1
VIPS Phase II executive summary:
Microarray patches (MAPs)
March 2020
2
Microarray patches (MAPs)
About MAPs
? MAPs consists of an array of micro -projections on a patch . The micro -projections are coated
with or are composed of, vaccine in a dry formulation. When a MAP is applied to the skin, the
vaccine is delivered into the dermis and/or epidermis layers.
? MAPs can be administered without an applicator , by applying pressure with fingers, or using
an integrated applicator.
? Like solid -dose implants (SDIs), MAPS are sharps -free devices that could potentially be used
with all injected vaccines (once they have been reformulated). However, development of MAPs
is more advanced than SDIs and current MAPs do not have a separate applicator, which will
likely be needed for SDIs.
Stage of development
? Various formats of MAPs are being developed for vaccine delivery by several different developers.
? Three developers have tested influenza vaccine MAPs in phase I clinical trials , and preclinical
development is underway with other vaccines, including measles -rubella (MR) .
? MAPs for delivery of non -vaccine products, such as teriparatide (for osteoporosis) and Zolmitriptan
(migraine), have been evaluated in phase II and III trials respectively.
Vaxxas
, 15 May 2019
micronbiomedical.com
b
WHO
c

 

VIPS PHASE 2 TECHNICAL NOTE

Solid -dose implants




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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF


Solid dose implants (SDIs )

SECTION ONE: Vaccine compatibility and problem statements addressed by the innovations
Technology overview:
SDIs consist of vaccines (including antigens, adjuvants and excipients) that have been reformulated into a solid single -dose format, typically needle -shaped, that is
sharp and strong enough to be implanted below the skin. After injection, the dose either d issolves immediately or is released slowly depending on the formulation.
Some SDIs are contained in a cartridge or cassette for easy handling prior to administration with a n applicator to propel the SDI into the skin using a spring or
compressed gas. The applicator might be separate and re -usable, or integrated and single use.

Summary of innovation applicability to vaccines :
Solid dose implants (SDIs) could potentially be used to deliver any vaccine that is currently administered by injection with nee dle and syringe (N&S). The
technology does have some features that might however preclude its use with some vaccines , as the product is developed , in particular:
1. Adjuvants: The need to dry the vaccine for incorporation into the SDI might preclude the use of some adjuvants, including those based on aluminium salts
(such as alum).
We have assumed that manufacturing process es will be developed that are compatible with aluminium salt based adjuvants, or that it might prove to be
technically feasible to rem ove the adjuvant from the formulation of some vaccines such as HPV and HepB whilst maintain ing immunogenicity. For some
vaccines however (RTS,S and HIV) we have assumed the adjuvant will not be suitable for SDIs, nor will there be interest in re moving the adjuvant. a

2. Payload. Antigens need to be available at a sufficiently high concentration ( which might be higher than standard bulk harvests) to enable a full dose to be
loaded into a SDI .
The amount of vaccine required to be loaded onto a SDI relative to the yields of the manufacturing process has NOT been considered in this analysis, and
no vaccines have been excluded on this basis .

3. Route of delivery . SDIs will not be suitable for use wit h vaccines that are currently delivered orally.
Live -attenuated rotavirus vaccines, and E TVAX , the candidate vaccine selected as the exemplar for Enterotoxigenic E. coli (ETEC) have therefore not
been considered for use with SDI s. The candidate M.t b vaccine VPM1002 is a recombinant BCG so will need to be delivered intradermally (ID) thus SDIs will not be
suitable for administration of this vaccine.
The vaccines considered, or not considered for use with SDI s in this Technical Note are summarised in Tables 1 and 2 respectively.
a Alumimium -salt based adjuvants and saponins might be compatible with SDIs, but oil -in-water adjuvants are unlikely to be suitable. [No data provided] EnesiPharma communication, 19 November 2019.

