VIPS Phase I executive summary:
Autodisable sharps - injury protection
syringes
June 2019
Autodisable (AD) sharps -injury protection (SIP)
syringes
About AD SIP syringes
? AD SIP syringes are single -use, disposable syringes with a mechanism that
covers the needle after use to reduce the risk of accidental needlestick
injury .
? Mechanisms include retraction of the needle into the barrel after injection
or a needle shield .
? Some syringes have SIP features that are automatically activated and
others require extra activation steps by the end user.
Stage of development
? AD SIP syringes are commercially available .
? A list of the current AD SIP syringes is available on the World Health
Organization?s (WHO?s) Performance, Quality, and Safety (PQS) catalogue b.
WHO
a
A VanishPoint ? retractable syringe
(Retractable Technologies, Inc.)
PATH
BD Eclipse? syringe (BD, Franklin
Lakes, NJ) with needle shield
ahttp://apps.who.int/immunization_standards/vaccine_quality/pqs_catalogue/LinkPDF.aspx?UniqueID=f3025136 -636d -4139 -9773 -fdbf82427 6e1&TipoDoc=DataSheet&ID=0 bW HO. PQS catalogue website. Category E008 auto -disable syringe for fixed dose immunization page. http://apps.who.int/immunizatio n_standards/vaccine_quality/pqs_catalogue/categorypage.aspx?id_cat=37. Accessed April 4, 2019.

12.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
A utodisable (A D ) sharps -injury protection (SIP)
syringe s
Comparator : AD needle and syringe ( N&S ) without SIP feature


Section 1: Summary of innovation
1.1 Example s of innovation types :

Image source : Provided by PATH
1.2. D escription of innovation:
Unsafe injections cause hepatitis B, hepatitis C, or HIV infections and can result in chronic disease or death
(1). To reduce the risk of unsafe injection, the World Health Organization (WHO) Expanded Programme on
Immunization ca lled for the design of safer injection devices in the 1980s. In 1999, WHO, the United
Nations International Children?s Emergency Fund ( UNICEF ), and the United Nations Population Fund
(UNFPA ) released a joint statement supporting the use of autodisable (AD) syringes for immunization (2),
and UNICEF started phasing out regular disposable syringes for immunization and replacing them with
WHO prequalified AD syringes (3). The 1999 WHO/UNICEF joint statement highlights that AD syringes
should be used for both routine immunization and mass campaigns (fixed dose immunizations) (2), and this
was reaffirmed in a 2019 joint statement that also promotes the use of reuse prevention ( RUP ) syringes for
reconstitution (4).
Safety syringes come in t wo types: RUP and sharps injury protection (SIP) .a AD syringes are considered a
specific subtype of RUP syringes, and RUP and AD syringes can both come with SIP features . AD SIP
syringe s are the focus of this evaluation. According to Gavi?s Vaccine Innovations Lexicon, a SIP
syringe is, ?A single -use, dispos able syringe with a mechanism that covers the needle after use to reduce
the risk of accidental needlestick injury. Mechanisms include retraction of the needle into the barrel after
injection or a needle shield. SIP syringes have an additional feature that helps prevent needle -stick injury
and can increase the safety of immunisation delivery and disposal (5).?
Like AD syringes, AD syringes with SIP features can be used for routine immunization and mass
campaigns for intramuscular, subcutaneous, or intrader mal vaccinations . By 2012 , International
Organization for Standardization (ISO ) standards were developed for SIP syringes (6). WHO also now
recommends the use of syringes with SIP features for health care workers delivering intramuscular,
subcutaneous or i ntradermal injectable medications to patients (6). The WHO Performance, Quality, and
Safety (PQS) group is planning a consultation in 2019 to assess whether SIP features should be required
for all immunization syringes (7,8).
a Unless specifically noted RUP syringes ordinarily refer to non -AD syringes used for reconstitution of freeze -dried vaccines and curative medicine (variable dosing).

VIPS Phase I executive summary:
Barcodes
June 2019
Barcodes
About Barcodes
? Barcodes are symbols that encode information such as product numbers, serial numbers,
supplier data, batch numbers and expiry dates which can be scanned electronically using two
dimensional (2D) scanners, laser or mobile device cameras to automatically capture information.
? Barcodes enable tracking and monitoring of vaccine products in supply chains, providing
information to manufacturers, transport providers, health facilities and other relevant parties
involved in the logistics management systems, assuming the supporting infrastructure is in place.
? 2D barcodes can hold a significant amount of information and there is a possibility to automatically
import data into patient electronic medical records (EMRs).
? This assessment is based on barcode placement on vaccine primary and higher packaging levels.
Stage of development
? 2D Barcodes are commercially available and pilots have been introduced in a number of countries.
? WHO currently recommends GS1 compliant barcodes for secondary and tertiary packaging of
vaccines containing the Global Trade Item Number (GTIN), vaccine expiry date and vaccine batch/lot
number. This recommendation is anticipated to soon become a critical characteristic necessary
for WHO prequalification.
Newswire.ca
a
a https://www.newswire.ca/news -releases/sanofi -pasteur -moves -national -immunization -strategy -forward -with -new -bar -code -technology -509575151.html
PATH
Barcode on primary packaging
Barcode on secondary packaging

12.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Barcodes
Comparator: Use without innovation (i.e. no barcodes )


Section 1: Summary of innovation
1.1 Example images :
Primary package barcode a




Secondary package
barcode b




Tertiary package barcode c




1.2. D escription of innovation:

? Barcodes are symbols that encode information such as product numbers, serial numbers, supplier data,
batch numbers and expiry dates which can be scanned electronically using 2 dimensional ( 2D )
scanners, laser or mobile device cameras to automatically captu re information.
? Barcodes can be placed on vaccine primary, secondary, and tertiary packaging. This evaluation
assumes barcode placement down to the primary packaging level.
? 2D barcodes are a Data Matrix capable of holding a significant amount of informati on (more than the
linear one -dimensional barcodes) in a smaller space. The 2D barcodes currently available on some
vaccines contain the vaccine product identification information, expiration date and lot number d.
? Barcodes enable tracking and monitoring of vaccine products in supply chains, providing information to
manufacturers, transport providers, health facilities and other relevant parties involved in the logistics
management systems, assuming the supporting infrastructure is in place.
? Providers can use barcode scanners to read the 2D barcodes on primary packaging and automatically
import data into patient electronic medical records (EMRs), if these EMRs are in place.

a Photo source: https://www.newswire.ca/news -releases/sanofi -pasteur -moves -national -immunization -strategy -forward -with -new -bar -code - technology -509575151.html
b Photo source: PATH/Matt Morio c Photo source: https://ediacademy.com/blog/freds -barcode -requirements/ d About Two -Dimensio nal (2D) Vaccine Barcodes, CDC. https://www.cdc.gov/vaccines/programs/iis/2d -vaccine -barcodes/about.html

VIPS Phase I executive summary:
Blow - fill - seal primary containers
June 2019
Blow -fill -seal (BFS) primary containers
About BFS primary containers
? BFS is a single, continuous, aseptic filling process in which a polymer resin is melted, blown into
a blister, filled with vaccine product, and sealed.
? BFS containers can be packaged either as separate single dose containers or conjoined as
multi -mono -dose (MMD) containers.
? Two sub -types of single dose presentation primary container BFS have been assessed:
? Ampoule formats: to withdraw the contents, the container has to be opened by twisting
off the top of the container.
? Vial formats: contents are withdrawn by inserting a needle and syringe through the septum.
Stage of development
? BFS containers are widely used to produce a variety of pharmaceuticals in polymer primary
containers.
? GlaxoSmithKline?s oral rotavirus vaccine is available in a BFS 5 -dose MMD strip and Serum
Institute of India, Pvt, Ltd uses BFS ampoules for packaging diluent for their influenza
vaccine .
PATH
Rommelag BFS ampoule
PATH
Rommelag BFS vial

11.06.2019 Page 1 of 19
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
B low -fill -seal primary container s
Comparator ?: Single dose vial (liquid vaccine)


Section 1: Summary of innovation
1.1 Example images :

Rommelag BFS ampoule


Rommelag BFS vial

Image source: provided by PATH Image source: Rommelag
1.2. D escription of innovation:
? Blow -fill -seal (BFS) is an aseptic filling process that is widely used to produce a variety of
pharmaceuticals in polymer primary containers. In the blow -fill -seal process, a polymer resin is
melted into a parison, which is blown into a mold, filled, and sealed, all in a continuous process
within a single piece of equipment. This is in contrast to preformed polymer primary containers, in
which the container is first produced and sterilized, and then shipped to a different sit e for filling and
sealing.
? A wide variety of different container designs are feasible with BFS .
? For single -dose parenteral vaccines, BFS containers can be used similar to glass ampoules,
with the top twisted off and an AD N&S used to draw up and inject the vaccine. BFS
containers can also be produced with septums, similar to a glass vial. Insert -mold ing of a
septum requires a different type of BFS production equipment and results in slower, much
more costly production process, and is therefore more likely to be suitable for a multi -dose
presentation. Th e ampoule and vial formats of BFS primary contain ers are assessed in this
technical note. Because they have different attributes they are assessed separately.
? BFS has the potential to be used for production of compact prefilled autodisable devices
(CPADs), which are reviewed in the CPAD Technical Note (T N) .
? For oral or intranasal vaccines, BFS containers can be designed as squeeze tube dropper or
dispenser devices for delivery of the container?s contents directly to the mouth or nostrils.
This is reviewed in the BFS Dropper/Dispenser Technical Note.
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when mu lti-dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised.

VIPS Phase I executive summary:
Bundling devices
June 2019
Bundling devices
About bundling devices
? Bundling devices allow vaccine components to be physically connected
or placed together in the same secondary packaging to reduce the
possibility of their separation and improve the likelihood of correct
preparation and administration.
Stage of development
? Different formats of bundling devices are commercially available .
Bundling clip connecting two vials
Preformed tray containing lyophilised vaccine,
diluent and syringe
https://cdn.vaccineingredients.net
a
PATH

12.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Bundling devices
Use without innovation (i.e. vaccine and diluent in separate packaging)


Section 1: Summary of innovation
1.1 Example s of innovation types :

GSK?s vial clip (1,2)
The bundling vial clip can be used between identical sized vials.
Bundling clip:

Bundling clip connecting two
vials:

Use of bundling clip for
vials in a secondary
package:

Vaccine vial and diluent ampoule
packaging combination (1)
As vials and ampoules have different
diameters and heights, it is
challenging to use the bundling clip to
package them together. One
approach is to use a moulded tray to
package the diffe rent formats of the
primary containers together .

