Transport and storage of vaccines in Hungary: the first cold chain monitor study in Europe.

Researchl Recherche Transport and storage of vaccines in Hungary: the first cold chain mo-nitor study in Europe L. Lugosi' & A. Battersby2 With assistance from WHO the Hungarian Ministry of Health organized two cold chain studies: the first in three counties in summer (1 July to 30 September 1987), the second in six counties (including the previous three) in winter (1 January to 31 March 1988). The counties were chosen according to their distance (50- 300 km) from Budapest, individual districts and child health centres being selected randomly. All participants were trained before beginning the studies. The vaccines (DPT, measles and BCG) for immunization, with attached cold chain monitors, were transported from the manufacturers to the child health centres using the normal distribution systems in the country. The whole cold chain process was analysed with regard to (1) actual exposures to adverse temperatures and delays in distribution; (2) the places where such exposure or delay occurred; (3) the percentage of vaccines at risk of deterioration (actual and predicted) at the end of the study; and (4) the performance of refrigerators of different types. Evaluation of the results (using WHO's EPIC software) showed significant deviations from acceptable standards. This first cold chain study in a European country proves that even in a temperate climate and with a reasonably well-organized public health service there can be significant weaknesses in the transportation and storage of vaccines. Recommendations to overcome these deficiencies are given. Introduction Although the cold chain is a prerequisite in tropical countries, it had been assumed that temperate climates would not be a problem for vaccine distribu- tion and that managerial and logistical difficulties in an industrialized country would be minimal."b How- ever, it appears that countries with a temperate climate can experience serious cold chain failure and should take care to protect vaccines against extreme National Coordinator and Head, Division for Control of Medical 3iologicals, National Institute of Hygiene, Budapest. Present address: Professor of Preventive Medicine and Director, rDNA- BCG Laboratory, Molecular Vaccines Inc., 19 Firstfield Rd, Gaithersburg, MD 20878, USA. 2 Consultant, Expanded Programme on Immunization, World Health Organization, Geneva, Switzerland. Present address: Tellisford, Bath BA3 6RL, England. Requests for reprints should be sent to this author. ' Training for mid-level managers to manage the cold chain system. Unpublished document WHO-EPI/MLM/CC/Rev. " WHO logistics and cold chain for primary health care. How to use the vaccine cold chain monitor. Unpublished document WHO- EPI/Log 84/27, 1984. Reprint No. 5093 winter and summer temperatures and ensure that they are used within a specified period of time. Cold chain studies in such countries provide essential information on the efficiency of the managerial pro- cess and functioning of the cold chain. To monitor the conditions during transportation and storage of vaccines from the manufacturer to the child immuni- zation centres a protocol for using the cold chain monitor (CCM) was introduced by WHO in 1979.c The present paper describes the organization, implementation and results of the two Hungarian CCM studies which were carried out in 1987 and 1988. Materials and methods Hungary (93030km2), a country with intermediate economic and technical development, has a total GNP of 900 x 1O forints for 10.7 million inhabitants (1 US$ = 50 forints). The adult to child ratio is about 3:1 and the live birth rate, 13 per 1000. Budapest has 2.1 million inhabitants in 22 districts; the rest of the I WHO protocol for a cold chain review using vaccine cold chain monitors. Unpublished document WHO-EPI/CCIS/85.2, 1985. Bulletin of the World Health Organization, 66 (4): 431-439 (1990) © World Health Organization 1990 431 L. Lugosl & A. Batteraby Table 1: Geographical and demographic features and detalls about the country Area 93 030 km2 Location Longitude 160 05' to 200 55' E Latitude 450 45' to 480 35' N Altitude From 78 to 1015 m above sea level Temperature: Average lO1C Minimum -120C Maximum 35°C Population: Total 10 700 000 Newborns 150 000 per annum 0-14 years old 2 400 000 In Budapest 2 100 000 No. of counties 19+ Metro Budapest No. of districts 140+22 (in Budapest) No. of health facilities Approx. 