February 15, 2012 (Vol. 32, No. 4)
Making outsourcing an efficient and effective option for biotechnology manufacturing often is dependent upon innovation, a keen awareness of potential risks, and close collaborative relationships between CMOs and their clients. Recipharm Pharmaceutical Development and PledPharma are reaping the benefits of their close collaboration now. In early January, Recipharm gained regulatory approval from the Swedish Medical Products Agency to begin manufacturing PledPharma’s mangafodipir, thus allowing Phase IIa trials in myocardial infarction to begin in January.
“After being contacted by PledPharma, both companies worked very hard to get the clinical trial material approved as fast as possible and were very happy with the result,” according to Maria Lundberg, GM at Recipharm. “PledPharma managed the regulatory contacts, and Recipharm compiled module 3 of the IMPD and justified the differences from the old manufacturing process.”
That experience speaks to the close collaborations that are expected between contract manufacturing organizations and their clients. In working with PledPharma, Lundberg says that close collaboration and frequent communication was essential. “Geographic proximity, as both companies are located in the Stockholm area, has allowed frequent fact-to-face meetings, which has greatly facilitated the collaboration.”
“The most important element to any collaboration like this is not the type of relationship—preferred supplier or functional service provider—but simply the strong sense of trust between the parties,” Lundberg says.
“It is impossible to foresee all problems at the outset that might occur and describe remedies in a contract. Therefore, you have to trust that your partner will solve any unexpected challenges.” Lundberg cites reliability; professional, strong technical and scientific competence; entrepreneurship; and tenacity as key. “Applying these principles in any development project will enable partners to build strong relationships and efficiently overcome any problems as they occur.”
DSM, as a full-service, global contract manufacturing organization, uses its capacity for innovation to increase its value proposition for clients. Its pharmaceutical products division focuses upon innovative biologics, pharmaceutical chemicals, pharmaceuticals, and biosolutions.
“DSM Pharma Biotech’s innovations result in a much lower cost of goods and better sustainability by significantly reducing water and energy usage per gram or kilogram of material produced,” according to Karen King, president, DSM Biologics.
During the past year, DSM Biologics has scaled up its XD® technology and began actively promoting its downstream technologies, Rhobust® and Kremer Method™. These three products are fully compatible with single-use as well as commercial-scale technologies and allow more advanced process control, which is particularly important for new molecules and biosimilars.
XD technology is designed for mammalian cell lines. “It allows clients to maximize output from disposable bioreactors. Typically, XD has increased product titers by a factor of 8–10 times,” King says. “Therefore, a 250 L bioreactor can provide the same amount of drug substances as a 2,500 L stainless steel bioreactor, at an overall lower cost.” It also speeds development time by reducing the need to optimize cell-line productivity.
The Rhobust technology is next-generation expanded bed chromatography, using cross-linked agarose beads with tungsten carbine to increase particle density. This direct-capture step increases the yield of mammalian and microbial harvests, and reduces the number of unit operations and costs of goods, King explains.
The Kremer Method is used after the capture step, streamlining the protein purification and polishing steps into one single unit operation. “Using this method, host cell proteins were removed to a level below the limits of detection, complete aggregate removal was observed that compares to the current state-of-the-art processes, and recoveries of 90% were achieved,” King says.
Within DSM Biosolutions, the custom manufacturing division that addresses fermentation processes, “customers are offered access to cutting-edge technologies in fermentation-based processes as they are continuously developed and improved for DSM’s in-house, large-scale production processes,” according to Villaume Kal, vp, DSM BioSolutions.
“Innovations range from the latest advances in production strain construction and improvement, to fermentation process concepts, and product isolation technologies, which fit classical fermentation products as well as modern biotechnology-based products,” he says. Application examples include advanced scale-compatible expression platforms for protein production, multiple modes of fermentation process execution, and high-performance product isolation and purification operations.
DSM Pharma Biotech offers multiple technologies, including mammalian cell culture-based antibodies and protein production, biomanufacturing, microbial fermentation, green chemistry for synthesis optimization, applying chemo/biocatalysis, and sterile filling of high-end pharmaceuticals.
