay full of sterile water), ingress and harbourage of vermin and soil and to facilitate inspection, servicing, maintenance and cleaning. 

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Blood transfusion is highly regulated worldwide by government institutions, such as the USFDA, and through associations of blood banks, such as the American Association of Blood Banks (AABB). Strict regulations on good manufacturing practices (GMP) have been estabhshed to ensure maximum safety of the transfused products. 

Lactic acid is generally recognized as safe (GRAS) for multipurpose food use. Lactate salts such as calcium and sodium lactates and esters such as ethyl lactate used in pharmaceutical preparations are also considered safe and nontoxic (7). The U.S. Food and Dmg Administration fists lactic acid (all isomers) as GRAS and sets no limitations on its use in food other than current good manufacturing practice (46). 

Two similar dosage forms, eg, tablets, that contain the same amount of the same dmg entity and meet USP/NF and current good manufacturing practices (FDA) are referred to as pharmaceutical equivalents (PE). When, upon adiriinistration, such tablets achieve similar profiles of AUC, and... 

Calibration. Cahbration of lab instmments is important to the accuracy of test results. CaUbration, the use of an accepted standard to adjust an instmment or measurement standard so as to improve the accuracy of the instmment or measurement, is an essential requirement of both the U.S. Food and Dmg Administration (FDA) Good Manufacturing Practice (GMP) (24) and the ISO 9000 standards (25). 

Quahty assurance must remain independent of manufacturing so that problems can be reported freely to upper management without fear of retribution. QA should have oversight responsibihty for QC. A reporting stmcture helps to ensure the independence of both quahty units and conforms to both Good Manufacturing Practice (GMP) and ISO 9000 requirements. 

Besides internal quaUty audits, there are audits conducted by external authorities for conformance to estabUshed quaUty systems. The two chief standards affecting the chemical industry are the U.S. Food and Dmg Administration Current Good Manufacturing Practice (GMP) regulation and the International Organization for Standardization ISO 9000 series. A quaUty system performance-related standard is the Malcolm Baldrige National QuaUty Award... 

Good Manufacturing Practice. The GMPs were issued by the U.S. FDA in 1978 to provide minimum quahty standards in the production of pharmaceuticals (qv) for the finished dosage form as well as their ingredients. The standard has been updated periodically. 

Current Good Manufacturing Practice for Finished Pharmaceuticals," Code of Federal Regulations, Tide 21, Part 211.25, U.S. FDA, Washington, D.C., 1988. 

Other offices within ODER may become involved in the review process via consults. Eor example, the Office of Epidemiology and Biostatistics analyzes statistical data, the Office of Research Resources provides bioavailabiHty reviews, and the Office of Compliance determines from the results of inspections whether the firms meet EDA s Current Good Manufacturing Practice (cGMP) regulations. Advisory committees composed of independent experts are often asked to meet and further analyze the data. Often they also advise as to what additional data and information may be needed. After PDA s review is completed, PDA issues either a Summary Basis of Approval (SBA) for the dmg or a recommendation against approval. If approved, PDA releases the SBA and a summary of the safety and effectiveness data to the general pubHc. 

Methyl salicylate is produced synthetically for commercial purposes by the esterification of salicylic acid with methanol or by extraction by steam distillation of wintergreen leaves or sweet birch bark. The source, natural or synthetic, is declared on the label. The methyl salicylate NF must assay not less than 98.0% and not more than 100.5% and be processed by Good Manufacturing Practice described in USP (20). 

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. 

Decaffeination Regulations. Eor decaffeinated roasted coffee, EEC standards indicate the maximum content of caffeine as 0.1% db for decaffeinated instant coffee it is 0.3% db. In the United States, decaffeination usually signifies that 97% of the caffeine has been removed. Permissible solvents for decaffeination processes are defined by national legislation, eg, EDA or EEC directive. The maximum residual solvent content after decaffeination, roasting, or instant coffee processing is to be kept within good manufacturing practice, ie, very low ppm levels or below at point of sale (46). 

No coloi additive oi product containing one can be used in the aiea of the eye, in surgical sutures, or in injections, unless so stated. Also, no colorant can be used to color foods for which standards of identity have been promulgated under Section 401 of the Federal Food, Dmg, and Cosmetic Act, unless the use of added color is authorized by the standard. Colorants without restrictions can be used for coloring foods generally, in amounts consistent with good manufacturing practice. 

FD C Red No. 40 shall conform to the following specifications and shall be free from impurities other than those named to the extent that such other impurities may be avoided by good manufacturing practice ... 

The use or presence of poisonous or deleterious substances in cosmetics and dmgs is prohibited. The presence of such materials makes the product "adulterated" or "misbranded" and in violation of good manufacturing practices (GMP), which ate appHcable to dmgs and, with minor changes, to cosmetics (6). 

Production Facilities. The manufacture of acceptable cosmetic products requires not only safe ingredients but also faciUties that maintain high standards of quaUty and cleanliness. Most countries have estabUshed regulations intended to assure that no substandard product or batch is distributed to consumers. Good Manufacturing Practices (GMP) represent workable standards that cover every aspect of dmg manufacture, from building constmction to distribution of finished products. GMPs in the United States that have been estabUshed for dmg manufacture are commonly used in cosmetic production (6,25). 

E-number and generic name, eg, lysozyme or glucose oxidase. AMEEP has defined Good Manufacturing Practice (GMP) for microbial food enzymes. 

If yes, additional review of good manufacturing practice and product quality requirements may be necessary. 

A division s system for compliance with ISO 9000 and/or Good Manufacturing Practice requirements... 

Current Good Manufacturing Practice for Finished Pharmaceuticals, Sampling and Testing of In-Process Materials and Drug Products, (1998), CFR, Title 21, Part 211, Volume 4, Section 211.110. 

Current Good Manufacturing Practices for Finished Pharmaceuticals, U.S. Food and Drug Administration, 21 CFR 210 and 211... 

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