Building Toolboxes through Cross-Functional Partnerships

As pharmaceutical companies contend with increased cost pressure and the need to accelerate development timelines, CMOs/CDMOs play a vital role. The author examines the alliance strategies of contract services providers as a means to build their development and manufacturing capabilities and facilitate more efficient projectmanagement and technology transfer in the outsourced relationship.

In the arena of pharmaceutical outsourcing, when speaking of partnerships, the discussion typically focuses on the relationship between a pharmaceutical/biopharmaceutical company as the sponsor company and a contract services provider. The emphasis is on the expectations between customer and supplier and the capabilities offered by the contract services provider to the sponsor company and the ways in which the project may be most effectively managed to meet specified deliverables. And while these partnerships remain the key focus of pharmaceutical outsourcing, partnerships among contract services providers, ingredient suppliers, and academia also are becoming a part of the outsourcing paradigm as companies seek to combine capabilities, services, and products to deliver a more integrated and efficient solution to a sponsor company.

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Formulation development andfinished-product manufacturing

In 2012, several CDMOs and CMOs formed partnerships as a means to expand their offerings. For example, Catalent Pharma Solutions and the CDMO Bend Research partnered to provide integrated solutions for pharmaceutical companies seeking to develop and manufacture specialized multiparticulate oral controlled-release products. The companies offer combined expertise in formulation development, and Catalent provides further capabilities in analytical and chemistry, manufacturing and control (CMC) development, solid-state optimization, and clinical and commercial manufacturing. As part of their agreement, Catalent and Bend Research are developing joint operations and technology-transfer protocols. The partnership is geared toward complex, multiparticulate controlled-release products, which traditionally have presented a high scale-up risk when they are transferred to commercial manufacturing sites. The companies are aligning their scientific expertise and processes to ensure that developments are undertaken using quality-by-design principles (QbD). Bend also brings laboratory-scale modeling expertise that complements Catalent's expertise in formulation development and manufacture of controlled-release compounds. Catalent's Winchester, Kentucky facility is a commercial facility for multiparticulate products.

Earlier in 2012, Catalent Pharma Solutions and BASF formed a broad collaboration and open alliance to provide solutions to overcome bioavailability challenges of new molecular entities with solubility or permeability challenges (i.e., Biopharmaceutics Classification System Class II and IV compounds). The alliance combines the expertise of both companies to provide feasibility studies across multiple technologies, solid-state chemistry, consulting and training, formulation services, excipients, and optimal dose-form development from scale-up to commercial supply. One specific application for addressing solubility issues is the use of hot-melt extrusion (HME). BASF has a portfolio of solubilizers and excipients for HME, including its Soluplus excipient, and Catalent offers HME technologies (OptiMelt). Catalent has made recent investment in its OptiMelt HME and fluid-bed laboratory- pilot-, and commercial-scale equipment at its Schorndorf, Germany, facility as well as in training and method development at its facility in Somerset, New Jersey.

On the clinical side, Catalent and the CRO PAREXEL formed an alliance in October 2012 to provide a fully integrated, end-to-end clinical-trial-material supply-chain solution. This solution is intended to streamline the clinical supply process and reduce development timelines while improving service quality. In the alliance, PAREXEL brings clinical-trial-management services and global clinical logistics capabilities, and Catalent brings manufacturing, packaging, and labeling solutions.

To build cross-functional expertise, Catalent Pharma Solutions also launched the Catalent Applied Drug Delivery Institute to promote innovation, knowledge-sharing, and collaboration between industry leaders, academic experts, customers, and regulators to enhance understanding of available, emerging, and future drug-delivery technologies. As part of its mission, the Catalent Applied Drug Delivery Institute, which was launched in 2012, will serve as a link between industry and academia by providing guidance, counsel, and resources on major issues pertaining to drug development, drug delivery, and formulation. The institute will develop programs that facilitate mutually beneficial collaborations, increase communication, and shed light on regulatory issues affecting drug developers and researchers. It also will pursue a multitiered approach of seed funding, strategic counsel, and educational programs to advance the adoption of emerging technologies.

Other companies also are pursuing collaborations. In October 2012, Bend Research and Dow Chemical formed an exclusive collaboration to provide science-based spray-dried dispersion (SDD) solutions and select new polymers for poorly soluble oral drugs. Under the agreement, Dow and Bend Research will work together to provide fully characterized polymers supported by QbD principles as well as tailor materials to meet the performance needs of specific drugs. In addition, the two companies will develop and commercialize new materials for SDDs that address technology gaps in manufacturability and delivery to provide greater drug-product utility and therapeutic performance. Specifically, Dow will provide the excipients hypromellose and hypromellose acetate succinate as well as cellulosic and noncellulosic polymers.

