Mectizan Program Notes No. 24 text only
Mectizan® Manufacturing Facility, Haarlem, The Netherlands
Mectizan® (ivermectin, MSD) is tabletted and packaged in The Netherlands, at the Merck Sharp & Dohme facility in Haarlem, a city about 20 kilometers or 20 minutes by train from Amsterdam. The Haarlem plant has been the sole source of the Mectizan® provided through the Mectizan® Donation Program (MDP) ever since 1987 when Merck & Co., Inc. announced its plan to donate as much of the drug as needed to treat onchocerciasis, wherever and for as long as required. Consequently, the MSD facility in Haarlem has produced the many hundreds of millions of Mectizan® tablets given in Africa and the Americas since 1987. For the year 2000, the plant is expected to produce around 110 million 3 mg tablets.
Although these production numbers are impressive on their own, to appreciate the full diversity and capacity of the plant, one should recognize that each year, the Haarlem facility produces 2,600 different pharmaceutical products for human health and 600 for animal health and distributes them to more than 140 countries worldwide.
In Haarlem, Mectizan® tablets are made by a skilled team of specialists who work in a section of the facility dedicated entirely to making Mectizan®. Physically, this part of the plant is totally separate from the rest of the MSD installation and operates 24 hours a day in order to keep up with current demand. Plans are underway for building a larger facility in Haarlem in 2000, one which can produce enough more Mectizan® to satisfy what is expected to be a two-fold increase in the amount needed to expand the MDP to treat lymphatic filariasis (LF) in African countries where onchocerciasis is also endemic.
With respect to making Mectizan® tablets, the first step involves preparation of a homogenous powder blend which includes ivermectin, the active ingredient of the drug produced in Merck's chemical plant in Puerto Rico, and several inactive components, namely two anti-oxidizing agents, a binder agent, and a disintegration agent. Once thoroughly blended, the powder is made into tablets (tabletted) by compression in a rotary tablet press with a capacity of up to 200,000 tablets per hour. Many in-process quality checks, based on the highest Food and Drug Administration (FDA) standards, are carried out during each 1,200,000 tablet batch.
The next step is packaging, whereby 500 of the 3 mg Mectizan® tablets are placed into high-density polyethylene (HDPE) plastic bottles with a tamper-evident seal. The bottles are then labeled and shipped to Merck's facility in Riom, France for secondary packaging, storage, inventory control or management, and, distribution to countries in Africa and the Americas, once individual applications have been approved.
The Mectizan® Expert Committee had the opportunity to tour the Haarlem facility in May 1999, during its meeting in The Netherlands. The Committee members were impressed with the automation, rigorous quality control, and continued enthusiasm of the MSD staff regarding their role in an important international health program.
Mectizan Expert Committee Meeting: Amsterdam, May 1999
The Spring 1999 Mectizan Expert Committee (MEC) Meeting was held in Amsterdam in May. The meeting focussed on the integration of treatment for lymphatic filariasis into the Mectizan Donation Program and coordination between partners involved in LF. In addition to the MEC, in attendance were representatives from SmithKline Beecham, WHO, APOC, OCP, The World Bank, and the Liverpool School of Tropical Medicine. A broad range of issues related to Mectizan treatment for LF were discussed including:
· The status of the lymphatic filariasis programs at SmithKline Beecham and WHO
· Safety and combination drug therapies
· World Bank emerging policies on LF
· Revision of Program Information and Application to include treatment for LF
· Design of community trials of Mectizan and Albendazole treatment of LF re: logistics, outcomes, SAE monitoring, and related matters; and design of protocol for case-control study evaluating occurrence of SAEs
· Transition to 3 mg tablets including packaging and stability
Focus on Democratic Republic of the Congo
Getting Mectizan to its final destination is often extremely challenging as demonstrated in this photograph depicting Ms. Georgette Nyawali, administrator of the Mectizan distribution program in DRC and Mr. Papy, the ivermectin distribution program (IDP) nurse in charge of Dingila Health Zone. They are returning from Dingila to Bunia via motorcycle - a trip totaling 590 miles (950 kilometers) one-way - the only mode of transportation available due to civil strife in the area. In order to reach Dingila to deliver the Mectizan (along with fuel and spare parts for motorcycles and bicycles), Ms. Nyawali spent more than two weeks traveling in the back of a truck. Because of her determination to see the Mectizan delivered, more than 30,000 people were treated in 1998.
