As much as one-third of the world’s population lacks access to essential medicines, and in the poorest regions of Africa and Asia, this figure rises to one-half (1). Along with other organizations, Medicins sans Frontieres (MSF, Doctors Without Borders) advocate for a combination of global and regional policies to lower drug prices sustainably, including local drug manufacturing. At this year’s annual meeting of the Biotechnology Industry Organization (BIO), during a session on building vaccine capacity in developing countries, Martin Friede of the World Health Organization (WHO) told the audience, “It is not only essential to manufacture vaccines locally, but we must allow each region to make its own decisions.”

One of the biggest barriers to meeting this objective is the lack of manufacturing capacity in developing regions. During the same BIO session, Eric Iverson of the Gates Foundation stated that the lack of capacity is “a rate-limiting constraint to achieving global health objectives.” Although Martin agreed the need is far beyond capacity, he also pointed to a lack of interest by industry and a lack of technical know-how and expertise in these regions. Thus, he concluded, there is a need to provide technology from public sources within intellectual property constraints. Manufacturing, supply chain, regulatory policy, training, and surveillance are other “monumental” issues, said Iverson.

But the concept of local production is gaining popularity in the private sector, especially in India, China, and Brazil. Manufacturing in a region where their products will be distributed makes economic sense, especially if costs can be minimized. Nonetheless, the presence of both public and private markets in these regions can complicate matters, especially for vaccine production and distribution. “For organizations such as WHO and UNICEF, a dollar per dose is the maximum they can spend, so there is a lot of pressure on the price of vaccines from those agencies on manufacturers. Manufacturers respond to that by keeping their costs of manufacturing to a bare minimum,” says Eric Patzer (president and founder of Aridis Pharmaceuticals), who adds that his company has had discussions with the nonprofit groups regarding production of its rotovirus vaccine.

Global Thinking

Public or private markets aside, most experts would agree that establishing local manufacture in a developing region isn’t trivial. “I don’t think people appreciate what some of the challenges are in being able to do that kind of localized manufacturing,” says Matthew K. Hudes, US managing principal, biotechnology, at Deloitte Services LP. “There are certainly incentives for investment, so it makes sense in the grand scheme, but people have had some difficulty going into a particular region and trying to manufacture when they don’t understand some of the capabilities, skill sets, and regulatory differences that occur in different places.” For example, a product or innovation that comes from the United States must comply with the Foreign Corrupt Practices Act (FCPA) in addition to other local and regulatory issues. “FCPA is not to be underestimated,” says Hudes, “Serious fines have been paid for violations and for going gobal without truly understanding those impacts.”

The industry’s move toward localized manufacturing and establishing truly global markets means companies will need to change the way they handle their operations from the beginning. “It starts with global thinking,” says Hudes. He suggests companies should think about technology transfer early and design manufacturing processes to enable that transfer. Such designs are not site or facility specific, and some expertise at transferring that process around the world will be required. Addressing technology transfer and other logistics issues at the beginning is a lot easier than trying to globalize an existing product or process,” he adds.

Anticounterfeiting

As global markets emerge, the need for protecting the supply chain and finished products grows ever more critical. The rise in the number of counterfeit drugs is not only a huge business concern, but also a great concern for public health. In 2005, more than 500,000 counterfeit pharmaceutical products were discovered by customs officials in the European Union alone. In 2006, that number skyrocketed to more than 2.7 million (2).

According to Christopher Wolf, director at Arvato Services Healthcare, the main industrial areas of interest in Europe are the “Big Five” countries of Germany, UK, France, Spain, and Italy. Many companies, however, are not fully aware of the complexities of the various regulations for each country, says Wolf. For example, although serialization with two-dimensional barcoding is already a widespread practice in most of Europe, the systems to apply and detect these codes are different and depend on the country of origin (3).

The biopharmaceutical industry continues its current discussions regarding global technologies and standards to combat counterfeits. Overall, serialization with 2D unit-level barcoding is gaining popularity as the preferred strategy, even over more expensive radio-frequency identification (RFID) tags. Most industry experts agree that solutions combining global standards and item-level serialization (e-pedigree) are most effective. “One example would be to have 2D barcoding at the unit level and then have RFID on pallets. The RFID tags would contain all of the unit barcodes that should be on that pallet,” says Rainuka Gupta, group manager of medical technology at Cambridge Consultants. Combinations of overt (e.g., holograms, color-chaning inks), covert (e.g., taggants), and forensic technologies can then provide authentication.