 

1
VIPS Phase II executive summary:
Solid - dose implants (SDIs)
March 2020
2
Solid -dose implants (SDIs)
About SDIs
? SDIs consist of vaccines (including antigens, adjuvants and excipients) that have been
reformulated into a solid format . This is typically shaped like a needle that is sharp and
strong enough to be implanted below the skin and the dose it contains either dissolves
immediately or is released slowly.
? In some cases, SDIs are contained in a cartridge or cassette for easy handling.
? An applicator is used to propel the SDI into the skin using a spring or compressed gas.
The applicator might be separate and re -usable, or integrated and single use.
? SDIs could be regarded as an alternative to microarray patches (MAPs) as they should not
have the reactogenicity of MAPs and possibly have a higher payload. But SDIs have other
drawbacks such as the need for an applicator and being earlier in development than MAPs.
Stage of development
? SDIs are in a very early stage of development .
? No clinical studies with vaccines have been published.
Hirschberg HJHB, 2008
a
Separate, compressed gas -
powered applicator ( Bioneedle )
www.enesipharma.com
b
Separate, spring -powered
applicator ( Implavax ?)
Nemaura
presentation
c
Optional, separate applicator (Micropatch TM)
aHirschberg HJHB, van de Wijdeven GGP, Kelder AB, van den Dobbelsteen GPJM, Kersten GFA. Bioneedles as vaccine carriers. Vaccine. 2008 May 2;26(19):2389 ?97. bhttps://www.enesipharma.com/technologies/platform/cNemaura presentation. Teriparatide microneedle patch for osteoporosis, December 2018. Presented during telecon 12 February 2019.

VIPS PHASE 2 TECHNICAL NOTE

Freeze Damage Resistant Liquid Formulations




30.03.2020
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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Freeze Damage Resistant Liquid Formulations

SECTION ONE: Vaccine compatibility and problem statements addressed by the innovation
Technology overview:
Many vaccines are freeze -sensitive, including those containing aluminium adjuvants. When vaccines containing aluminium adjuvant are frozen, the antigen -
adjuvant particles agglomerate and sediment which results in the irreversible loss of potency. Developing novel freeze stabl e formulations using different
excipients could prev ent agglomeration and stabilize the potency of vaccines. The addition of excipients such as glycerin, polyethylene glycol 300, or propylene
glycol (PG) have been demonstrated to reduce the freeze sensitivity of hepatitis B vaccine (1) and other vaccines containing aluminum adjuvant including
diphtheria, tetanus and pertussis (DTP); and pentavalent (hepatitis B, DTP, Haemophilus influenza type b) vaccines (2). Testing and pre -clinical studies using
these excipients have been conducted with hepatitis B, pentavalent, diphtheria, tetanus toxoid and pertussis vaccines, but overall, the approach is at an early
phase of development.
Summary of innovation applicability to vaccine s:
This innovation applies only to freeze -sensitive liquid vaccines and diluents , especially those containing aluminium adjuvants . The innovation addresses the issues
of vaccine freeze -damage leading to delivery of sub -potent vaccine and suspected vaccine freeze -damage leading to vaccine wa stage. In the VIPS Phase II online
survey of country stakeholders, vaccine freeze sensitivity was rated as the top problem for hepatitis B, human papillomavirus , inactivated poliovirus, and
pentavalent vaccines ; and the fifth most important problem for typ hoid conjugate vaccine. The innovation is complex to apply to existing vaccines, requiring novel
formulation development, characterization and immunobridging, so is best applied to pipeline freeze -sensitive vaccines during product development and existing
freeze -sensitive vaccines that are undergoing reformulation for other reasons .
Problem statements to be addressed:
The problem statement that can be applied to each vaccine which could potentially be addressed by freeze damage resistant for mulations is presented in Table 1.
The key properties of freeze damage resistant liquid formulations that are relevant to these pro blem statements are:
? Vaccine ineffectiveness/wastage due to freeze exposure: The innovation addresses the issues of vaccine freeze -damage leading to delivery of sub -
potent vaccine and suspected vaccine freeze -damage leading to vaccine wastage.

