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)

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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:
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/

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VIPS is a Vaccine Alliance project from Gavi, World Health Organization, Bill & Melinda Gates Foundation, PATH and UNICEF
Compact prefilled auto -disable device 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)

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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.

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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

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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.

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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