New Interim Director of Lymphatic Filariasis Elimination Program
On September 15, Professor Charles Mackenzie, a pathologist, began a one year leave from Michigan State University to assist as Program Director, a.i. for the Lymphatic Filariasis drug donation program for Merck & Co., Inc. and SmithKline Beecham.
Professor Mackenzie has worked on onchocerciasis, with a focus of clinical presentation, immunology and pathology, for more than twenty years. While at the London School of Hygiene he worked on models of lymphatic filariasis. He has worked extensively in Sudan, as well as in Cameroon, Sierra Leone, and Latin America. He will now be responsible for program development and scientific support in Lymphatic Filariasis.
In addition to his work on nochocerciasis and lymphatic filariasis, Professor Mackenzie has a wide range of research interesets including breast cancer, animal behavior, dental microbiology and inflamation due to parasites.
The Mectizan® Donation Program visits the Region of Tambacounda, Sénégal
In April, Dr. Mary Alleman visited the onchocerciasis control program in the Region of Tambacounda in Sénégal. Accompanying Dr. Alleman for the visit was Dr. Seydo Mariko of the Organisation Pour la Prévention de la Cécite (OPC). In collaboration with ministries of health, OPC coordinates Mectizan® treatment programs in Sénégal, Mali, and Guinea-Conakry.
Drs. Alleman and Mariko spent two days discussing the control program with Dr. Mamadou Dia, Chief Medical Officer-Region of Tambacounda, Mr. Kekouta Diallo, Onchocerciasis Program Administrative Assistant-Region of Tambacounda, Dr. Moussa Sarr, Chief Medical Officer-District of Kédougou, and Mr. Mactai Mansaly, Health Center Nurse-Community of Bandafassy-peulh. The discussions focused upon the transition to the new 3 mg tablet formulation and the new 500 tablet bottles.
The program staff stated that they were pleased that tablets no longer needed to be broken in half, and the new tablet formulation was well accepted by the population. Concerns regarding the packaging and the "8-week recommended window of usage" were expressed. For example, the "8-week window" made it difficult to treat ineligibles at a later date, and passive treatments had been suspended since the opening of a 500-tablet bottle to treat one or two people in an 8-week period could not be justified. They asked if Merck & Co., Inc. might consider an increase in the recommended window of usage or packaging of only 50-100 tablets/bottle. Their concerns, ideas, and gratitude for the donation of Mectizan® were expressed to the Mectizan® Expert Committee at the May meeting in Amsterdam.
Onchocerciasis is endemic in two regions in the south of Sénégal, Tambacounda and Kolda. Treatments with Mectizan® have been administered annually in this country since 1988. In 1999, the program treated 110,597 persons and covered 99% of the villages eligible for treatment. The program has a goal of reaching 100% of the eligible villages in 2000.
Joint Review Mission - TanzaniaDr. Stefanie Meredith and Ms. Minne Iwamoto participated in a joint review mission of the Tanzanian onchocerciasis program. The review team consisted of representatives from WHO/APOC, WHO/AFRO, The MectizanÒ Donation Program, Interchurch Medical Assistance, Helen Keller International, Sight Savers International, SmithKline Beecham, the World Bank, and the NGDO Coordinator.
The review began with a visit to The Medical Stores Department (MSD), the semi-governmental institution which receives, processes, and distributes drugs (including Mectizan) coming into Tanzania. This was the first year the Mectizan Donation Program shipped the drug directly to the MSD. Discussions were held on the proper disposal of MectizanÒ and the new incinerator that is being installed at the MSD. Also discussed were logistical processes surrounding drug importation and the process of distribution in the field.