1
VIPS Phase II executive summary:
Freeze damage resistant liquid
formulations
March 2020
2
Freeze damage resistant (FDR) liquid formulations
Stage of development
? Excipients that could be used to improve freeze resistance of vaccines are known and
available but are not used in any approved vaccines ? though they are used in other parenteral
drugs, including some for pediatric use.
? There have been pre -clinical studies with freeze -damage resistant formulations of hepatitis
B, pentavalent, and DTP vaccines , but overall, the approach is at an early phase of
development.
www.myelomacrowd.org
a
Freeze damage resistant liquid vaccines
www.publichealthontario.ca
b
Freeze damage resistant liquid vaccines
ahttps://www.myelomacrowd.org/wp -content/uploads/2015/05/vials.jpg bhttps://www.publichealthontario.ca/en/BrowseByTopic/InfectiousDiseases/PIDAC/Pages/Infection -Prevention -and -Control -for -Clinica l-Office -Practice -Multidose -Vials.aspx
About freeze damage resistant liquid formulations
? Many vaccines are freeze -sensitive , including those containing aluminium -salt adjuvants. When
vaccines containing aluminium -salt adjuvants are frozen, the antigen -adjuvant particles
agglomerate (form a cluster) and sediment resulting in irreversible loss of potency.
? The addition of excipients (stabilising agents) to vaccine formulations could prevent
agglomeration and freeze damage; stabilising the potency of vaccines .
? G lycerin , polyethylene glycol 300, and propylene glycol (PG) have been demonstrated to reduce
the sen sitivity to damage due to freezing of hepatitis B and other vaccines containing
aluminum -salt adjuvants including diphtheria, tetanus and pertussis (DTP); and pentavalent
(hepatitis B, DTP, Haemophilus influenza type b) vaccines.

VIPS PHASE 2 TECHNICAL NOTE

Heat stable/CTC qualified liquid formulations




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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Fo undation, PATH and UNICEF


Heat stable/Controlled temperature chain (CTC) qualified liquid
formulations

SECTION ONE: Vaccine compatibility and problem statements addressed by the innovation
Technology overview:
Heat stable liquid formulations (such as those incorporating stabilizing agents) enable vaccines to be exposed to high temper atures (e.g., a minimum of 3 days at
?40 ?C) without losing their potency and can thus be controlled temperature chain ( CTC ) qualifi ed. a Some formulations require optimized properties (e.g. buffer, pH,
salt concentrations and stabilizing excipients) to prevent denaturing of proteins and reduce the occurrence of damaging chemi cal reactions caused by increasing
temperature. Heat -stabilized vaccines will differ in the length of time they can be stored in a CTC and the maximum temperature they can endure while remaining
stable and potent, and some vaccines will not be able to be reformulated into heat -stable liquid s.
Summary o f vaccine and innovation compatibility :
This innovation applies to all vaccines in liquid formulations that are sufficiently heat -stabl e to enable licensing and World Health Organization (WHO)
prequalification approvals for use in a CTC. By WHO?s current d efinition of CTC, the vaccine must be sufficiently heat stable at the end of its shelf life to allow
exposure at ambient temperatures not exceeding 40 ?C for a minimum of 3 days just prior to administration. The assessment of whether this innovation is
tech nically feasible for a specific vaccine type relied on existing stability data. In general, vaccines for which a lyophilised format is the only format available were
excluded as they are unlikely to be sufficiently heat -stable in liquid format. Some vaccines that are currently lyophilised were included where there was evidence
available that the vaccine could be reformulated into a heat -stable liquid and/or ongoing efforts to do so . An optimistic perspective was taken with some pipeline
vaccines that are currently lyophilised or frozen as their heat stability may not yet be optimized and opportunity may yet exist to formulate them as heat stable
liquids. In particular:
? Measles -rubella (MR) vaccine is included . While all currently available MR vaccines are lyophilised , research efforts are ongoing to attempt to achieve a
vaccine that is a stable liquid suspension (1).b
? Meningitis A vaccine is included. While the existing WHO prequalified MenAfriVac is lyophilised , meningitis vaccines are available in liquid format from
other manufacturers. c
a World Health Organization (WHO) . WHO website. WHO Controlled temperature chain (CTC): The Controlled Temperature Chain (CTC) Working Group page [publication s and guidance]. https://www.wh o.int/immunization/programmes_systems/supply_chain/ctc/en/index1.html . Accessed February 29, 2020. b Personal communication, Bill & Melinda Gates Foundation. c WHO website. WHO prequalified vaccines page. https://extranet.who.int/gavi/PQ_Web/ .