The collaboration combines Dow's capabilities in materials design, high-throughput screening, and pilot-plant and commercial scale-up operations with Bend Research's SDD screening, formulation, scale-up, and technology-transfer capabilities. Dow is supporting the collaboration with several technologies, including high-throughput synthesis with API/polymer screening, laboratory-scale product development, and structure/property optimization as well as a cGMP market-development plant capable of supporting clinical development.

In January 2013, Xceleron, a provider of bioanalytical accelerator mass spectrometry (AMS) services for early drug development, partnered with Crystal Pharmatech, a China-based solid-state research CRO, to offer drug developers early bioavailability data for producing optimized solid-state forms and formulations. The partnership seeks to apply AMS technology and related expertise to address pharmacokinetic uncertainty by providing early clinical and solid-state information to provide better information earlier in drug development about a drug candidate's later-stage readiness. Xceleron applies human microdose and microtracer techniques using ultra-sensitive AMS to investigate the pharmacokinetics and metabolism of developmental drugs in Phase 0, Phase I, and Phase II/III clinical trials.

Building strength in APIs

Contract API manufacturers and fine-chemical producers also are partnering to expand their collaboration. For example, in 2012, DSM and Almac formed an alliance in biocatalysis. The agreement grants both parties access to their enzyme platform technologies, services, and expertise for the manufacturing of APIs. Almac brings to the table capabilities in enzyme identification, scale-up, and implementation into early-phase projects, and DSM brings capabilities in commercial-scale bioprocesses to enable production from preclinical to commercial-scale manufacturing. This collaboration will also enable Almac to offer its customers a preferred partner for large-scale production.

In 2012, Carbogen Amcis and ADC Biotechnology formed an alliance to provide customers with development and manufacturing services for antibody drug conjugates (ADCs). ADC Biotechnology is developing a "lock and release" solid-phase immobilization technology for production of ADCs. The alliance will offer services for the development, scale-up, manufacturing, and formulation of protein-based drug conjugates. ADC Biotechnology will provide access to proprietary solid-phase immobilization technologies for conjugation and long-term storage of ADCs, and Carbogen Amcis will focus on focus on small- to large-scale GMP supply and on the formulation of ADCs.

Onyx Scientific and Molecular Profiles partnered in 2012 to deliver end-to-end services from initial drug discovery to early- and late-phase manufacturing. The complementary alliance involves Onyx Scientific's specialty in API production and initial solid-state screening and Molecular Profiles' expertise in formulation and analytical development and early-phase clinical-trial-material manufacturing. Onyx Scientific also has sites in India, at which it provides late-stage clinical-trial and commercial manufacturing services.

Academic–CDMO/CMO relationships

Alliances with academia also provide an opportunity for a CDMO or CMO to enhance its capabilities. For example, in January 2012, Almac completed its Knowledge Transfer Partnership (KTP) with Queens University, Belfast, to develop, improve, and embed bioprocesses to facilitate the delivery of novel products for its biocatalysis business. The overall aim of the partnership was to allow technology transfer of fermentation and molecular/microbiology expertise from Queens University to Almac. Almac met the specific partnership objectives by sharing a program of work with academics at Queens and by attending training courses organized through University College London, which allowed Almac to embed key learning back into the company. Since completion of the KTP, Almac has successfully scaled fermentation and bio-oxidation reactions to thousands of liters.

Aesica formed a partnership with the Center for Pharmaceutical Engineering Science at the University of Bradford in the United Kingdom to enable the team at the University of Bradford to use the GMP capabilities and assets held at Aesica while Aesica will benefit from the center's research facilities. The partnership builds upon the relationship between the two parties. The center offers several processing technologies, including HME, but relies on the GMP expertise of the formulation development team at Aesica to manufacture GMP clinical-trial supplies.

Other models

The goal to offer integrated and more seamless delivery of services is also achieved through individual company strategy and focus. For example, in 2012, AMRI launched SMARTSOURCING, an approach that further focuses its research and contract manufacturing services to the various needs of the life-sciences and other industries. It is designed as a series of strategic sourcing options for customers.

The rationale for the SMARTSOURCING arose in response to changing industry fundamentals, namely increased pressure on pharmaceutical companies to deliver accelerated and increased drug-discovery success with reduced budgets and resources. Moreover, due to downsizing in the United States and Europe, many large pharmaceutical companies have lost experienced scientists with drug-discovery and development expertise, and as a result, may rely more on their contract service providers to fill knowledge gaps. This provides further opportunity for CROs and CMOs to reconsider their current service strategies to find more appropriate ways to meet the market's changing needs. SMARTSOURCING is an approach that seeks to address that by offering insourcing or outsourcing, or a hybrid model of both, to deliver scientific expertise, according to an Apr. 30, 2012, AMRI press release.

