By H. Uruk. Dowling College. 2018.

When account for the solubility characteristics of the drug sub- validating a suspension manufacturing process discount benicar 20 mg amex hypertension in the elderly, determine stance; inadequate controls can adversely affect product how to ensure that the product remains homogeneous dur- potency cheap benicar 40 mg on line blood pressure chart 60 year old, efficacy, and safety. For example, in one instance, ing the filling process and establish the data that support residual water remaining in the manufacturing vessel, used the adequacy of the firm’s process. When the batch size is to produce an ophthalmic ointment, resulted in partial large and the bulk suspension is in large tanks, determine solubilization and subsequent recrystallization of the drug how the low levels of bulk suspension near the end of the substance; the substance recrystallized in a larger particle filling process are handled. If the bulk suspension drops 87 88 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products below a level, can this be adequately mixed? This question It is therefore important that the following consider- must be answered. If the residual material transferred to a ations be adequately addressed in a cleaning validation smaller tank, how is the reliance made on handmixing of protocol and in the procedures that are established for the residual material? Heat identify equipment, cleaning methods, solvents and may also be generated by the action of high-energy mix- detergents approved for use, inspection and release ers. It is important to control the temperature within spec- mechanisms, and documentation. For some of the more ified parameters, not only to facilitate those operations but complex systems, such as clean-in-place systems, it is also to ensure that product stability is not adversely usually necessary both to provide a level of detail that affected. Excessive temperatures may cause physical or includes drawings and to provide provision to label chemical degradation of the drug product, vehicle, active valves. The time that may elapse from completion of a ingredient or ingredients, or preservatives. Furthermore, manufacturing operation to initiation of equipment excessive temperatures may cause insoluble ingredients to cleaning should also be stated where excessive delay may dissolve, reprecipitate, or change particle size or crystal- affect the adequacy of the established cleaning proce- line form. For example, residual product may dry and become Temperature control is also important where microbial more difficult to clean. As part of the validation of the cleaning method, the However, elevated temperatures may also promote incu- cleaned surface is sampled for the presence of residues. Sampling should be made by an appropriate method, Temperature uniformity within a mixer should be selected on the basis of factors such as equipment and controlled. For example, representative swab- should consider the complex interaction among vat size, bing of surfaces is often used, especially in areas that are mixer speed, blade design, viscosity of contents, and rate hard to clean or where the residue is relatively insoluble. Where temperature control is critical, use Analysis of rinse solutions for residues has also been of recording thermometers to continuously monitor and shown to be of value where the residue is soluble or document temperature measurements is preferred to fre- difficult to access for direct swabbing. Where temperature control is not useful when there is a direct measurement of the residual critical, it may be adequate to manually monitor and substance. However, it is unacceptable to test rinse solu- document temperatures periodically by use of handheld tions (such as purified water) for conformance to the purity thermometers. This is especially critical where contamination establish appropriate limits on levels of post–equipment- may present direct safety concerns, as with a potent drug cleaning residues. The rationale for residue limits should some equipment, such as mixing vessels, pipes, and plastic be established. Often piping and transfer lines form, it should be recognized that a detected residue level are inaccessible to direct physical cleaning. Some firms may not represent the maximum amount that may be address this problem by dedicating lines and hoses to present. This is particularly true when surface sampling specific products or product classes. The extent of microbiological controls needed for a given Other methods of controlling deionizing systems topical product will depend on the nature of the product, include establishment of water-quality specifications and the use of the product, and the potential hazard to users corresponding action levels, remedial action when micro- posed by microbial contamination. Microbiological Specifications that manufacturers assess the health hazard of all organ- and Test Methods isms isolated from the product. Deionizers tions should cover the total number of organisms permitted, are usually excellent breeding areas for microorganisms. The microbial population tends to increase as the length These specifications must be based on use of specified of time between deionizer service periods increases. Where appropriate, factors that influence microbial growth include flow rates, the specifications should describe action levels where addi- temperature, surface area of resin beds, and, of course, the tional sampling or speciation of organisms is necessary. These factors should Manufacturers must demonstrate that the test methods be considered in assessing the suitability of deionizing and specifications are appropriate for their intended pur- systems where microbial integrity of the product incorpo- pose. Where possible, firms should use methods that iso- rating the purified water is significant. There should be a late and identify organisms that may present a hazard to suitable routine water monitoring program and a program the user under the intended use.