As part of their logistics planning, local manufacturers will need to become familiar with local policies already in place for serialization. Italy was one of the first European Union nations to implement a bar-code based system. In 2005, the country introduced the “bollini,” which is a label that features the Italian product license number and a sequential number (4). Brazil, another emerging biologics hot spot, also has leveraged innovative solutions to supply chain protection. In January 2009, the Brazilian government passed a law mandating that drug manufacturers and distributors act on specific serialization and track-and-trace requirements. The deadline for compliance is January 2012 (3). In addition, Germany, France, and Turkey have either passed legislation or will soon pass legislation that will require a data matrix code encoded with the GS1 data standard (www.gs1.org). France instituted a labeling requirement that the global trade identification number (GTIN, developed by GS1), expiration date, and lot information must be marked on every product, preferably with a 2D data matrix bar code (compliance date is January 2011) (3).

In the United States, the FDA maintains an online information page on counterfeit medicines as well as reports from its Counterfeit Drug Task Force (5). In March, the agency issued new guidelines for labeling on prescription drug packaging that recommend inclusion of a serialized national drug code (sNDC, compatible with the GS1 data standard) on each package. The FDA’s previous guidelines required an NDC, so the addition of a serial number enables item-level traceability for prescription drugs for the first time in the country.

Supply Chain and Raw Materials

One of the biggest barriers to making the economics of local manufacturing work is ensuring access to the same quality of materials and equipment. The availablity of single-use units, flexible components, and modular systems have made it easier to set up smaller manufacturing sites in multiple locations (6). Nonetheless, securing the same quality of raw materials (e.g., media, resin) and supplies when sent from one country to another can be complicated, especially dealing with the tariffs, taxes, licenses, and importation requirements of each region.

“Often, access to those raw materials and supplies is more of a challenge than it is for equipment (though some are now disposable units), because some countries don’t allow imports,” says Susan Dexter, principal consultant at BioPharm Services, Inc. To import into India, for example, companies need a distribution network approved by the Indian government that allows them to access the same raw materials and supplies that are used in all of its locations (see www.dst.gov.in/index.htm). “Without the same raw materials and supplies, the government agencies can’t call it the same product,” says Dexter.

Cold Chain Management

More than 40% of all pharmaceutical products, including biologics, are temperature sensitive (7). The importance of temperature control and monitoring for biopharmaceuticals is clear: For example, Samat et al. conducted a study that evaluated the cold chain for an oral polio vaccine in a rural district of central India. Their study found that 24% of vaccine carriers across all the levels of the cold chain did not comply with WHO-India cold chain maintenance protocol (8). WHO itself has indicated that as much as 25% of all vaccine products reach their destination in a degraded state (9); and in December 2009, in the midst of the H1N1 pandemic, the Centers for Disease Control announced that Sanofi Pasteur was voluntarily recalling four lots totaling 800,000 doses of its vaccine because it had weakened in potency due to natural degradation (10).

TIPS FOR WORKING WITH THIRD-PARTY LOGISTICS PROVIDERS
Reaching close to $150 billion in the United States, the third-party logistics (3PL) business can help companies extend to global markets and focus on their core competencies. To successfully start working with a 3PL company, you should

• investigate areas of opportunity by developing a team to evaluate current and future requirements of business and the ability of the company to meet those requirements.
• critically assess strengths and weaknesses in terms of each logistics area such as transportation, supply chain management, warehousing, and importing.
• decide which of the logistics functions you would be willing to and be comfortable in turning over to a third party
• develop a short list of 3PL providers, possibly using a logistics network optimization study to identify locations of import and export gateway and other important factors. Evaluate the internal infrastructure of each potential partner.
• establish partnership with key personnel and ensure compatible corporate cultures.

* Adapted from: Blanchard D., How to Select a Third-Party Logistics Provider, Industry Week, June 1, 2008, www.industryweek.com/articles/how_to_select_a_third_party_logistics_provider_16302.aspx

Manufacturing for local markets can lead to some savings in transport costs, especially for biologics, because the cold chain is shorter. However, as Patzer observes, ensuring that the cold chain is maintained throughout the entire route can be challenging. “One of the problems we’ve been told by WHO and UNICEF is that although shipping in the 2–8 °C range into a developing world country is possible, and storage at a central location is possible, the tricky part is when you lengthen the cold chain to outlying areas,” says Patzer. “That’s where it can become complicated and costly.”