Sidebar 1: The marriage of contract service providers and biopharmaceutical/pharmaceutical companies

Providing contract-manufacturing services is not in of itself new for bio/pharmaceutical companies, and several companies have well-established contract activities for API development and manufacturing, formulation-development, drug delivery, and finished drug-product manufacturing. In general, these third-party services provide a way for pharmaceutical/biopharmaceutical companies to leverage internal expertise and manufacturing capacity to augment revenues through contract services, and these companies have become an important part of the outsourcing market.

Some examples of companies positioned in the market this way include: the contract services business of Pfizer (Pfizer CentreSource), Sanofi (Commercial and External Partnership, Industrial Affairs [CePiA]), GlaxoSmithKline, Hospira (One 2 One), Mitsubishi Tanabe Pharma (API Corporation), Bayer (Bayer Healthcare Pharmaceuticals), Boehringer Ingelheim, AbbVie (AbbVie Contract Manufacturing), Baxter International (Baxter BioPharma Solutions), Merck & Co. (MSD API), Sandoz (the generic-drug business of Novartis), Teva Pharmaceutical Industries (Teva Active Pharmaceutical Ingredients [TAPI]), and Mylan. A review of these companies' activities shows capabilities in both API and finished product manufacturing.

For example, Pfizer CentreSource, headquartered in Kalamazoo, Michigan, is a provider of APIs and dosage-form manufacturing. It is a supplier of fine chemicals, steroid APIs (e.g., corticosteroids and hormonal steroids), and steroid intermediates. It also provides custom fermentation services as well as sterile manufacturing (blow/fill/seal/services) and solid-dosage manufacturing, including high-containment services.

One 2 One, the contract manufacturing arm of the specialty pharmaceutical company Hospira, provides development services and finished-dose manufacturing of parenteral drugs. One 2 One specializes in fill–finish of biologics and lyophilization and can provide access to leading biopharmaceutical markets by using several manufacturing facilities in the US, Europe, and Asia.

AbbVie Contract Manufacturing is the new name for the contract manufacturing activities of AbbVie, following the formation of AbbVie as an separate research-based biopharmaceutical company in January 2013 following the separation of AbbVie from Abbott. AbbVie Contract Manufacturing provides contract manufacturing services for biologics, drug products, and potent compounds.

The CMO division of Sanofi, CEPiA, provides corticosteroids, steroid diuretics, vitamin ±2, cardiovasculars, analgesics, anti-inflammatories, antihistamines, antibiotics, prostaglandins, and opiods (morphine and codeine salts). The company has expertise in multistep custom synthesis, steroid chemistry, prostaglandins chemistry, enzymatic conversions, synthesis of high-potency compounds, peptide and protein chemistry, micronization, and large-scale chromatography. The contract arm uses Sanofi's chemical, fermentation, and biotechnological facilities in France, Germany, Italy, Hungary, Eastern Europe, Singapore, and India.

On the API side, Bayer Healthcare Pharmaceuticals uses several plants for its contract activities. Its supply center in Bergkamen, Germany is Bayer Pharma's major facility for the production of intermediates, active ingredients, and bulk pharmaceutical chemicals for steroid hormones through chemical and microbiological synthesis. It also has a micronization plant in Berlin-Charlottenburg, another API plant in Elberfeld, Germany, and a second major chemical facility for hormone and steroid production in Orizaba, Mexico. Also, on the API side, the contract-services arm of Boehringer Ingelheim provides contract manufacturing of biologic-based APIs, chemical APIs, and fine chemicals. On the biologics side, a key offering is its BI Hex high-expression system for monoclonal antibody production.

Sidebar 2: The anatomy of a partnership: API development and manufacturing for an orphan drug

FDA approval of a new molecular entity (NME) is a crucial milestone for the commercialization of a drug. Bringing a NME through the drug-development and regulatory-review process to eventual commercialization requires the application of a myriad of capabilities, which may be internally provided by a biopharmaceutical company or externally by a contract services provider. For smaller biopharmaceutical companies, the role of a CDMO and/or CMO is particularly important for advancing a NME, with the partnership between a sponsor company and the CDMO/CMO often beginning early in development and continuing through drug development and commercialization.

Such was the case for the biopharmaceutical company Aegerion Pharmaceuticals, which received FDA approval in December 2012 for Juxtapid (lomitapide), a small-molecule, microsomal triglyceride transfer protein inhibitor that Aegerion developed as a once-day capsule for treating patients with certain severe lipid disorders, including homozygous familial hypercholesterolemia (HoFH). Aegerion Pharmaceuticals develops drugs for rare diseases, and the orphan drug lomitapide was approved as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein (LDL) apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non-high-density-lipoprotein cholesterol (non-HDL) in patients with HoFH, according to a Dec. 24, 2012, Aegerion Pharmaceuticals press release. HoFH is a serious, rare genetic disease that impairs the function of the receptor responsible for removing LDL-C (i.e., "bad" cholesterol) from the body. A loss of LDL receptor function results in extreme elevation of blood cholesterol levels, according to the company release. HoFH patients often develop premature and progressive atherosclerosis, a narrowing or blocking of the arteries.

