28 Pharmaceutical Technology SEPTEMBER 2002 www.pharmtech.com

he advent of syringes dates back more than100 years, when in the 1850s AlexanderWood, a Scottish physician, and Charles

Gabriel Pravaz, a French surgeon, indepen-dently developed the signature drug adminis-tration implement with the hollow, pointedneedle. Despite generally being considered amedical device, when prefilled, the syringe alsoserves as a method of primary packaging.

Today, prefilled syringes provide product dif-ferentiation for a host of drugs and vaccines.

They are particularly com-patible with emergency andself-administered medica-tions because of their easeof use and immediate avail-ability. Prefilled syringesalso are well suited for hold-ing diluent for lyophilizeddrugs and eliminating thefirst step in the reconstitu-tion process.

Ben Venue Laboratories(Bedford, OH), a contractmanufacturer of sterilepharmaceuticals, designed a checklist to aid customerswho are transitioning to theuse of prefilled syringes.According to this checklist,

prefilled syringes offer numerous safety benefitssuch as tamper evidence, incompatibility withreuse, highly accurate dosing, and “reducedpotential for mixups, because the product can beclearly identified by labeling or printing on itsbarrel.” Ben Venue's closed filling system can accommodate glass or plastic syringes that can besupplied with needle shields (Schott PrefillableSyringe System, Schott Pharmaceutical Packag-ing, Inc., Cleona, PA). The syringe is producedfrom borosilicate glass to high tolerance stan-dards in diameter and thickness (Schott forma3s). Inert cycloolefin polymer imparts a glass-like transparency and a high chemical resistanceto the plastic syringe (Schott TopPac).

Prefilled syringe designs vary but tend to beoffered in both assembled needle and Luer Lock

configurations. Volumes generally range from0.5–10 mL. Because each syringe holds a unitdose, the labor and error potential inherent indose calculation and measurement are reduced.Less time spent handling the medication alsomeans less chance of exposure to particulates orother contamination as well as improved pro-ductivity for the administrator.

One caveat, according to the Ben Venuechecklist, is that “prefillable syringes are onlyappropriate when a dosage is to be uniformacross the entire patient base.” Compatibility issues can arise, particularly with designs thathave product contact parts made of steel, plas-tic, or silicone-coated glass. Latex parts also may pose a problem if used as part of the design. Finally, prefillable syringes may requiremore storage space and carry a higher pricecompared with single- and multiuse vials.

Ben Venue’s checklist advises adopting theprefillable syringe early in the drug develop-ment process, ideally during Phase II clinicaltrials so that no additional compatibility stud-ies are required. Delaying the adoption of aprefillable syringe until much later in theprocess will necessitate filing a packaging sup-plement. For products already on the market,converting to prefilled syringes will requirenew stability studies.

NeedlesticksNo doubt the first accidental needlestick occurrednot long after the syringe was invented. In theinterim, population growth, an ever-expandinguse of syringes and other sharp objects or“sharps,” and the emergence of deadly blood-borne viruses have combined to make needle-stick incidents far too frequent and a significanthazard for healthcare workers. In March 2000,the Centers for Disease Control (CDC, Atlanta,GA) estimated that 600,000–800,000 injuries peryear result from contaminated sharps. Accord-ing to data from CDC and the Exposure Preven-tion Information Network (EPINET) databasecoordinated by the University of Virginia(Charlottesville, VA), syringes are the mostcommon culprit of sharps injuries. Worse still,

New Syringe Designs CombinePrefilled Convenience with SafetyHallie Forcinio

Today’s bloodborne

diseases necessitate

that healthcare

providers and patients

alike be protected from

needle-related injuries

when administering

medications by prefilled

syringe.

T

Hallie Forciniois PharmaceuticalTechnology’s PackagingForum editor, 4708Morningside Drive,Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684,editorhal@cs.com.

PACKAGINGFORUMPACKAGINGFORUM

30 Pharmaceutical Technology SEPTEMBER 2002 www.pharmtech.com

several hundred of these injured health-care workers subsequently will becomeinfected with HIV or hepatitis B or C.

With the congressional passage in late2000 of the Needlestick Safety and Pre-vention Act and subsequent revision of the Bloodborne Pathogens Standardby the Occupational Safety & Health Administration (OSHA, Washington,DC), needlestick prevention is garneringeven greater attention.

Although it’s too early to determinewhether the revised Bloodborne Patho-gens Standard and various state laws related to needlesticks will reduce thenumber of injuries, one determinable reduction factor is the growing numberof safety syringes available in both con-ventional and prefilled configurations.

