Volume 35, Issue 17, 19 April 2017, Pages 2265–2271
Abstract below; full text is at http://www.sciencedirect.com/science/article/pii/S0264410X17300178
Exploring new packaging and delivery options for the immunization supply chain ☆
Received 22 September 2016, Revised 11 November 2016, Accepted 28 November 2016, Available online 30 March 2017
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A variety of vaccine packaging and delivery technologies may benefit the immunization supply chain. These include alternative primary packaging, such as blow-fill-seal polymer containers, and novel delivery technologies, such intradermal delivery devices, microarray patches, and sublingual formulations of vaccines, and others in development. The potential timeline to availability of these technologies varies and depends on their stage of development and the type of data necessary to achieve licensure. Some new delivery devices are anticipated to be introduced in 2017, such as intradermal devices for delivery of inactivated poliovirus vaccine to stretch vaccine supplies due to a supply limitation. Other new technologies requiring vaccine reformulation, such as microarray patches and sublingual vaccines, may become available in the long term (2021 and beyond). Development of many new technologies requires partnership between vaccine and technology manufacturers and identification of the applicable regulatory pathway. Interaction with public-sector stakeholders early on (through engagement with forums such as the World Health Organization’s Immunization Practices Advisory Committee Delivery Technologies Working Group) is important to ensure suitability for immunization program use. Key considerations for programmatic suitability of a new vaccine, packaging, and delivery device include cold chain volume, costs, and health impact.
In early 2016, 22 vaccines were recommended for delivery through the immunization supply chain (ISC) in low- and middle-income countries (LMICs)  as compared to the original four vaccines recommended against six diseases in 1974—vaccines against diphtheria, pertussis, tetanus, tuberculosis, poliomyelitis, and measles . As the number of vaccines delivered through the World Health Organization (WHO) Expanded Programme on Immunization (EPI) has increased, so has the overall ISC burden. Gavi, the Vaccine Alliance, projected that by 2020, four times the cold chain capacity will be needed compared to 2010 . Beyond 2020, new vaccines for diseases such as malaria and respiratory syncytial virus will likely be incorporated into the EPI, with likely expansion of the schedule in the second year of life. New packaging and delivery technologies that have either been developed or are currently being developed are urgently needed to reduce the ISC and cold chain burden, while simultaneously achieving or improving upon immunization program goals.
This article reviews the status of four different types of delivery or packaging technologies that may reduce overall cold chain volume, enable dose sparing, enhance thermostability, or facilitate a non-parenteral (needle-free) route of delivery. Representative examples of technologies and developers are described to illustrate the variety of devices and formulations in development. Additionally, we highlight the benefits of early consideration of such technologies in the vaccine development process, particularly for technologies that could improve vaccine accessibility in LMIC.
2. New technologies
2.1. Blow fill seal
Blow-fill-seal (BFS) technology is an automated primary packaging process by which polymeric containers made from polyethylene or polypropylene material are formed, filled, and sealed in a continuous operation, thereby reducing risk of contamination and batch loss. In the BFS process, (1) polymer resin is extruded into a mold forming the container, (2) a filling mandrel fills the target pharmaceutical into the container, (3) the mandrel is retracted, and (4) the top of the container is sealed. BFS manufacturing can potentially be lower cost than filling in glass vials and preformed polymer tubes, especially at high production volumes; however, it requires significant investment by manufacturers. Cold chain volume savings might be realized with BFS in comparison to other single-dose containers, as BFS containers can be designed to be compact and pack efficiently. BFS containers are widely used for pharmaceuticals, including ophthalmic and injectable medications, and are undergoing evaluation with live attenuated rotavirus and influenza vaccines . BFS squeeze tubes can directly deliver vaccines via the oral or intranasal route (Fig. 1A). For parenteral delivery, needles and syringes could deliver vaccines from BFS polymer ampoules and vials, or compact, prefilled, autodisable devices could be produced using BFS (Fig. 1B).
Example vaccine packaging and delivery technologies that may benefit the immunization supply chain: blow-fill-seal squeeze tubes designed for oral rotavirus vaccines (Rommelag/PATH) (A); compact, prefilled, autodisable device using blow-fill-seal technology (Angela Brevetti) (B); intradermal adapter for conventional needle and syringe (West Pharmaceutical Services) (C); disposable-syringe jet injector (PharmaJet Tropis) (D); microarray patches (Georgia Institute of Technology) (E); and fast-dissolving tablet (PATH) (F).