3200+100 (in Budapest) country is divided into 19 counties and 140 districts (Table 1). Fig. 1 shows the counties that participated in the study. The Hungarian climate is temperate continental with summer temperatures rarely exceed- ing 35 °C and a winter temperature which infrequent- ly falls below -12 'C. Public health organization The public health policy is coordinated by the Epidemiological Division of the Ministry of Health in Budapest (EDMOH), and each of the 19 counties has a county public health headquarters (CPHH). Within Budapest and the 19 counties there are 162 district public health services (DPHS), and within the districts there are 3300 child health centres (CHC) with preventive and curative sections. The preventive section is responsible for the immunizations. Vaccines. The triple DPT (diptheria, pertussis, tetanus) vaccine is manufactured and distributed every 3 months by the Human Institute (Budapest) to the DPHS using the normal postal system. Measles vaccine is manufactured in Moscow by the Viral Vaccine Institute and transported to Budapest where it is stored in the National Institute of Hygiene (NIH); after testing for potency it is distributed twice a year in cold boxes from the NIH to the county and district levels and finally to the child health centres. BCG vaccine is manufactured by the NIH in Buda- pest and distributed every 3 months to the maternity service clinics (MS) by post. Cold chain monitors (CCM). These were supplied by WHO's Expanded Programme on Immunization (EPI) and, after activation by the Human Institute and the National Institute of Hygiene for their res- pective vaccines, were attached to the vaccine parcels according to the EPI guidelines and the studies' protocol. Each CCM records the cumulative effect of exposure to temperatures above 10°C ("ABC") and 34°C ("D"), the monitors changing colour at varying rates depending on the temperatures. The "ABC" monitor, which has four indexes (-, A, AB and ABC), will completely change colour in 11 days at 21°C or 14 days at 12°C. The "D" monitor, which has two indexes (- and D), changes within 2 hours at tem- Fig. 1. Map of Hungary showing selected countes In the study. 0 50 100 km I I .. I Summer and winter Winter only WHO Bulletin OMS. Vol. 68. 1990432 Cold chain monitoring study In Hungary peratures above 34°C. The monitors are not potency indicators, but show whether the vaccines had been exposed at or above the stated temperatures for longer than the stated time limits. This information is useful to the programme manager to find weaknesses in the cold chain and to decide whether a vaccine consignment may be used. The Freeze Watch moni- tor, which was used in the second study, has two indexes (- and F) changing below -30C.d Implementation of the studies The counties were chosen according to their distance from Budapest: short (50-100 km: Fejer, Nograd and Pest); medium (100-200 km: Gyor-Sopron); and long (200-300 km: Csongrad and Szabolcs-Szatmiar). These six counties cover 28% of the total population of Hungary. The district health services and the child health centres were selected randomly for the cold chain monitoring of the DPT and measles vaccines (40% of the selected counties' child health centres were chosen in summer, and 20% for the winter study); all the maternity services in the six counties were included for the BCG cold chain evaluation. The basic principle and the technical aspects of the monitors were described and demonstrated to the participants during a preliminary consultation with an EPI consultant from WHO in February 1987 and at a meeting of the chiefs of the epidemiological departments of the county public health services in April 1987.' The two studies were carried out from 1 July to 30 September 1987 in Fejer, Gyor-Sopron and Szabolcs-Szatmar counties, and from 1 January to 31 March 1988 in these three as well as Pest, Nograd and Csongrad counties. Follow-up and consultations during the studies were maintained by the national coordinator and the WHO consultant. Four criteria were evaluated: (1) exposures to adverse temperatures and delays in distribution; (2) places where such exposure