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Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.
Focusing on niche and specialty service offerings gives contract biomanufacturing organizations an opportunity to differentiate in a crowded market.
Assessing the capabilities of a contract manufacturing organization (CMO) is a collaborative process, involving numerous communications between the biopharmaceutical company and the CMO. Choosing a manufacturing partner solely based on scale, on prior experience with the CMO client, or on the supposed reputation of the CMO may have been fruitful strategies in the past-but as the requirements for purity, quality, and comparability become more precise, the selection of an appropriate business partner for the manufacture of a sensitive biologic product can sometimes prove to be as challenging as the bioprocessing techniques themselves.
The current biomanufacturing CMO landscape
While the demand for outsourcing services is steadily increasing, say Eric Langer and Ron Rader of BioPlan Associates, sizing up the various partner options and capabilities among CMOs and contract development and manufacturing organizations (CDMOs) can be difficult. Experts within the outsourcing industry are unclear about the total number of CMOs/CDMOs. Even gauging the percentage of CMOS/CDMOs focused specifically on biomanufacturing is a challenge. In June 2014, 15 CMOs/CDMOs united to become part of the Pharma & Biopharma Outsourcing Association (PBOA)-a nonprofit trade association for CMOs/CDMOs representing the interests and concerns of the industry on matters affecting the development and/or manufacture of pharmaceutical products-but the organizations that have joined the trade group (now at 18 members) encompass outsourcing companies from both pharma and biopharma. Led by journalist-turned-advocate, Gil Roth, who is president, the trade group covers issues such as the assignment of Generic Drug User Fee Amendment (GDUFA) fees for facility inspections, and the quality agreements between CMOs and their clients.
CMOs have different approaches to quality agreements, and the PBOA hopes that the FDA’s draft guidance on the topic will help lead to harmonization or a proliferation of best practices in that area. In an adjacent area, the association is working with FDA to help clarify the agency’s recent draft guidance, Request for Quality Metrics (1). Roth spoke at an FDA public meeting on the draft guidance, where he pushed for clarity on the role of CMOs in providing quality metrics to help assure product safety, without creating a huge compliance burden. The PBOA is also concerned that certain metrics could favor in-house manufacturing over outsourcing, and Roth hopes PBOA can ensure that the CMO perspective is represented when FDA ultimately implements the quality metrics (2).
Langer and Rader estimate that there are as many as 80 biologics CMOs, and approximately 20 of these actually make biologics. The three companies in the top tier-Lonza, Boehringer Ingelheim (BI), and Patheon-make up the majority of the biologics market, according to BioPlan. Other industry insiders argue, however, that while Lonza, BI, and Patheon are among the biggest players in the field, Celltrion and Samsung have significant capacity in mammalian cell culture-and Sandoz is likely the biggest CMO for microbial biologics. Two CMO players that follow the aforementioned companies in terms of business activities with biologics include Fujifilm Diosynth Technologies and CMC Biologics, followed by approximately 10 other companies that make up the rest at clinical scale. Jon S. Gingrich, manager of business development at Avid Bioservices, says that Avid’s planned commercial facility expansion will “triple its present commercial capacity.” The remaining 60-plus biologics CMOs are “specialty” CMOs, according to Langer and Rader, many of which are local businesses. In short, approximately 15–20% of the biologics CMOs actually manufacture drugs, but five times as many CMO facilities provide services that support the production of large-molecule medications.
“The market for biological CDMO services-both in drug substance and drug product-is certainly robust,” observes Roth. Areas such as biosimilars and antibody-drug conjugates (ADCs) present huge opportunities for drug makers and CDMOs alike, he notes, adding that these fields require significant levels of expertise and capital-and players lacking in these attributes will be kept out of the game. “The biologic space isn’t for the fainthearted, and there are a range of CDMO models,” says Roth. “This demonstrates that there isn’t one clear ‘plan of attack’ for services and technology solutions providers.”
The successful CMOs are those that have continuously diversified their service offerings, note Langer and Rader, and those that have specialized in a particular niche area in the process stream outside of the basic service offerings of typical CMOs. Some examples of this variety-outside of the typical CMO service offerings, such as process development-include expertise in bioconjugation and ADCs (SAFC, Catalent, Lonza, and Goodwin Biotechnology); Baxter Biopharma Solutions’ proficiency in formulation development and lyophilization cycle development for biopharmaceuticals; Althea’s ability to create stable crystalline formulations for therapeutic products in suspension and its expertise in protein expression using a non-endotoxic bacterial platform; KBI Biopharma’s expanded microbial development and manufacturing services via its acquisition of a Merck facility; Fujifilm Diosynth’s aptitude in diverse gene therapy; WuXi AppTec’s mammalian cell culture capabilities through the use of disposable bioreactors and its dedication to enhancing the manufacture of cell therapeutics; Lonza’s experience with viral gene and virally modified cell products; and MicroProtein Technologies’ proficiency in a fully automated, plate-based protein production method using Escherichia coli. Langer calls MicroProtein Technologies’ recombinant protein platform “quite revolutionary”; the company touts itself as the “first company to produce recombinant biologics on an industrial scale without employing the conventional fermentation process” (3).
