Parenterals testing

Pikal, M. I, and Lang, J. E. (1978), Rubber closures as a source of haze in freeze-dried parenterals Test methodology for closure evaluation, J. Parent. Drug. Assoc., 32, 162-173. 

Oxilorphan has been subjected to parenteral chronic toxicity and Phase I oral and parenteral testing. In a double-blind comparison of oxilorphan with cyclazocine 234 conducted at the Addiction Research Center at Lexington, Kentucky, oxilorphan was found to have an hallucinogenic potential one-fourth that of cyclazocine. 

Increasingly, plastics are being used as parenteral packaging (qv) materials. Plastics such as poly(vinyl chloride), polyethylene, and polypropylene are employed. However, plastics may contain various additives that could leach into the product, such as plasticizers (qv) and antioxidants. PermeabiUty of plastics to oxygen, carbon dioxide, and water vapor must be tested in the selection of plastic containers. Furthermore, the plastic should withstand sterilization. Flaking of plastic particles should not occur and clarity necessary for inspection should be present. 

For enzymes intended for parenteral use, the manufacturer must assure that the enzyme preparation is essentially pure and free of endotoxins. Electrophoretic and immunologic tests provide the requisite evidence of purity and homogeneity. Most importandy, the manufacturer must remove toxic impurities, eg, bacterial hpopolysacchati.de (endotoxins) which might cause severe toxic reactions such as anaphylactic shock, fever, and vascular coUapse. 

All preparations of enzymes intended for parenteral use are tested for safety in lower animals under the conditions anticipated in clinical trials ie, their use must be nonpyrogenic in the USP rabbit assay (255), and must be sterile. Such toxicologic studies are usually a prerequisite for approval by the FDA for the sale of such pharmaceuticals. 

More than half of the patients receiving this drug by the parenteral route experience some adverse reaction. Severe and sometimes life-threatening reactions include leukopenia (low white blood cell count), hypoglycemia (low blood sugar), thrombocytopenia (low platelet count), and hypotension (low blood pressure). Moderate or less severe reactions include changes in some laboratory tests, such as the serum creatinine and liver function tests. Other adverse reactions include anxiety, headache, hypotension, chills, nausea, and anorexia Aerosol administration may result in fatigue a metallic taste in the mouth, shortness of breath, and anorexia... 

Chitosan acetate and lactate salt films have been tested as wound-healing materials. Mechanical, bioadhesive and biological evaluation of the films were carried out. The results were compared to Omiderm . Chitosan lactate exhibited a lower tensile strength, however, it was more flexible and bioadhesive than chitosan acetate. Chitosan lactate and Omiderm did not cause any allergic reactions in contrast, chitosan acetate produced skin irritation clearly due to the anion. Nevertheless, no sign of toxicity was encountered when the extracts of three preparations were administered parenterally [244]. 

For parenteral use, the antibiotic is packed in sterile vials as a powder (reconstituted before use) or suspension. For oral use it is prepared in any of the standard presentations, such as film-coated tablets. Searching tests are carried out on an appreciable number of random samples of the finished product to ensure that it satisfies the stringent quahty control requirements for potency, purity, freedom horn pyrogens and sterility. 

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. 

Vitamin B12 (cyanocobalmin) administered both orally and parenterally is equally effective in treating anemia from vitamin B12 deficiency. However, use of parenteral cyanacobalamin is the most common method of vitamin B12 replacement because it may be more reliable and practical. Subcutaneous or intramuscular administration is appropriate. Vitamin B12 is absorbed completely following parenteral administration, whereas oral vitamin B12 is absorbed poorly via the GI tract. Furthermore, use of parenteral vitamin B12 to treat megaloblastic anemia may circumvent the need to perform a Schilling test to diagnose lack of intrinsic factor. 

Parenteral iron anaphylaxis (test dose required for iron dextran and observe for 1 hour after), injection-site pain/ irritation, arthralgias, myalgias, flushing, malaise, and fever... 

Iron-deficiency anemia in chronic PN patients may be due to underlying clinical conditions and the lack of iron supplementation in PN. Parenteral iron therapy becomes necessary in iron-deficient patients who cannot absorb or tolerate oral iron. Parenteral iron should be used with caution owing to infusion-related adverse effects. A test dose of 25 mg of iron dextran should be administered first, and the patient should be monitored for adverse effects for at least 60 minutes. Intravenous iron dextran then may be added to lipid-free PN at a daily dose of 100 mg until the total iron dose is given. Iron dextran is not compatible with intravenous lipid emulsions at therapeutic doses and can cause oiling out of the emulsion. Other parenteral iron formulations (e.g., iron sucrose and ferric gluconate) have not been evaluated for compounding in PN and should not be added to PN formulations. 

Large-volume parenterals (LVPs) and small-volume parenterals (SVPs) containing no antimicrobial agent should be terminally sterilized. It is common practice to include an antimicrobial agent in SVPs that cannot be terminally sterilized or are intended for multiple-dose use. The general exceptions are products that pass the USP Antimicrobial Preservative Effectiveness Test [1] because of the antimicrobial activity of the active... 

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. 

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. 

Particulate matter is defined in the USP as extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions. Test methods and limits for particulates are stated in the USP for large-volume injections and small-volume injections. 

M. J. Akers, in Parenteral Quality Control Sterility, Pyrogen, Particulate, and Package Integrity Testing, Vol. 1 (J. R. Robinson, ed.), Marcel Dekker, New York, 1985, pp. 207-209. 

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

It is recognized that physical and mechanical properties of a parenteral system affect seal integrity. However, physical and/or microbiological testing approaches may be used to challenge seal integrity or demonstrate that a seal has been achieved and is being maintained over the shelf life of the container system. 

Polyethylene and polystyrene are examples of plastics subject to environmental stress cracking. Crack resistance tests have shown that surfactants, alcohols, organic acids, vegetable and mineral oils, and ethers provide an active environment for stress cracking of polyethylene. Table 6 lists typical sterile devices and plastic materials used to fabricate them, while Tables 7-9 list the potential effects of sterilization processes on polymeric materials. The effect of gamma irradiation on elastomeric closures has been studied by the Parenteral Drug Association [15]. 

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. 

Aqueous products that are at greatest risk from microbial spoilage include solutions, suspensions, and emulsions for repeated oral, parenteral, or external use and include critical products such as multidose injections and eye drops. Unpreserved products without adequate antimicrobial efficacy should not be presented in containers intended for use on more than one occasion unless justified. When antimicrobial preservatives are used, their efficacy has to be demonstrated using the Ph Eur test for antimicrobial preservative efficacy. Factors to be taken into account in designing a preserved product include the nature of the preservative, its concentration in the product, the... 

---