The National Alliance for the Primary

Prevention of Sharps Injuries (NAPPSI,Carlsbad, CA) divides needlestick safetyproducts into two groups: primary pre-vention and secondary prevention. Pri-mary prevention eliminates the needleor other medical sharp, and secondaryprevention adds a level of protection toany sharps in the workplace. “NAPPSI is focused on primary prevention,” saysexecutive director Brad Poulos. “Butsometimes you can’t eliminate the needlebecause the technology doesn’t exist; it’sstill developing.” For example, todayneedleless injectors are not suitable forsome vaccines or deeply injected drugs.

The operational key to needleless injectors is to send the liquid or powderthrough a tiny orifice with enough forceto penetrate tissue subcutaneously or,in some cases, intramuscularly. Most designs rely on interchangeable vials asthe repository for the medication (Bio-

jector 2000, Bioject, Inc., Rockland, MA;SyriJet Needleless Injector, Keystone Industries, Cherry Hill, NJ), but single-use designs are available and used. Manu-facturers of needleless drug delivery sys-tems are developing standards under theauspices of the Association of Needle-Free Injection Manufacturers (EastSyracuse, NY).

A prefilled, single-use needleless injector has been commercialized bothby Pharmacia Corp. (Peapack, NJ) forFragmin anticoagulation therapy and by GlaxoSmithKline (Research TrianglePark, NC) for Imigran/Imitrex migrainetreatment. The device is constructed ofa borosilicate glass ampul prefilled with�1 mL of product, an actuator or powersource, and the trigger mechanism.During use, the patient or caregiver re-moves the snap-off tip, tears the safetyband, and presses the device lightly butfirmly against the skin. The contact trig-gers the actuator and propels the drugsubcutaneously or intradermally. Dis-pensing typically requires less than 5 s.An ordinary trash receptacle can beused for disposal of the needle-free injector (Intraject, Weston MedicalGroup Plc, Cambridge, England).

A somewhat different needleless injec-tor is designed for dispensing powdersrather than liquids (Dermal PowderJectND-Disposable, PowderJect Technolo-gies, Fremont, CA). The unit relies onhelium gas to propel a premeasured doseof dry solid powder at a velocity suffi-cient to breach the skin. This deliverymethod is compatible with traditionalsmall molecules, peptides, proteins,vaccines, or DNA. In operation, when

Packaging Forum

To meet requirements of the Needlestick Safety andPrevention Act, OSHA revised its 1991 BloodbornePathogens Standard. Published in the Federal Registeron 18 January 2001, the new regulations (21 CFR1910.1030) took effect on 18 April 2001, althoughenforcement did not begin until 17 July 2001.

New provisions require employers to maintain asharps injury log, involve nonmanagerial employeesin an annual review and selection of safer needledevices, and update the organization’s writtenexposure control plan documenting the evaluationprocess and implementation of any new engineering

controls.The revised standard also clarifies what theoriginal meant by “engineering controls” by definingthe term as “e.g., sharps disposal containers, self-sheathing needles, safer medical devices such assharps with engineered sharps injury protections,and needleless systems.”

The standard applies to any employer whoseworkers are exposed to blood or other potentiallyinfectious materials.Workplaces with 10 or feweremployees are exempt from OSHA recordkeepingmandates and aren’t required to establish a sharpsinjury log.

OSHA Bloodborne Pathogens Standard

Top: SafetySyringe’s color-coded UltraSafeneedle guards can attach to most prefilledglass syringes.Above: The UltraSafe Passive DeliverySystem from SafetySyringe with passiveactivation combines compliance andprotection with a standard injectiontechnique.

32 Pharmaceutical Technology SEPTEMBER 2002 www.pharmtech.com

placed in position on the skin, anactuation pin breaks the tip of thehelium-filled microcylinder. Theforce of the escaping compressedgas opens the drug cassette anddelivers the drug.

Other suppliers are focusingon secondary protection andadding active or passive needle-shielding features to both standard

and prefilled syringes. Passive devices are considered by many to besuperior because the protective featureworks automatically without any inter-vention by the caregiver. Unfortunately,CDC data show about one-fourth of allneedlestick injuries occur in situationsin which a safety feature is present butnot activated.

One of the first promoters of a pre-filled safety syringe for a vaccine is GlaxoSmithKline. Compliant with theBloodborne Pathogens Standard, theGSK Safety Tip-Lok system (Tip-LokSyringe/BD SafetyGlide, Becton, Dickin-son and Co., Franklin Lakes, NJ) is usedfor pediatric doses of Havrix (hepatitisA vaccine inactivated) and Engerix-B(hepatitis B vaccine recombinant).When activated, a shield drops over the needle tip.

A retractable needle is the protectivefeature on a prefilled syringe with eithera prefixed needle or a Luer Lock (PrefilledSyringe, Apis Medical BV, The Hague,The Netherlands). The single-use designreportedly is inexpensive to produce,simple to assemble, and compatible withstandard injection systems.

Morphine sulfate from Amphastar(Rancho Cucamonga, CA) combines asafety needle with latex-free constructionfor a range of concentrations (Dilute-A-Jet Prefilled Syringe, InternationalMedication Systems, Ltd., South ElMonte, CA).

