A growing preference for ready-to-administer vaccines: new guidelines, evidence, and trends

The Becton Dickinson Neopak syringe, one of the company’s latest offerings, was designed specifically for iopharmaceuticals. The prefillable device is manufactured with tighter dimensional tolerances to reduce silicone lubrication levels and less dead-volume space. Credit: BD

Beginning about 50 years ago, around the time the measles and polio vaccines were introduced, immunization began a subtle transition in the public’s mind from miracle cure to everyday necessity. As evidence of vaccination success grew with each new decade, families and insurers raised their expectations. Doctors and nurses demanded ever-higher levels of efficacy and safety. Advisory committees published schedules and guidelines.

And to a large degree, those heightened expectations and demands have now been met: Childhood vaccination programs are unquestionably one of the greatest achievements of public health.

But today, while one might think that the market for vaccines in developed countries is fully mature—with only limited room for improvement or innovation—a spirit of continuous improvement exists in many areas across the immunization enterprise, from programs to help drive increased coverage, to new delivery devices (for nasal and intradermal administration for example) and a renewed focus on best practices in storage, preparation and administration. And as it turns out, an important component of continuous improvement in preparation and administration is not only linked to the clinician’s practice routine or in the manufacturer’s vaccine formulation—but also in the humble vaccine container.

This article briefly reviews how vaccine packaging has shifted from an arguably lower priority to an important topic of discussion for healthcare organizations, public health agencies, and the many providers of immunizations including nurses, physicians, and pharmacists. More specifically, ready-to-administer prefilled syringes (PFS) are increasingly the preferred choice over multi-dose vials (MDVs) and single-dose vials (SDVs) for injectable vaccine and drug administration. As support, consider 1) the new best-practice guidelines from the US Centers for Disease Control (CDC); 2) recent published evidence of vaccine administration safety and efficiency; and 3) noteworthy trends in vaccine primary packaging choice and user (clinician) preferences.

The take-home message: A growing proportion of stakeholders in the vaccine marketplace—from patients, to clinicians, to payers, to policy makers—are paying attention to the impacts of injectable vaccine packaging on immunization program safety and efficiency, and this growing awareness is translating directly into increased usage of prefilled vaccines and drugs.

New CDC guidance

Greater awareness of potential problems with the practice of “predrawing” vaccines to save time has led the CDC to change its immunization guidelines. Predrawing—that is, filling a number of syringes from either a multiple-dose vial or a single dose at the same time and storing them for later use—is a practice employed in many busy immunization settings to help speed the process. But now, acknowledging the potential for error and contamination, the new (November 2012) CDC guidance reads as follows:

Manufacturer-filled syringes are recommended instead of predrawing vaccine. Manufacturer-filled syringes are labeled and prepared under sterile conditions that meet standards for proper storage and handling. They have been designed and tested to assure vaccine potency and sterility over prolonged storage times. As long as they are stored under appropriate conditions, manufacturer-filled syringes may be kept and used until their expiration dates unless contaminated. (www.cdc.gov/vaccines/recs/storage/toolkit/storage-handling-toolkit.pdf)

The heart of the issue for the CDC is consistency and safety. Their new recommendation seeks to shift the repetitive task of filling and properly labeling the predrawn syringe away from hundreds of thousands of nurses, physicians, pharmacists, nurse practitioners, medical technicians, etc. Instead, with PFS, the preparation/filling task is managed by the vaccine company—a consistent FDA-inspected, cGMP-compliant process that avoids the inherent variability found in the diverse predraw environments.

Driving these safety-related changes from the CDC as well as other organizations is the growing evidence base documenting exactly how variability in vaccine packaging and preparation may affect safety and reduce efficiency. Examples from this evidence base are discussed next.

A Johns Hopkins time-motion study

A 2010 time-motion study performed by The Johns Hopkins University Bloomberg School of Public Health demonstrated the safety and workflow advantages of PFSs. [1] Investigators observed over 1,500 vaccine injection preparations, and determined time differences and subsequent cost differences associated with the use of PFSs vs. MDVs. They also observed preparation and handling practices.