or delay occurred; (3) Percentage of vaccines at risk of deteriora- tion because of such exposure or delay (actual and predicted); and (4) the performance of refrigerators of different types. At the end of the study the cold chain monitors were collected at the county level and sent to NIH in d Freeze Watch manufactured by PyMatt Corp., Somerville, NJ, USA. ' WHO Expanded Programme on ImmunlzaUon. Vaccine cold chain monitor. Unpublished document WHO-EPI/CCIS/85.1/Rev. 4, 1985. Fig. 2. DPT vaccine cold chain. Summer Budapest Wlnter a= 179 n 166 1 =98.3% 1 31.2% 2 - 0.8% 2 10.4% D - 4.5% F - 0.6% - 13.9% I 5.0 DItrct leveil 11.6% IF -15.6% 1I 5.2% 1 2.8%2 0.6% D - 3.4% D-0.6% Id1e.-11a15.0% 2 10.1% Chiidhealth 2 - 1.2% D - 8.9% contrWH D - 0.6% F -20.2%I A -56.4%A 474AB 17.3% AB - 47.4%ABC -7.3% A 06 AD -11.2% ABC- 1.7% ABD -1.1% Final Index AD - 0.6% ABCD - 3.9% F = 37.61% Budapest. Because at the time a suitable computer was not available in the Ministry of Health the monitors were sent to WHO headquarters for com- puterized analysis using the EPIC software. Data on stock levels, vaccine consumption and type of refri- gerator were also collected. Results This paper presents only the main results, the detailed analysis of the studies appearing in the ftill report which is available on request.' DPT vaccine Adsorbed DPT vaccine has to be protected against extreme heat and freezing; it is distributed by the postal service every 3 months to the district level. Fig. 2 shows in diagrammatic form the changes Bsatersby, A. & Lugosl, L Report on the storage and transport of vaccines in Hungary. Analysis of cold chain monitors used be- tween 1.7.87 and 30.9.87 and between 1.1.88and 31.3.88. Unpub- lished document WHO-CD, Copenhagen, 1989. WHO Bulletin OMS. Vol. 68, 1990 433 L. Lugosl & A. Batteraby observed in the cold chain monitors attached to the DPT vaccine between Budapest and the destinations. The summer exposures are shown on the left and the winter exposures on the right. The ! symbol indicates exposures that could seriously affect the potency of the vaccine. For the ABC monitor the exposure is shown as a rate of change, with a maxi- mum of three changes. One single change may be from - to A, or A to AB, or AB to ABC. It is important to remember that these monitors recorded the cumulative effect; thus, one change during storage in a child health centre could have been from AB to ABC while that during transport from Budapest to the district level could have been from - to A. With Fig. 3. Delays during distribution of DPT vaccines from Budapest. Summer n= 179 the D and F indicators, only one change is possible and this is recorded as D and F, respectively. The final index (Fig. 2) gives the percentage of monitors that recorded changes by the end of the study period. The results show that, for both summer and winter periods, the cold chain for DPT was not satisfactory. Almost all the vaccine was exposed to heat during transport between Budapest and the districts. At the district stores the exposure to heat was much less, but exposure to cold during the winter was considerable. Excessive hot and cold temperatures were experienced during storage at the child health centres so that, by the end of the sum- mer, 4% of the vaccines were seriously compromised; Winter n - 166 .N6gfid | X1 1 d-2 = I100% Fj16r 1-2 days = 83% -: 2-3days= 10% >3days = 7% I: II I -----A I I I I I I 300 250 200 150 100 50 0 0 50 100 150 200 250 300 Distance from Budapest (km) WHO Bulletin OMS. Vol. 68. 1990 I A u4 Whole sample 1 - 2 days = 93% >2 days = 7% FeW 1-2 daYe = 98% :P-2 days - 2% Cold chain monitoring study In Hungary in the winter; 38% had been exposed to below freezing temperatures. Fig. 3 shows the time in days for transport of DPT by the postal service from Budapest to the district level in summer and winter. The ! symbol indicates a problem. The fact that 10.4% of the winter samples recorded two changes in index (Fig. 2) may be attributed to delays of over two days in the post, which is unacceptable considering the relatively short distances involved. At the end of the study not all the vaccines had been utilized. By comparing the final exposure index and the rate of utilization of the vaccines with the quantities in stock, it was possible to predict how much of the remaining vaccine would be exposed to unacceptable conditions by the time it was used. This is described as vaccine which is at risk in Table 2. A long period of storage has two consequences: - qualitative, if there is a loss of potency of the vaccine; and - economic, if excess unused quantities of vaccine are wasted. Fig. 4. Measies vaccine cold chain. Districi A = 5.6% AB = 2.8% ABC = 1.1% D =11.1% AD = 0.6% ABD = 2.8% ABCD = 1.1% WHO Bulletin OMS. Vol. 68. 