Packaging / Drug Delivery / Aseptic Processing / QRM Process

Safety Guides New Syringe Designs

Global efforts driving safer syringes for developing nations are spurring interest in new single-use, auto-disable syringes. Parenterals manufacturers should be prepared and evaluate the new designs with new products.

By Don Gerson, President, Axenic, Inc.

The World Health Organization (WHO), the Red Cross and the Safe Injection Global Network (SIGN) are supporting programs to improve injection safety worldwide. In developing nations, 10 billion syringes are used each year, but unfortunately, unsafe injection practices are common and cause at least 1.3 million deaths and 10 million cases of hepatitis annually.

WHO recommends single-use, auto-disable (AD) syringes and is attempting to eliminate the use of traditional syringes as soon as possible. A worldwide effort to improve injection safety is being coordinated by SIGN with the guiding principle that a safe injection should not harm the recipient, the healthcare worker administering the injection, or the community at large.

Abandoning traditional barrel-plunger-needle syringes in favor of auto-disable technologies offers an effective way to solve a major problem that is difficult to control procedurally. However, the new designs will require efficient device manufacturing technologies, effective sterile filling equipment and extensive testing.

Although new designs have not yet penetrated the market, purchasing contract requirements by large organizations like UNICEF or PAHO may force parenterals suppliers to adopt new technologies. A proactive approach, and close evaluation of alternatives, can pay off.

This article will review hollow-needle type AD injection devices, and discuss the manufacturing issues and challenges they pose.

Scoping the problem

In developed nations, disposable plastic syringes have been in widespread use for 30 years, virtually eliminating re-use in a professional medical setting.

In developing nations, however, the cost of a new, sterile syringe and needle is often enough to prevent the use of vaccines and legitimate therapeutic drugs. When the vaccine or drug is available in a multidose form, economic realities mean that all too often unclean and unsterilized syringes and needles will be reused, and spread disease.

Some solutions to this problem are procedural. However, technical solutions, such as the following, promise to be much more effective:

  • Alternative injector design and methodology

  • Syringe plungers that lock once used

  • Plastic liquid compartments that collapse on use

  • Needles that can be used only once

  • Needle-free injectors based on high-velocity sprays — these can be extremely cost-effective, but permit aerosolization of the recipient’s bodily fluids, creating the possibility of cross-contamination [3].

  • Oral, inhaled or skin administration, via patches or inhalers — an approach that, other than its notable success with the oral polio vaccine, hasn’t worked with many vaccines.
Global standards

International standards also promise to help drive new technologies. The International Standards Organization, ISO, has addressed auto-disable injection devices through consultation with WHO, industry and other interested parties.

Its most current standard, ISO-7886-3-2005, provides specifications for syringe-like injection devices that deliver a known fixed dose, are of plastic and stainless steel construction and become non-functional once used. ISO-7883-4 deals with general purpose syringes with automatic re-use prevention. Injection devices meeting these standards can be used with multidose vials and, by their nature, will prevent re-use and the spread of blood-borne diseases.

Mandating specifications for bulk purchases based on internationally accepted standards will allow organizations such as UNICEF to meet their goal and encourage innovation and market development. The Global Alliance for Vaccines and Immunization (GAVI) has promoted the use of AD syringes, and from 2001 to 2004 has catalyzed the use of almost 1 billion AD syringes [5].

Injectables article: B-D Uniject syringe
The BD Uniject Prefill Injection Device. Courtesy of Becton, Dickinson and Co.

Filling and packaging of sterile injectable products requires specifically engineered facilities and highly specialized equipment. Sterile injectables are subject to high levels of regulatory scrutiny and are always a costly activity utilizing a highly trained workforce and considerable QA and QC support. Up to half of the cost of manufacturing traditional vaccines occurs during filling and packaging, as a combination of operational, container and packaging materials expenses.

Manufacturers have approached cost challenges by making multidose vials for use in developing nations. However, these designs pass on syringe costs to the user, and fail to address safety issues.

The amount of losses in use, important in the efficiency of mass vaccination programs, is moderate, and balanced between low overfills per dose and losses due to partially used vials. Providing AD syringes for each dose taken from a multidose vial should bring the actual cost to approximately the same as was intended. However, there may be operational issues related to matching the supply of AD syringes to the expected number of delivered doses.

Single-dose approaches using a vial and a separate syringe, whether the syringe is traditional or AD, add filling, packaging and shipping costs and may add to losses in use due to a higher overfill per dose. However, they reduce the possibility of vial contamination. Single-dose approaches using a pre-filled injector provide individual application, the least losses, and the greatest safety.

However, not all single-dose syringes are created equal. Prefilled traditional syringes are costly, create a waste-disposal problem and present opportunities for intentional re-use. Prefilled AD syringes of traditional design but with locking devices greatly reduce re-use, but do not offer any cost advantages. However, prefilled specialized AD injection devices such as Becton, Dickinson and Co.’s Uniject (photo) offer the possibility of high safety and a relatively reduced cost [4].