Investigators found that preparing a dose using MDVs took 37 seconds longer than with PFSs due to the increased number of steps required to prepare a vaccine packaged in a vial. Assuming standard costs for materials and labor, researchers concluded that administration via PFSs could save a clinic approximately $1,100 per 1,000 doses assuming the same price per vaccine dose.

More significantly, PFSs reduce the risks associated with deviation from best practices as established by the CDC. [2] For example, researchers observed the following with MDVs:

• Neglecting to write on a vial the date it was opened
• Not properly sterilizing the rubber stopper prior to withdrawing vaccine dose
• “Trusting” memory for transcribing lot number
• Predrawing the day before or using leftover predrawn syringes from a prior day
• Predrawn syringes were often left out (not refrigerated) for long periods of time and, in some cases, for a whole day
• Drawing vaccine from multiple vials, especially without checking if the lot numbers are the same [3]

By eliminating many preparation steps required with a vial, a prefilled syringe is simpler and easier to use. Vaccination workflow may be faster and smoother for clinicians and may improve speed of patient throughput.

An additional and important advantage offered by PFSs is that they come from the (vaccine) manufacturer labeled by the manufacturer. All too often, syringes predrawn from vaccine vials are left unlabeled, or are subject to variable labeling practices, clinic by clinic or perhaps even clinician by clinician.

As emphasized in the new CDC guidelines, this predrawing increases the risk of a wrong or improperly stored injectable vaccine being given; dosing errors also increase when a vaccine is prepared and labeled by hand. [4] Prefilled and prelabeled syringes can help avoid these errors and omissions, ensure accurate dosing, and offer clinics a ready-to-use safe and simple time-saving alternative to predrawing several vaccine syringes in advance.

What an insurer-backed group found

Variations from clinical best practices can be influenced by many different factors including experience, education, and “real-life” clinician scenarios (multitasking, distractions, work-flow pressure, etc.). While the vaccine enterprise in the US is considered safe, there have been cases, studies, and data developed that show errors in preparation and administration can occur.

In 2010, Premier Safety Institute conducted a study with more than 5,000 clinicians to understand the current injection practice patterns. This was done in response to “increasing reports of outbreaks in the US involving transmission of hepatitis B and C to patients associated with unsafe injection practices and breakdowns in basic infection control”. [5] An example of this occurred in the 2007—08 influenza campaign where a physician’s office in Long Island, NY was engaged in a practice of drawing six 0.5ml flu vaccine doses into a 3ml syringe and subsequently vaccinating six individuals with the same syringe and only changing the needle. [6]

The Premier study revealed that this practice may be more widespread than anticipated. Among study participants, 0.9% reported that they change the needle but reuse the syringe on multiple patients, 6% reported using single-dose or single-use vials for more than one patient, and 1.1% reused a syringe to enter a multi-dose vial and then save that vial for use on another patient. [7]

Citing CDC definitions of injection safety, the study authors concluded, “Our findings provide evidence that healthcare professionals continue to engage in unsafe injection practices, which represent an ongoing threat to patient safety in the United States and are devastating to all those patients who are impacted.”

Shifting market perspectives

Driven partly by evidence of the type just cited, and partly by market factors, decisionmakers in immunizations programs in developed countries have been steadily shifting to adoption of the PFS format. Consider two market factors accelerating that shift.

Evolving vaccination settings

The typical vaccination setting in the US is diversifying from the clinic/hospital to non-traditional settings such as retail, schools, and pharmacies. In the 2010—11 influenza vaccination campaign, nearly one in five adults received their flu shot in a retail setting. [8] Vaccinators in these new settings bring widely varying clinical experiences, education, and skills. At the same time, these new immunization enterprises, facing inescapable cost pressures, are seeking every opportunity to shave costs in delivering vaccinations.

These dual factors—a diversifying vaccine workforce and a push for program efficiency—have prompted immunization leaders to seek out new practices that standardize and simplify the vaccination process.