2.2. Intradermal delivery devices
Intradermal (ID) delivery targets the dermis layer of the skin, rich in antigen processing cells. The traditional Mantoux injection technique using a needle and syringe is currently used for ID delivery of bacillus Calmette–Guérin vaccine for tuberculosis and in some developing countries for rabies vaccines; and influenza vaccine is available in a prefilled mini-needle ID delivery device . However, the Mantoux technique may be challenging to use in all immunization scenarios, particularly in campaign settings, and the available prefilled ID devices are not suitable for use in LMIC immunization programs due to cost and large cold chain storage requirements. A number of novel ID delivery devices have been developed to simplify the process of delivering an ID injection. These include adapters for conventional needles and syringes (Fig. 1C), hollow microneedle hubs for syringes (e.g., NanoPass MicronJet600™ device), mini-needle syringes (e.g., BD Soluvia™ prefillable microinjection system and the Star ID Syringe), and needle-free disposable-syringe jet injectors (DSJIs) (Fig. 1D). Based on clinical research of ID delivery of inactivated poliovirus vaccine (IPV) ;  ; , WHO recommends that two fractional doses of 0.1 mL of trivalent IPV delivered intradermally can substitute for a single 0.5 mL intramuscular dose, which is currently being provided along with bivalent (poliovirus types 1 and 3) oral polio vaccine in routine immunization to provide immunity against vaccine-derived type 2 poliovirus . Due to recent supply limitations , countries such as India and Sri Lanka are introducing ID delivery of IPV in routine immunization , and it has also been used in large-scale campaigns . Although novel ID devices are generally more expensive than autodisable needles and syringes for ID delivery, dose sparing may enable cost savings, particularly for relatively expensive vaccines, and can reduce the cold chain burden. No vaccine reformulation is needed, and use of needle-free ID devices will reduce needlestick injuries  ; .
2.3. Microarray patches
An alternative technology for delivering vaccines to the skin is microarray patches (MAPs; also known as microneedle patches) (Fig. 1E). These use dry formulations of vaccine antigen, either coated on an array of solid micro-projections or molded into a dissolving array. Phase I clinical studies have been completed for influenza vaccine on dissolving microarrays  ; , and preclinical studies have demonstrated feasibility of microarrays for vaccines including IPV  ; , measles  ; , rotavirus , human papillomavirus , and pneumococcal conjugate vaccine . MAP delivery has shown potential for dose reduction in animal studies for some vaccines , though this has yet to be assessed in humans. Patches may also enable increased thermostability  ; , potentially enabling storage in a controlled temperature chain (CTC) .1Increased acceptability, ease of delivery by lesser-trained health care workers, and reduced or eliminated sharps waste are other potential benefits of MAPs which could help expand access to vaccination. However, MAPs are currently in an early stage of development. Their clinical efficacy and cost to produce at large scale has yet to be established; attributes of increased immunogenicity and thermostability may not apply to all vaccines. If a MAP must be stored in the cold chain for any part of its shelf life, this could be a challenge, as some MAP designs use a co-packaged applicator, which may exceed the per-dose storage volume of current multi-dose vials. This scenario may represent an additional burden to the immunization supply chain and cold chain capacity in LMIC. While promising, additional research on MAPs is necessary to better understand their potential for use in immunization.
2.4. Sublingual delivery
Several vaccines are delivered orally, including vaccines for poliovirus and rotavirus, and some products for typhoid and cholera, which target delivery of live attenuated viruses or bacteria to the intestinal tract. Sublingual delivery to the mucosa under the tongue is another form of oral delivery that can be applied to inactivated or subunit vaccines, and has advantages such as avoiding degradation by gastric acid and the potential to enhance mucosal immunity by eliciting high levels of mucosal immunoglobulin A antibodies as well as a systemic immunoglobulin G response. Sublingual vaccines are currently marketed in Europe, including for immunotherapy for allergic hypersensitivity and prevention of recurring urinary tract infections  ; . Preclinical studies have demonstrated immunogenicity of sublingual delivery for several prophylactic vaccines, including human papillomavirus , IPV , HIV , and influenza . Most of these vaccines are inactivated or subunit and therefore poorly immunogenic, requiring an adjuvant to enhance or improve the response to specific vaccines. A variety have been investigated, including a double-mutant of a bacterial heat-labile toxin, alpha-galactosylceramide (a stimulator of natural killer T cells), and TLR9 agonist CpG-oligodeoxynucleotide  ; . Vaccines can be delivered sublingually in various forms, including liquid drops and sprays, and fast-dissolving thin films and tablets  (Fig. 1F). The choice of formulation requires consideration of the age of the intended recipients and the delivery setting, as well as ease and safety of administration. The flow of saliva can limit the duration of exposure of vaccines to the sublingual mucosa. One potential solution is a thermoresponsive gel formulation, which changes from a liquid to an adherent gel upon exposure to body temperature . Fast dissolving thin films and tablets disintegrate rapidly in a small volume of saliva to also form a gel for improved local retention, maximizing uptake and minimizing swallowing of the vaccine. Sublingual formulations of vaccines are early in development but have potential to benefit the ISC through improved efficacy and ease of delivery.
