Parenteral products

Intravenous aqueous injections provide an excellent means of achieving a rapid therapeutic response. Parenteral product design, eg, vehicle and other excipient selection, as well as choice of route of adrninistration, can prolong therapeutic activity and increase onset times. Thus, oily solutions, suspensions, or emulsions can be adrninistered by subcutaneous or intramuscular routes to create prolonged effect, ie, depot injection (28). 

Commercially available containers for use with parenteral products include single-dose ampuls that are heat sealed and opened by snapping at the point of least diameter, vials for multidose use, and botdes and pHable bags that are used for large volumes such as needed in intravenous infusions. Container size can vary from 1 mL to 1 L. Generally volumes up to 100 mL are available as ampuls or vials. 

The industrial areas used for parenteral production call for careful design and conscientious maintenance of an aseptic environment (see... 

Although a broad range of P-lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid (12, R = CH2OH, R = H), manufactured by SmithKlinp Beecham, is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin [34787-01-4], C25H2gN20 S, has the trade name, Timentin. In 1990 worldwide sales of clavulanic acid containing products were about 725 million. 

Sulbactam (25, R = R = H, R" = R " = dl ) is produced by Pfizer. The oral version of sulbactam in combination with ampicillin is called Unasyn Oral which is the mutual prodmg sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone [62893-19-0] called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any P-lactam antibiotic as Betamaze. In 1990 worldwide sales of sulbactam containing products were over 280 million. 

Specific details of the sterility testing of parenteral products, ophthalmic and other non-injectable preparations, catgut, surgical dressings and dusting powders will be found in the British and European pharmacopoeias. 

Minimize use of narcotic analgesics wherever possible ° Enteral naloxone (parenteral product)... 

Parenteral product should be mixed with saline instead of dextrose diluents... 

In contrast, parenteral suspensions have relatively low solids contents, usually between 0.5 and 5%, with the exception of insoluble forms of penicillin in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intralesional, intraarticular, or subcutaneous injection. Syringeability is an important factor to be taken into consideration with injectable dosage forms. The viscosity of a parenteral suspension should be sufficiently low to facilitate injection. Common suspending vehicles include preserved isotonic saline solution or a parenterally acceptable vegetable oil. Ophthalmic and optic suspensions that are instilled into the eye/ear must also be prepared in a sterile manner. The vehicles are essentially isotonic and aqueous in composition. The reader should refer to Chapter 12 for further discussion on parenteral products. 

Like all parenteral products, parenteral emulsions are required to be sterile, isotonic, nonpyrogenic, nontoxic,... 

Large-volume parenterals designed to provide fluid (water), calories (dextrose solutions), electrolytes (saline solutions), or combinations of these materials have been described. Several other specialized LVP and sterile solutions are also used in medicine and will be described here, even though two product classes (peritoneal dialysis and irrigating solutions) are not parenteral products. 

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

Parenteral products should be formulated to possess sufficient buffer capacity to maintain proper product pH. Factors that influence pH include product degradation, container and stopper effects, diffusion of gases through the closure, and the effect of gases in the product or in the headspace. However, the buffer capacity of a formulation must be readily overcome by the biological fluids thus, the concentration and ratios of buffer ingredients must be carefully selected. 

Five sterilization processes are described in the USP steam, dry-heat, filtration, gas, and ionizing radiation. All are commonly used for parenteral products, except gas and ionizing radiation, which are widely used for devices and surgical materials. To assist in the selection of the sterilization method, certain basic information and data must be gathered. This includes determining... 

Dry heat is widely used to sterilize glassware and equipment parts in manufacturing areas for parenteral products. It has good penetration power and is not as corrosive as steam. However, heat-up time is... 