The review team also visited several MectizanÒ distribution sites, including the St. Francis Mission Hospital in the Mahenge focus, Mzereze village, and Morogoro town. In these APOC funded areas, the distribution strategy is Community Directed Treatment with Ivermectin (CDTI). Villagers in these areas voiced their approval of CDTI because it creates involvement, encourages participation and has increased coverage.
Ministry of Health representatives emphasized the fact that Tanzania's disease control activities are working with limited resources, facilities, manpower, and expertise. Coordination of disease control activities and communication is becoming increasingly important, therefore the team recommended that the National Onchocerciasis Task Force (NOTF) convene regular meetings that should include district health representatives.
At the community level, the review team recommended that program staff work together to improve: health education and health education materials, registries to facilitate the highest coverage of the eligible population, field equipment, and NOTF communication.
Further recommendations were made by the team on: communications within and outside Tanzania, transportation, sustainability, supervision, side-effect management, roles and responsibilities of all partners involved in onchocerciasis control in Tanzania, and community involvement.
The review team was very impressed by the achievements at the regional, district and community levels.
The Mectizan® Donation Program participates in the Ethiopian National Workshop on APOC-CDTI Philosophy
In late August, Dr. Mary Alleman, Associate Director of the Mectizan® Donation Program, attended the Ethiopian National Workshop on APOC-CDTI Philosophy. The four-day meeting was held in Nazareth, a town 100 km southeast of Addis Ababa. The goals of the workshop were to finalize Ethiopia's national plan of action for onchocerciasis control and to draft CDTI project proposals for three endemic foci.
Meeting participants included representatives from the Ethiopian Ministry of Health (regional and national levels), World Health Organization, Technical Consultative Committee of APOC, National Onchocerciasis Task Force of Sudan, Bahai Community of Ethiopia, Global 2000-The Carter Center, Africare, The World Bank, and United States Agency for International Development.
It is estimated that nearly one million people are infected with Onchocerca volvulus in Ethiopia. Three endemic foci have been identified thus far through REMO exercises. Two of these three foci are in the southwest (Gambella, SNNP, and Oromia regions). The third focus is in the northwest (Benshangul-Gumuz, Tigray, and Amhara regions). REMO exercises are planned in 2000 for the remaining areas suspected of being endemic.
The clinical manifestations of onchocerciasis in Ethiopia are primarily dermal (itching, nodules, thickened skin, and leopard skin). Onchocerciasis-associated blindness is thought to be rare, but confirmation of this requires more thorough opthamalogical surveys.
Selected References
Alexander ND, et. al. Acute disease episodes in a Wuchereria bancrofti endemic area of Papua New Guinea. American Journal of Tropical Medicine and Hygiene. August 1999; 61(2): 319.
Beach MJ, et. al. Assessment of combined ivermectin and albendazole for treatment of intestinal helminth and Wuchereria bancrofti infections in Haitian schoolchildren. American Journal of Tropical Medicine and Hygiene. March 1999. 60(3): 479-86.
Bockarie MJ, et. al. Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival. Medical and Veterinary Entomology. May 1999; 13(2): 120-3.
Fischer P. et. al Long-Term Suppression of Mansonella streptocerca Microfilariae after Treatment with Ivermectin. Journal of Infectious Diseases. October 1999; 180(4): 1403-1405.
Homeida MM, et. al. Medical achievements under civil war conditions. Lancet. August 1999; 354(9178).
Medeiros Z, et. al. Screening of army soldiers for Wuchereria bancrofti infection in the metropolitan Recife region, Brazil: implications for epidemiological surveillance. Tropical Medicine and International Health. July 1999; 4(7): 499-505.
Onwujekwe OE, et. al. Willingness to pay for the maintenance of equity in a local ivermectin distribution scheme in Toro, Northern Nigeria. Public Health. July 1999; 113(4): 193-194.
Payne PA, et. al. Strategic use of ivermectin during pregnancy to control toxocara canis in greyhound puppies. Veterinary Parasitology. September 1999. 85(4):305-12.
