Documentation parenteral

The formulation of a RTA product should be based on currently available information on active substance stability and compatibility (see Sect. 22.6). Definition of specific characteristics is relevant for the design and description of a RTA product. In several European countries this information is included a locally, regionally or nationally standardised document Parenteral Manual... 

Parenteral iron therapy may be appropriate in cases where patients are unable to tolerate the oral formulation because of toxicities or compliance. In addition, those who have documented iron-deficiency anemia and have not responded to... 

Parenteral iron therapy currently is available in three different formulations, which are listed in Table 63-3. Iron dex-tran was the first parenteral iron formulation to be approved, followed by ferric gluconate, and then iron sucrose. Although these newer agents are only approved by the Food and Drug Administration (FDA) to treat anemia associated with CKD in patients receiving erythropoietin products, they are effective in treating iron-deficiency anemia as well. Iron dextran is FDA approved for treating documented iron deficiency in patients who are unable to tolerate the oral formulation. 

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],... 

As has been pointed out earlier in this chapter, the dietary consumption and historical medicinal use of carotenoids has been well documented. In the modern age, in addition to crocin, 3.7, and norbixin, 3.8, several carotenoids have become extremely important commercially. These include, in particular, astaxanthin, 3.6 (fish, swine, and poultry feed, and recently human nutritional supplements) lutein, 3.4, and zeaxanthin, 3.3 (animal feed and poultry egg production, human nutritional supplements) and lycopene, 3.2 (human nutritional supplements). The inherent lipophilicity of these compounds has limited their potential applications as hydrophilic additives without significant formulation efforts in the diet, the lipid content of the meal increases the absorption of these nutrients, however, parenteral administration to potentially effective therapeutic levels requires separate formulation that is sometimes ineffective or toxic (Lockwood et al. 2003). 

In penicillin-allergic patients, oral or parenteral clindamycin may be used. Alternatively, a first-generation cephalosporin such as cefazolin (1 to 2 g IV every 6 to 8 hours) may be used cautiously for patients who have not experienced immediate or anaphylactic penicillin reactions and are penicillin skin test negative. In severe cases in which cephalosporins cannot be used because of documented methicillin resistance or severe allergic reactions to /1-lactam antibiotics, IV vancomycin should be administered. 

Title 21 Code of Federal Regulations (21 CFR Part 11), Electronic Records Electronic Signatures, FDA, 2003 (http //www.fda.gov). Validation/compliance documents found under the Parenteral Drug Association (PDA) (http //www.pda.org). 

One must also stress the importance of quality considerations during compounding and full adherence to current good manufacturing practices while producing parenteral products. Personnel responsible for the process design and scale-up of the equipment must assure proper documentation... 

Parenteral therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone. This includes patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, various postgastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, and malabsorption syndromes. 

A few years ago, the Parenteral Drug Association (PDA) Task Force on Cleaning issued a Points to Consider document [10] that enumerated various types of s amplings currently in use in the industry. They were (at that time)... 

Aspartame is GRAS listed, and is accepted as a food additive in Europe and is in the FDA Inactive Ingredients Guide. It is included in non-parenteral medicines licensed in the UK, and is listed in the USP-NF, BP, JP, and EP. Aspartame is the subject of a monograph in the Food Chemicals Codex issued by the National Academy of Sciences. This document is very similar to the corresponding USP-NF monograph. 

Several cases of ricin exposure via parenteral routes were documented. A 20-year-old man was admitted to the hospital 36 h after subcutaneously injecting castor bean extract. Symptoms were characteristic of nausea, weakness, dizziness, and myalgias. He developed anuria and hypotension, followed by hepatorenal and cardiorespiratory failure, and died 18 h following admission. In another report, a 36-year-old chemist extracted ricin from a castor... 

The side effects observed in the clinic with the early 100% and 90% w/v concentrated PFOB formula-tions and with Oxyfluor consisted of early effects, during or shortly after infusion, including headache and occasional lower backache, and delayed effects (2-12 h), referred to as flu-like symptoms e.g., fever, occasional chills and nausea.These reactions, generally categorized as mild, were transient and fully reversible within 4-12 h. A transient, moderate drop (about 15%) in platelet count was seen about 3 days after dosing. Similar effects have been documented for parenteral fat emulsions and liposomes, indicating that these effects were likely related to the particulate nature of the emulsion. 

The Guide to Inspections of High Purity Water Systems, Guide to Inspections of Lyophilization of Parenterals, and also the CGMP document 212.721 Filters state the following ... 

There are no standard methods for verifying microbiological integrity of container-closure systems. Documents such as that published by the Parenteral Society in 1992 ° and the PDA in 1998 may be helpful in relating microbiological integrity to secondary physical tests, but they do not specify detailed microbiological test methods. 

This guideline has been the most influential document in LAL testing to date. Annual updates of the Appendix E, endotoxin limits for established parenteral products, were published by the FDA until 1994. With the upgrades in test procedures and endotoxin limits published in individual product monographs, the FDA no longer has a need to revise the 1987 guideline. 

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