Intravenous irons: practical and pharmaceutical aspects of glass ampoules versus single-dose vials Back

Abstract

Replenishment of body iron stores is a necessity for effective use of recombinant epoetin therapy in patients with chronic kidney disease. The clinical efficacy and safety of intravenous iron therapy is well documented in the medical literature. Currently available intravenous iron preparations are supplied in glass ampoules which require opening by breaking the neck of the ampoule prior to use. Whilst fulfilling high specifications for product stability and microbiological integrity, glass ampoules suffer from some important practical drawbacks. When the ampoule is opened, glass particles gain entry to the contents and may end up being injected into the patient. Opened ampoules are also a common cause of laceration injuries for nursing staff and physicians. This paper reviews the literature of the practical limitations of glass ampoules, and argues the case of the single-dose injection vial as a safer alternative.

Introduction and background

The introduction of recombinant epoetins in the 1980s transformed the treatment of anaemia in patients with chronic kidney disease (CKD), and epoetins are now an established part of the overall management of CKD. Iron therapy is an essential adjuvant to recombinant epoetin therapy to ensure that body iron stores are adequately replenished prior to and during therapy [Himmelfarb, 2005].

Whilst oral administration of iron therapy is deemed sufficient for CKD patients who have not yet begun dialysis, or who are on peritoneal dialysis (PD) [NKF/KDOQI, 2006; Mikhail, 2010], a recent systematic review and meta-analysis of randomised controlled clinical trials concluded that intravenous administration of iron is associated with a significantly better haemoglobin response compared with oral therapy at all stages of CKD, although the difference is less pronounced for non-dialysis patients [Rozen-Zvi et al, 2008]. A Cochrane review comparing oral and intravenous iron in adult and paediatric CKD patients is currently in preparation.

Like many other solutions and concentrates for intravenous injection, the currently available options for intravenous iron therapy are supplied in sealed glass ampoules. From a manufacturing and quality assurance point of view, glass ampoules are a highly convenient dosage form as they comprise a single, inert component, and ensuring sterility and physical stability of the product is a comparatively straight-forward task. However, from a healthcare practice point of view, glass ampoules have some drawbacks which may limit their use. This paper will review published reports of laceration injury from opened ampoules and/or particulate and microbial contamination of ampoule contents in the medical literature, and discuss the options for overcoming these risks with particular emphasis on novel formulations of intravenous iron therapy in single-dose rubber-capped glass vials.

Intravenous iron therapy in renal clinical practice

Intravenous drug administration is time consuming and therefore costly; hence when optimising the treatment of CKD patients it is necessary to take into account factors such as the dosage form and the practicalities of dispensing, administration and disposal. Currently available ampoule formulations of intravenous iron leave much to be desired in terms of both patient and user safety. Breaking ampoules open means there is a real risk of glass fragments ending up in the solution and in the worst-case scenario being injected into the patient’s bloodstream. The sharp edges of the broken glass also pose a risk of potentially severe injury to the nurse administering the treatment. An obvious and positive alternative to avoid the hazards associated with ampoules is to formulate injectable drugs in single-use, rubber-capped vials. Whilst multi-dose injection vials have been linked to a high levels of microbial contamination[Longfield et al, 1984; Arrington et al, 1990], single-use vials eliminate drug wastage and easily fulfil sterility requirements [Buckley et al, 1994].

A recent survey of the practical handling of ampoules versus single-dose rubber capped injection vials has been carried out in dialysis centres in the UK, France, Spain, Poland, Portugal and the Czech Republic [FME Data on File]. This survey involved 144 renal nurses who completed a 12-item questionnaire focusing on the preparation and administration of intravenous iron to patients with CKD. An overwhelming majority of the respondents (80%) prioritised the reduced risk of sharp injury as the most important advantage of formulating injectable drugs in vials rather than ampoules. In addition, 70% prioritised the reduced risk of contamination of the contents with vials compared with ampoules (Figure 1). Other factors that made respondents prefer single-dose vials over ampoules included a lower risk of stab injuries from needles with vials compared with ampoules, and 30% also mentioned the risk of spilling iron solution from ampoules and thus wasting drug and staining clothing and surfaces [FME Data on File].

Importantly, a majority of the respondents in the survey also estimated that using vials instead of ampoules will reduce the time needed to prepare the injection, with an expected time saving of at least 1/3 with vials compared with ampoules (Figure 2) [FME Dataon File].