Resources such as USP General Chapter “Good Storage and Shippng Practices,” PDA Technical Report 39, and WHO’s Good Distribution Practices for Pharmaceutical Products can help resolve cold chain issues (11,12,13). In addition, a number of service and support firms specializing in logistics and cold chain management are available. According to Clifford W. Wyllie, vice president of BioPharma Healthcare Services for Cavalier Logistics, drug manufacturing companies have historically outsourced warehousing and logistics operations because their main focus is research and development as well as licensing of new products (14).

But many companies still control their logistics and distribution operations themselves because of the requirement for training and controls compliant with current good manufacturing practices (CGMP). “[A company’s] own people already has the experience and training to effectively distribute the products, and it has already invested in the training and CGMP environment.” Nonetheless, pressures to innovate and establish local manufacturing sites quickly have increased the number of logistics providers investing in GMP training and facilities (see box on this page).

Stabilization Solutions

Local manufacturers of temperature-sensitive biotherapies must take extra precautions in the distribution chain to ensure that the product remains stable. Currently, temperatures outside of the 2–8 °C range pose the greatest threat for stability loss (including freezing, which could inactivate biopharmaceuticals). “The greatest need for stable products is that last piece [of the cold chain], where refrigeration is difficult. If we could get room temperature stability — or for biologics and vaccines attemperature excursions up to 45 or 50 °C but for shorter periods of time — for distribution to outlying areas, that would be of great value” says Patzer.

The cost of distribution and the difficulty in maintaining a cold chain in the developing world is a common issue, and some researchers are addressing that issue by developing stabilized formulations of their products, especially vaccines. “If you can develop more stable products, you wouldn’t have to maintain the cold chain, especially in outlying areas when distributing in the developing world,” says Patzer.

Scientists at Noval Laboratories, for example, have developed a sugar-stabilized membrane technique for keeping vaccines stable in tropical temperatures (15). Oxford University carried out a proof-of-concept study in the first part of this year.

Further along in development is a thin-film technology by Ardis, for protein stabilization, applicable for vaccines (whole viruses as well as live attenuated viruses) and antibodies. The company figured out a way to incorporate a spray-dried vaccine into oral thin films that are quickly dissolvable. Patzer says the thin films address two other important issues in the cold chain: package size and weight. Thin films have small packages compared with liquid vaccine, which is a real concern for refrigerated products. For a freeze-dried product, the weight and volume of water can be difficult to transport, and if water is not supplied, trying to reconstitute a vaccine locally could be a problem.

According to Patzer, Ardis developed a “reasonably stable” liquid rotovirus vaccine as well as a spray-dried powder that was extremely stable. “The liquid vaccine could be stored at 4 °C and under refrigeration for several years and withstand room temperature of 25 °C for several months. However, the spray-dried formulation could withstand a year or more at 25 °C and temperature excursions of up to 37 °C for months.”

Costs of Technology

The problem with protein stabilization technology is the cost. For thin films, companies would need to install spray dryers, which can be a big expense, as well as pay for the energy and operators costs to run the equipment. Additional processing steps are an extra expense. And it doesn’t take much additional cost to be problematic and increase the complexity of the manufacturing processes. If a company has never done it before, trying to transfer a new technology can be difficult.

That extra cost (which could amount to an additional 50 or 75 cents per dose, depending on where it’s sold) may not be an impediment in the US and European markets, but in the developing world and in public markets, it is difficult to justify. Patzer that believes larger international companies would be more willing to implement the thin film technology. “We have had discussions about this technology with some nonprofits that do the development work in those regions, and there is a reluctance. I think they would rather develop the liquid, even if it’s less stable but simpler to use.” This sensitivity to the cost of manufacturing may be a hindrance to implementing new technologies in local manufacturing sites. “For liquids, the technology is readily available and the cost of goods is lower, so they have an incentive to chose the less expensive technology.”

Author Details
Maribel Rios is managing editor of BioProcess International, 1574 Coburg Road, #242, Eugene, OR 97401; phone/fax 646-957-8884; mrios@bioprocessintl.com; www.bioprocessintl.com

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