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Mectizan Program Notes No. 24 text only
Mectizan® Manufacturing Facility, Haarlem, The Netherlands
Mectizan® (ivermectin, MSD) is tabletted and packaged in The Netherlands, at the Merck Sharp & Dohme facility in Haarlem, a city about 20 kilometers or 20 minutes by train from Amsterdam. The Haarlem plant has been the sole source of the Mectizan® provided through the Mectizan® Donation Program (MDP) ever since 1987 when Merck & Co., Inc. announced its plan to donate as much of the drug as needed to treat onchocerciasis, wherever and for as long as required. Consequently, the MSD facility in Haarlem has produced the many hundreds of millions of Mectizan® tablets given in Africa and the Americas since 1987. For the year 2000, the plant is expected to produce around 110 million 3 mg tablets.
Although these production numbers are impressive on their own, to appreciate the full diversity and capacity of the plant, one should recognize that each year, the Haarlem facility produces 2,600 different pharmaceutical products for human health and 600 for animal health and distributes them to more than 140 countries worldwide.
In Haarlem, Mectizan® tablets are made by a skilled team of specialists who work in a section of the facility dedicated entirely to making Mectizan®. Physically, this part of the plant is totally separate from the rest of the MSD installation and operates 24 hours a day in order to keep up with current demand. Plans are underway for building a larger facility in Haarlem in 2000, one which can produce enough more Mectizan® to satisfy what is expected to be a two-fold increase in the amount needed to expand the MDP to treat lymphatic filariasis (LF) in African countries where onchocerciasis is also endemic.
With respect to making Mectizan® tablets, the first step involves preparation of a homogenous powder blend which includes ivermectin, the active ingredient of the drug produced in Merck's chemical plant in Puerto Rico, and several inactive components, namely two anti-oxidizing agents, a binder agent, and a disintegration agent. Once thoroughly blended, the powder is made into tablets (tabletted) by compression in a rotary tablet press with a capacity of up to 200,000 tablets per hour. Many in-process quality checks, based on the highest Food and Drug Administration (FDA) standards, are carried out during each 1,200,000 tablet batch.
The next step is packaging, whereby 500 of the 3 mg Mectizan® tablets are placed into high-density polyethylene (HDPE) plastic bottles with a tamper-evident seal. The bottles are then labeled and shipped to Merck's facility in Riom, France for secondary packaging, storage, inventory control or management, and, distribution to countries in Africa and the Americas, once individual applications have been approved.
The Mectizan® Expert Committee had the opportunity to tour the Haarlem facility in May 1999, during its meeting in The Netherlands. The Committee members were impressed with the automation, rigorous quality control, and continued enthusiasm of the MSD staff regarding their role in an important international health program.
Mectizan Expert Committee Meeting: Amsterdam, May 1999
The Spring 1999 Mectizan Expert Committee (MEC) Meeting was held in Amsterdam in May. The meeting focussed on the integration of treatment for lymphatic filariasis into the Mectizan Donation Program and coordination between partners involved in LF. In addition to the MEC, in attendance were representatives from SmithKline Beecham, WHO, APOC, OCP, The World Bank, and the Liverpool School of Tropical Medicine. A broad range of issues related to Mectizan treatment for LF were discussed including:
· The status of the lymphatic filariasis programs at SmithKline Beecham and WHO
· Safety and combination drug therapies
· World Bank emerging policies on LF
· Revision of Program Information and Application to include treatment for LF
· Design of community trials of Mectizan and Albendazole treatment of LF re: logistics, outcomes, SAE monitoring, and related matters; and design of protocol for case-control study evaluating occurrence of SAEs
· Transition to 3 mg tablets including packaging and stability
Focus on Democratic Republic of the Congo
Getting Mectizan to its final destination is often extremely challenging as demonstrated in this photograph depicting Ms. Georgette Nyawali, administrator of the Mectizan distribution program in DRC and Mr. Papy, the ivermectin distribution program (IDP) nurse in charge of Dingila Health Zone. They are returning from Dingila to Bunia via motorcycle - a trip totaling 590 miles (950 kilometers) one-way - the only mode of transportation available due to civil strife in the area. In order to reach Dingila to deliver the Mectizan (along with fuel and spare parts for motorcycles and bicycles), Ms. Nyawali spent more than two weeks traveling in the back of a truck. Because of her determination to see the Mectizan delivered, more than 30,000 people were treated in 1998.