Administration hazards

Injuries from needles and broken glass containers are common amongst healthcare professionals [Hanrahan and Reutter, 1997]. Several surveys from hospitals all over the world have shown that opening glass ampoules is one of the most common causes of injury to physicians and nursing staff.

An audit of a total of 97 anaesthetic sessions at the Bristol Royal Infirmary in the UK published in 1995 showed an overall incidence of hand lacerations due to ampoule opening of 6% (six cases); five of these cases occurred in trainee anaesthetists and one in a consultant. In 26% of the audited sessions, the anaesthetist showed evidence of old hand injuries [Parker, 1995].

These findings are consistent with the results of audits of healthcare professionals in Taiwan, and of professional and student nurses at teaching hospitals in Australia, Korea and Japan. In Taiwan, Guo et al reported an incidence of ampoule-related injury of 7.2%, most commonly sustained on patient wards or in the operating theatre [Guo et al, 1999]. More recent audits showed an incidence of ampoule-related injury of 4% amongst Australian student nurses [Smith and Leggat, 2005], and 35% and 32%, respectively, in professional nurses in Korea and Japan [Smith et al, 2006a; Smith et al, 2006b]. These studies also analysed specific risk factors and found that third-year nursing students had significantly higher rates of sharp injuries than first- and second-year students, whereas younger professional nurses and nurses working in small out-patient departments or on demanding night shift rotas were at significantly higher risk of sustaining a sharp injury [Smith and Leggat, 2005; Smith et al, 2006a; Smith et al, 2006b]. Figure 3 illustrates the devices predominantley causing injuries in the nursing field [Smith et al, 2005]

Data from the Thai Anaesthesia Incidents (THAI) study showed that the majority of sharp injuries reported by Thai anaesthesia nurses were caused by broken ampoules, and that sharp injuries were more common in regional and general hospitals than in university hospitals [Pulnitiporn et al, 2005].

In the recent survey of ampoules and vials discussed already half of the spondents reported having suffered an ampoule- or needle-related sharp injury in the last year; lacerations from opened ampoules occurred more than four times a year on average. The survey also showed that the practical handling of ampoules involve a greater number of hazardous preparation tasks compared with vials – not only is the breaking of the ampoule itself a potential hazard, but each subsequent step (dilution of the contents, aspiration, etc) will be potentially hazardous because of the exposed broken glass edges [FME Data on File].

In the clinical situation, healthcare professionals often attempt to protect themselves from hand lacerations and potential flying glass splinters that may cause eye damage, by wrapping the ampoule in a paper towel or gauze pad before opening. Deceptively simple, this is time consuming and makes manipulating the ampoule difficult, and also increases the risk of particulate contamination of the ampoule contents [Stoker, 2009].

In addition to the injury to individuals and the risk of transmission of infections between patients and healthcare professionals, there is a substantial cost to society associated with glass ampoules and the hazards these present. Isolated cases of severe injury have been reported. In one case, a laceration to the thumb required plastic surgery, and the injured anaesthetist reported persistent numbness [Ali, 1997]. In another similar case, the laceration only just missed the digital nerve of the injured thumb, and the anaesthetist was unable to work for seven days [Chandan, 2007].

The use of additional protective equipment to prevent sharp injuries from opened ampoules adds to the overall preparation time and introduces additional hidden costs to each procedure [Waller and George, 1986], as does discarding medications due to contamination from an injury where the skin barrier is broken. A variety of commercial protective tools and devices are available, designed to reduce the risk of injury to the user and prevent glass splinters from forming. However, such devices are likely to increase the overall treatment cost and the number of preparation steps involved. In the above survey, less than 20% reported that they use a protective tool for breaking open glass ampoules when administering intravenous iron [FME Data on File].

Risk of contamination of ampoule content

Sealed ampoules for parenteral drug formulations are most commonly made from glass. Empty ampoules are supplied to the production plant with open tops; once filled, the process of sealing the ampoule by fusing the top together reduces the air pressure inside the ampoule. Cutting the ampoule open at the neck will inevitably create microscopic glass shards; the difference in air pressure will cause these shards to be pulled into the ampoule, mixed with the contents, and subsequently administered to the patient [Borchert et al, 1986; Ernerot, 1993].