1
VIPS Phase II executive summary:
Heat stable/Controlled temperature
chain (CTC) qualified liquid formulations
March 2020
2
About heat -stable/CTC qualified liquid formulations
? This innovation refers to liquid vaccine formulations that are sufficiently heat stable to be kept in a
CTC. CTC use of vaccines allows a single excursion of the vaccine into ambient temperatures not
exceeding +40 ?C for a minimum of 3 days, just prior to administration.
? Heat -stable vaccines differ in the length of time they can be in a CTC and the maximum temperature
they can endure while retaining potency. The necessary CTC duration is vaccine and context specific.
? WHO has prioritised vaccines used in campaigns or special strategies for CTC qualification
because the benefits of CTC cannot be fully realised for routine vaccines that are stored and
transported together unless all these vaccines are qualified for CTC use.
Stage of development
? As of February 2020 there are two heat stable liquid vaccines qualified for CTC use .
? Merck?s Gardasil? 4 (quadrivalent human papillomavirus vaccine)
? Shantha Biotechnics Shanchol? (oral cholera vaccine).
? Other vaccine manufacturers are in the process of qualifying their existing and pipeline liquid
vaccines for CTC use.
? Several developers have created approaches, some of which are proprietary, that may be applicable
to a variety of vaccines to improve their heat stability in liquid formulations.
Heat -stable/controlled temperature chain (CTC)
qualified liquid formulations

VIPS PHASE 2 TECHNICAL NOTE

Dual -chamber delivery device




30.03.2020
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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF


Dual -chamber delivery device

SECTION ONE: Vaccine compatibility and problem statements addressed by the innovations
Technology overview:
Dual -chamber delivery devices are a type of integrated reconstitution technology (including the delivery device) that can be used to deliver any vaccine that
requires mixing of multiple components to simplify preparation. This innovation is typically used for injectable vaccines tha t require mixing of a liquid (diluent) and
dry (vaccin e) component. However, the innovation also applies to oral vaccines as well as other products that require mixing such as two incompatible liquid
components that must be mixed at the point of use.
There are two subtypes of dual -chamber delivery devices inc luded in this analysis:
? Syringe - or cartridge -based devices.
? Frangible seal -based devices.
Summary of vaccine and innovation compatibility :
This innovation could be applied to all dry vaccine presentations that require reconstitution with a diluent, or other multi component vaccines that require mixing.
Vaccines where the components are currently stored separately (i.e. not co -packaged) typical ly benefit the most from this innovation compared to vaccines where
the components are already stored together to prevent mismatching. This innovation could be particularly useful for lyophilized vaccines that are delivered through
campaigns/outreach in or der to task shift to lesser trained health workers, simplify logistics and training requirements, and increase coverage in re mote areas.
Examples of VIPS priority antigens that could be suitable include MR and yellow fever. Dual -chamber delivery devices ar e also well -suited for simplifying the
preparation of vaccines with multiple components and complex preparation steps like ETEC to reduce preparation errors.
The vaccines considered, or not considered for use with MAPs in this Technical Note are summarised in Tables 1 and 2 respectively.
Problem statements addressed by innovation:
The problem statements applying to each vaccine that could potentially be addressed by dual -chamber delivery devices are presented in Table 1. The key
properties of dual -chamber delivery devices that are relevant to these problem statements are:
? Difficulties preparing and/or delivering the vaccine requiring trained personnel: Dual -chamber delivery devices simplify vaccine preparation , which
improves ease of use and training requirements .
? Vaccine wastage or missed -opportunities due to multi -dose vials : Dual -chamber delivery devices are a single -dose format. As such they avoid issues
of missed opportunities for vaccination due to reluctance to open preservative -free multi -dose vials (MDVs).
? Reconstitution related safety issues : Dual -chamber deliver devices prevent errors associated with traditional reconstitution systems includ ing use of the
incorrect volume of diluent; reuse of reconstitution syringes, causing contamination; failure to discard reconstituted vaccine in multi -dose vials in the