Vaccine vial, diluent and
syringe combination a

Vaccine vial and diluent
packaging combination (1)
Individual cartons ca n also be
used as a secondary
packaging strategy to bundle a
pair of vials (vaccine and
diluent) together.




a https://cdn.vaccineingredients.net/wp -content/uploads/2017/03/hib -hiberix.jpg

VIPS Phase I executive summary:
Combined Vaccine Vial Monitor (VVM) and
Threshold Indicators (TI)
June 2019
Combined Vaccine Vial Monitor (VVM) and
Threshold Indicators (TI)
About Combined VVM and 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 distributed separately
from the vaccine and kept at temperatures below their threshold. They are placed in vaccine carriers and cold boxes (without
icepacks) 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 types of combined VVM -TIs:
Temptime
Reading of integrated VVM -TI
? VVM and TI together: both indicators are placed on the same label and require a review of VVM
and TI separately.
? 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.
Stage of development
? WHO prequalification (PQ) specification and verification protocols have been developed and published.
? One integrated VVM -TI (VVM250 -TI40) has received WHO prequalification , however this is a product that does not have the
appropriate specifications for currently qualified CTC vaccines.
? Other integrated VVM -TIs have been developed, but will need to pass regulatory and WHO PQ approvals.

11.06.2019 Page 1 of 15
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Combined Vaccine Vial M onitor (VVM) and Threshold
Indicator s (TI)
Comparator : VVM on primary containers used with stand -alone TI

Section 1: Summary of innovation
1.1 Example of innovation types :
Combined VVM -TI on vaccine primary containers

Image source : a




1.2. D escription of innovation:
? A combined VVM and TI (VVM -TI) functions as a single indicator and can be directly attached to a
vaccine primary container (e.g., vial , tube, ampoule ? see section 1.1) and one version of the
combined VVM -TI looks identical to existing VVMs . The purpose of a VVM -TI is to address
high /peak temperature excursions of vaccine products ? especially for vaccines used in a controlled
temperature chain (CTC) ? in addition to providin g the standard functions of the VVM . Heat -stable
and CTC -qualified vaccine formulations will be assessed in more detail in their respective technical
notes. WHO recommends that a TI be used with vaccines that are kept in a CTC. At present s tand -
alone TIs are kept with vaccines in a CTC.
Stand alone TI

Image source : b





a https://apps.who.int/iris/bitstream/h andle/10665/192741/WHO_IVB_15.08_eng.pdf;jsessionid=A224999E6854225E8A5822E864FB67DF?sequence =1 b https://www.who.int/immunization/programmes_system s/supply_chain/ctc_vaccine_carrier_2.JPG

VIPS Phase I executive summary:
Compact prefilled auto - disable devices
June 2019
Compact prefilled auto -disable devices (CPADs)
About CPADs
? CPADs are integrated primary containers and injection devices prefilled with liquid
vaccines . They have design features to prevent reuse and minimize the space required for
storage and shipping.
Three CPAD subtypes have been assessed:
? Preformed CPADs: Manufactured ?open? and supplied sterile and ready to fill/seal by the vaccine
manufacturer.
? Blow -fill -seal (BFS) CPADs: Manufactured using BFS automated technology; produced, filled,
and sealed in a continuous process. Pre -assembled (with needle attached) and user -assembled
devices are under development.
? Other CPAD types.
Stage of development
? One preformed CPAD, Uniject TM , is commercially available .
? Uniject TM presentations of pentavalent , hepatitis B and tetanus toxoid vaccines were WHO
prequalified in 2006, 2004 and 2003 respectively. The pentavalent and tetanus toxoid products
have been discontinued. Medroxyprogesterone acetate is also commercially available in Uniject TM .
? BFS and other CPADs are in design phases.
drugdeliverysystems.bd.com
a
Preformed CPAD (Uniject TM)
PATH
BFS CPAD ( Apiject )
INJECTO
TMb
Other CPAD ( Easyject )
a https://drugdeliverysystems.bd.com/products/prefillable -syringe -systems/vaccine -syringes/uniject -auto -disable -pre -fillable -injec tion -system b http://injecto.eu/easyject/

12.06.2019 Page 1 of 30
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Compact prefilled auto -disable device s (CPAD s )
Comparator ? : Single dose vial (liquid ) and autodisable ( AD ) needle and syringe (N&S )


Section 1: Summary of innovation
CPADs fall into two main subtypes based on their manufacturing method: (1) preformed CPAD s and (2)
Blow -Fill -Seal ( BFS ) CPAD s. Devices that d o not fall into one of these categories were considered under a
third subtype: (3) other types of CPADs (as described in detail below) . CPADs are by definition smal l in size
(compact), prefilled with the vaccine by the manufacturer, and contain an auto -disable mechanism.
However, as described in th is technical note, the re are differences between the types such as with their
vaccine filling process, number of componen ts and assembly requirements .
The following devices were selected as examples to evaluate the three CPAD subtypes for this
assessment .
? Preformed CPAD: UNIJECT TM (commercially available and licensed to deliver Hepatitis B vaccine ).
? 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 TM easyject (in development) .

1.1 Example images :

Preformed CPAD


Image source: (1)

Image source: a






? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation . However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. a https://drugdeliverysystems.bd.com/products/p refillable -syringe -systems/vaccine -syringes/uniject -auto -disable -pre -fillable -injection -system

VIPS Phase I executive summary:
Disposable - syringe jet injectors (DSJIs)
June 2019
Disposable -syringe jet injectors (DSJIs)
About DSJIs
? DSJIs are devices that deliver vaccines in a narrow, high -pressure liquid
stream that can penetrate through tissue without the use of needles .
? DSJIs consist of a needle -free syringe , a filling adapter , and a reusable
injector .
? Some designs are manually powered through an internal spring, which is reset
through either an integrated mechanism or a separate reset station.
? Two DSJI subtypes have been assessed:
1. DSJIs for subcutaneous (SC) and intramuscular (IM) delivery.
2. DSJIs for intradermal (ID) delivery.
Stage of development
? Several DSJI devices have device regulatory clearances .
? The PharmaJet Stratis and Tropis devices are WHO prequalified.
PharmaJet
PATH
PharmaJet? Stratis (SC/IM)
PharmaJet? Tropis (ID)

12.06.2019 Page 1 of 21
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Disposable -syringe jet injector s (DSJI s )
Comparator sa:
? SC/IM DSJI subtype is compared with autodisable (AD) needle & syringe
(N&S) ;
? ID DSJI subtype is compared with Bacille Calmette -Guerin (BCG) AD N&S

Note to VIPS Steering Committee (SC) : In the November 2018 VIPS SC meeting, in an effort to reduce the
number of innovations reviewed in Phase 1, the SC recommended to remove intradermal ( ID ) DSJIs from
the list as WHO had recently purchased a stockpile of devices (enough for 5 million injections) and further
market incentives may not be needed. However, only one device has been WHO prequalified and it has
been only used for one vaccine. The two countries that have been willing to do pilots have done so with
free devices provide d from a one -time WHO stockpile ? so not really an indication of a sustainable market.
The team therefore recommends th at th e SC reconsider inclusion of ID DSJIs . This Technical Note
assesses and scores the DSJIs grouped into the following two subtypes: (i ) DSJI for SC/IM delivery and (ii)
DSJI for ID delivery.
Section 1: Summary of innovation
1.1 Example s of innovation types :

PharmaJet? Stratis (SC/IM)


PharmaJet? Tropis (ID)


Med -Jet? H4
Image source: Provided by
PharmaJet
Image source: provided by
PATH
Image source: provided by PATH
1.2. D escription of innovation:

? DSJIs are delivery devices that deliver vaccines in a narrow, high -pressure liquid stream that can
penetrate through tissue without the use of needles.
? DSJIs can inject vaccines intradermally (ID), subcutaneously (SC), or intramuscularly (IM) from
standard vial presentations , replacing use of an autodisable needle & syringe. For some DSJI
platforms, d ifferent devices are required for different depths of delivery ; other devices deliver to
multiple depths of injection .
? Previous -generation multi -use nozzle jet injectors (MUNJIs) were used for decades in mass
immunization campaigns to deliver hundreds of millions of doses of vaccines globally, including
vaccines for measles, smallpox, and yellow fever. However, these devices were later found to pose
a Though DSJIs are most likely to be used with multi -dose vials of vaccines, for consistency with the other Technical Notes they h ave been scored assuming use with a single -dose vial. Use with multi -dose vial presentations will be assessed in Phase 2, if applicable based on the vaccine pairing.

VIPS Phase I executive summary:
Heat - stable/Controlled Temperature Chain
(CTC) qualified dry formulations
June 2019
Heat -stable/controlled temperature chain (CTC)
qualified dry formulations
About Heat -stable/CTC qualified dry formulations
? Dry formulations that are heat -stable and CTC -qualified have attributes enabling them to be
exposed to ambient temperatures below a defined threshold without losing their potency .
? CTC -qualification allows vaccines to be kept at temperatures outside of the traditional cold
chain of +2 ?C to +8 ?C for a limited period of time under monitored and controlled conditions.
? CTC qualification involves regulatory approval and prequalification by WHO .
? Dry formulations vary in their sensitivity to heat and suitability for use in a CTC.
? Currently all dry vaccine formulations that are commercially available require reconstitution with a
diluent and are delivered as a liquid (injectable and oral routes).
? Common drying processes include:
? Freeze -drying (lyophilisation) is a complex multi -stage process used on an industrial scale, in
particular for live -attenuated vaccines. The steps involve ( i) freezing, (ii) primary drying and (ii)
secondary drying, resulting in a dried cake in the final container.
? Foam -drying is a desiccation process whereby a solution is transformed into a dried foam
structure by boiling or foaming under reduced vapour pressure followed by rapid evaporation.
Unlike lyophilisation, there is no freezing step, so it can be used with freeze -sensitive vaccines.
? Spray -drying , spray -freeze drying, and supercritical fluid drying are processes that can be
used to produce ?free -flowing? dry -powders with defined particle sizes.
Lyophilised formulation
Lovalenti
a
Foam -dried, freeze -dried,
and spray -dried
formulations
Lovalenti
a
aLovalenti , P.M., Anderl , J., Yee, L. et al. Pharm Res (2016) 33: 1144. https://doiorg.ezp.welch.jhmi.edu/10.1007/s11095 -016 -1860 -1.