To this end, the vaccine package—which occupies an underappreciated space at the clinical interface between vaccine, patient, and caregiver—has been re-evaluated as a potential leverage point in vaccination safety and efficiency. And when considering the three main types of vaccine packages in use—prefills, multi-dose vials (MDVs), and single-dose vials (SDVs)—many clinician decisionmakers have elected to switch to the PFS format. The main reason: the unit-dose ready-to-administer vaccines essentially eliminate multiple steps that must be repeated flawlessly throughout the day. This simplification is critical since it allows immunization programs to neutralize much of the skillset and practice variability in their staff—in both traditional and emerging vaccination venues. Potential gains in efficiency with the PFS product are another important factor.

Growing user awareness

Both clinicians and patients have recently voiced opinions on vaccine packaging. Here is one comment on vaccine safety issues from a recent article in the American Journal of Infection Control:

“Although there is a clear need for more education, this may not necessarily eliminate all unsafe practices. Adopting principle from human factors engineering, we must consider redesigning devices, equipment, and processes to reduce or eliminate risk of bloodborne pathogen transmission.” [9]

This statement is consistent with FDA’s increasing requirements around the integration of Human Factors Engineering (HFE) and device design. HFE is the science and the methods used to make devices easier and safer to use … helping to improve human performance and reduce the risks associated with use. [10]

To better understand the user interface of clinician and various vaccine packages, and the associated potential for errors, a comprehensive study was conducted in 2011 by Interface Analysis Associates. [11] The researchers outlined the process of vaccine preparation from storage through disposal for the three vaccine package types, and then developed a list of all potential errors associated with each step. The study identified all distinct, significant operations within each risk category for potential contribution to risk.

The top five potential risk categories and number of associated potential that could cause them were determined as follows:

Risk Category

Distinct Operations

Contamination of Vaccine

43

Loss of Vaccine Integrity/Stability

26

Wrong Vaccine Dose Administered

25

Wrong Vaccine Administered

17

Expired Vaccine Administered

11

Furthermore, the study concluded that, in general, the more complex the particular workflow and the more risk factors involved, the more apparent were the benefits of PFSs compared with vials.

For example, of the 43 distinct operations determined for Contamination, both MDVs and SDVs were subject to 38 of these risk opportunities while PFSs were subject to only 23 of them. Similar differences were seen across the rest of the top five risk categories.

We can also relate the findings of the study to Six Sigma principles. Six Sigma principles are used to help mistake-proof products and/or processes and rely on the following general approaches:

• Eliminating the possibility of error
• Replacing a risky process with one that is more reliable
• Facilitating or making the task easier to perform
• Detecting errors before carrying out further operations
• Mitigating or minimizing the effects of error

In the user interface study, the number of distinct steps involved in delivering vaccine from the three packaging platforms—up to 50 for multi-dose vials, 45 for single-dose vials, and 28 for PFSs—suggests an advantage to the simpler PFS protocol. By eliminating the number of steps, there is less opportunity for error. For example, PFSs have a demonstrated advantage in contamination control because needle changes and drawing practice (and all the contamination potential those steps entail) do not occur with prefills. Similarly, replacing a highly variable step like syringe filling by a clinician with highly precise aseptic machine filling can help assure administration of the correct dose, as well as reduce the likelihood of contamination. Finally, opportunities for administering the wrong dose or expired vaccine are minimized by labels being automatically applied on every PFS by the manufacturer.

This thereby facilitates the task so it is easier, and provides a means of detection as the PFS reaches the end user and point of use with a label. Readily apparent labels also enable corrective protocols to be followed immediately in the event an incorrect drug or incorrect dosage is injected, thus mitigating further effects of the error.

Being pre-labeled, unit-dose and ready-to-administer, PFSs embody “safety-by-design” by inherent simplicity to use, elimination of several error-prone steps in vaccine preparation and administration, reduced opportunity for syringe reuse and cross-contamination, and assurance of the correct dose with every injection. Clearly printed peel-off labels on vaccine prefills facilitate recording of batch numbers and updating the patient’s immunization record.