1
VIPS Phase II executive summary:
Dual - chamber delivery devices
March 2020
2
Dual -chamber delivery devices
About dual -chamber delivery devices
? Dual chamber delivery devices are prefilled with liquid and dry vaccine
components, which are mixed within the device and administered.
? They could be regarded as alternative innovations to microarray patches (MAPs)
or solid dose implants (SDIs), and they should not have the payload restrictions of
these innovations. However, they offer fewer potential benefits than MAPs or SDIs.
Stage of development
? Technologies are at various stages of development, from early design stage through to
commercial availability, however most dual -chamber device formats are still early in
development .
? No liquid/dry vaccines are licensed in dual -chamber delivery devices. Two liquid/liquid
vaccine products are licensed: ( ViATIM [Sanofi] & hepatyrix [GSK], both are hepatitis A
plus typhoid polysaccharide vaccines).
www.pharmaceutical
-
networking.com
a
Dual chamber syringe
(Vetter Lyoject)
PharmaPan
b
Dual chamber blister with
frangible seal
Neopac
c
Dual chamber blister with
frangible seal
ahttps://www.pharmaceutical -networking.com/vetter -dual -chamber -delivery -systems/ bhttps://www.pharmapan.com/sites/default/files/downloads/2017 -
10/PHARMAPAN_Dual_Chamber_Blister_1.1.pdfchttps://www.webpackaging.com/en/portals/webpac/assets/11138717/neopacs -fleximed -now -in-large -format/

VIPS PHASE 2 TECHNICAL NOTE

Combined Vaccine Vial Monitor and Threshold Indicator




30.03.2020
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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Combined Vaccine Vial Monitor and Threshold Indicator
SECTION ONE: Vaccine compatibility and problem statements addressed by the innovations
Technology overview
Vaccine vial monitors (VVMs) change gradually change colour in response to cumulative heat exposure, however their response is not rapid enough at higher
temperatures (e.g. above 37?C or 40?C) for use with vaccines kept in a controlled temperature chain (CTC) . Therefore , a separate threshold indicator ( TI) must be
used in addition to VVMs when vaccines are kept i n a CTC. The TI reacts rapidly if exposed at or above a defined threshold temperatu re. Currently, VVMs and TIs
are not integrated. VVMs on vaccine primary containers and standalone TIs are used when vaccines are kept in a CTC. These TIs must be purchased and
distributed separately from the vaccine and kept at temperatures below their thr eshold. They are placed in vaccine carriers and cold boxes (without icepacks)
during CTC storage and transport.
A combined VVM -TI on primary containers is a single indicator that undergoes gradual colour change up to a specified peak threshold temperature and rapidly
reacts if exposed at or above the threshold temperature.
Summary of innovation applicability to vaccine s:
It is technically feasible to apply this innovation to all vaccines. VVM -TIs are more accurate indicator s of potential heat damage than existing VVM s as the
integrated indicator allows for both cumulative monitoring of heat exposure as well as the additional rapid indication when vaccines are exposed to high
temperatures. VVM -TIs are especially appropriate fo r vaccines intended for use in a CTC as these vaccines are intentionally exposed to ambient temperatures for
a limited time period in order to facilitate vaccine outreach. The VVM -TI innovation is evaluated for all VIPS priority vaccines in this technical note with special
consideration given to its applicability to vaccines that are currently used in a CTC or those vaccines that could potentiall y be used in a CTC in the future .
The vaccines considered or not considered for use with VVM -TIs in this Technica l Note are summarised in Tables 1 and 2 respectively.
Problem statements to be addressed:
VVM -TIs provide benefits in terms of improv ed temperature monitoring and facilitation of CTC use of vaccines, but do not address vaccine specific problems
identified by stakeholders .

