Manufacturing Capability Key to Global Health Advances

The international community has launched a massive campaign to combat the AIDS epidemic and other major diseases raging throughout the third world. Last year, numerous international conferences highlighted the need for a huge investment in the development of new vaccines and medicines to combat AIDS, malaria and tuberculosis (TB). At the World AIDS Conference in Barcelona, Spain (July 2002), pharmaceutical manufacturers announced additional price reductions for AIDS therapies and increased support for research into new treatments. Further discussion of these issues took place at the Johannesburg World Summit on Sustainable Development in September. World AIDS Day in December generated pledges from the West to increase support for international disease prevention and treatment programmes.

Innovation spurs access

Manufacturing gains attention

Up until now, efforts to combat AIDS and other diseases have focussed largely on increasing public access to existing therapies, and investing in research into new compounds and biomedical approaches that are likely to lead to new vaccines and disease treatments. Donor organizations and health foundations have been expanding research and development (R&D) programmes and establishing international clinical trial networks to study promising therapies. Pharmaceutical companies are involved in tests of 14 vaccine candidates, including one that has begun Phase III clinical trials in Thailand, the US and Europe.

As programmes to develop new vaccines and therapies show promise, health experts are recognizing the need to plan to manufacture any new treatments on a global scale. To be able to produce a vaccine as soon as it is licensed, plant construction has to begin before sponsors have assurance that a test product will work. Construction of a vaccine manufacturing plant that meets GMP (good manufacturing practice) standards normally requires several years and at least $50 million to build. However, the numbers are much higher for an AIDS vaccine that would be needed by much of the world.

Many of the difficulties related to new vaccine production have been apparent for years, as international health organizations have struggled with vaccine production, distribution and safe administration challenges involved in expanding third-world access to existing vaccines and medicines (see sidebar "Innovation spurs access"). Drug manufacturing capability still barely exists in most third-world nations, and vaccine shipping and storage often requires rigid monitoring. The need to find ways to produce billions of vaccine doses that will be affordable in Africa and Asia is nothing short of overwhelming.

Consequently, sponsoring organizations are launching programmes to map out manufacturing approaches and investment requirements. Process development challenges dwarf the difficulties of getting a test product into clinical trials, observed Edward Pollock, director of business development and strategic planning of the International AIDS Vaccines Initiative (IAVI). "We can't just focus on clinical candidates," but need to follow up with "real manufacturing capability to go along with it," he commented at the Partnering for Global Health Forum (2002) sponsored by the Biotechnology Industry Organization (BIO) and the Bill & Melinda Gates Foundation in Washington DC in December. The Forum brought together funding organizations, such as Gates and groups associated with the World Bank and the United Nations, with biotech companies seeking support for R&D programmes for AIDS and other third-world diseases.

Formulation changes threaten vaccine access

Whereas most presentations discussed R&D, several addressed issues related to manufacturing and product development:

• The Global Alliance for TB Drug Development is paying more attention to whether potential test products will lend themselves to affordable manufacturing in deciding what new technologies to fund.

• The International Financial Institution, a member of the World Bank Group, is funding large-scale private sector drug manufacturing projects in India, South Africa and other countries to enhance third-world production capacity.

• California-based VaxGen has formed a $120 million joint venture with South Korean investors to build manufacturing facilities for AIDS and anthrax vaccines and other cell culture products. A plant in

San Francisco (California, USA) will be able to produce up to 10 million vaccine doses per year by 2005. A South Korean facility (Celltrion) will produce 200 million doses annually and will eventually have eight 12000 litre bioreactors that are capable of a much greater production volume.

Link to manufacturing

IAVI is devoting considerable resources to formulating a plan for massive AIDS vaccine production as part of its "virtual company" model for managing vaccine R&D projects. The non-profit organization was founded in 1996 to spur AIDS vaccine development and is funded by Gates and other foundations, the World Bank, industry and Western governments. A prime goal is to link academic research efforts with networks that are able to conduct clinical trials in developing nations and have the product development skills found in the vaccine industry. To speed vaccines to Phase I trials, IAVI uses contract manufacturers to produce pilot lots for preclinical testing and for early clinical studies.

Recently, the organization hired Don Gerson, who has led vaccine manufacturing programmes at Wyeth and Acambis, to move to the next step: large-scale development and manufacturing partnerships. As IAVI's managing director for manufacturing, Gerson's task is to formulate a programme for producing a vaccine to meet the needs of 5 billion people in the Third World. He estimates that it will take 6–7 years to build and validate the necessary production facilities, which coincides with the time frame that scientists estimate will be needed to fully test and license an effective product.

Gerson has begun by preparing a preliminary engineering study for meeting such an enormous goal. The initial plan is to establish five regional plants, each able to serve 1 billion people and to produce 150 million doses a year. Each plant will be able to accommodate a variety of vaccine products in three production areas for egg or cell production of viral vectors and bacterial plasmid production. Each plant will cost approximately $300 million to build, for a total manufacturing construction budget of $1.5 billion. That amount will get the facilities built in compliance with GMPs, but does not cover actual production costs.

The next steps for Gerson are to develop more detailed construction plans with real cost estimates and to locate suitable construction sites.