1990 Table 2: DPT vaccine: percentage of remaining vaccine at risk after the end of the studies Summer (n= 179): Minimal exposures (no risk) 88% Exposures at risk 12% ABCD+ for >3 months 1.7% ABD+ for >3 months 2.2% ABC + for >3 months 2.2% AB+ for >6 months 1.7% A + for >9 months 4.5% Winter (n= 166): Nil exposure 20% Minimal exposures (no risk) 21% Exposures at risk 59% Frozen 38% AB+ for >6 months 13.5% A+ for >9 months 7.6% Measles vaccine Measles vaccine, which is more heat sensitive than DPT but not susceptible to damage by freezing, is distributed twice a year to the district level. Fig. 4 summarizes the cold chain for measles pes Winter No exposure F No exposure No exposure 1 = 0.6% iealth 1 = 2.0% A =2.6% res ndex 435 I L. Lugosl & A. Battersby vaccine. In the summer, during transport and storage of vaccines from the county to district and then to the child health centres, 8% of the monitors recorded changes to "AB" or more, indicating exposures to 21°C or higher for >6 days. In the winter study the only change recorded was 3% for the "A" index. During the summer, delays in transport were slight, with 3% of the monitors taking more than one day to reach their destination. During the winter, delays were longer, with 4% taking more than two days to reach the district level and 7% taking more than 2 days to reach the child health centres; these delays were concentrated in Csongrfad (30% of the subsample) for the former and in Pest (30% of the subsample) for the latter. The delay in transportation was much less than for DPT and BCG vaccines, both of which were sent through the postal service. Given the relatively short distances in Hungary a delay of more than one day is not acceptable. Table 3 shows the percentage of measles vaccine at risk after the end of the studies. It should be noted that although the percentage of critical exposure at the end of the summer study was only 8%, the gross overstocking of vaccine resulted in 21% of the vac- cine being at risk of deterioration before use. Table 3: Measles vaccine: percentage of remaining vaccine at risk after the end of the studies Summer (n= 180) Nil exposure Minimal exposures (no risk) Exposures at risk ABCD+ for any duration ABD + for > 3 months AD+ for >3 months D + for >6 months AB + for >6 months A+ for >6 months Nil+ for >12 months ABC+ for any duration Winter (n= 173) Nil exposure Minimal exposures (no risk) Exposures at risk Nil+ for >12 months 64% 15% 21% 1.1% 2.8% 0.6% 3.9% 0.6% 1.7% 9.7% 0.6% 96% 3% 1% 1.2% BCG vaccine The Hungarian BCG vaccine, when new, is able to tolerate temperatures of 25°C for 60 days without loss of potency below the minimum effective viable units (VU) per dose (100 000 VU/0.1 ml intrader- mally). This vaccine is distributed through the postal service direct to the maternity services (MS). Fig. 5 illustrates the cold chain for BCG vaccine. In summer, all the monitors recorded changes by the Fig. 5. BCG vaccine cold chain. time of their arrival at the maternity services; 31.3% had reached temperatures in excess of 34°C and 6.3% also recorded an exposure equivalent to 11 days at 21°C. In winter, 85.2% of the monitors recorded changes; 22.2% were due to exposures in excess of 21°C for at least 11 days. By the end of the summer study 31.3% of the monitors recorded changes to the "D" index; of these, 18.8% also recorded a change of "ABC". An additional 31.2% had been exposed above 21°C for at least 11 days (ABC). During the winter, by the end of the study 3.7% had been exposed to temperatures above 34°C and 59.3% had experienced temperatures above 21'C for at least 11 days. The effect of heat on a vaccine of low thermal mass, during unprotected transportation, is very marked both in summer and in winter. This suggests that the effects of central heating in postal sorting offices is at least as sig- nificant as the summer ambient