For the purposes of this sec- (ii) The fat content of the solids of a tion vinegar is considered to be acetic cold-pack cheese made from two or acid discount 10mg benicar otc blood pressure chart dr oz. The weight of each variety of "Cold-pack lll cheese" order 20 mg benicar otc pulse pressure vs heart rate, "lll cold- cheese in a cold-pack cheese made from pack cheese" or "lll club cheese", three or more varieties of cheese is not the blanks being filled in with the less than 15 percent of the total weight name or names of the varieties of of all, except that the weight of blue cheese used, in order of predominance cheese, nuworld cheese, roquefort by weight. These limits do not apply be designated "Cold-pack American to the quantity of cheddar cheese, cheese"; or when cheddar cheese, washed curd cheese, colby cheese, and washed curd cheese, colby cheese, granular cheese in mixtures which are granular cheese, or any mixture of two designated as "American cheese" as or more of these is combined with prescribed in paragraph (d)(2) of this other varieties of cheese in the cheese section. Such mixtures are considered ingredient any of such cheeses or such as one variety of cheese for the purpose mixture may be designated as "Amer- of this paragraph (a)(6). Wherever any word or state- contain substances prepared by con- ment emphasizing the name of any in- densing or precipitating wood smoke. The or any mixture of two or more of these, weight of each variety of cheese in the may be designated as "American cold-pack cheese food made with three cheese". These limits do not cheese or such mixture may be des- apply to the quantity of cheddar ignated as "American cheese". Such mixtures are considered as one variety of cheese for (a)(1) Cold-pack cheese food is the the purposes of this paragraph (a)(6). The full name of the hydrated cream, skim milk cheese for food shall appear on the principal dis- manufacturing, and albumin from play panel of the label in type of uni- cheese whey. Wherever dients used in cold-pack cheese food any word or statement emphasizing the are pasteurized or made from products name of (other than in an ingredient that have been pasteurized. When two or more of the following: Any prop- one or both such optional ingredients erly prepared fresh, cooked, canned, or is used, dioctyl sodium sulfosuccinate dried vegetable; any properly prepared complying with the requirements of cooked or canned meat. Rennet and/or or meats contain fat, the method pre- other clotting enzymes of animal, scribed for the determination of fat by plant, or microbial origin. Each of the in- kaese, is the food prepared by the pro- gredients used in the food shall be de- cedure set forth in paragraph (a)(3) of clared on the label as required by the this section or by any other procedure applicable sections of parts 101 and 130, which produces a finished cheese hav- except that enzymes of animal, plant, ing the same physical and chemical or microbial origin may be declared as properties. The milkfat content is not jected to the action of a lactic acid- less than 4 percent by weight of the fin- producing bacterial culture. One or ished food, within limits of good manu- more of the clotting enzymes specified facturing practice. The finished food in paragraph (b)(2) of this section is contains not more than 80 percent of added to set the dairy ingredients to a moisture, as determined by the method semisolid mass. The whey is drained from the cluding, but not limited to, milk or curd and the curd is cured for 2 or 3 substances derived from milk. It is then heated to a tempera- gredients used that are not derived ture of not less than 180 °F until the from milk shall serve a useful function hot curd will drop from a ladle with a other than building the total solids consistency like that of honey. The hot content of the finished food, and shall cheese is filled into packages and be used in a quantity not greater than cooled. One or more of the other op- is reasonably required to accomplish tional ingredients specified in para- their intended effect. The creaming graph (b)(3) of this section may be mixture shall be pasteurized; however, added during the procedure. The following terial starters, may be added following safe and suitable ingredients may be pasteurization. I (4–1–10 Edition) (1) The words "cottage cheese" which enzyme that produces equivalent curd shall appear in type of the same size formation, are added and it is held and style. The co- (2) The statement "not less than l agulated mass may be cut; it may be percent milkfat" or "l percent warmed; it may be stirred; it is then milkfat minimum", the blank being drained. The curd may be washed with filled in with the whole number that is water and further drained; it may be closest to, but does not exceed, the ac- pressed, chilled, worked, seasoned with tual fat content of the product. This salt; or statement of fat content shall appear (ii) Food grade phosphoric acid, lac- in letters not less than one-half of the tic acid, citric acid, or hydrochloric height of the letters in the phrase spec- acid, with or without rennet and/or ified in paragraph (c)(1) of this section, other safe and suitable milk-clotting but in no case less than one-eighth of enzyme that produces equivalent curd an inch in height. The curd is on the label so conspicuously as to be washed with water, stirred, and further seen under customary conditions of drained. It may be pressed, chilled, purchase, the statement specified in worked, seasoned with salt. The cept that milk-clotting enzymes may coagulated mass may be cut; it may be be declared by the word "enzymes". It con- centrated skim milk or nonfat dry tains not more than 80 percent of mois- milk is used, water may be added in a ture, as determined by the method pre- quantity not in excess of that removed scribed in §133. The curd may be milkfat" which shall all appear in let- pressed, chilled, and worked and it may ters not less than one-half of the be heated until it becomes fluid.