New Interim Director of Lymphatic Filariasis Elimination Program
On September 15, Professor Charles Mackenzie, a pathologist, began a one year leave from Michigan State University to assist as Program Director, a.i. for the Lymphatic Filariasis drug donation program for Merck & Co., Inc. and SmithKline Beecham.
Professor Mackenzie has worked on onchocerciasis, with a focus of clinical presentation, immunology and pathology, for more than twenty years. While at the London School of Hygiene he worked on models of lymphatic filariasis. He has worked extensively in Sudan, as well as in Cameroon, Sierra Leone, and Latin America. He will now be responsible for program development and scientific support in Lymphatic Filariasis.
In addition to his work on nochocerciasis and lymphatic filariasis, Professor Mackenzie has a wide range of research interesets including breast cancer, animal behavior, dental microbiology and inflamation due to parasites.
The Mectizan® Donation Program visits the Region of Tambacounda, Sénégal
In April, Dr. Mary Alleman visited the onchocerciasis control program in the Region of Tambacounda in Sénégal. Accompanying Dr. Alleman for the visit was Dr. Seydo Mariko of the Organisation Pour la Prévention de la Cécite (OPC). In collaboration with ministries of health, OPC coordinates Mectizan® treatment programs in Sénégal, Mali, and Guinea-Conakry.
Drs. Alleman and Mariko spent two days discussing the control program with Dr. Mamadou Dia, Chief Medical Officer-Region of Tambacounda, Mr. Kekouta Diallo, Onchocerciasis Program Administrative Assistant-Region of Tambacounda, Dr. Moussa Sarr, Chief Medical Officer-District of Kédougou, and Mr. Mactai Mansaly, Health Center Nurse-Community of Bandafassy-peulh. The discussions focused upon the transition to the new 3 mg tablet formulation and the new 500 tablet bottles.
The program staff stated that they were pleased that tablets no longer needed to be broken in half, and the new tablet formulation was well accepted by the population. Concerns regarding the packaging and the "8-week recommended window of usage" were expressed. For example, the "8-week window" made it difficult to treat ineligibles at a later date, and passive treatments had been suspended since the opening of a 500-tablet bottle to treat one or two people in an 8-week period could not be justified. They asked if Merck & Co., Inc. might consider an increase in the recommended window of usage or packaging of only 50-100 tablets/bottle. Their concerns, ideas, and gratitude for the donation of Mectizan® were expressed to the Mectizan® Expert Committee at the May meeting in Amsterdam.
Onchocerciasis is endemic in two regions in the south of Sénégal, Tambacounda and Kolda. Treatments with Mectizan® have been administered annually in this country since 1988. In 1999, the program treated 110,597 persons and covered 99% of the villages eligible for treatment. The program has a goal of reaching 100% of the eligible villages in 2000.
Joint Review Mission - TanzaniaDr. Stefanie Meredith and Ms. Minne Iwamoto participated in a joint review mission of the Tanzanian onchocerciasis program. The review team consisted of representatives from WHO/APOC, WHO/AFRO, The MectizanÒ Donation Program, Interchurch Medical Assistance, Helen Keller International, Sight Savers International, SmithKline Beecham, the World Bank, and the NGDO Coordinator.
The review began with a visit to The Medical Stores Department (MSD), the semi-governmental institution which receives, processes, and distributes drugs (including Mectizan) coming into Tanzania. This was the first year the Mectizan Donation Program shipped the drug directly to the MSD. Discussions were held on the proper disposal of MectizanÒ and the new incinerator that is being installed at the MSD. Also discussed were logistical processes surrounding drug importation and the process of distribution in the field.
