Multi-dose vial: difference between revisions
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| Revision 5 — 07:19, 26 Feb 2025 CiteBot (talk) bot: normalise citation format 4,366 bytes ±0 | Revision 6 — 05:48, 11 Mar 2025 Chromatokid (talk) the example withdrew more than the syringe holds; corrected 7,432 bytes +3,066 | ||
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| 5 | | Requirement = Antimicrobial preservative, with effectiveness demonstrated | 5 | | Requirement = Antimicrobial preservative, with effectiveness demonstrated |
| 6 | | Default period after initial puncture = 28 days, unless otherwise specified | 6 | | Default period after initial puncture = 28 days, unless otherwise specified |
| + | 7 | <!-- Preservatives in injectable use --> | |
| + | 8 | | Benzyl alcohol = 0.9–2.0% w/v | |
| + | 9 | | m-Cresol = 0.15–0.32% w/v | |
| + | 10 | | Phenol = 0.25–0.5% w/v | |
| + | 11 | | Methylparaben with propylparaben = approximately 0.18% with 0.02% w/v | |
| + | 12 | | Thimerosal = 0.003–0.01% w/v; largely withdrawn | |
| 7 | }} | 13 | }} |
| 8 | 14 | ||
| ⋮ | ⋮ | ||
| 13 | The 28-day convention is frequently misread as a statement about chemical stability. It is not: it derives from the antimicrobial effectiveness of preserved formulations and from infection-control practice, and it is independent of whether the active substance remains within specification. A preparation may be chemically stable for a year and still be discarded at 28 days, and a preparation may lose potency well before 28 days despite its preservative performing perfectly.{{r|usp797,cdc_injection}} | 19 | The 28-day convention is frequently misread as a statement about chemical stability. It is not: it derives from the antimicrobial effectiveness of preserved formulations and from infection-control practice, and it is independent of whether the active substance remains within specification. A preparation may be chemically stable for a year and still be discarded at 28 days, and a preparation may lose potency well before 28 days despite its preservative performing perfectly.{{r|usp797,cdc_injection}} |
| 14 | 20 | ||
| + | 21 | Documented outbreaks of blood-borne and bacterial infection traced to multiple-dose vials have been reported repeatedly, almost always from practices that reuse a syringe or needle to re-enter a vial rather than from failure of the preservative itself. This distinction — between the container as a vector and the container as a reservoir — shapes the infection-control guidance and explains why that guidance concentrates on the syringe.{{r|fischer2010,cdc_injection}} | |
| + | 22 | ||
| 15 | == Definition and compendial basis == | 23 | == Definition and compendial basis == |
| 16 | USP <659> distinguishes several container categories, and the distinctions govern labelling and use. | 24 | USP <659> distinguishes several container categories, and the distinctions govern labelling and use. |
| ⋮ | ⋮ | ||
| 22 | The requirement for a preservative in a multiple-dose container appears in the general requirements for injections, and the demonstration of effectiveness is by the antimicrobial effectiveness test in USP <51>. That test challenges the formulation with specified organisms — ''Staphylococcus aureus'', ''Pseudomonas aeruginosa'', ''Escherichia coli'', ''Candida albicans'' and ''Aspergillus brasiliensis'' — and requires defined log reductions at defined intervals over 28 days. For injectable products the criteria are the most demanding of the product categories the chapter defines.{{r|usp51}} | 30 | The requirement for a preservative in a multiple-dose container appears in the general requirements for injections, and the demonstration of effectiveness is by the antimicrobial effectiveness test in USP <51>. That test challenges the formulation with specified organisms — ''Staphylococcus aureus'', ''Pseudomonas aeruginosa'', ''Escherichia coli'', ''Candida albicans'' and ''Aspergillus brasiliensis'' — and requires defined log reductions at defined intervals over 28 days. For injectable products the criteria are the most demanding of the product categories the chapter defines.{{r|usp51}} |