3.1. Programmatic suitability—vaccines and technologies
For a new vaccine presentation (the format in which it is packaged in its primary container), demonstration of programmatic suitability requirements as well as overall immunization program effectiveness is required for vaccine WHO prequalification, policy recommendation and program implementation. Consideration of suitable primary and secondary packaging technologies as well as the utilization of delivery technologies that offer potential programmatic benefits represents opportunities to achieve greater market and public health success for the vaccine, but is often delayed until after licensure in high-income countries that offer a more immediate return on investment.
The development of a vaccine begins with the generation of a target product profile (TPP) describing the intended labeling and indications for the vaccine and is a documentation tool used in communications with National Regulatory Authorities such as the US Food and Drug Administration in preparation for regulatory submission . TPPs have also been more widely adopted and recommended by global-level stakeholders for vaccines intended for introduction and use in LMIC  ; . The product development process usually takes more than ten years, through preclinical and clinical proof of concept, followed by safety and efficacy testing in Phase III studies, and finally, regulatory approval. However, for a vaccine to be recommended and procured for use in LMIC, programmatic fit within the EPI schedule (referred to as suitability) and prequalification (PQ) by WHO Performance, Quality and Safety process are needed. The Programmatic Suitability of Vaccine Candidates for WHO Prequalification (PSPQ) describes mandatory, critical, and preferred characteristics as they pertain to vaccine presentations and programmatic suitability . The PSPQ guidance is intended to be a reference for vaccine developers to inform vaccine presentation selection to include primary container, secondary, and tertiary packaging as well as delivery technology use. It is anticipated that the PSPQ will be updated during the course of 2017. A generic preferred product profile document is also available to guide vaccine developers on the incorporation of programmatic suitability characteristics that should be considered in TPP development for new vaccines .
Consideration of immunization program requirements and optimization of presentation packaging should be completed prior to implementation of the pivotal Phase III clinical study, in alignment with chemistry, manufacturing, and controls (CMC) considerations , as subsequent changes to the vaccine presentation, primary container, and delivery technology are likely to require bridging and approval by regulatory authorities. Consideration of these product attributes earlier on in development will facilitate and reduce the timeline to WHO PQ and minimize delays to program introduction and public health impact of the vaccine in LMIC. Therefore, it is critical that consideration of vaccine presentation occur earlier in the vaccine product development process to result in a format that is programmatically suitable and optimized for use in LMIC. For this reason, early engagement by vaccine developers with the PQ and PSPQ is encouraged by WHO to provide guidance and input on not only potential PQ considerations and requirements but also PSPQ requirements and recommendations to inform the TPP.
3.2. Timeline for availability
Advancing new technologies for vaccine packaging and delivery often requires a long-term process (Fig. 2). The timeline for availability of a new product is dependent on the status of technology product development, the need for preclinical and clinical supporting data, regulatory authority licensing, and manufacturing scale-up. ID delivery devices for IPV delivery are available for introduction in the short term (within 0–2 years), as WHO has recommended adoption of ID delivery based on available clinical evidence and several ID devices have regulatory clearance. Changes to the primary packaging of existing vaccines requires identifying or developing a suitable container design, installing specialized filling equipment (e.g., for BFS containers) if facilities do not exist, and stability studies to inform regulatory approval of the vaccine in the new container. GlaxoSmithKline has advanced BFS containers for Rotarix® vaccine , which may be available in the short term. Use of BFS for parenteral vaccines is under consideration for the medium term. Novel delivery methods that require reformulation of existing vaccines, such as MAPs and sublingual delivery, will have a longer timeline to availability, due to the need for Phase I–III clinical studies to demonstrate safety and immunogenicity (assuming the correlate of protection is known), and the need for development of scaled-up manufacturing processes.
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