1
VIPS Phase II executive summary:
Combined Vaccine Vial Monitor (VVM)
and Threshold Indicator (TI)
March 2020
2
Combined Vaccine Vial Monitor (VVM) and Threshold
Indicator (TI)
Temptime
Reading of integrated VVM -TI
Stage of development
? WHO prequalification (PQ) specification and verification protocols have been developed and published.
? One VVM -TI has received WHO prequalification (PQ) , however this product does not have the appropriate specifications for currently
qualified CTC vaccines.
? Other integrated VVM -TIs have been developed but will need to pass WHO PQ approvals as standalone products. Vaccine manufacturer s
adding VVM -TIs to their vaccine products will need to seek national regulatory and WHO PQ approvals for the label change.
About Combined VVM -TIs
? Currently, VVMs and TIs are not integrated. VVMs are placed on primary containers and standalone TIs are used in addition to
VVMs when vaccines are kept in a controlled temperature chain (CTC). These TIs must be purchased and initially distributed separately
from the vaccine and kept at temperatures below their threshold. They are placed in vaccine carriers and cold boxes (without ice packs)
during CTC storage and transport.
? Although a VVM alone changes colour in response to cumulative heat exposure, its response is not rapid enough at higher
temperatures (e.g. above 37 ?C or 40 ?C), whereas the TI reacts rapidly if exposed at or above a defined threshold temperature.
? A combined VVM -TI on primary containers undergoes gradual colour change up to a specified peak threshold temperature and rapidly reacts
if exposed at or above the threshold temperature.
? There are two potential types of VVM -TIs:
? VVM and TI together: both indicators are placed on the same label and require a review of VVM and TI
separately. There are no examples of the technology in this format.
? TI is integrated into the VVM: combined features of both VVM and TI in one indicator, which looks and is
interpreted identically to the existing VVMs. This type is commercially available .

VIPS PHASE 2 TECHNICAL NOTE

Compact prefilled auto -disable device (CPAD)




30.03.2020
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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF



Compact prefilled auto -disable device (CPAD)

SECTION ONE: Vaccine compatibility and problem statements addressed by the
innovations

Technology overview
Compact prefilled autodisable devices (CPADs) are prefilled syringes with design features that prevent their reuse and minimise the space required for storage
and distribution. CPADs fall into two main subtypes based on their manufacturing method: (1) preformed CPAD and (2) blow -fill-seal (BFS) CPAD. Devices that
do not fall int o one of these categories were considered under a third subtype: (3) other types of CPADs (as described in detail below). CPA Ds are by definition
small in size (compact), prefilled with the vaccine by the manufacturer, and contain an auto -disable mechanism . However, as described in this technical note,
there are differences between the types such as with their vaccine filling process, number of components and assembly require ments.
The following devices were selected as examples to evaluate the three CPAD s ubtypes for this assessment.
? Preformed CPAD: Uniject? (commercially available).
? BFS CPAD: ApiJect prototype (in development).
o Pre -assembled (with integrated needle hub).
o User -assembled (with separate needle hub).
? Other types of CPADs: INJECTO ? easyject (in development).
Summary of vaccine and innovation compatibility :
This innovation could be applied to any liquid parenteral vaccine. The innovation may be most useful with vaccines that would benefit from a n easy -to-use
single -dose presentation, for instance, for outreach settings.
The vaccines considered, or not considered for use with CPADs in this Technical Note are summarised in Tables 1 and 2 respect ively.
Problem statements to be addressed:
The problem statements applying to each vaccine tha t could potentially be addressed by CPADs are presented in Table 1. The key properties of CPADs that
are relevant to these problem statements are:
? Reduced acceptability due to painful administration: Since CPADs are prefilled there is a perception by caregivers that the injection is less painful,
which can improve acceptability.