11.06.2019 Page 1 of 22
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Heat -stable/ controlled temperature chain ( CTC )
qualified dry formulations
Comparator s? : Use without innovation (i.e. c urrent liquid or lyophilized formulation )


Section 1: Summary of innovation
1.1 Examples of innovation types :
Lyophilised formulation

Foam -dried , freeze -dried , and spray -dried formulations

Image source: a Image source: a
1.2. D escription of innovation:
The controlled temperature chain (CTC) is an innovative approach to vaccine management allowing
vaccines to be kept at temperatures outside of the traditional cold chain of +2?C to +8?C for a limited period
of time under monitored and controlled conditions , as appropriate to the stability of the antigen. A CTC
typically involves a single excursion of the vaccine into ambient temperatures not exceeding +40?C and for
a defined duration , just prior to administration. b An example of a CTC qualified vaccine is the
meningococcal A conjugate vaccine, MenAfriVac, which was granted a label variation by the appropriate
National Regulatory Authority and WHO for its use in a CTC at temperatures of up to 40 oC for four days. c
The innovation being assessed refers to dry formulations that are heat -stable and CTC -qualified . Vaccines
with these attributes are able to be exposed to ambient temperatures below a defined threshold
temperature without losing their potency and have received regulatory and WHO prequalification approvals
to allow CTC storage. Dry formulations vary in their sensitivity to heat and suitability for use in a CTC.
Therefore, this innovation only considers a subset of dry formulations that meet these criteria.
Curr ently all dry vaccine formulations that are commercially available require reconstitution with a diluent
and are delivered in a liquid presentation (injectable and oral routes) . New delivery technologies, such as

? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when mu lti-dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. a Lovalenti, P.M., Anderl, J., Yee, L. et al. Pharm Re s (2016) 33: 1144. https://doiorg.ezp.welch.jhmi.edu/10.1007/s11095 -016 -1860 -1. b https://www.who.int/immunization/programmes_systems/supply_chain/ctc/en/ c https://www. who.int/immunization/documents/WHO_IVB_13.04_5_6/en/

VIPS Phase I executive summary:
Dual - chamber delivery devices
June 2019
Dual -chamber delivery devices
About Dual -chamber delivery devices
? Dual chamber delivery devices are fully integrated
reconstitution technologies that are prefilled with liquid and dry
vaccine components, which are mixed within the device and
administered.
Stage of development
? A wide variety of technologies are at various stages of
development, from early design stage through commercial
availability.
? No vaccines are licensed in dual chamber delivery devices.
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.pdf chttps://www.webpackaging.com/en/portals/webpac/assets/11138717/neopacs -fleximed -now -in-large -format/

11.06.2019 Page 1 of 20
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Dual -chamber delivery d evice s
Comparator ? : Single dose vial , diluent , reuse prevention recon N&S and autodisable
(AD ) needle and syringe (N&S )


Section 1: Summary of innovation
1.1 Examples images:
Dual -Chamber delivery device:
Vetter Lyo -Ject? Syringe


Fleximed? Easymix


Image source : b Image source: Neopac c

1.2. Description of innovation:
? Integrated reconstitution technologies such as d ual -chamber delivery devices and dual -chamber
vials pair dry vaccine with diluent in one technology to simpl ify the process of reconstitution.
Vaccine components are stored in different compartments of the same device and then more easily
mixed and administered at the time of use. Dual -chamber delivery devices are fully integrated
reconstitution technologies that include the delivery device.
? The reconstitution of vaccines for immunization represents a public health challenge due to the
potential for error during the transfer of diluent to the vial cont aining lyophilized (freeze -dried)
vaccine using a reconstitution syringe . Errors in using t raditional reconstitution systems include use
of the incorrect volume of diluent ; reuse of reconstitution syringes, causing contamination; use of
improperly stored diluent that can render a vaccine ineffective ; use of an incorrect diluent ; or worse,
using a potentially deadly liquid drug as a diluent by mistake. Adverse events as a result of
reconstitution errors can include local abscesses, toxic shock syndrome, or even death (1).
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. b https://www.pharmaceutical -networking. com/vetter -dual -chamber -delivery -systems/ c https://www.webpackaging.com/en/portals/webpac/assets/11138717/neopacs -fleximed -now -in-large -format/

VIPS Phase I executive summary:
Dual chamber vials
June 2019
Dual chamber vials
About dual chamber vials
? Dual -chamber vials are integrated primary containers with a
reconstitution feature.
? They contain both liquid and dry vaccine components , which are mixed
together within the device prior to administration which requires a separate
delivery device.
Stage of development
? Most dual -chamber technologies are at an early stage of development .
? No vaccine products are currently approved for use in dual -chamber vials, but some
other pharmaceutical products are licensed in dual -chamber presentations, such as the Act -
O -Vial which is used with Pfizer?s Solu -Cortef and Solu -Medrol products (both
glucocorticoids to treat allergic reactions and/or inflammation).
? Although some of these dual -chamber technologies are available for market use, they
would need to be approved with a specific antigen .
? Preliminary research with some prototype devices has been carried out with vaccines.
PATH
Dual chamber vial (Pfizer Act -O-Vial)

11.06.2019 Page 1 of 15
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Dual chamber v ial s
Comparator ? : Single dose vial (lyophilised ) + diluent + reuse prevention (RUP)
reconstitution needle and syringe ( N&S )


Section 1: Summary of innovation
1.1 Examples images:
Dual -chamber vial:
Pfizer Injectable Act -O-Vial System.

1.2. Description of innovation:
? Integrated reconstitution technologies such as d ual -chamber delivery devices and dual -chamber
vials pair dry vaccine with diluent in one technology to sim plify the process of reconstitution. Dual -
chamber vials are integrated primary containers with a reconstitution feature , but require a separate
delivery device. The separate v accine components are stored in different compartments of the
same device and the n reconstituted and administered (with a separate delivery device) at the time
of use.
? The reconstitution of vaccines for immunization represents a public health challenge due to the
potential for error during the transfer of diluent to the vial cont aining lyophilized (freeze -dried)
vaccine using a reconstitution syringe . Errors in using t raditional reconstitution systems include: use
of the incorrect volume of diluent ; reuse of reconstitution syringes, causing contamination; use of
improperly stored diluent that can render a vaccine ineffective ; use of an incorrect diluent ; or worse,
using a potentially deadly liquid drug as a diluent by mistake. Adverse events as a result of
reconstitution errors can include local abscesses, toxic shock syndrome, or even death (1).
? Immunization programs may benefit from reconstitution technologies that eliminate or reduce the
risk of error and are more convenient and safe when compared to the traditional, reconstitution
method of diluent transfer using a needle and sy ringe.
? Dual -chamber vials can be used for any vaccine that requires mixing of multiple components. This
TN focuses on dual -chamber vials for vaccines for parenteral delivery that require mixing of a liquid
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation . However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised.
Image source: provided by PATH.

VIPS Phase I executive summary:
Freeze damage resistant liquid formulations
June 2019
Freeze damage resistant liquid formulations
About Freeze damage resistant liquid formulations
? Many vaccines are freeze -sensitive , including those containing aluminium adjuvants. When
vaccines containing aluminium adjuvant are frozen, the antigen -adjuvant particles
agglomerate (form a cluster) and sediment resulting in the irreversible loss of potency.
? Developing novel freeze -stable formulations using different excipients (stabilising agents)
could prevent agglomeration and stabilise the potency of vaccines .
? The addition of excipients such as glycerin, polyethylene glycol 300, or propylene glycol (PG)
has been demonstrated to reduce the freeze -sensitivity of hepatitis B vaccine and other
vaccines containing aluminum -salt adjuvants including diphtheria, tetanus and pertussis
(DTP); and pentavalent (hepatitis B, DTP, Haemophilus influenza type b) vaccines.
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 for pediatric use.
? There has been some testing and pre -clinical studies with hepatitis B, pentavalent,
diphtheria, tetanus toxoid and pertussis 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

12.06.2019 Page 1 of 15
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Freeze damage resistant liquid formulations
Comparator : Use without innovation (i.e. current liquid formulations)

Section 1: Summary of innovation
1.1 Example images :

Image s ource : a


Image s ource : b


1.2. D escription of innovation:
? Vaccines need to be stored at their proper temperature to maintain their potency, which is
commonly at 2 -8oC.
? Vaccines can be exposed to multiple freeze -thaw cycles and long durations of sub -zero
temperatures along the different segments of the cold chain . For freeze -sensitive vaccines, this can
result in physical, chemical and immunological changes to the formulation, reduced potency of the
vaccine, administration of sub -optimal vaccine , local reactions to the vaccine such as st erile
abscesses, and increased wastage (if the freeze exposure is identified and the vaccine is
discarded) (1) .
? Many vaccines are freeze -sensitive, including those containing aluminium adjuvants. When
vaccines containing aluminium adjuvant are frozen, the anti gen -adjuvant particles agglomerate and
sediment which results in the irreversible loss of potency.
? Freeze damaged vaccines can be detected using the ?shake test?, but it is not always performed
given lack of training and the need for a control vaccine to c onduct the test.
? Developing novel freeze stable formulations using different excipients could prevent 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 (2) and other vaccines
contai ning aluminum adjuvant including diphtheria, tetanus and pertussis (DTP); and pentavalent
(hepatitis B, DTP, Haemophilus influenza type b) vaccines (3) .

a https://www.myelomacrowd.org/wp -content/uploads/2015/05/vials.jpg b https://www.publichealthontario.ca/en/BrowseByTopic/Infectio usDiseases/PIDAC/Pages/Infection -Prevention -and -Control -for-Clinical -Office - Practice -Multidose -Vials.aspx