Changing to improved injection devices

Shifting final product container for an existing product is risky from a business perspective. Clearly, with the new designs, manufacturing costs would increase and it remains unclear whether the purchaser can or will bear the burden.

However, purchasing contract requirements by large organizations like UNICEF or PAHO may either force suppliers into new technologies or force them out of the market. Injection device standards will help to clarify the requirements without defining the device, splintering the market into a number of devices will inhibit volume-related reductions in the cost of the devices, and will be confusing to the ultimate user.

Changing the final container and delivery style of a product is a significant product development activity. Assuming the new AD injector is made of plastic and stainless steel, numerous studies will have to be performed to achieve product registration, including:
  • Product compatibility, leachability and stability studies, which must be performed on each product formulation;

  • Container integrity testing covering the range of temperatures and pressures that the final product may encounter;

  • If there is an applied label, adhesiveness studies and penetration or migration of adhesive components into the container and product must be performed at all manufacturing and storage temperatures and humidities, often with real-time stability studies that may last several years;

  • Container closure integrity and microbial ingress must also be evaluated before a product can be launched in a new container.
If the product is new, the risks of new product development must be combined with the risks and benefits of moving to a new container. The ideal time to consider a new container is during new product development, when all container studies must be performed for the first time. This approach allows formulation studies to be compared in different final product containers to minimize product-container interactions and maximize shelf-life.

However, if there is any indication of additional risk and that the container system could jeopardize the success of the new product, a traditional and well-known final container approach will be strongly favored. Ultimately, the best approach would be to do comparative studies early in the development of a new product, so that product development, commercial and social objectives converge on the best solution [4].

Many factors must be considered from a manufacturing perspective before it is possible to introduce alternate injector devices into a filling and packaging operation. To introduce a new filling line with a new container type takes a very considerable effort: market evaluation, planning, capital commitment, engineering, construction, facility start-up, validation, stability studies, regulatory inspection and product launch are only some of the activities required to be able to fill into a new final product container. Adaptation of an existing line to a modified final fill container is somewhat less effort, but consideration must still be given to line use allocation, validation and regulatory approval.

In terms of facility planning, filling and packaging space is cleanroom space and is very expensive to build and operate. In addition, there must be appropriate filling machinery that will fill the new AD injector device at economical speeds, providing economic return for the time-space utilization of the facility and equipment.

From an operational perspective, there must be a way to introduce pre-sterilized devices into the filling machine without contamination, to achieve consistent container closure integrity, to perform a 100% final container inspection with acceptable rates of particulate contamination discovery, and to achieve particulate generation controls that meet international regulatory standards.

Although new syringe designs pose a number of manufacturing challenges, evaluating them makes good business sense. It’s also the “right thing” to do, in helping stem the tide of iatric diseases in the developing world.



References
  1. Simonsen, L., et al. Unsafe Injections in the Developing World and Transmission of Bloodborne Pathogens: A Review. Bull. WHO, 77:789-800, 1999.

  2. Hutin, Y. and R. T. Chen. Injection Safety: A Global Challenge. Bull WHO 77: 787-788, 1999.

  3. Hutin, Y. and W. Dierick, WHO-ISO collaboration for the development of international standards for safer injection technologies, WSC Workshop, Geneva, Feb. 2004.

  4. Ekwueme, D. U., B. G. Weniger and R. T. Chen. Model-based estimates of risks of disease transmission and economic costs of seven injection devices in sub-Saharan Africa. Bull WHO, 80:859-870, 2002.

  5. Godal, T., Presentation at the 4th GAVI Board Meeting, December, 2004.

  6. Lloyd, J.S. and J.B. Milstein, Auto-Disable Syringes for Immunization: Issues in Technology Transfer, Bull. WHO, 77:1001, 1999.

  7. Dubin, C., Drug Discovery and Delivery: Tear Down Those Walls!, Drug Delivery Technology, 5: 28-32, 2005.


About the Author

Dr. Gerson is principal of Axenic, Inc., a global consulting firm specializing in process development, manufacturing, facility design and cGMP operations for the biopharmaceutical industries. He has worked as managing director for manufacturing and development at the International AIDS Vaccine Initiative, VP of manufacturing and development at Acambis, where he developed the process for and manufactured over 200 million doses of Smallpox vaccine. Prior to that, he worked as managing director of vaccine manufacturing at Wyeth-Lederle Vaccines, and before that, as VP of R&D at Apotex Fermentation, Inc., and as Assistant VP of manufacturing and process development for Connaught Laboratories in Toronto.

He has a Ph.D. in Biophysics from McGill University, has taught at the University of Western Ontario, and worked as an independent researcher at the Basel Institute for Immunology.

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