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HPV

2 December 2008

Vaccine Presentation and Packaging Advisory Group (VPPAG):
Human Papillomavirus (HPV) vaccine presentation and packaging

 

Purpose

To provide recommendations to industry for Human Papillomavirus (HPV) vaccine packaging and presentations suitable for use in public sector immunization programmes in developing countries.

 

Previous VPPAG recommendations

The Vaccine Presentation and Packaging Advisory Group (VPPAG) has to date produced recommendations for pneumococcal conjugate vaccine (PCV). The VPPAG has not yet made a recommendation for the optimal number of doses per vial for PCV, because key data on prices and wastage are not yet available.  However, VPPAG did recommend a target product profile for PCV:  

·         Fully-liquid vaccine (ie, does not require preparation by vaccinator)

·         Multi-dose vials formulated to allow use of opened vials at subsequent session (ie, with preservative added)

·         Use of VVM, and ideally a VVM30

·         If freeze sensitive, allow use of shake test or other indicator of freezing

·         Maximum storage volume to be based on Guidelines on the international packaging and shipping of vaccines (WHO/IVB/05.23.) with maximum: 4.0, 6.5, 13.0, and 15.0 cm³ for 10-, 5-, 2-, 1-dose vials, respectively. [Note: the WHO guidelines do not currently state these as maxima for all vaccines; VPPAG derived these suggested maxima for PCV from the ones specified for similar vaccines, and they could apply to all injectable liquid vaccines in future recommendations]

 

HPV vaccines

While VPPAG’s recommendations for PCV (as above) are applicable for HPV vaccines, the use of HPV vaccines in developing country programmes will be mostly in school and other mass-delivery settings with relatively large session sizes. As session size distribution is one of the key factors in determining optimal number of doses per vial (see workplan paper), there could be different recommendations for HPV than for PCV on the optimal number of doses per vial, as well as consideration of multi-dose vials without preservative.

For PCV, VPPAG recommended multi-dose vials only if was formulated to allow use in subsequent sessions – ie, with preservative.  This was because of the high cost of wastage for these expensive new vaccines.  Although the final AMC TPP did not include this recommendation, VPPAG continues to maintain that for expensive new vaccines in multi-dose vials it is highly preferred to have a preservative to reduce wastage.  In addition, delivery of HPV may allow consideration of a multi-dose without preservative because of large session sizes. 

Adding a preservative to the current HPV vaccine formulations is a possibility, but is likely to reduce vaccine thermostability and possibly efficacy.  The modified product would also require clinical trials and resubmission for regulatory and WHO pre-qualification approvals, though this would require less clinical data than the original submission.  One vaccine manufacturer estimates that this process would entail a financial investment of >$10m and would take at least three years [comment on cost from IFPMA representative]. It could increase the price per dose sufficiently to reduce the potential benefits of such a presentation (from reduced cold chain costs). Hence, an industry analysis of costs and benefits is needed.  For manufacturers with second generation vaccines in early development the addition of a preservative could be a more feasible option.

A key consideration for preferred profile is the price per dose.  For developing country public sector markets, tiered pricing will make vaccines available at lower and ‘not for profit’ prices compared to the prices in industrialized countries and private markets.  Public sector prices for HPV vaccines for developing countries have not yet been set, and prices may be dependent in part on the presentation and packaging, in addition to the quantities demanded and the competitive situation.

Presentation options

There are currently four potential options for an injectable HPV vaccine.  These are outlined in the table below with advantages and disadvantages for each.

Option

Advantages

Disadvantages

Single dose vial

·         Readily available now

·         Minimizes wastage.