“In the third quarter of 2013, DSM will open a new production facility in Brisbane, Australia, providing these same technologies at development and commercial scale, as well as larger bioreactor sizes that are well-suited to commercial-scale fed batch processes,” King adds. “We also offer regulatory support and analytical services.”
Supply Chain Risks
“The biggest risk for cGMP supply chains is qualifying, maintaining, and monitoring suppliers and their raw materials,” according to Chris Duffy, vp of operations at Althea Technologies. To ensure transparency with clients regarding their raw materials, “we must perform due diligence to qualify our suppliers and determine the real manufacturer of the material and where the manufacturer is located.”
Althea’s supplier assessments are based on cooperation between supply chain and quality departments “to identify potential suppliers, evaluate the product portfolio to determine whether the supplier can meet Althea’s needs, and perform the qualification process.”
Its three-pronged approach includes a comprehensive cGMP supplier questionnaire, an on-site audit by a qualified cGMP auditor, and a transmissible spongiform encephalopathy/bovine spongiform encephalopathy (TSE/BSE) statement for all materials used by Althea for GMP activities approved and on file.
“After a supplier is qualified, a change-control agreement is set up. Whenever there is a change in the supplier’s material—including packaging changes, manufacturer’s location changes, product discontinuation, etc.—the supplier must notify Althea in writing,” Duffy continues.
“Reacting to supply shortages in the face of an uncertain demand is another challenge,” Duffy says. “As a contract manufacturer, you have to make a calculated decision to hold more inventory than necessary to satisfy the current demand to react to unforeseen shortages.”
Lean Six Sigma
Mark Bell, vp, site operation, Gallus BioPharmaceuticals, says the economic and technical rationale for Lean operations are the same for any producer of biopharmaceuticals. Lean Six Sigma methodologies focus on removing variation from processes to improve efficiency and quality, using the customer’s definition of quality.
The impetus to integrate Lean Six Sigma into operations includes such global issues as constrained access to capital, pricing competition among CMOs, public scrutiny of healthcare costs, as well as the immediate concerns of optimizing each process to run as efficiently as possible. “Lean provides standardized methods in both development and manufacturing to keep costs under control and projects on schedule while potentially improving quality,” Bell explains.
Implementing a Lean approach relies upon standardization. “Deploying standardized approaches provides tremendous efficiency to everyday work,” he adds, particularly in terms of building more efficient report formats, protocols, and communications technology. “Products and processes are unique, so the goal is not to press a customer into a predetermined mold, but to create a Lean approach that engages the customer.
“Producing cost-effective drugs rapidly ultimately determines a CMO’s success,” Bell notes. “If Lean systems and technology are part of the CMO culture, these methodologies can deliver tangible savings to the customer measured in time, cost, and product quality. As an example, our Condo model lowers the barrier to the cost of manufacturing GMP biopharmaceuticals by reducing up-front capital for facility and equipment, with a rapid point of entry.”
Lean strategies can succeed even if they are only implemented at the CMO, Bell says. “The ability to share and engage in Lean methodologies is more powerful when the two parties engage together, but both parties can benefit even without the client’s active engagement.” Maintaining a Lean culture requires alignment among all of the internal stakeholders—quality, cost, development, operations, sales, and marketing.
Steve J. Evans, marketing manager and business development for Butterworth Laboratories, a contract analytical lab, says the main benefits of outsourcing involve costs, overflow capacity, staffing, and impartiality. CMOs and functional service providers also have the advantage of deep expertise in a broad variety of tests and processes, thereby enhancing productivity and helping improve accuracy.
Disaster recovery is an additional potential benefit. “It’s unusual to find a laboratory (or manufacturing facility) that is overstaffed and that has excessive instrumentation,” Evans says. When routine operations are disrupted, most facilities will suffer. Projects that have been outsourced beyond the involved region or that rely upon a different mix of suppliers, however, may be unaffected.
“Working with a contract facility should be considered a partnership to achieve best results,” Evans stresses. He advises organizations considering outsourcing to not only evaluate GMP/GLP status, available services and techniques, accurate results, and the ability to meet deadlines, but also their demonstrated communications ability, staff expertise, customer focus, and trustworthiness.