VIPS Phase I executive summary:
Freeze indicator on primary vaccine
containers
June 2019
Freeze indicator on primary vaccine containers
About Freeze indicator on primary vaccine containers
? Freeze indicators are labels that respond by changing color or activating alarm
devices in case of exposure to freezing temperatures and that can be attached
to a vaccine primary container.
? There are two types of freeze indicators:
? Electronic , which are digital devices
? Chemical -based
? The indicators are single -use only and are irreversible, so even if the
surrounding temperature in which the vaccine is stored increases after a freezing
event, the alarm or colour change on the freeze indicator will remain unchanged.
Stage of development
? Many freeze indicators are commercially available , however, some have not yet
been miniaturized to make them suitable for placement on a vaccine primary
container.
Tempmate
a
Electronic device ( Tempmate .?-i1)
C TI Links
b
Freeze alert technology ( BlindSpotzTM )
Temptime
c
A self -adhesive label
(Temptime FREEZEmarker ?)
ahttps://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf bhttps://www.ctiinks.com/blindspotz -freeze -alert chttp://temptimecorp.com/temperature -indicators -sensors/freeze -indicator/

11.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Freeze Indicator on primary vaccine container s
Comparator s: No freeze indicator on the primary vaccine container and use of
standalone freeze indicators and temperature monitoring devices


Section 1: Summary of innovation
1.1 Examples of innovation types:

Electronic Freeze indicators Chemical indicators
Tempmate.? -i1(electronic
device)

BlindSpotz TM freeze alert
technology

Temptime FREEZEmarker ?? A
self -adhesive label


Image source: a Image source: b Image source: (1)

1.2. D escription of innovation:
? The innovation is a freeze indicator that can be attached to a vaccine primary container. These devices
are single -use only and irreversible , so even if the ambient temperature goes back to normal or
increases, the alarm or colour change on the freeze indicator will remain unchanged.
? There are two types: electronic indicators and chemical indicators (refer to Section 1.1).
? For detailed explanation about the different indicators refer to Table 1.



a Photo source: https://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf b Photo source: https://www.tempmate.com/wp -content/uploads/sites/2/tempmate -i1-Datasheet -EN.pdf

VIPS Phase I executive summary:
Intradermal (ID) Devices
June 2019
Intradermal (ID) Devices
About ID Devices
? ID devices and delivery devices used to inject vaccines into epidermal and dermal layers of the
skin . They have been developed to improve the ease and accuracy of ID injections which are
given at an acute angle to the skin to deposit the vaccine just below the surface (Mantoux technique).
? ID devices are grouped into three sub -types for this assessment:
1. Needle hubs and syringe adapters (with needles) that fit onto the end of luer syringes. They
have an integrated short needle or needles (typically less than 1.5 mm) that only penetrate the
skin to the depth of the dermis.
2. Syringe adapters (without needles) that attach to standard Bacille Calmette -Guerin (BCG) or
insulin syringes with needles are designed to control the angle & depth of needle penetration.
3. Field -filled ID syringes that resemble a standard syringe but incorporate some form of needle
(e.g. plastic needle) for filling and a short (less than 1.5 mm) needle for injection.
Stage of development
? Some ID devices have received regulatory approval as medical devices e.g. 510(k) in the USA or
CE mark in Europe. One ID adapter and one needle -hub are available commercially.
? ID devices are not combination products and might not require approval with a specific vaccine
from a named manufacturer.
? Several other devices are in very early stage of development and most/all of the devices in
development do not include auto -disable (AD) features .
www.nanopass.com
Needle -hub
Tsals I, Jarrahian C
b
Syringe -adapter
(without needle)
www.cugh.org
a
Field -filled ID syringe.
Star intradermal safety
device
ahttps://www.cugh.org/sites/default/files/TS01.2_Zehrung.D.pdfbTsals I, Jarrahian C, Snyder FE, Saganic L, Saxon E, Zehrung D, et al. Clinical performance and safety of adapters for intradermal delivery with conventional and auto disable syringes. Vaccine. 2015 Sep 8;33(37):4705 ?11.

12.06.2019 Page 1 of 28
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Intradermal (ID) syringes
(not in cluding prefilled ID syringes or ID D isposable Syringe Jet Injector s)
Comparator: Bacille Calmette -Guerin ( BCG ) autodisable ( AD ) needle and syringe
(N&S) a, using Mantoux technique

Section 1: Summary of innovation
1.1 Examples of innovation types :

Syringe -adapter (without
needle): ID adapter


Needle -hub: MicronJet 600




Syringe adapter with needle:
Vax -ID (classified as a needle -
hub in this assessment)


Image source: (1) Image source: b Image source: c
1.2. D escription of innovation:
ID vaccination uses inexpensive and widely available BCG N&S. To achieve the correct depth of injection
the needle is inserted at an acute angle to the skin to deposit the vaccine just below the surface (Mantoux
technique) . The v olume administered is less than for subcutaneous ( SC ) or intramuscular ( IM ) injection,
typically 0.05 ml or 0.1 ml. This technique is widely used in lower and middle income countries ( LMICs ) as
BCG is given at birth to all infants in LMICs (2) .
Relatively few vaccines are given ID compared with the IM and SC routes . In recent years, there has been
interest in using the ID route with other vaccines because the epidermal and dermal layers of the skin are
rich in immune cells , so delivery of vaccines to these sites could increase vaccine immunogenicity, resulting
in the same immune response being induced with less antigen (?dose -sparing?) (3) . This can be important
for vaccines that are supply -constrained, or expensive, or that have sub -optimal immunogenicity in hard -to-
immunise subgroups. ID delivery does not result in dose -sparing for all vaccines however, and in some
cases (e.g. yellow fever), dose -sparing is possi ble without changing the route of the injection (4) .
Inactivated poliovirus vaccine (I PV) (5?7) and rabies virus vaccines (8) , are administered ID to large
numbers of people in some settings to take advantage of dose -sparing, and are given using the Mantoux
technique . Experience with these vaccines has shown that it is feasible to implement an immunization
campaign using BCG N&S to deliver ID IPV (9) , and to switch from IM to ID administration of rabies vaccine
for post -exposure prophylaxis (10) .
Some researchers however consider the Mantoux technique to have several drawbacks including :
a The N&S used for ID vaccination is referred to using several names including: 1 ml, 0.1 ml, BCG, insulin or allergy syringes. For clarity, these are all referred to as BCG syringes in this report. The technique used for ID injection is referred to as the Mantoux technique. b https://www.nanopass.com/technology/ c Vax -ID spec sheet https://novosanis.com/delivery -solutions/vax -id

VIPS Phase I executive summary:
Heat - stable/Controlled Temperature Chain
(CTC) qualified liquid formulations
June 2019
Heat -stable/controlled temperature chain (CTC)
qualified liquid formulations
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 for 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 stored in a CTC and the maximum
temperature they can endure while remaining stable and potent.
? CTC qualification involves regulatory approval and prequalification by WHO.
Stage of development
? There are currently two liquid vaccines that are thermostable and qualified for CTC use .
? Merck?s Gardasil? 4 (quadrivalent human papillomavirus vaccine) that could be used at
temperatures up to 42 ?C for 3 days
? Shantha Biotechnics Shanchol ? (oral cholera vaccine) that could be used at temperatures up
to 40 ?C for 14 days.
? A number of vaccine manufacturers are in the process of qualifying their existing and pipeline liquid
vaccines for CTC use.
? Several developers have created approaches to stabilising formulations, some of which are proprietary,
that may be applicable to a variety of vaccines to improve their heat stability in liquid formulations.

11.06.2019 Page 1 of 17
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Heat -stabl e /c ontrolled temperature chain (C TC )
qualified liquid formulation s
Comparator s: Use without innovation a (i.e. current liquid or lyophilised formulation)


Section 1: Summary of innovation
1.1 Example images :



1.2. D escription of innovation:
? Historically, vaccines are most commonly formulated and packaged as liquids . Liquid formulations
require simpler fill/finish and administration processes than other formulations.
? Heat stable liquid formulations (such as those inc orporating stabilizing agents) enable vaccines to
be exposed to high temperatures (e.g., a minimum of 3 days at ?40 OC) without losing their potency
and can thus be CTC qualified. b Such formulations require optimized properties (e.g. buffer, pH,
salt conce ntrations and stabilizing excipients) to prevent denaturing of proteins and reduce the
occurrence of damaging chemical reactions caused by increasing temperature.
? Heat -stabilized vaccines will differ in the length of time they can be stored in a CTC and th e
maximum temperature they can endure while remaining stable and potent, and some vaccines will
not be able to be reformulated into a heat -stable liquid.
Each vaccine will require an individual development process to identify an appropriate stabilizing
formulation. High -throughput screening method s can be used to expedite formulation optimisation
(1) .
1.3 Examples of innovations and developers:
There are currently two liquid vaccines that are thermostable and qualified for CTC use. These are:
Merck?s Gardasil? 4 (quadrivalent human papillomavirus vaccine) that is labelled to allow use at
temperat ures up to 42?C for 3 days and Shantha Biotechnics Shanchol? (oral cholera vaccine) that is
labelled to allow use at temperatures up to 40?C for 14 days .
A number of vaccine manufacturers are in the process of qualifying their existing and pipeline liquid
vaccines for CTC use.
a no comparator or equivalent existing device. b WHO. Controlled Temperature Chain publications and guidance. https://www.who.int/immunization/programmes_systems/supply_chain/ctc/en/index1.html

VIPS Phase I executive summary:
Microarray patches (MAPs)
June 2019
Microarray patches (MAPs)
About MAPs
? MAPs consists of an array of micro -projections on a patch .
? These 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 a
Stage of development
? Various formats of MAPs are being developed for vaccine delivery by a number of different
developers.
? Three developers have tested influenza vaccine MAPs in phase I clinical trials , and
preclinical development is underway with other vaccines, including 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
a Lead candidate MAPs for vaccine delivery either have no applicator or an integrated applicator. Therefore, MAPs with a separa te applicator are not considered in this assessmen t bhttp://micronbiomedical.com/technology/chttps://www.who.int/immunization/research/meetings_workshops/PDVAC_2017_Delivery_Tech_Update_Zehrung_PATH.pdf?ua=1