VIII. CLINICAL CONSIDERATIONS IN PARENTERAL PRODUCT DESIGN... 

The manufacture and sale of parenteral products is regulated by federal and state laws, as well as by the USP. Federal drug regulations are discussed in detail in Chapter 20. The USP provides specifications, test procedures, standards, etc. for parenteral products and their packaging components. In addition to individual monographs, the USP limits the use of certain additives (see Table 4), limits the size of multiple-dose containers to 30 mL, and requires a suitable preservative to be added to containers intended for multiple use. 

People are the principal source of contamination in clean room operations. All personnel involved throughout the development and production of a parenteral product must be aware of the factors that influence the overall quality of a product as well as the factors on which they directly impinge. It is of particular importance that production personnel be properly trained so that human error is minimized. They should be made aware of the use of the products with which they are involved and the importance of following all procedures, especially proper aseptic techniques. Procedures must be set up to verify that the product is being manufactured as intended. After manufacture of a batch, production tickets must be carefully checked, sterilization charts examined, and labels verified for correctness and count. 

Process controls include daily testing of water for injection (USP), conformation of fill doses and yields, checking and approving intermediate production tickets, and checking label identity and count. Finished product control includes all the tests necessary to ensure the potency, purity, and identity of the product. Parenteral products require additional tests, which include those for sterility, pyrogens, clarity, and particulate analysis, and for glass-sealed ampoules, leaker testing. 

The significance of particulate contamination in all parenteral preparations and devices has received much attention. Although it has not been established that particles can cause toxic effects, the pharmaceutical industry, the medical profession, hospital pharmacists, and FDA all realize the importance of reducing particulate levels in all parenteral products and devices. 

When oils are used as vehicles in ophthalmic fluids, they must be of the highest purity. Vegetable oils such as olive oil, castor oil, and sesame oil have been used for extemporaneous compounding. These oils are subject to rancidity and, therefore, must be used carefully. Some commercial oils, such as peanut oil, contain stabilizers that could be irritating. The purest grade of oil, such as that used for parenteral products, would be advisable for ophthalmics. 

Glass containers for small volume parenteral products Factors for selection and test methods for identification. Parenteral Drug Association Inc., Technical Methods Bulletin No. 3, 1982. 

In an industrial process, this large number of experiments is usually not a problem, since the process will be run over and over again. The application of this technique to tablets has been advocated by Rubinstein [7]. It has also been applied to an inspection system for parenteral products [8]. 

This section specifically concerns itself with filters that must be used that do release fibers. It is noted that an additional filter with a maximum pore size of either 0.2 or 0.45 pm must also be used to finish the filtration. This is an absolute requirement with asbestos filters used because of the total concept of safety and effectiveness of the drug. This section simply sets the time limit for instituting good filtration procedures for parenteral products. 

The incorporation of certain excipients in products is deemed to be undesirable. Examples are the inclusion of mercurial preservatives, the inclusion of benzyl alcohol in parenteral products for use in children, the use of benzoic acid esters in injections, and the inclusion of sulfites and metabisulfites in products in general. If it is intended to use any of these materials, then a full justification will be required. 

For parenteral products specific consideration needs to be included for tonicity adjustment, emulsion globule size, ease of resuspension and sedimentation rate, particle size and particle size distribution, viscosity and syringeability, and crystal form changes. Full consideration should be included of the proposed instructions for dilution or reconstitution of products and of compatibility with the proposed solvents or diluents. This should include a demonstration that the proposed storage temperature and extremes of concentration are suitable. 

The preservation efficacy aspects of parenteral products are particularly important for those products that are permitted to contain preservatives. This is not allowed for large-volume injections or for any product gaining access to the cerebrospinal fluid or for intra- or retro-ocular injection (according to the Ph Eur). Unpreserved products should be labeled to state this unequivocally. 

For nonparenteral/ophthalmic use the plastics should meet the requirements of relevant EU food use legislation, and if the material has not been so approved then toxicology data will be required. If the container is to be used for ophthalmic or parenteral products then compliance with the relevant requirements of the Ph Eur or other relevant member state pharmacopeial requirements will be required or appropriate additional data provided. 

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