temperatures. Table 4 shows the percentage of the BCG vac- cine at risk of deterioration after the end of the studies. The length of time the vaccine is likely to remain in the maternal services results in a very high percentage of the vaccine (50%) being at risk before use. Refrigerator performance There are three main types of refrigerator used for the storage of vaccines in Hungary and their perfor- WHO Bulletin OMS. Vol. 68 19904M Cold chain monitoring sudy In Hungary Table 4: BCG vaccine: percentage of remaining vaccine at risk aftr the end od the studies Summer (n= 16) Minimal exposures (no risk) 50% Exposures at risk 50% ABCD+ for >3 months 18.8% ABC+ for >3 months 12.5% AB+ for > 6 months 12.5% A+ for >9 months 6.3% Winter (n=27) Nil exposure 4% Minimal exposures (no risk) 79% Exposures at risk 17% ABCD + for >3 months 3.7% ABC + for >3 months 11.1% A+ for <9 months 3.7% mance was assessed by measuring the percentage of monitors that underwent change while stored in the refrigerators. Data were combined from the two studies; the freezer compartment was monitored with the CCM and the main compartment with both the CCM and Freeze Watch. The results are summarized in Fig. 6. The Lehel model 50 and 60 refrigerators were not able to ensure safe temperatures. While replace- ment of these models should be the ultimate objec- tive, in the short term their performance could be improved by ensuring that water bottles are kept in the lower part of the refrigerator, thus providing an energy store when the refrigerator is only partly full. Fig. 6. Performance of three models of refrigerator for vaccines In the cold chain (change of Index In CCM and Freeze Watch). 80 0EiZ. CL L 60 L 40 -.......... 0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~00 ~20 .... C 0 Lehei 120 Lehel 60 Lehel 50 Lehel 120 Lehel 60 Lehel 50 CCM' Freeze Watchb At least one change in index. b CCM was placed In the main compartment and the freezer; Freeze Watch was placed in the main compartment only. WHO Bulletin OMS. Vol. 68. 1990 437 L. Lugosi & A. Batteraby Discussion and conclusions This first cold chain study in a European country with a temperate climate has provided information to the Hungarian Ministry of Health and to WHO on the quality of vaccine transportation and storage. The introduction of the cold chain monitor showed that it could strengthen the management of the cold chain, especially in countries with developed pro- grammes. The immunization policy in Hungary is conduc- ted according to the guidelines for the WHO European Region,"h but the results of the present study show considerable weaknesses in the cold chain during transportation and storage of the vaccines. The main matters for concern are as follows: (1) The temperatures the vaccines are exposed to are sufficiently high to cause loss of potency for DPT, measles and BCG vaccines; DPT is also damaged by freezing. (2) The delays and exposures during transporta- tion of BCG and DPT vaccines are sufficient to put them at risk of deterioration. (3) The quality of two models of refrigerators and the method of storage cannot ensure safe storage of the vaccines at all times. (4) Vaccines, especially for measles immuniza- tion, are stored for too long at child health centres. (5) Detailed analysis of the results shows that there are wide variations between the best and worst counties in the present study. The main positive points are: * The cold chain monitors can be used to monitor the cold chain accurately and efficiently. The cost of using them is approximately one tenth of that of conducting comparable serological studies. * The use of the monitors has revealed deficiencies which could not have been observed during routine managerial visits and increased the awareness of the need for efficient cold chain management. * In some counties the quality of cold chain manage- ment is high. * The inadequacies of the cold chain can be pin- pointed to specific locations, at particular levels of ° WHO Immunization policies in Europe. Report on a WHO meet- ing, Karlovy Vary, Czechoslovakia, 10-12 December 1984. Unpub- lished document WHO-EURO ICP/EPI 001, Copenhagen, 1986. Vass, A. The Hungarian practice of immunization and its results. In: Fillastre, C., ed. Childhood immunization acceptability. Seminar on 24-26 February 1986, International