·         No preservative needed

·         Safety – limits potential program errors associated with multi-dose vials of vaccine

·         More time to prepare each injection

·         Burden on cold chain and logistics (CCL) systems

 

Single dose, compact pre-filled Auto Disable device (eg, Uniject – see below)

·         Minimizes wastage

·         Uses current formulation (no preservative)

·         Ease of use – saves time

·         Safety - limits potential programme errors associated with multi-dose vials and prevents syringe reuse

·         Reduces overall carried weight for outreach (dose, needle, and syringe)

·         Easy to train non-health workers in safe injection

·         Minimises injection waste

·         Not currently available

·         Expense and time to bring to market (+)

·         ?Cost  per dose likely to be higher– to be further investigated

·         Bulky (2-3 more volume compared with 1-dose vial), so more burden on CCL – except for health workers doing outreach

 

Multi-dose vial without preservative

·         Reduces CCL burden

·         Time-saving in preparation (compared with 1-dose)

·         Reduced cost per dose

·         Short time to availability, as uses current formulation  (2-dose vial already available)

·         Not currently available

·         Expense and time to bring to market  (but less than above)

·         Potentially higher wastage (precise difference uncertain)

·         Risk of contamination from incorrect re-use

·         Regulatory pathway not established (ref: MDVP)

Multi-dose vial with preservative

Same as for multidose without preservative but:

·         Potentially less wastage (precise difference uncertain)

·         Safer than multi-dose vial without preservative as preservative mitigates contamination risk

·         Not currently available

·         Expense and time to bring to market (+++)

·         Potentially more expensive per dose than multi-dose without preservative because of development and production costs

 

As can be seen from the advantages and disadvantages of the above four options, there is potential for any of these to used, depending on various issues.  More information is needed for countries to determine which would be their optimal presentation, and at present, only a single dose vial is available, for which the main challenge is its cold chain burden.  A two-dose vial may be available shortly that would halve the cold chain burden, but these savings would be balanced by the additional costs of wastage.

Single-dose, compact pre-filled auto-disable (AD) devices known as Uniject devices have been used successfully in developing countries for delivery of tetanus toxoid and hepatitis B vaccine birth doses. These vaccines were taken beyond the cold chain (because of heat stability of these products) in Uniject using vaccine vial monitors (VVMs) to monitor heat exposure and were administered by non-traditional health personnel (ie, traditional birth attendants and lay health workers).  [see references].

Becton-Dickinson (BD) has also advised that Uniject can be cost-saving especially for expensive vaccines as less ‘over-fill’ is required compared to a single dose vial, and the cost of the Uniject shell is similar to the cost of vial plus injection equipment.  But industry has not yet been convinced, and only one manufacturer has a vaccine in UNIJECT prequalified by WHO. Currently prices for this presentation are much higher per dose compared to the per dose price of 1- or 10-dose vials. 

A multidose vial without preservative is a viable option if the WHO MDVP is revised along the lines recommended by VPPAG in the MDVP paper.  This is expected by around end 2009 .The Expert Committee for Biological Safety (ECBS, 2006) approved in principle the development of HPV vaccines in multidose vials without preservative:

Current human papilloma virus (HPV) vaccines are manufactured in single-dose presentations without the addition of preservative. In the future, the availability of multi-dose vaccine vials would facilitate the adoption of innovative vaccination strategies targeting pre-adolescents and adolescents in developing countries. If these vaccines do not contain preservative, the use of such vaccine vials should be time-restricted as is the case of reconstituted vaccines such as Bacillus Calmette-Guérin (BCG) and measles-containing vaccines. If a preservative were to be added, the effect on antigenicity and immunogenicity must be assessed and known not to have a negative impact as has been observed with thiomersal.

At present, the only HPV vaccine formats available for use from the vaccine manufacturers are 1-dose and 2-dose vials without preservative. Both are currently under review for WHO prequalification.

 

Thermostability

HPV vaccine is very heat stable and freeze sensitive.[1] Yet, the current labelling, based on routine practice, recommends refrigerated storage temperatures (+2 to +8oC).  This labelling does not allow for potential use of this vaccine without a cold chain (eg, transport at controlled ambient temperatures for outreach services to schools and individuals or in health centres with no functioning refrigerators).  The ability to keep the vaccine at higher temperatures would reduce the risk of freeze damage[2] to the vaccine in the cold chain, reduce the burden on cold chain and logistics capacity, and extend potential utilization for ‘deep’ outreach to very hard-to-reach communities.