Expectations of a CMO handling unstable products
As it relates to the handling of products made in living cells, “a good CMO will be able to support both development and manufacturing programs with a raft of orthogonal techniques to analyze both in-process samples and final purified material,” says Daniel Smith, chief scientific officer, Cobra Biologics. CMOs in the biologic space must comprehend the factors affecting product stability (parameters such as temperature, pH, and buffer concentration, among others); have a good grasp on potential product stressors (shear force and pump type); have information on proven hold times for intermediates and final products; have a solid scientific understanding of protein degradation pathways; and access to excellent characterization methods to measure purity and detect aggregation.
Trends in contract biomanufacturingBioassays are still on top
Contract service providers are expected to benefit from the surge of interest in biosimilar development, especially when it comes to product characterization assays used to assess comparability between a reference product and a biosimilar. The demand for accurate and sensitive biosimilar comparability tools has prompted a renewed interest in the use of orthogonal techniques to characterize elusive structural differences between molecules (4). Disciplined formulation practices for biosimilars are of paramount importance, says Wendy Saffell-Clemmer, research and development director at Baxter BioPharma Solutions. With innovator medications, the process defines the product-whereas for biosimilars, the process must be designed to deliver the targeted product, she adds. Thus, product characterization through the use of orthogonal bioanalytical test methods can help provide insight on whether the development process has been appropriately designed.
“FDA’s totality of evidence approach has analytical characterization at its foundation, which will likely result in an increase in analytical service requests during cell-line selection, fermentation, and purification development,” says Saffell-Clemmer. A recent survey from BioPlan Associates found that biomanufacturers rely primarily on CMOs for analytical testing and for bioanalytical methods that measure the purity or biological activity of a drug product (5). Approximately 86% of biologics manufacturers use CMOs for analytical testing services; a slightly lower number compared to 89% in 2014 (6). The other four activities making the top five most commonly outsourced services in 2015, according to the BioPlan survey, are the same as they were in 2014: plant maintenance services, fill/finish operations, validation services, and toxicity testing. Plant maintenance services jumped from the fifth most commonly outsourced activity in 2014 to the second most commonly outsourced service in 2015, perhaps indicating that biopharmaceutical companies’ aging facilities may drive businesses to outsource to CMOs in lieu of investing in new equipment for their own facilities. The increased use of automation and disposable technologies in aseptic processes are also expected to drive business to CMOs, as many CMOs have already invested in the technology to do this work, such as the purchase of large-scale isolators for the preparation of potent compounds (7).
An uptick in service requests related to the development of biosimilars has been observed by many of the CMOs that spoke to BioPharm International. These services are primarily related to analytical testing, with a special interest in the understanding of product glycosylation patterns, notes Smith. Gingrich confirms that his company has seen a significant increase in glyco-profiling requests; this assay is currently one of the most-requested types at Avid.
Other analytical services expected to gain popularity as more biosimilar candidates flood the pipeline include formulation screenings, high-throughput screenings, and quality and comparability studies, according to Sébastien Ribault, PhD, director of Provantage Biodevelopment/end-to-end services, Merck BioDevelopment, Millipore S.A.S., France. To find the optimal clone, comparative analytics for biosimilars should ideally begin as early in the process as cell-line development, suggests Marion Schrader, PhD, senior director of marketing at Rentschler. Despite the increased interest in biosimilars, Schrader mentions that Rentschler expects “to see some consolidation in the area, as not all of the current clinical projects will have commercial success.”
Other commonly outsourced activities include: API manufacture, cell-line development, cell banking (master cell banks and working cell banks), process development, formulation development, conjugation development, media development, and routine production processes. Activities that present unique facility concerns-such as the manufacture of ADCs, cell and gene therapies, compendial and stability testing, or viral vaccines and vectors-are usually outsourced as well. Firelli Alonso-Caplen, PhD, senior director of biotherapeutics and vaccines outsourcing at Pfizer Biotech, notes that keeping more complex projects in house, however, helps her company in particular retain internal full-time employees. She says these challenging projects “become motivational drivers for more innovation for our own scientists.”
There was no consensus among industry experts as to whether viral clearance studies are usually outsourced or not. According to Gingrich, most CMOs do not have experience working with viral banks and many of them do not want to have any viral material onsite. On the other hand, Pfizer’s Alonso-Caplen says that viral vaccines and vectors pose a risk to in-house biopharmaceutical manufacturing facilities, and such activities are, therefore, likely be outsourced to CMOs.