11.06.2019 Page 1 of 23
VIPS is a Vaccine Alliance project fro m Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Microarray patch es (MAP)
Comparator s? : Single dose vial ( liquid ) and autodisable (AD) needle and syringe (N&S) ;
SDV + diluent + reuse prevention (RUP) reconstitution N&S and AD N&S


Section 1: Summary of innovation
1.1 Example images :

Image source: a

Image source: b

Image source: c

1.2. D escription of innovation:
MAPs consist of an array of hundreds or thousands of micro -projections on a ?patch?. The projections are
coated with, or composed of, vaccine in a dry formulation. When applied to the skin, the vaccine is
delivered into the dermis and/or epidermis, which are rich in antigen presenting cell ( APCs ).
Several different formats of MAPs are being developed:
? With, or without, appl icators; when present, the applicator can be a separate component or
integrated with the MAP . The most advanced MAPs in development either have no applicator or an
integrated applicator. Therefore, MAPs with a separate applicator are not considered in this
assessment ;
? Solid micro -projections coated with vaccine;
? Micro -projections formed of vaccine plus biocompatible excipients that dissolve or biodegrade in the
skin;
? Hydrogel micro -projections that swell in the skin and act as a conduit fo r diffusion of the active
ingredient from a backing layer (primarily in development for drug delivery).
In theory, MAPs could be used for administration of any type of vaccine, although there might be some
vaccine -specific limitations: it might not be possible to formulate some vaccines so that they remain potent
during the manufacture or storage of MAPs; some vaccines ( in particular those formula ted with an
adjuvant) might have unacceptable levels of local reactogenicity when delivered into the skin; a nd in some
cases, MAPs might not have the payload capacity for the vaccine plus necessary excipients, or it might not
be possible to concentrate the antigen sufficiently so that it can be loaded onto the MAP.

? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases, the innovation being considered is a single -dose presentat ion. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. a Image provided by David Hoey, V axxas, 15 May 2019 b http://micronbiomedical.com/technology/ c https://www.who.int/immunization/research/meetings_workshops/PDVAC_2017_Delivery_Tech_Update_Zehrung_PATH.pdf?ua=1

VIPS Phase I executive summary:
Oral fast dissolving tablets
June 2019
Oral fast dissolving tablets
About Oral fast dissolving tablets (FDTs)
? Fast dissolving tablets are freeze dried vaccine tablets that disintegrate
rapidly in saliva.
? Oral FDTs are swallowed and rapidly disintegrate, delivering the
vaccine to the gastrointestinal tract.
Stage of development
? There are several pharmaceutical companies with drug products on
the market using a similar technology for producing oral FDTs.
? Oral FDTs are in preclinical development for vaccines such as
ETEC.
CIMA
a
PATH
ahttp://www.cimalabs.com/technology/lyoc.aspx

12.06.2019 Page 1 of 21
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Oral fast dissolving tablet s
Comparator s? :
? Single dose vial ( lyophilised ) + diluent + reuse prevention (RUP) reconstitution
syringe and dropper ;
? Single dose vial (liquid) and autodisable (AD) needle and syringe ( N&S )


Section 1: Summary of innovation
1.1 Examples images:



Photo source: provided by PATH
1.2. D escription of innovation:
? Fast dissolving tablets (FDTs) are freeze dried vaccine tablets that disintegrate rapidly in saliva,
requiring no/minimal fluid for oral administration. This feature allows the FDTs to be dispersed in
situ for adults or dispersed in minimal volume for administration to infants, thus eliminating any
hazards associated with choking.
? Oral FDTs are swallowed and rapidly disintegrate (not f orming a gel under the tongue like
sublingual dosage forms described in the Sublingual Dosage Form TN). This innovation is thus
delivered to the intestines and not absorbed in the mouth. This is particularly relevant for vaccines
against enteric pathogens that replicate in the gut.
? FDTs can be delivered through several routes of administration including oral, sublingual, buccal,
vaginal, or rectal. This TN will focus on FDTs for oral delivery. Referred to as oral FDTs in this
document. Sublingual FDTs, wh ich are placed under the tongue and form a gel upon contact with
saliva, will be discussed in the Sublingual Dosage Form TN.
? The small tablets are packaged in unit -dose blisters made from foil or other pharmaceutical grade
material, offering an inexpensive, scalable, and easy -to-use product presentation for live attenuated
vaccines.
? Some n ew oral enteric vaccines in development are complex vaccines with multiple components
(e.g., multiple strains, mucosal adjuvant, and antacid buffer ) that often must be packaged separately
due to cross -reactivity during testing or formulation incompatibility (1,2). With traditional
lyophilization being carried out in glass vials, this results in multiple vials and large footprint in
?Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation . However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised.

VIPS Phase I executive summary:
Plastic needles (for reconstitution)
June 2019
Plastic needles (for reconstitution)
About Plastic needles (for reconstitution)
? Polymer needles designed to be capable of penetrating vial
septums could be used for reconstitution and access vaccine
products.
? These needles could be designed to be attached to a reuse
prevention (RUP) syringe or integrated into a RUP syringe itself .
Stage of development
? Plastic needles have obtained regulatory approval as medical
devices .
? At present, there are no commercially available reconstitution
syringes with plastic needles . However, there are prototypes
available and commercial products could be adapted for this purpose.
PATH
K Spike Reconsitution syringe
a Busillo E, Colton JS. Characterization of plastic hypodermic needles. J Med Device. 2009;3(4):41004.
Plastic hypodermic needle
Busillo & Colton, 2009
a

11.06.2019 Page 1 of 17
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
P lastic needl e s (for recon stitution )
Comparator : Reuse prevention reconstitution (RUP) needle and syringe (N&S) with
metal needle


Section 1: Summary of innovation
1.1 Examples of innovation types:
Plastic hypodermic needle

Image source: (1)
K Spike Reconsitution syringe


Image source: a

1.2. Description of innovation:

? Various designs and prototypes of polymer needles have been produced and tested in terms of
functionality and comparability to metal needles (1,2) .
? Plastic needles can be designed with a luer hub for attachment to a separate syringe or can be
integrated into the syringe itself.
? Some polymer needle designs are intended to have sharpness similar to metal hypodermic needles
and could be used to puncture vial stoppers as well as to penetrate the skin for parenteral injection.
Some developers have focused on plastic needles that would be intended to be suitable only for
use for accessing a vial. Other niches for plastic needles could include veterinary, pha rmacy, or
industrial purposes. This Technical Note (TN) is focused solely on vaccine reconstitution with plastic
needles intended for vial access use , and not for injection, because of their potential safety benefits.
? At present, there are no commercially available reconstitution syringes with plastic needles.
However, there are prototypes available and commercial products that could be adapted for this
purpose.


a Courtesy of PATH, personal communication.

VIPS Phase I executive summary:
Prefilled polymer blow - fill - seal droppers /
dispensers
June 2019
Prefilled polymer blow -fill -seal (BFS) droppers /
dispensers
About prefilled polymer BFS droppers/dispensers
? Blow -fill -seal is an aseptic filling process that is widely used to produce a variety of
pharmaceuticals in polymer primary containers.
? In BFS process, a polymer resin is melted into a parison , which is blown into a mould , filled, and
sealed, all in a continuous process within a single piece of equipment. This is in contrast to
preformed polymer squeeze tubes, in which the container is first produced and sterilized, and then
shipped to a different site for filling and sealing.
? A BFS dropper produces metered -size droplets and could be used for small dose volume
vaccines such as oral polio vaccine (OPV) , including multidose presentations. A BFS dispenser
emits a stream of vaccine and could be used for oral vaccines such as rotavirus and cholera that
typically have a larger dose volume.
Stage of development
? BFS dispensers are currently manufactured and commercially available .
? In 2019, GlaxoSmithKline?s (GSK?s) Rotarix oral rotavirus vaccine was the first vaccine to be
WHO prequalified in a BFS container.
? Other vaccines are being evaluated for BFS dispenser presentations.
PATH
BFS squeeze tube dispensers (GSK Rotarix)

11.06.2019 Page 1 of 17
VIPS is a Vaccine Alliance project from Ga vi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Prefilled polymer BFS dropper s /dispenser s
Comparator ?: Single dose vial (liquid ) and dropper/dispenser


Section 1: Summary of innovation
1.1 Example images :
PATH prototype of BFS oral squeeze
tube in a five -dose strip

Image: provided by PATH
1.2. D escription of innovation:
? Blow -fill -seal (BFS) is an aseptic filling process that is widely used to produce a variety of
pharmaceuticals in polymer primary containers. In the blow -fill -seal process, a polymer resin is
melted into a parison, which is blown into a mould , filled, and sealed, all in a continuous process
within a single piece of equipment. This is in contrast to preformed polymer primary containers, in
which the container is first produced and sterilized, and then shippe d to a different site for filling and
sealing.
? A wide variety of different container designs are feasible with BFS .
o For oral or intranasal vaccines, BFS containers can be designed as squeeze tube dropper or
dispenser devices for delivery of the container?s contents directly to the mouth or nostrils.
This approach is the focus of this Technical Note.
o For single -dose parenteral vaccines, BFS containers can be used similar to glass ampoules,
with the top twisted off and an AD N&S used to draw up and inject the vaccine. BFS
containers can also be designed with inset septum, similar to a glass vial. These innovation s
are reviewed in the Parenteral BFS Primary Container Technical Note.
o BFS has the potential to be used for production of compact prefilled autodisabl e devices
(CPADs), which are reviewed in the CPAD Technical Note.
? For the existing vial presentations of liquid and lyophilised vaccines, single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases, the innovation being considered is a single -dose presentation. However, when multi -dose vials are currently used by countries and would be the true comparator for countries , a comparison against the multi -dose vial will also be condu cted under Phase II if this innovation is prioritised and for antigens where multi -dose vials are used by countries.