The review team also visited several MectizanÒ distribution sites, including the St. Francis Mission Hospital in the Mahenge focus, Mzereze village, and Morogoro town. In these APOC funded areas, the distribution strategy is Community Directed Treatment with Ivermectin (CDTI). Villagers in these areas voiced their approval of CDTI because it creates involvement, encourages participation and has increased coverage.
Ministry of Health representatives emphasized the fact that Tanzania's disease control activities are working with limited resources, facilities, manpower, and expertise. Coordination of disease control activities and communication is becoming increasingly important, therefore the team recommended that the National Onchocerciasis Task Force (NOTF) convene regular meetings that should include district health representatives.
At the community level, the review team recommended that program staff work together to improve: health education and health education materials, registries to facilitate the highest coverage of the eligible population, field equipment, and NOTF communication.
Further recommendations were made by the team on: communications within and outside Tanzania, transportation, sustainability, supervision, side-effect management, roles and responsibilities of all partners involved in onchocerciasis control in Tanzania, and community involvement.
The review team was very impressed by the achievements at the regional, district and community levels.
The Mectizan® Donation Program participates in the Ethiopian National Workshop on APOC-CDTI Philosophy
In late August, Dr. Mary Alleman, Associate Director of the Mectizan® Donation Program, attended the Ethiopian National Workshop on APOC-CDTI Philosophy. The four-day meeting was held in Nazareth, a town 100 km southeast of Addis Ababa. The goals of the workshop were to finalize Ethiopia's national plan of action for onchocerciasis control and to draft CDTI project proposals for three endemic foci.
Meeting participants included representatives from the Ethiopian Ministry of Health (regional and national levels), World Health Organization, Technical Consultative Committee of APOC, National Onchocerciasis Task Force of Sudan, Bahai Community of Ethiopia, Global 2000-The Carter Center, Africare, The World Bank, and United States Agency for International Development.
It is estimated that nearly one million people are infected with Onchocerca volvulus in Ethiopia. Three endemic foci have been identified thus far through REMO exercises. Two of these three foci are in the southwest (Gambella, SNNP, and Oromia regions). The third focus is in the northwest (Benshangul-Gumuz, Tigray, and Amhara regions). REMO exercises are planned in 2000 for the remaining areas suspected of being endemic.
The clinical manifestations of onchocerciasis in Ethiopia are primarily dermal (itching, nodules, thickened skin, and leopard skin). Onchocerciasis-associated blindness is thought to be rare, but confirmation of this requires more thorough opthamalogical surveys.
Selected References
Alexander ND, et. al. Acute disease episodes in a Wuchereria bancrofti endemic area of Papua New Guinea. American Journal of Tropical Medicine and Hygiene. August 1999; 61(2): 319.
Beach MJ, et. al. Assessment of combined ivermectin and albendazole for treatment of intestinal helminth and Wuchereria bancrofti infections in Haitian schoolchildren. American Journal of Tropical Medicine and Hygiene. March 1999. 60(3): 479-86.
Bockarie MJ, et. al. Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival. Medical and Veterinary Entomology. May 1999; 13(2): 120-3.
Fischer P. et. al Long-Term Suppression of Mansonella streptocerca Microfilariae after Treatment with Ivermectin. Journal of Infectious Diseases. October 1999; 180(4): 1403-1405.
Homeida MM, et. al. Medical achievements under civil war conditions. Lancet. August 1999; 354(9178).
Medeiros Z, et. al. Screening of army soldiers for Wuchereria bancrofti infection in the metropolitan Recife region, Brazil: implications for epidemiological surveillance. Tropical Medicine and International Health. July 1999; 4(7): 499-505.
Onwujekwe OE, et. al. Willingness to pay for the maintenance of equity in a local ivermectin distribution scheme in Toro, Northern Nigeria. Public Health. July 1999; 113(4): 193-194.
Payne PA, et. al. Strategic use of ivermectin during pregnancy to control toxocara canis in greyhound puppies. Veterinary Parasitology. September 1999. 85(4):305-12.