The hazard of glass particles contaminating ampoule contents is well known. A paper published in 1972 reported glass particles aspirated from opened ampoules of furosemide [Turco and Davis, 1972]; similar findings were reported the year after in an anaesthesiology clinic in California [Katz et al, 1973]. The author of a subsequent report of glass particles in solutions of local anaesthetics suggested that tissue injury and inflammation caused by injected glass particles may explain some neurological sequelae of regional anaesthesia [Furgang, 1974]. An investigation at the Royal Hospital for Sick Children in Edinburgh published in 1985 showed residual glass particles in ampoules of water for injection that had been snapped open by hand, some which were visible to the naked eye and could be aspirated through a 19-gauge hypodermic needle, a size which may potentially lodge in the pulmonary capillaries [Shaw and Lyall, 1985].

A randomised controlled study published in 1989 showed that the extent of glass particle contamination of ampoule contents is dependent on the type of glass used; ampoules made of transparent, metal-etched glass yielded significantly higher numbers of glass particles than ampoules made of amber glass or transparent ampoules with chemical scoring [Sabon et al, 1989]. A more recent report warned against ampoules with paint stripes on the neck to facilitate identification, after flecks of this paint had come unstuck from the glass and appeared in a solution for intrathecal injection [Glube and Littleford, 2000].

Other than the choice of glass, suggestions in the literature for overcoming the issue of glass particle contamination have included using a tool to snap open to ampoule rather than opening it by hand. However, a controlled study published in 1991 showed no significant difference in the number and size of glass particles aspirated through an 18-gauge needle when comparing ampoules opened by hand to ampoules opened using a commercially available ampoule opener Giambrone, 1999].

In-line filtration will reduce the risk of particles being injected when administering parenteral therapy [Preston and Hegadoren, 2004; Hemingway et al, 2007]; however, it should be borne in mind that such filters are expensive and add an additional step when nursing staff are preparing the injection or infusion, and also add a potential disconnection point. Microfilters may also restrict the delivery of colloid solutions and lipid suspensions, and certain drugs such as insulin may be retained in filters [Waller and George, 1986].

In addition to contamination by glass particles from the ampoule itself, once opened, the ampoule contents will be exposed to microbial and particulate contamination from the surrounding environment [Kempen et al, 1989; Oie and Kamiya, 2005; Yorioka et al, 2006]. Cleaning the outside of the ampoule with alcohol prior to opening may reduce the risk to some extent [Zacher et al, 1991; Hemingway et al, 2007]; however, the importance of careful aseptic procedures during intravenous drug delivery cannot be overstated [Pedler and Elliott, 1986].

Conclusion

This review clearly shows that a strong rationale exists to consider alternative formulations for injectable drugs, as the practical drawbacks with glass ampoules may have consequences with respect to safety and, as a result, cost. Not least do the results of the recent survey illustrate that this is an issue of considerable interest to healthcare professionals in the CKD field; as a vial formulation of iron sucrose is expected to be introduced shortly on the European CKD market, professional expectations will be set high both in terms of improving user and patient safety and increasing handling efficiency.

References

1. Ali PB. Persistent problem with propofol ampoules. Anaesthesia 1997; 52 (10): 1020

2. Arrington ME, Gabbert KC, Mazgaj PW, Wolf MT. Multidose vial contamination in anesthesia. AANA J 1990; 58 (6): 462–466

3. Borchert SJ, Abe A, Aldrich DS, Fox LE, Freeman JE, White RD. Particulate matter in parenteral products: a review. J Parenter Sci Technol 1986; 40 (5): 212–241

4. Buckley T, Dudley SM, Donowitz LG. Defining unnecessary disinfection  procedures for single-dose and multiple-dose vials. Am J Crit Care 1994; 3 (6):
448–451

5. Chandan GS. Propofol ampoule: take care while opening. The Internet Journal of Anesthesiology 2007; 12 (2)

6. Ernerot L. Particulate matter in parenteral products. In: Sandell E (Ed).Industrial aspects of pharmaceutics. Stockholm: Swedish Pharmaceutical Press, 1993

7. Fresenius Medical Care. Data on File.

8. Furgang FA. Letter: Glass particles in ampules. Anesthesiology 1974; 41 (5): 525

9. Giambrone AJ. Two methods of single-dose ampule opening and their influence upon glass particulate contamination. AANA J 1991; 59 (3): 225–228