VIPS Phase I executive summary:
Prefilled dry - powder intranasal (DPIN)
devices
June 2019
Prefilled dry -powder intranasal (DPIN) devices
About Prefilled dry -powder intranasal (DPIN) devices
? A wide range of DPIN devices are being developed or are already on the market for delivering
medicines. DPIN devices fall into two basic categories based on the activation method:
? Passive devices that use mechanical energy from fingers or thumb to generate
pressure to disperse the powder;
? Active devices (breath actuated powder inhalers) that use breath flow to activate expulsion
from the container filled with the powder to enable dispersion into the nasal passageway.
? Powders would likely reach only the nare (s) to which they are administered, and it is possible to
administer doses to each nare .
? Dry powder vaccines for intranasal delivery require specialised drying methods to achieve a
formulation that is aerosolizable and of appropriate particle size for efficient delivery to the nasal
cavity.
? Various studies have demonstrated the feasibility of preparing dry powder aerosolized vaccines
using a variety of methods such as spray -drying, bubble drying (a gentle version of spray
drying), spray -freeze drying or freeze -drying methods.
Stage of development
? Most of the devices are commercially available , however their uses for vaccine delivery
are in early phase preclinical studies and early phase clinical trials.
Bespak
a
Passive device ( Unidose Bespak )
Optinose
? b
Active device
(Bi-Directional? nasal delivery
technology, Optinose ?)
aPersonal communication from Ian Anderson, Bespak , February 2015 bhttps://www.optinose.com/exhalation -delivery -systems/powder -delivery -device

11.06.2019 Page 1 of 22
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Prefilled dry -powder intranasal (DPIN ) device s
Comparator ? : Single dose vial (lyophilised ) + diluent + reuse prevention (RUP)
reconstitution needle and syringe (N&S) and autodisable N&S a


Section 1: Summary of innovation
1.1 Example images :
.
Unidose b Bespak

Bi-Directional? nasal delivery
technology , Optinose?


Image source: c Image source : d

1.2. D escription of innovation:
? There are a whole range of dry powder intranasal (DPIN) devices that are being developed or
already on the market for delivering medicines.
? DPIN d evices fall into two basic categories based on the activation method used . Most of the
devices use (i) mechanical energy from fingers or thumb to generate pressure to dispers e the
powder, and others use (ii) passive or active breath flow to disperse the powder. Powders would
likely reach only the nare (s) to which they are administered, and it is possible to administer doses to
each nare. There may be some increased risk of pulmonary deposition of powders if the particle
size range includes small particles ( 5 micron).
? Powder sprayers are d evices that deliver IN dry powder sprays by c reating an internal pressure on
the compartment containing the formulation through an external mechanical force driving the
release of powder particles into the nasal passageway , they use mechanical energy to create and
internal pressure and these are know n as passive devices . Examples include the UniDose ,
DriDose TM, Fit -lizer TM .
? Breath a ctuated powder inhalers are active devices that allow the patients ? breath to activate
expulsion from the ca psule or blister containing the dry powder formulation into the nasal
passageway . An example is the Rhinocort? Turbuhaler? . The Rhinocort device uses nasal
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation bein g considered is a single -dose presentation. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is priorit ised. a A comparison against IN sprays will be required under Phase II if there is a vaccine (antigen) that is currently delivered as liquid spray in the scope of vaccines. b Universal Stabilization technologies. https://www.vitrilife.com/ c Personal communication from Ian Anderson, Bespak, February 2015 d https://www.optinose.com/exh alation -delivery -systems/powder -delivery -device

VIPS Phase I executive summary:
Radio Frequency Identification (RFID)
June 2019
Radio Frequency Identification (RFID)
About Radio Frequency Identification (RFID)
? RFID tags can be affixed to vaccine primary containers and store a wide range of information
useful for inventory control, patient monitoring and providing data for electronic medical
record systems.
? An RFID system consists of three components; ( i) a tag, (ii) a reader and (iii) the middleware ,
which is the computer hardware and software that connects the reader to computer systems by
converting data captured from tags into tracking or identification information.
? RFID tags also enable all the tags within range to be identified and every tag does not need to be
individually scanned.
There are three types of RFID tags:
? Passive tags ? which do not contain a built -in power source and cannot initiate communication
with a reader.
? Semi -passive RFID tags ? which have built -in batteries and function with a lower signal power
and act over long distances.
? Active RFID tags ? which are battery powered devices that have an active transmitter and can
communicate over greater distances.
Stage of development
? RFID tags are commercially available and are widely used as a tracking system in a variety of
industries including agriculture, food, pharmaceuticals and various healthcare practices for the
tracking of patients, medical supplies and medical equipment in hospitals.
a http://endtimestruth.com/wp -content/uploads/2014/01/RFID -chip -and -antenna -3.png b http://ww1.prweb.com/prfiles/2014/10/05/12223944/HCL%20 -%20Seal%20Tags%20Kit%20Check.jpg c https://www.abr.com/products/rfid -products/
http://endtimestruth.com
a
RFID Tag
ww1.prweb.com
b
RFID tags used for hospital medication trays
www.abr.com
c
Handheld RFID readers & scanners

12.06.2019 Page 1 of 20
VIPS is a Vaccine Alliance project fro m Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Radio Frequency Identification (RFID)
Comparator: Use without innovation (i.e. no RFID)


Section 1: Summary of innovation
1.1 Example images :
RFID tags RFID readers
RFID tag


Image source : a
RFID tags used for
hospital medication trays

Image source : b
RFID tag attached to drug

Image source : c
Handheld RFID readers &
scanners

Image source : d
Android App to
scan RFID

Image source : e




a http://endtimestruth.com/wp -content/uploads/2014/01/RFID -chip -and -antenna -3.png b http://ww1.prweb.com/prfiles/2014/10/05/12223944/HCL%20 -%20Seal%20Tags%20Kit%20Check.jpg c http://www.radiofrequency -tags.com/photo/pl13237005 - programming_printable_rfid_tags_for_identifying_medicine_bottles_to_track_prescription_drugs.jpg d https://www.abr.com/ products/rfid -products/ e https://dribbble.com/shots/1142633 -Android -App -RFID -Scan

VIPS Phase I executive summary:
Reconstitution vial adapters
June 2019
Reconstitution vial adapters
About Reconstitution vial adapters
? Vial adapters can facilitate either:
? Vial to vial reconstitution using a reuse prevention (RUP) syringe without needle for diluent transfer
(this sub -type is assessed in the TN);
? Vial to vial reconstitution by directly connecting the two vials without the use of a syringe for diluent
transfer; or
? Reconstitution between a syringe prefilled with diluent and vaccine vial . A prefilled syringe (without a
fixed needle) containing the diluent is attached to the vaccine vial using the vial adapter as a connecting
device. The diluent is then released into the vial through the vial adapter for mixing.
? Vial adapters are manufactured in a variety of sizes , and function by fitting over the top of a vial, while
utilising a plastic spike to puncture the rubber stopper. Most designs are compatible with luer lock and
luer slip syringes for liquid transfer.
? For oral or intranasal delivery, the delivery syringe can be connected to the vial adapter to draw the dose.
? For parenteral vaccines, the vial adapter would be removed after reconstitution and an autodisable (AD)
needle and syringe (N&S) used to draw and inject the vaccine.
Stage of development
? A variety of reconstitution vial adapters are commercially available .
? ROTASIIL vaccine is supplied with a vial adapter for reconstitution and
drawing doses for oral delivery. The vaccine is a lyophilised (freeze -dried)
presentation packaged in single -dose vials alongside a diluent.
West Pharmaceutical
a
Vial adapters for reconstitution using a syringe
West Pharmaceutical
a
Vial adapters for reconstitution using a syringe
West Pharmaceutical
b
Vial adapters for direct vial to vial reconstitution
ahttps://www.westpharma.com/products/reconstitution -and -transfer -systems/vial -adapters bhttps://www.westpharma.com/products/reconstitution -and -transfer -systems/mix2vial -and -needle -free -transfer -device Chttps://www.google.com/search?q=Rotasiil+Rotavirus+Vaccine&hl=en&source=lnms&tbm=isch&sa=X&ved=0ahUKEwj -986zh -jgAhW Fa1AKHbkdCucQ _AUIDigB&biw=1920&bih=861#imgrc=8XeGpeGcrBc7W M:&spf=1551687780860
Serum Institute of India PVT. Ltd
c

11.06.2019 Page 1 of 19
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Reconstitution vial adapters
Comparator ? : Use without innovation (i.e. reuse prevention reconstitution needle and
syringe (N&S) )

Section 1: Summary of innovation
1.1 Examples of innovation types:

Reconstitution vial adapters

Vial adapters
West Pharma





Mix2Vial ?
reconstitution
system
West Pharma


MixJect ? reconstitution &
delivery system
West Pharma


EZ LINK ? Duoject


Image source: a Image
source: b Image source: c Image source: d
1.2. Description of innovation:

? Vial adapters facilitate the reconstitution of two vaccine components from their separate primary
containers. The objective of the innovation is to eliminate the needle from the reconstitution
process, making it safer.
? Vial adapters are manufactured in a variety of sizes and used to facilitate reconstitution and/or
drawing up of a wide variety of pharmaceutical products including medicines and vaccines.
? A vial adapter functions by fitting over the top of a vial, while utilizing a plastic spike to puncture the
rubber stopper. Most designs are compatible with Luer lock and Luer slip syringes for liquid transfer.
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation . However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritis ed. a https://www.westpharma.com/products/reconstitution -and -transfer -systems/vial -adapters b https://www.westpharma.com/products/rec onstitution -and -transfer -systems/mix2vial -and -needle -free -transfer -device c https://www.westpharma.com/products/reconstitution -and -transfer -systems/mixject d http://duoject.com/wp -content/uploads/2016/01/EZLink_InformationCard.pdf

VIPS Phase I executive summary:
Single - chamber cartridge injectors
June 2019
Single -chamber cartridge injectors
About single -chamber cartridge injectors
? Vaccine delivery device that has a needle and that requires insertion of a
prefilled cartridge of vaccine product.
? Based on the design of the device, the needle could be either exposed or not
exposed.
? Some cartridge injector devices have auto -disable (AD) mechanisms and/or
sharps injury protection (SIP) needle retraction mechanisms .
Stage of development
? Currently all the single -chamber cartridge injector devices are in the design or
development phase for use with vaccines.
? There are no independent testing or user studies available on the use of the
devices in comparison to standard practice using the AD needle and syringe
(N&S), and therefore no independent information exists on ease of use, time
required to prepare and deliver, or cost and storage volume of the devices.
Pradel G et al, 2017
a
Pre -assembled device
(JUDO glass cartridge injector)
Vaccject
TM b
User -assembled devices with
integrated needle with no sharps
exposed (Vaccject TM)
a Pradel G, Leader CT, Carestia S, Manager M. JUDO A new paradigm on compact and low cost vaccine delivery devices. 2017; bhttp://duoject.com/wp -content/uploads/2016/01/Vaccject_InformationCard -1.pdf