In addition to the ready-to-use PFS vaccine format, it should be noted that there is a growing discussion around other PFS strategies aimed at improving best practices and minimizing the chance for errors. For example, for vaccines that require reconstitution, there is renewed interest in converting diluents from vials to PFS, an option that reduces some of the complexity around reconstitution. Furthermore, there is growing discussion across stakeholders in co-locating the diluent and lyophilized vaccine side by side in the same syringe, a technology that has been available for over a decade with other injectables (for example human growth hormone) but that would need to be adapted for the needs of the vaccine segment.

Comparing the US and Europe

Today, the vaccine market finds itself at a tipping point that involves packaging. The percent of US vaccines packaged in unit-dose, ready-to-administer formats is now approaching 40%, or almost double what it was seven years ago. This is entirely driven by the growing awareness and user demands based on the advantages afforded by PFS packaging formats. As a point of contrast, in Europe, these same vaccines are packaged in PFS at a level that exceeds 90%.

Further adoption of vaccines packaged in PFSs is expected to continue, for both new and currently marketed vaccines, particularly as clinicians and vaccine enterprise stakeholders look more closely at the implication of packaging at the user interface and understand the benefits PFSs offer in terms of greater efficiency and advancing best care.

Conclusion

The clinical and workflow benefits of PFSs compared with vials are clear. Preparing a dose of a vaccine, or any injectable, packaged in a unit-dose, ready-to-administer format is simply much easier than preparing a non-ready-to-use format whether single or multi-dose vial.

With their inherently simple design, prefilled syringes do not rely on consistently flawless user technique and aseptic practices to reduce injection-related risks. Instead, they completely eliminate the need for several of the preparation steps that open the door to avoidable risks and consume additional clinician time. They embody safety-by-design principles important when considering human factors and the user interface.

These simple but powerful changes in product packaging are taking a well-established and trusted class of products—injectable vaccines and drugs—and, in the spirit of continuous improvement, ratcheting up the efficiency standards and an already safe process to even higher levels.

ABOUT THE AUTHORS

All authors work at BD Medical-Pharmaceutical Systems, a unit of Becton Dickinson. Janice Adkins is marketing leader; Brian Lynch is program lead, health science and technology; and Philip Song is quality assurance staff engineer.

[1] Pereira, C.C. and Bishai, D. (2010). Vaccine presentation in the USA: Economics of Pre-filled Syringes Versus Multi-dose Vials for Influenza Vaccination. Expert Reviews 9(11): 1343-1349.

[2] The Pink Book — CDC, Epidemiology and Prevention of Vaccine-Preventable Diseases, Atkinson W, Wolfe S, Hamborsky J, eds, 12th ed. Washington DC, Public Health Foundation

[3] 2010 World Vaccine Congress, Washington DC. Presentation by Dr. David Bishai — Johns Hopkins University Bloomberg School of Public Health

[4] ACIP. MMWR. 2006;55 (RR15):1-48.

[5] Pugliese et al. Injection practices among clinicians in US health care settings. Am J Infect Control, 2010 Dec; 38(10):789-98.

[6] www.health.ny.gov/press/releases/2008/2008-01-15_health_department_alerts_patients_to_infection_control_error.htm, Accessed September 11, 2012

[7] Pugliese et al. Injection practices among clinicians in US health care settings. Am J Infect Control, 2010 Dec; 38(10):789-98.

[8] 2010—2011 Influenza Vaccine Production and Distribution Market Brief, HIDA, September 2011.

[9] Pugliese G et al, RN MS, Am J Infect Control, 2010: 387, 789.

[10] U.S. Food and Drug Administration. Medical Devices. General Human Factors and Resources: What is human factors/usability engineering? Accessed at www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/ucm124829.htm, September 11, 2012.

[11] Vaccine Primary Drug Container: Single-Dose, Multi-Dose, Pre-Filled Syringe Risks Analysis Report. Report on file at BD. Commissioned by BD.