Various square-bodied, easy-to-gripneedle guards that are designed espe-cially for prefilled glass syringes and cartridges snap onto the barrel. Trans-

Packaging Forum

AlaskaArkansasCaliforniaConnecticutGeorgiaIowaMaineMarylandMassachusettsMinnesotaMissouriNew Hampshire

New JerseyNew YorkOhioOklahomaPennsylvaniaRhode IslandTennesseeTexasWest Virginia

— Centers for Disease Control

States that have adopted needle-safety legislation (as of June 2002)

Circle/eINFO 32

In March 2000, the

CDC estimated that

600,000–800,000 injuries

per year result from

contaminated sharps.

34 Pharmaceutical Technology SEPTEMBER 2002 www.pharmtech.com

parent plastic reveals cartridge and syringe markings, labels, and contents.Different colors designate different syringe sizes; e.g., yellow for 0.5 mL,purple for 1.0 mL, orange for 1.0 mLlong, blue for 1.5 mL, and red for 2.25mL. After the injection is given, theguard slides forward to cover the needleand locks into place (UltraSafe, Safety-Syringes, Inc., Carlsbad, CA).

Like their prefilled syringe counter-parts, medication cartridges also rely onsafety devices such as a protective sheath.The preplaced sheath is activated throughpressure against a flat surface after thecartridge has been inserted and the injection given (Needle-Pro for Carpu-ject Prefilled Medication Cartridges,Portex, Inc., Keene, NH).

FDA considers rulesFDA may expand its role in the fight toprevent needlestick injuries. On 20 June2002 the agency published an advancenotice of proposed ruling (ANPR) related to needle-bearing devices(Docket No. 01P-0120). On the basis of a petition filed jointly by Public Citi-zen’s Health Research Group (Washing-ton, DC) and the Service EmployeesInternational Union (Washington, DC),FDA is requesting comments about ban-ning i.v. catheters, blood collection de-vices (needles and tube holders), bloodcollection needle sets, glass capillarytubes, and needle-containing i.v. infu-sion equipment that do not meet thecriteria identified in FDA’s 16 April 1992 safety alert. The petition also asked FDA to issue performance stan-dards based on the five design criteriaidentified in its safety alert and requestedthat conventional syringes be labeledwith the statement “to prevent possibleexposure to HIV and hepatitis, do notuse for standard blood draws.”

FDA already has received many responses to the advance notice. Com-menting in favor of the ban, James Reedof Medamicus Inc. (Minneapolis, MN)

Packaging Forum

Circle/eINFO 34

About one-fourth of

all needlestick injuries

occur in situations in

which a safety feature

is not activated.

Schott Pharmaceutical Packaging’s forma3s prefillable syringes are made ofborosilicate glass.

Pharmaceutical Technology SEPTEMBER 2002 35

states, “Many healthcare providers [par-ticularly physicians] indicate that theywill only use safety products if andwhen they are forced to do so. . . . Until a complete ban on nonsafe devices isimplemented, the financial and humancosts of sharps injuries will continue tomount.”

A comment against the ban from Victor Kovner, PhD, of the Travelers Immunization Center (Studio City, CA)attributes needlestick injuries to “poortraining, poor habits, and the hurriedenvironment caused by a failed UShealthcare system. New devices and newregulations will only add to the burdenand cost without solving the problem.”

Beth Slingluff of Carondelet HealthNetwork (Tucson, AZ) believes a banwould cause shortages because manufac-turers of needleless and safety devices are already struggling to keep up withdemand. She also notes that new devicedesigns sometimes are incompatiblewith existing systems, rendering such aban impractical.

The deadline for comments aboutFDA’s ANPR is 19 September 2002.Electronic submissions may be made athttp://www.fda.gov/dockets/ecomments.

Meanwhile, the ECRI (formerly theEmergency Care Research Institute,Plymouth Meeting, PA) recommends“go needleless whenever you can.” Tohelp healthcare facilities learn what options are available, the group tests

Packaging Forum

In the article “Novel Approaches for Topical Delivery of Acetazolamide,” in our July2002 issue, the structure of acetazolamide in Figure 1 mistakenly was publishedwithout sulfur as a component.The correct figure is as follows:

We apologize for this error and any inconvenience or misunderstanding it mayhave caused.

Correction

Acetazolamide is N-(5-sulphamoyl-1,3,4-thiadiazol-2-yl)-acetamide

H2NO2S NHCOCH3

C4H6N4O3S2 MW = 222.24N N

S

and evaluates products and publishes aselection guide. The 2001 Sharps Safetyand Needlestick Prevention report isavailable for $195 for members ofECRI’s Health Devices System, Select-Plus, and Healthcare Risk Control System and $295 for nonmembers. PT