A key challenge is creating plant designs that will meet GMPs no matter where the plant is located. "There can be no compromise on quality," he emphasized; a plant in Africa will meet standards just as well as one in New Jersey. He envisions constructing five essentially identical plants, a strategy used by major high tech manufacturers around the world to gain economies of scale and to facilitate regulatory compliance.

IAVI hopes to complete this massive construction programme through partnerships with large pharmaceutical companies (whether involved or inactive in vaccine production) plus biotech and contract manufacturing firms. IAVI may also consider alternative partnering strategies for bulk manufacturing, packaging and distribution programmes for vaccines in developing countries. A related project is to define a core regulatory dossier to support product licensure and registration in all regions.

Push and pull

Funding organizations are also exploring ways to expand incentives that can encourage private sector investment in vaccine manufacturing and distribution for poor nations. These include "push" approaches, such as tax breaks and research grants, likely to spur industry participation in these programmes. The UK government, for example, has announced plans to offer a tax credit to UK companies for R&D on vaccines and drugs to treat AIDS, TB and malaria, and a similar measure has been proposed in the US. Manufacturers would like R&D tax credits to apply to plant construction in third-world countries. Industry would also like to add a "roaming" element to credits, so that tax incentives could be applied to other more profitable products.

"Pull" strategies, which involve guaranteeing markets and future prices to promote private sector investment, are also gaining more attention. A McKinsey (www.mckinsey.com) report for the Global Alliance for Vaccines and Immunization (GAVI) emphasizes the importance of accurately forecasting vaccine demand in developing markets early in the product development cycle so that manufacturers will be able to build sufficiently large production facilities to meet realistic future demand. Uncertainty regarding future consumption is considered the key barrier to ensuring adequate vaccine supply.

Similarly, a report on the "State of the World's Vaccines and Immunization" from the World Health Organization (WHO), UNICEF and the World Bank notes that even though the Third World constitutes a potentially vast market for vaccines, considerable roadblocks have limited access to new treatments. A "firm commitment upfront to purchase safe and effective vaccines," it states, will reduce the risks faced by manufacturers and stimulate vaccine research needed by developing countries.

The report describes numerous difficulties in ensuring vaccine quality and safety, such as a lack of regulatory capacity in many developing nations that makes it difficult to guarantee that vaccines are manufactured to meet appropriate safety and potency standards. WHO seeks to strengthen national regulatory authorities by assisting them in developing clear requirements for product licensing, field surveillance programmes, lot release systems, laboratory testing capabilities and regular manufacturer inspection programmes to ensure compliance with GMPs. It also questions whether all policies appropriate for the West meet the needs of third-world nations (see sidebar "Formulation changes threaten vaccine access").

These analyses and others identify a number of obstacles to providing a reliable, affordable supply of vaccines and medicines for poorer nations:

Prices and diversion. GlaxoSmithKline (GSK), Merck, Bristol-Myers Squibb, Roche and others have slashed prices on anti-retroviral drugs for developing nations, largely since their disastrous attempt to enforce drug patents in South Africa. Unfortunately, two-tier pricing has encouraged illegal diversion of discounted products to high-priced markets in Europe. In October (2002), GSK reported that three million doses of AIDS drugs worth $18 million were diverted by European wholesalers from Africa to Germany, The Netherlands and other nations between July 2001 and July 2002, when the fraud was discovered. The investigation indicates that African organizations that distribute the medicines locally may be involved in the illegal activity, testifying to the need to improve monitoring and oversight of low-price drug distribution in developing nations.

Patent protection. A key issue in vaccine and drug development is to provide sufficient intellectual property protection for innovator firms, which want the rights to develop additional uses for a new technology. Many donors seek partnership arrangements that retain incentives for innovation as well as public access.

However, international patent rights currently face a serious challenge from developing nations that seek to amend the World Trade Organization (WTO) TRIPS (Trade-Related Aspects of Intellectual Property Rights) agreement to expand access to generic copies of patented medicines. The TRIPS agreement negotiated at Doha, Qatar, in 2001 permits poor nations without domestic pharmaceutical production capacity to import generic versions of medicines to combat national health emergencies. Now, more newly industrialized nations also want the right to import generics, and they want to extend the policy beyond treatments for AIDS, malaria and TB. US trade negotiators and pharmaceutical companies seek to limit both the list of nations eligible to import under compulsory license and the range of applicable health conditions. Poor nations fear that the current policy limits their access to cheap therapies, but also recognize the need for incentives to spur new research. Agreement appears far away.

Insufficient funding. Patient advocates and developing nations continue to pressure richer nations to boost support for the campaign against AIDS and other third-world diseases. At the Barcelona AIDS conference last July, participants blasted Health and Human Services (HHS) secretary, Tommy Thompson, for failing to provide the $2–3 billion needed to fully fund the global anti-AIDS effort. Secretary of State, Colin Powell, had a similar experience in Johannesburg in September when describing the Bush administration's "stepped up" support for development in Africa.

In Washington DC, Congressional committees expanded funding for international AIDS programmes in foreign aid budget bills for 2003, but the legislators were unable to reach final agreement on the budget plan last autumn. Many Congressional leaders support major increases in US funding of international AIDS programmes, and the Bush administration has offered a new approach to foreign aid that could boost the funding pool for international health programmes. Political leaders in the US and other industrial states increasingly recognize that if not addressed, the spread of AIDS and other diseases will impose high economic and political costs, and threaten stability and growth in Africa and other parts of the world.