11.06.2019 Page 1 of 18
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Single -chamber cartridge injectors
Comparator : Single Dose Vial (SDV) liquid and Autodisable ( AD ) Needle and Syringe
(N&S )


Section 1: Summary of innovation
1.1 Examples of innovation types:

JUDO ? a cartridge injector prototype


Image source : (1)
Vaccject TM

Image source : a
1.2. Description of innovation:
? There is a large market for delivery devices that utilize prefilled cartridge technology, e.g., the
pen injectors that deliver drugs for chronic conditions such as diabetes and hormone
deficiencies whereby repeat injections are necessary and administered by the patient
themselves or the caregiver. Prefilled cartridges are also widely used to deliver anaesthesia for
dental applications.
? Prototypes of s ingle -chamber cartridge injectors for vaccines are single -dose presentations that
use pre -filled glass cartridges and are manually operated devices.
? The pre -filled cartridge is inserted into the delivery device that has a needle attached which is
either exposed or not exposed based on the design of the device , this is known as the user -
assembled device which is the main focus of this technical note (TN) for the assessment.
a https://www.who.int/immunization/research/meetings_workshops/PDVAC_2017_Delivery_Tech_Update_Zehrung_PATH.pdf

VIPS Phase I executive summary:
Solid - dose implants with applicator
June 2019
Solid -dose implants (SDIs) with applicator
About SDIs
? SDIs consist of vaccines (including antigens, adjuvants and excipients) that have been
reformulated into a solid format .
? A SDI 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 prior to
administration.
? 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.
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 W ijdeven 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.

11.06.2019 Page 1 of 22
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Solid -dose implants (with applicator) a

Comparator s? : Singl e dose vial (liquid ) and autodisable (AD) n eedle and syringe (N&S) ;
Single dose vial (lyophilised) + diluent + reuse prevention (RUP) reconstitution
N&S and AD N&S.

Section 1: Summary of innovation
1.1 Example s of innovation types :
Separate, compressed gas -
powered applicator: Bioneedle

Separate, spring -powered
applicator: Implavax?

Optional, separate applicator:
Micropatch TM


Image source: (1) Image source: b Image source: c
1.2. D escription of innovation:
Solid -dose implants (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 b elow the skin. After injection, the dose either dissolves immediately or is released slow ly
depending on the formulation. SDIs are also described as bioneedles (one of the SDI developers is also
called Bioneedles), pellets, bars, bio -degradable mini -implan ts, or mini -projectiles.
SDI devices have two or three components:
? The vaccine dose : This is in a solid format. Some SDIs have a central cavity of known volume filled
with liquid vaccine that is then dried. In other SDIs the vaccine and excipients are dis tributed
uniformly throughout the implant. Ideally the dose would be sufficiently thermostable to allow
storage and distribution outside the cold chain for a defined period of time.
? Vaccine dose container or cassette : In some cases, the solid vaccine dose is contained in a
cartridge or cassette for easy handling. This is expected to have a relatively small volume, possibly
similar to a single dose vial.
? An applicator or actuator : is used to propel the implant into the skin, using a spring or
compressed -gas . The applicator might be separate and re -usable, or integrated and single use. In
one device (Micropatch), manual pressure is used to deliver the implant .
a All SDIs require an applicator including separate gas - or spring -powered, or integrated applicators ? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation. However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the mu lti- dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritised. b https://www.enesipharma.com/technologies/platform/ c Nemaura presentation. Teripa ratide microneedle patch for osteoporosis, December 2018. Presented during telecon 12 February 2019.

VIPS Phase I executive summary:
Sublingual dosage forms
June 2019
Sublingual dosage forms
About Sublingual dosage forms
? Sublingual dosage forms are tablets and thin films that are placed under the tongue and
rapidly dissolve to form a gel in a small amount of saliva.
? The gel is absorbed via the mucosal surfaces under the tongue inducing systemic
immunity, similar to an injectable vaccine, and potentially inducing robust mucosal immunity.
? In contrast to oral ingestion vaccination, sublingual dosage forms are not intended to be
swallowed or delivered to the intestinal tract.
Stage of development
? Sublingual dosage forms are in early -stage preclinical development for several vaccines including HIV Env
protein and ETEC. The mucosal adjuvant dmLT is also being evaluated.
? Some have progressed to clinical trials including a seasonal influenza vaccine combined with a novel adjuvant in a
sublingual tablet.
? Most studies of sublingual vaccines to date have not utilised optimised sublingual dosage forms that form a gel ,
which resulted in poor immune responses.
? Commercially available sublingual dosage forms are used to deliver allergy immunotherapies, low molecular weight
drugs, and therapeutic vaccines.
PATH
Gel -forming sublingual
tablet being placed under
the tongue

11.06.2019 Page 1 of 30
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Sublingual dosage form s
Comparator s?:
? Single dose vial (liquid ) and dropper or spray er a;
? Single dose vial (lyophilised) + diluent + reuse prevention (RUP) reconstitution
syringe and dropper sprayer;
? Single dose vial (liquid) and autodisable (AD) needle and syringe (N&S);
? Single dose vial (lyophilised) + diluent and RUP reconstitution syringe and AD N&S.
Section 1: Summary of innovation
1.1 Examples images:


Photo source : Provided by PATH

Photo source : LTS Lohmann
1.2. D escription of innovation (1,2):
? Sublingual (under the tongue) administration allows direct absorption into the systemic circulation .
? The sublingual region under the tongue is highly vascularized, rich in blood supply , allowing for
direct absorption of the active into systemic circu lation. It also contain s numerous subsets of antigen
presenting cells ( APCs ) and plays a critical role in induction of immune response s offering a non -
invasive route for vaccine administration .
? The sublingual dosage forms reported in this TN have been developed to contain penetration
enhancers and mucoadhesive agents to assist with antigen uptake by the underlying APCs similar
to an injectable formulation (IM/SC/ID routes) . Sublingual delivery is a needle -free and simplified
alternative presentation to a parenteral vaccine.
? In addition to systemic immunity, sublingual delivery also has the potential to induce robust mucosal
immunity.
? Oral mucosal vaccination (i.e. sublingual and buccal route s) is distinct from oral ingestion
vaccination be cause the dosage form is not intended to be swallowed or delivered to the intestines.
? The sublingual route has the potential to induce mucosal immune responses in a broad range of
tissues at more distance sites compared to other mucosal routes (i.e. the r espiratory ,
gastrointestinal, or reproductive tract) (1).
? Sublingual dosage forms can be produced via different manufacturing processes such as direct
compression, melt extrusion, liquid blending or freeze drying.
? Single dose vials, rather than multi -dose vials (MDVs) were used for the comparator, because in most cases the innovation being considered is a single -dose presentation . However, when multi -dose vials are commonly used by countries for specific vaccines, a comparison against the multi - dose vial will also be conducted under Phase II for those vaccines if this innovation is prioritis ed. a The dropper or sprayer comparator is expected to be delivered by the oral or intranasal route.

1
VIPS Phase II executive summary:
Autodisable Sharps - Injury Protection
Syringes (AD SIPs)
March 2020
2
Autodisable (AD) sharps -injury protection (SIP)
syringes
About AD SIP syringes
? AD SIP syringes are single -use, disposable syringes with a mechanism that
covers the needle after use to reduce the risk of accidental needlestick
injury .
? Mechanisms include retraction of the needle into the barrel after injection or a
needle shield .
? Some syringes have SIP features that are automatically activated, and others
require extra activation steps by the end user.
Stage of development
? AD SIP syringes are commercially available .
? A list of available World Health Organization (WHO) -prequalified AD SIP syringes
can be found in the WHO Performance, Quality, and Safety (PQS) catalogue. b
WHO
a
A VanishPoint ? retractable syringe
(Retractable Technologies, Inc.)
PATH
BD Eclipse? syringe (BD, Franklin
Lakes, NJ) with needle shield
ahttp://apps.who.int/immunisation_standards/vaccine_quality/pqs_catalogue/LinkPDF.aspx?UniqueID=f3025136 -636d -4139 -9773 -fdbf82427 6e1&TipoDoc=DataSheet&ID=0 . bWHO PQS Category E008 auto -disable syringe for fixed dose immunisation page :http://apps.who.int/immunisation_standards/vaccine_quality/pqs_catalogue/categorypage.aspx?id_cat=37 .