While many activities are outsourced in a piecemeal fashion, and the need for certain services can vary widely depending on a biopharmaceutical sponsor’s existing core capabilities, there is always the possibility that a product sponsor could come to a CMO with a completely defined process and ask the CMO to solely assume a production role. The reason for this production-driven request could be because the pharma client has overwhelmed its in-house capacity, or because it wants the CMO to manufacture “a secondary supply of clinical or commercial products for [the purpose of] risk mitigation,” explains Smith.
When outsourcers outsource
A CMO may decline a project if the client requests fall outside of the scope of its capabilities. When a CMO suspects it cannot complete certain tasks as requested, it is important for that company to “be upfront and transparent with the client so that [the client is] able to pursue discussions with other CMOs,” notes Jennifer Cannon, PhD, senior director of commercial strategy at Ajinomoto Althea.
Out-of-scope requests are one of the “great challenges that can continually test the CDMO/development company relationship,” says Cynthia Wooge, global strategic marketing at SAFC. Specifically, the analytical tasks required for a project create the greatest chance for out-of-scope work requests, she says. “Upfront diligence in defining the scope, deliverables, and requirements of a program provides the best opportunity to limit out-of-scope occurrences.”
An outsourcing firm can also expand its capabilities by partnering with a second CMO for activities such as PEGylation or antibody conjugation. Cobra Biologics has such a partnership with Quiapeg to complement its service offerings. Other options include asking the client to perform product-specific tasks itself, says Johannes Reiter, head of biotech cooperations at Sandoz, or building the technology at the CMO level, “but this evaluation is done on a case-by-case basis only when it makes sense,” adds Reiter.
According to Gingrich, every CMO has a list of core capabilities and a running list of outsourced service providers they rely on. “The goal is to match what can be done in-house and what needs to be outsourced,” Gingrich asserts. To establish a successful partnership with a client, it’s best for a CMO to conduct a thorough technical evaluation of a client request for proposal (RFP), notes Saffell-Clemmer, and possibly meet with the client after review of an RFP to clarify any outstanding concerns. Wooge concurs that managing customer expectations is crucial: “CDMOs are wise to apply significant rigor in assembling detailed proposals that clearly articulate the assumptions and expected work identified in the RFP process.”
If a selected CMO cannot perform all of the duties required for the manufacture of a biologic from start to finish, three to four points of contact with different CMOs can be typical. Smith emphasizes that if a product were to be developed from cell-line selection through to distribution to clinical trials, seven to eight CMO partners could even be probable. For example, multiple points of contact could conceivably be used for the following steps: a primary CMO to handle linker-payload production, a second CMO to handle conjugation of the drug substance, a third to handle the formulation and aseptic fill/finish of the drug product, and a final CMO for the purpose of release and stability testing. This supply chain design adds a significant amount of complexity, says Alonso-Caplen, more room for error, and “higher externalization risks, especially if [the] CMOs are globally situated.” When it comes to the coordination of multiple service providers, Gingrich says that the cGMP CMO is usually responsible for the management of all of the other outsourced activities.
In the circumstance that a customer outsources a drug substance from a different location than a drug product, a client can, and typically will, ask a CMO to perform a more rigorous API testing and release program than it normally would for a drug substance manufactured by the customer itself or by a domestic partner, notes Saffell-Clemmer.
In the case of biosimilar comparability testing, multiple samples of a drug product are sourced from various regions or production sites-and it’s up to the primary CMO to determine the degree of similarity between the originator product and the biosimilar, notes Gingrich.
1. FDA, Draft Guidance for Industry, Request for Quality Metrics, (Rockville, MD, July 2015).
2. The editors of Pharmaceutical Technology, “A Voice of Their Own,” Outsourcing Resources, supplement to Pharm. Technol. 39, pp. s24–30 (2015).
3. MicroProtein Technologies, Inc., company homepage, www.mptbiotechs.com, accessed July 24, 2015.
4. The editors of BioPharm International, “Biopharma Advances Demand Specialized Expertise,” Outsourcing Resources eBook, BioPharm Int., pp. 12–19 (June 2015).
5. BioPlan Associates, Inc., 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, E.S. Langer, Ed. (Apr. 2015).
6. BioPlan Associates, Inc., 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, E.S. Langer, Ed. (Apr. 2014).
7. E.S. Langer, “Fill/Finish Trends,” Outsourcing Resources eBook, BioPharm Int., pp. 20–25 (June 2015).
Article DetailsBioPharm International
Vol. 28, No. 9
Citation: When referring to this article, please cite it as R. Hernandez, "Contract Biomanufacturing Firms Become More Specialized," BioPharm International28 (9) 2015.