Sterile Formulation

Michael J. Akers, CurtisS Strother, MarkR, Walden 

This chapter focuses on the preparing and filling of injectable solid bulk pharmaceutical formulations. The material presented is general in nature but with references to direct the reader to more in-depth treatment of the subject matter. Coverage includes sterile bulk product preparation. 

The solutions used for the dissolution of injectable products are prepared by using Water for Injection (WFI) USP that has been made as described in Ch. 13 of this handbook. In some cases, solutions are prepared using organic solvents (e.g., acetone, methanol, ethanol, isopropanol) alone or in combination with WFI. The potential for preventing microbial contamination should dominate the delivery and storage systems for water and solvents. 

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During the development of a sterile formulation of pirlimycin, a semisynthetic, veterinary lincosaminide antibiotic derived from lincomycin 4, three lots of material were subjected to thermal stress at 40°C for a period of 4 months, which led to the observation of a previously unreported degradant present at 0.2% [69]. 

The first nanoparticulate delivery system studied was Piloplex, consisting of pilocarpine ionically bound to poly(methyl)methacrylate-acrylic acid copolymer nanoparticles [44], Klein et al. [1,98] found that a twice-daily application of Piloplex in glaucoma patients was just as effective as three to six instillations of conventional pilocarpine eye drops. However, the formulation was never accepted for commercialization due to various formulation-related problems, including the nonbiodegradability, local toxicity, and difficulty of preparing a sterile formulation [208],... 

Fluorescein in solution is highly susceptible to bacterial contamination, especially by Pseudomonas aeruginosa, which grows easily in the presence of fluorescein. Major methods of reducing the possibility of bacterial growth include sterile formulation and air-tight seal of solutions (e.g., injection fluorescein), use of effective... 

Two comprehensive references are available that list type and concentration of all excipients used in commercial sterile formulations that should be part of every sterile formulation scientist s library. ... 

It is essential that the microbiological particle passage test is performed as part of the development of new sterile formulations. Because of its very specialized nature, the test is normally performed only by the filter manufacturers, who then provide limits for secondary physical tests (e.g., bubble point, pressure decay, forward flow, etc.), which can be applied to verify the pore size rating and integrity of the membrane filters. 

Commercial kits contain the freeze-dried, sterile formulation in a multidose vial, sealed under a nitrogen atmosphere. The lyophilized preparation is readily soluble in Tc-pertechnetate injection and in saline. For labeling, the vial is placed into a lead-shielded container. Aseptically sterile Tc-pertechnetate shonld be injected into the vial in a volume of 1-8 ml, with an activity up to 2.22 GBq (60 mCi). Before removing the syringe, 2-5 ml of gas should be withdrawn from the space above the solution to normalize the pressure inside the vial. The shielded vial should be agitated gently to dissolve the lyophilized material. The reaction should proceed at room temperature for about 20 min, with occasional agitation. 

In vitro labeling of RBC with " Tc-Na-pertechnetate. HematoCis (TCK-11) consists of two vials. Vial A contains a lyophilized, sterile formulation of 0.67 mg sodium pyrophosphate decahydrate and 0.01 mg stannous chloride dihydrate under nitrogen atmosphere. Vial B contains 10 ml of sterile saline under nitrogen atmosphere. Three milliliters of saline from vial B should be injected into vial A (this reducing solution must be used within 1 h). It should be stirred with a vortex for complete dissolution of freeze-dried material (Cis International 1985b). 

Amerscan Stannous Agent contains a freeze-dried, sterile formulation of 6.8 mg sodium medronate, corresponding to 5.4 mg medronic acid as disodium salt, and 4.0 mg stannous fluoride. Upon reconstitution with 6 ml saline, the recommended amount for adults (70 kg) by intravenous injection is 2 ml, corresponding to 1.8 mg medronic acid and 1.3 mg stannous fluoride. 

Enzymes produced by fermentation processes are recovered and refined through downstream processing into the slurry or paste form which can directly be used for industrial applications. For example, the concentrate from a polyethylene glycol (PEG) extraction step may directly be used if the enzyme is sufficiently pure and free of microbial contamination. In this case, the formulator must work closely with the recovery engineer to produce a clean and sterile formulation. The addition of a sterile filtration step prior to a concentration step, in a clean, sterile tank, might be all that is necessary to obtain the final product. Another option is to force the precipitation or crystallization of the enzyme and then disperse it into a formulation that is compatible... 

As with all therapeutic applications, aseptic techniques are necessary for production. It has been shown, using in vitro cell cultures, that both bacteria and fungi will readily colonize pSi, thus establishing a need for steriHzation prior to their use in clinical appHcations [77]. Although some preliminary studies on pSi sterilization, including autoclaving, have been presented, few reported data are available. Current clinical applications, which are limited to BioSilicon carriers, use irradiated products and a sterile formulant [93]. 

The major euthanasia agents used in veterinary medicines are the barbiturates and these have already been discussed in Chapter 5. When formulated for euthanasia, these products, and indeed other products used for this purpose, are not normally sterile unlike other parentally, and especially intravenously, administered formulations as this is considered unnecessary as the patients concerned will not recover from the effects of the drug and so the secondary effects of bacteria and other extraneous agents are irrelevant. The products are often frequently formulated with a dye to distinguish them from other similar but sterile formulations. Euthanasia agents differ from all other veterinary medicinal products in pharmacovigilance terms in that lack of efficacy, that is failure to cause death of the patient, is a reportable adverse event (lack of expected efficacy). 

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