Children's Centre, Paris. each cold chain, thus making the task of taking remedial action easier. * It is now possible, using the cold chain monitors, to assess the level of risk of vaccine deterioration during transport and storage. In order to improve the Hungarian cold chain system the following are recommended: (1) Improve the quality of vaccine storage dur- ing transport with better packaging or by using more ice packs (1,2). (2) Minimize delays during dispatch through the postal service by mailing at the beginning of the week and using express delivery. (3) Improve the performance of the existing refrigerators by following the WHO guidelines on maintaining refrigerators; when replacing existing refrigerators, choose the model with the best perfor- mance. (4) Provide sufficient storage space at county and district levels to accommodate the whole of the vaccine stock for one supply period, thus enabling the storage time at health centres to be no longer than six weeks. (5) Provide refresher training for staff con- cerning the storage and handling of vaccines, main- tenance of the cold chain, and estimation of vaccine requirements. (6) Assess the quality of the cold chain in the remaining counties. (7) Request the Ministry of Health (Division of Epidemiology), which is responsible for the coordina- tion of the Public Health Services, to organize ran- dom cold chain monitor studies to evaluate the progress being made in improving the cold chain. This progress should be reported to the Expanded Programme on Immunization at the WHO Regional Office for Europe in Copenhagen. Acknowledgements Thanks are due to the following who contributed in many ways to enable these studies to take place, and to ensure that they were conducted in a thorough manner: Dr A. Vass and Dr A. John (Division of Epidemiology, Ministry of Health); Dr M. Adam, Dr M. Drinoczy, Dr F. Fornosi, Mr M. Korom, Dr 1. Lontai, Dr G. Nyerges and Dr 1. Straub (National Institute of Hygiene); Dr J. Zsidai (Human Institute); and Dr J. Asztalos, Dr 1. Kiss, Dr G. Lencses, Dr M. Melles, Dr 1. Petho, and Dr M. Rethy (County Epidemiological Department). 43 WHO Bulletin OMS. Vol. 68. 1990 Cold chain monitoring study In Hungary R6sum6 Transport et stockage des vaccins en Hongrie: premlire 6tude sur la chatne du frold en Europe Avec l'aide de l'OMS, le Minist6re hongrois de la Sante a organise deux etudes de la chaine du froid: la premi6re a eu lieu dans trois d6par- tements en 6t (1jr juillet au 30 septembre 1987), et la seconde dans six d6partements (y compris les trois prec6dents) en hiver (1je janvier au 31 mars 1988). Les departements ont Wt choisis en fonction de leur 6loignement de Budapest (50-300 km). A l'interieur de chaque d6partement, un certain nom- bre de districts et de centres de sant6 infantile ont ete choisis au hasard. Tous les participants ont recu une formation avant le d6but des etudes. Les vaccins (DCT, anti-rougeoleux et BCG), munis d'in- dicateurs de contr6le de la chatine du froid, ont et6 transport6s depuis les 6tablissements producteurs jusqu'aux centres de sant6 infantile grfce au sys- tome normal de distribution existant dans le pays. L'efficacite de la chaine du froid a 6t analys6e en ce qui concerne: 1) les cas reels d'exposition a des temperatures anormales et les retards de distribution; 2) les endroits ouc ces expositions du retards se sont produits; 3) le pourcentage de vaccins presentant un risque de d6t6rioration (r6el ou pr6vu) a la fin de 1'6tude; et 4) I'efficacit6 des diff6rents types de r6frig6rateurs utilis6s. L'evaluation des r6sultats a I'aide du logiciel EPIC de I'OMS a permis de constater des 6carts significatifs par rapport aux normes consid6r6es comme acceptables. La premibre 6tude de la chaine du froid realisee en Europe montre que, meme dans un pays au climat temp6r6 o'u les services de sante publique sont relativement bien organis6s, le transport et le stockage des vaccins peuvent pr6senter des points faibles. Des recom- mandations visant A corriger la situation ont t formulIes. References 1. Lundbock, H. et al. A cold box for the transport and storage of vaccines. Bulletin of the World Health Organization, 56: 427-432 (1978) 2. Battermby, A. & Jansdaal, P. How to choose and make a cold box. London, AHRTAG, 1983. WHO Bulletin OMS. Vol. 68. 1990 439