| 23 | 31 | ||
| + | 32 | The 28-day duration of the test and the 28-day default period after puncture are related but not identical claims. The test demonstrates that the preservative system suppresses growth of a substantial deliberate inoculum over 28 days under laboratory conditions; the use period is a practice rule informed by that demonstration. Guidance is explicit that a manufacturer may specify a shorter period, and that a shorter period so specified governs.{{r|usp797,usp51}} | |
| + | 33 | ||
| + | 34 | == Antimicrobial preservatives == | |
| + | 35 | Preservatives used in injectable products are a small set, constrained by systemic toxicity at the concentrations required, by compatibility with peptides and proteins, and by the pH range over which they remain active. | |
| + | 36 | ||
| + | 37 | |+ Antimicrobial preservatives in injectable preparations | |
| + | 38 | | !Preservative | Typical concentration | Mechanism | Notes on peptide compatibility | | |
| + | 39 | |---|---|---|---| | |
| + | 40 | | Benzyl alcohol | 0.9–2.0% w/v | Membrane disruption | The preservative in bacteriostatic water; has been reported to promote aggregation of some proteins | | |
| + | 41 | | m-Cresol | 0.15–0.32% w/v | Membrane disruption; protein interaction | Used in insulin formulations, where it also stabilises the hexameric assembly | | |
| + | 42 | | Phenol | 0.25–0.5% w/v | Membrane disruption | Used in insulin and in some peptide products; similar structural role to m-cresol | | |
| + | 43 | | Methylparaben with propylparaben | approximately 0.18% with 0.02% w/v | Membrane and enzyme effects | Common in older products; activity falls at higher pH | | |
| + | 44 | | Thimerosal | 0.003–0.01% w/v | Organomercurial, thiol reactive | Largely withdrawn; reacts with free cysteine | | |
| + | 45 | | Chlorobutanol | 0.5% w/v | Membrane disruption | Volatile; loses concentration on storage | | |
| + | 46 | ||
| + | 47 | Concentrations are those conventionally used in marketed injectable products; the effective concentration is formulation-specific and must be demonstrated for the product rather than assumed from the class.{{r|usp51,brange1993}} | |
| + | 48 | ||
| 24 | == References == | 49 | == References == |
| 25 | {{reflist}} | 50 | {{reflist}} |
| ⋮ | ⋮ | ||
| 28 | <ref name="usp797">United States Pharmacopeia, General Chapter <797>, "Pharmaceutical Compounding — Sterile Preparations", 2023 revision.</ref> | 53 | <ref name="usp797">United States Pharmacopeia, General Chapter <797>, "Pharmaceutical Compounding — Sterile Preparations", 2023 revision.</ref> |
| 29 | <ref name="cdc_injection">Centers for Disease Control and Prevention. ''Guide to Infection Prevention for Outpatient Settings: Minimum Expectations for Safe Care'', and associated injection-safety questions and answers on multi-dose vials.</ref> | 54 | <ref name="cdc_injection">Centers for Disease Control and Prevention. ''Guide to Infection Prevention for Outpatient Settings: Minimum Expectations for Safe Care'', and associated injection-safety questions and answers on multi-dose vials.</ref> |
| + | 55 | <ref name="fischer2010">Fischer GE, Schaefer MK, Labus BJ, et al. "Hepatitis C virus infections from unsafe injection practices at an endoscopy clinic in Las Vegas, Nevada, 2007–2008." ''Clinical Infectious Diseases'' 51(3):267–273 (2010).</ref> | |
| + | 56 | <ref name="brange1993">Brange J, Langkjaer L. "Insulin structure and stability." ''Pharmaceutical Biotechnology'' 5:315–350 (1993).</ref> | |
| 30 | 57 | ||
| 31 | {{DEFAULTSORT:Multi-dose vial}} | 58 | {{DEFAULTSORT:Multi-dose vial}} |