VIPS PHASE 2 TECHNICAL NOTE

Autodisable sharps injury protection syringes




30.03.2020
Page 1 of 39
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Autodisable (AD) sharps -injury protection (SIP) syringe s

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

Technology overview
AD SIP syringes are single -dose, disposable syringes with a mechanism that covers the needle after use to reduce the risk of accidental needlestick inju ry.
Summary of vaccine and innovation compatibility :
This innovation applies to all parenteral vaccines and addresses safety issues related to vaccine handling by preventing needlestick injuries and syringe re use.
The innovation is best applied to vaccines intended for routine immunization and mass campaigns (fixed dose immunizations) ,a where health care workers will be
delivering intramuscular, subcutaneous or intradermal injections b (as shown in Table 1) . For all vaccines to which the innovation applies, the comparator is delivery
of the vaccine with an autodisable needle and syringe ( AD N&S) that lacks the SIP feature. Not all vaccines are compatible with the innovations based on mode of
administration (Table 2); for example, vaccines that are delivered non -parenterally.
The problem statement which applies to each vaccine that could p otentially be addressed by AD SIPs is presented in Table 1. The key property of AD SIPs that is
relevant to the problem statement is their ability to either shield or retract the needle after administration, which could reduce the likelihood of needlestick injury and
transfer of bloodborne pathogens to patients, health care workers, and the community after vaccine administration.
The vaccines considered, or not considered for use with AD SIP syringes in this Technical Note are summarised in Table s 1 and 2 respectively.
Problem statement to be addressed:
The problem statement applying to each vaccine that could potentially be addressed by AD SIP syringes is:
? Needle -stick injuries: AD SIP syringes have a feature to reduce the risk of needle -stick injury (NSI) , as shown in Table 1 .



a World Health Organization (WHO), United Nations Children?s Fund (UNICEF), United Nations Population Fund. WHO -UNICEF -UNFPA Joint Statement* on the Use of Auto -disable Syringes in Immunization Services . WHO/V&B/99.25. Geneva: WHO; 2003. https://apps.who.int/iris/bitstream/handle/10665/63650/WHO_VB_99.25_eng.pdf?sequence=1 b WHO. WHO Guideline on the U se of Safety -Engineered Syringes for Intramuscular, Intradermal and Subcutaneous Injections in Health Care Settings . Geneva: WHO; 2016. https://apps.wh o.int/iris/bitstream/handle/10665/250144/9789241549820 -eng.pdf?sequence=1

1
VIPS Phase II executive summary:
Barcodes on primary containers
March 2020
2
Barcodes on primary containers
About Barcodes
? Barcodes are symbols that encode information such as product numbers, serial numbers, supplier data,
batch numbers and expiry dates which can be scanned electronically using two dimensional (2D) scanners,
laser or mobile device cameras to automatically capture information.
? Barcodes enable tracking and monitoring of vaccine products in supply chains, providing information to
manufacturers, transport providers, health facilities and other relevant parties involved in the logistics
management systems, assuming the supporting infrastructure is in place.
? 2D barcodes can hold a significant amount of information and there is a possibility to automatically import
vaccination data into patient electronic medical records (EMRs).
Stage of development
? 2D Barcodes are commercially available and are widely used on products globally across various
industries including for products used in healthcare . Many US and European vaccine suppliers provide 2D
barcodes on primary containers, though not for the Gavi/UNICEF markets.
? WHO currently recommends GS1 compliant barcodes for secondary and tertiary packaging of vaccines
containing the Global Trade Item Number (GTIN), vaccine expiry date and vaccine batch/lot number. Gavi and
UNICEF recently announced that GS1 barcoding on vaccine secondary packaging will be a requirement by
31 December 2021 to improve visibility and traceability of vaccines from manufacturer to beneficiary.
Newswire.ca
a
a https://www.newswire.ca/news -releases/sanofi -pasteur -moves -national -immunisation -strategy -forward -with -new -bar -code -technology -509575151.html
PATH
2D barcode on primary container
Barcode on secondary packaging

VIPS PHASE 2 TECHNICAL NOTE

Barcodes




30.03.2020
Page 1 of 31
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

2D Barcodes
Technology overview:
This innovation is defined as the application of 2D barcodes to vaccine primary packaging labels. They are symbols that encode information such as
vaccine product numbers, serial numbers, supplier data, batch numbers and expiry dates which can be scanned electronically us ing laser scanners
or mobile device cameras to automatically capture information.
Cu rrently, barcodes are used on secondary and tertiary packaging of vaccine s providing product identification information, expiration date and lot
number a. The use of barcodes on secondary and tertiary packaging primarily provides vaccine inventory, supply and efficiency benefits. However,
this evaluation assumes barcode placement down to the primary packaging level and t he predominant public health benefit s will be at the health
facilit y levels to improve accurate documentation of vaccine information in patient records , help reduce programmatic errors, facilitate tracking of
AEFIs and vaccine recalls, and improve timely and equitable vaccine coverage.
Radio -frequency identification (RFID) versus barcodes on primary vaccine containers:
The RFID tag is a type of labelling technology used in many different industries that can store vast amount s of information useful for inventory
control, equipment tracking, patient monitoring and providing data for electronic medical record systems. Similar t o barcodes, RFID tags can track
and trace items and link to other systems like GPS, temperature, or vaccination records. The original intention was to review both RFID tags and
barcodes on primary vaccine packaging during the VIPS phase II analysis. Howeve r, deeper evaluation of the technologies revealed that , for the
foreseeable future, RFID tags on primary vaccine packaging are not appropriate for the lower - and middle -income public sector markets that Gavi
serves .
RFID tags differ from barcodes in the pr ocess of capturing data/information as they require a dditional computer hardware and software to connect
the reader to computer systems and data repositories, by converting data captured in the form of radio signals from tags into tracking or
identificatio n information . There are different types of RFID tags (passive, semi -passive and active) that can transmit radio signals over variable
distance s, using different levels of power. As a result, RFIDs can quickly capture data in mass , whereas barcodes are des igned to be scan ned on
items one at a time in the line of sight of a laser. RFIDs are therefore particularly suited for higher levels of packaging (e.g., tertiary) for inventory
control at higher levels of health systems, for example, where all vaccine boxes on a pallet can be scanned at on ce and where the costs of the
scanning system can be spread across higher product volumes .
For the primary packaging level, RFIDs have some drawbacks in comparison to barcodes including:
? Barcodes can be read with smart phones or simple scanners, while RFID tags require more complex and expensive equipment for scanning.
barcodes are therefore much more appropriate for use at the health facility levels where they can be scanned for patient reco rdkeeping as
well as inventory purposes.
a About Two -Dimensional (2D) Vaccine Barcodes, CDC. https://www.cdc.gov/vaccines/programs/iis/2d -vaccine -barcodes/about.html

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

Combined Vaccine Vial Monitor and Threshold Indicator




30.03.2020
Page 1 of 41
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:
Compact prefilled auto - disable devices
(CPADs)
March 2020
2
Compact prefilled auto -disable devices (CPADs)
About CPADs
? CPADs are integrated primary containers and injection devices prefilled with liquid vaccines .
They have features to prevent reuse and minimize the space required for storage and shipping.
Three CPAD subtypes have been assessed:
? Preformed CPADs: Squeezable polymer device, m anufactured ?open? and supplied sterile and ready
to fill/seal by the vaccine manufacturer.
? Blow -fill -seal (BFS) CPADs: produced, filled, and sealed in a continuous BFS process.
? Pre -assembled (with needle attached) and user -assembled configurations are possible 1.
? Other CPAD types: D esigns are in development leveraging prefilled syringe components.
Stage of development
? One preformed CPAD, Uniject TM , is commercially available .
? Uniject TM presentations of P enta , HepB and TT vaccines were WHO prequalified in 2006, 2004
and 2003 respectively. The pentavalent and tetanus toxoid products have been discontinued.
Medroxyprogesterone acetate (similar to Depo -Provera) is also commercially available in Uniject TM .
? BFS and other CPAD types are in design phases.
drugdeliverysystems.bd.com
a
Preformed CPAD (Uniject TM)
PATH
BFS CPAD ( Apiject )
INJECTO
TMb
Other CPAD ( Easyject )
a https://drugdeliverysystems.bd.com/products/prefillable -syringe -systems/vaccine -syringes/uniject -auto -disable -pre -fillable -injec tion -system ; b http://injecto.eu/easyject/
1During the Phase I VIPS review, the Steering Committee suggested de -prioritising user -assembled BFS CPAD configurations because they ha ve fewer
potential benefits than all other CPAD types, due to the greater number of components and preparation steps, and risk of prep ara tion and delivery errors and
contamination.

VIPS PHASE 2 TECHNICAL NOTE

Compact prefilled auto -disable device (CPAD)




30.03.2020
Page 1 of 60
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.

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

Dual -chamber delivery device




30.03.2020
Page 1 of 50
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:
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

Freeze Damage Resistant Liquid Formulations




30.03.2020
Page 1 of 37
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:
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

Heat stable/CTC qualified liquid formulations




30.03.2020
Page 1 of 63
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:
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

Microarray patches




30.03.2020
Page 1 of 75
VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF

Microarray patches ( MAPs )

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

Technology overview :
MAPs consist of an array of hundreds or thousands of micro -projections on a ?patch?. The projections are coated with, or composed of, vaccine in a dry
formulation. When applied to the skin, the vaccine is delivered into the dermis and/or epidermis, which a re rich in antigen presenting cell (APCs).
Several different formats of MAPs are being developed:
? With, or without, applicators; when present, the applicator can be a separate component or integrated with the MAP. The most advanced MAPs in
development either have no applicator or an integrated applicator. Therefore, MAPs with a separate applicator are not considered in this
assessment;
? Solid micro -projections coated with vaccine;
? Micro -projections formed of vaccine plus biocompatible excipients that dissolve or biodegrade in the skin;
? Hydrogel micro -projections that swell in the skin and act as a condui t for diffusion of the active ingredient from a backing layer (primarily in development for
drug delivery).
In theory, MAPs could be used for administration of any type of vaccine, although there might be some vaccine -specific limitations: it might not be possible to
formulate some vaccines so that they remain potent during the manufacture or storage of MAPs; some vaccines (in particular th ose formulated with an adjuvant)
might have unacceptable levels of local reactogenicity when delivered into the skin; a nd in some cases, MAPs might not have the payload capacity for the vaccine
plus necessary excipients, or it might not be possible to concentrate the antigen sufficiently so that it can be loaded onto the MAP.
Summary of vaccine and innovation compatibility :
Microarray patches ( MAPs ) could potentially be used to deliver any vaccine that is currently administered by injection with needle and syringe (N&S). The
technology does have some features that might however preclude its use with some vaccines, in particular:
1. Reactogenicity: MAPs deliver vaccines to the skin rather than intramuscularly (IM) or sub -cutaneously (SC). The subsequent initial immune response
takes place near the skin surface and is more visible as local reactogenicity, than with IM or SC injections. While this administration route may offer the
potential for dose -sparing for some vaccines, reactogenicity seen with MAP delivery of some ?more -reactogenic? formulations might not be acceptable to
recipients.
The reactogenicity seen with MAP delivery of some ?more -reactogenic? vaccines might not be acceptable to recipients.
The inherent reactogenicity of any of the priority vaccines has NOT been considered in this analysis, and no vaccines have been excluded on this basis.
Reactogenicity due to inclusion of an adjuvant HAS been considered (see below).

 

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

Solid -dose implants




30.03.2020
Page 1 of 63
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.