VPPAG recommendations and workplan

At  present,  VPPAG  can recommend all HPV presentation options (single dose vial, single dose pre-filled compact device, multi-dose vial with preservative, or multi-dose vial without preservative), with the caveat that a multi-dose vial without preservative requires an update to WHO’s multi-dose vial policy (MDVP).

A recommendation on preferred presentation(s) is contingent upon further information and analysis, much of which needs to  be undertaken by industry, to provide VPPAG with an indication of the cost per dose in the different presentations compared to programme costs and benefits.

VPPAG recommends the following to help define optimal HPV vaccine presentations:

1.      The Optimize Project is requested to recruit a consultant to finalize development of the Vaccine Presentation Assessment Tool (VPAT), including building in the costs for cold chain and logistics expansion (ie, average costs for additional storage space), and on session sizes. The VPAT should be developed to guide generic recommendations on the optimal number of doses per vial, to help countries to make choices, as well as to analyse the relative cost-benefit of CCL expansion vs. the costs of developing a new presentation.

2.      The VPPAG secretariat (and PATH member) should liaise with the PATH HPV vaccine demonstration projects and other sources to gather data (such as session size, session time, feedback on Uniject, and potential out of cold chain temperature exposures) and other relevant programmatic data that will influence the ideal target product profiles for HPV vaccines.

3.      Industry is encouraged to develop a business case (with BD) for HPV vaccine in Uniject, including analysis of country demand as provided by PATH.  Filling HPV vaccine in other pre-filled auto-disable devices should also be explored.

4.      Industry is requested to provide to VPPAG an indication, in general terms that would not interfere with commercial sensitivity, of the costs and time that it would take to develop multi-dose vials with and without preservative, and the relative per-dose price (or range) that could be offered for supply for developing country public sector use of the different presentations in the short and long term for IFPMA and DVCMN manufacturers. 

5.      If supported by available stability data, industry is encouraged to register HPV vaccines for use at higher temperatures as opposed to the usual storage requirement of 2-8oC.

6.      Assuming that HPV vaccines have heat stability that exceeds 30 days at 37 oC,  WHO and Temptime are encouraged to develop a wider range of VVMs beyond the VVM30 to facilitate the use of products with improved thermostability and, in turn, encourage manufacturers to develop them.

Uniject references:

Quiroga R et al. A prefilled injection device for outreach tetanus immunization by Bolivian traditional birth attendants. Pan American Journal of Public Health. 1998;4(1):20–25.

Sutanto A et al. Home delivery of heat-stable vaccines in Indonesia: outreach immunization with a prefilled, single-use injection device. Bulletin of the World Health Organization. 1999;77(2):119–126.

Otto B et al. At-birth immunisation against hepatitis B using a novel pre-filled immunisation device stored outside the cold chain. Vaccine. 2000;18:498–502.

d’Alois LA et al. Impact of delivery technologies on increased access. TT-Uniject report, Mali. BASICS-II, 2004.

Levin CE et al. The costs of home delivery of a birth dose of hepatitis B vaccine in a prefilled syringe in Indonesia. Bulletin of the World Helath Organization. 2005;83:456–461. 



[1] Shank-Retzlaff ML, et al.Evaluation of the Thermal Stability of Gardasil. Human Vaccines  2006; 2:4: 147-54.

[2] Freezing has been found to be a common occurrence in nearly all cold chain surveys See: Matthias DM, Robertson J, Garrison MM, Newland S, Nelson C. Freezing temperatures in the vaccine cold chain: a systematic literature review. Vaccine. 2007;25(20):3980-6.

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Dec 28, 2010, 2:54 PM
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dkristensen@path.org,
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