10. Glube ML, Littleford J. Paint chips and glass ampoules. Can J Anaesth 2000; 47 (6): 601–602

11. Guo YL, Shiao J, Chuang YC, Huang KY. Needlestick and sharps injuries among health-care workers in Taiwan. Epidemiol Infect 1999; 122 (2): 259–265

12. Hanrahan A, Reutter L. A critical review of the literature on sharps injuries: epidemiology, management of exposures and prevention. J Adv Nurs 1997; 25 (1): 144–154

13. Hemingway CJ, Malhotra S, Almeida M, Azadian B, Yentis SM. The effect of alcohol swabs and filter straws on reducing contamination of glass ampoules used for neuroaxial injections. Anaesthesia 2007; 62 (3): 286–288

14. Himmelfarb, J. Hematologic manifestations of chronic kidney disease. In: Greenberg A, Cheung AK (Eds). Primer on kidney diseases (4th Ed). Philadelphia:
Saunders, 2005

15. Katz H, Borden H, Hirscher D. Glass-particle contamination of color-break ampules. Anesthesiology 1973; 39 (3): 354

16. Kempen PM, Sulkowski E, Sawyer RA. Glass ampules and associated hazards. Crit Care Med 1989; 17 (8): 812–813

17. Longfield R, Longfield J, Smith LP, Hyams KC, Strohmer ME. Multidose medication vial sterility: an in-use study and a review of the literature. Infect Control 1984; 5 (4):165–169

18. Mikhail A, Shrivastava R, Richardson D. Clinical practice guidelines: anaemia of CKD (5th Ed). UK Renal Association, February 2010

19. National Kidney Foundation. KDOQI clinical practice guidelines and clinical  practice recommendations for anemia in chronic kidney disease. NKF/KDOQI, 2006

20. Oie S, Kamiya A. Particulate and microbial contamination in in-use admixed parenteral nutrition solutions. Biol Pharm Bull 2005; 28 (12): 2268–2270

21. Parker MR. The use of protective gloves, the incidence of ampoule injury and the prevalence of hand laceration amongst anaesthetic personnel. Anaesthesia 1995; 50 (8): 726-729

22. Pedler SJ, Elliott TS. Ampoules, infusions and filters. Br Med J (Clin Res Ed) 1986; 292 (6530): 1275

23. Preston ST, Hegadoren K. Glass contamination in parenterally administered medication. J Adv Nurs 2004; 48 (3): 266–270

 24. Pulnitiporn A, Chau-in W, Klanarong S, Thienthong S, Inphum P. The Thai  Anesthesia Incidents Study (THAI Study) of anesthesia personnel hazard. J Med Assoc Thai 2005; 88 Suppl 7: S141–S144

25. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U.  Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and metaanalysis. Am J Kidney Dis 2008; 52 (5): 897-906

26. Sabon RL Jr, Cheng EY, Stommel KA, Hennen CR. Glass particle
contamination: influence of aspiration methods and ampule types. Anesthesiology 1989; 70 (5): 859–862

27. Shaw NJ, Lyall EG. Hazards of glass ampoules. Br Med J (Clin Res Ed) 1985; 291 (6506): 1390

28. Smith DR, Leggat PA. Needlestick and sharps injuries among nursing students. J Adv Nurs. 2005; 51 (5): 449–455

29. Smith DR, Mihashi M, Adachi Y, Nakashima Y, Ishitake T. Epidemiology of needlestick and sharps injuries among nurses in a Japanese teaching hospital. J Hosp Infect 2006a; 64 (1): 44–49

30. Smith DR, Choe MA, Jeong JS, Jeon MY, Chae YR, An GJ. Epidemiology of needlestick and sharps injuries among professional Korean nurses. J Prof
Nurs 2006b; 22 (6): 359–366

31. Stoker R. Preventing injuries from glass ampoule shards: advances in glass ampoule breakers. Managing Infection Control 2009; October: 45–47

32. Turco S, Davis NM. Glass particles in intravenous injections. N Engl J Med 1972; 287 (23): 1204–1205

33. Waller DG, George CF. Ampoules, infusions, and filters. Br Med J (Clin Res Ed) 1986; 292 (6522): 714–715

34. Yorioka K, Oie S, Oomaki M, Imamura A, Kamiya A. Particulate and microbial
contamination in in-use admixed intravenous infusions. Biol Pharm Bull 2006; 29 (11): 2321–2323

35. Zacher AN, Zornow MH, Evans G. Drug contamination from opening glass ampules. Anesthesiology 1991; 75 (5): 893–895