Catalent Pharma Solutions is providing the finished product for Juxtapid following a seven-year clinical-trial-materials supply relationship with Aegerion. The partnership, which included analytical development, clinical-trial-material supply and manufacturing, will now be expanded with Catalent as the exclusive supplier of Juxtapid in 5-mg, 10-mg, and 20-mg strengths for the US and European markets from Catalent's Kansas City, Missouri facility. Catalent will also support Juxtapid packaging and qualified-person release from Catalent facilities in Bolton and Swindon, United Kingdom, for the European market.

On the API side, in January 2013, Aptuit signed a long-term supply agreement with Aegerion Pharmaceuticals for commercial quantities of the API lomitapide. Aptuit provides integrated early- to mid-phase development services, including drug design and discovery, preclinical biosciences, API development and manufacture, solid-state chemistry, drug-product formulation development and manufacture, sterile fill–finish, clinical sciences, and consulting. The company maintains five global facilities with approximately 800 employees in Europe and the United States and has a strategic relationship with Laurus Labs in India.

To gain a perspective on this partnership and overall trends in outsourcing, Patricia Van Arnum, executive editor of Pharmaceutical Technology, recently spoke to Kevin Duffield, senior director, API, at Aptuit.

PharmTech: Aptuit and Aegerion Pharmaceuticals recently signed a long-term supply agreement for commercial quantities of the API lomitapide, a newly approved drug. Can you provide some background on the partnership with the company? Was Aptuit also involved with clinical supply of the drug and how did the relationship begin?

Duffield: The companies began working in 2007 to support early clinical trials with API and drug product. Aptuit had made the API to support clinical trials and product launch and will continue to supply over the coming years.

PharmTech: Can you explain how the integration of various service deliverables occurred across the company's US and European sites and with the sponsor company? What were the critical success factors in terms of project management and communication?

Duffield: Aegerion's approval for lomitapide provides a new treatment for an orphan indication with few alternatives. The ability to rapidly develop the API process, analytical methods, and solid-state formulation was critical to meeting the aggressive commercialization timeline of Aegerion. During the development cycle, many overlapping project activities were conducted to speed the process to the new drug application filing. For instance, three different Aptuit R&D sites worked on process-justification studies. A large number of analytical methods needed to be developed and validated. This work was spread across Aptuit sites to conduct the work in parallel and to take advantages of a larger network of expertise.

Another critical factor was the ability to identify and resolve solid-state chemistry issues and to rapidly translate fundamental science in this area to plant-scale control of API morphology and particle size. Aptuit's West Lafayette, Indiana team are leaders in this science and worked hand-in-hand with the Aegerion and Aptuit's Harrisonville, Missouri production unit to scale up and validate the process.

PharmTech: Can you provide further insight in the synthesis of lomitapide to understand the context of the services delivered?

Duffield: The synthesis is a multistep convergent synthesis that requires several weeks to complete. Services delivered included raw-materials sourcing, auditing, and qualification. More than 20 quality-control methods for raw materials, intermediates, and final product were developed and validated. Basic R&D into the chemical process was conducted at Aptuit, along with the process-justification design-of-experiment work to establish a foundation for the critical process parameters. Solid form and particle-size control technology was developed and implemented at plant scale. A prospective process-validation campaign, during a multimonth timeframe, was completed. All services were conducted under cGMP-compliant practices and a pre-approval inspection was successfully completed with all appropriate documents to support filings with FDA. Overall, five Aptuit sites contributed to the successful activity with the bulk of the work being done in 2011 and 2012.

PharmTech: On an industry level, how is the outsourcing model evolving between contract service providers and sponsor companies? What factors have shaped relationships during the past five years, and what do you see the future holding?

Duffield: To bring potent/orphan compounds to market in the shortest possible time requires collaborations that rely on incredibly open communication, trust, and responsiveness to changing needs and circumstances. Mutual resource commitments and dedicated people working in collaboration to solve problems on short timescales are essential to drive parallel activity and to manage the risks that go with accelerated timing. The supplier has to provide compliant science with exceptional commitment to service and a will to win on behalf of the sponsor and its prospective patients. The sponsor has to provide open communication of goals and recognition of the efforts of the supplier to meet their goals (both verbal and financial). Flexibility and speed to response, along with broad technical capability, are driving the business and will continue to be the difference maker between suppliers in the coming years.

Sidebar 3: An emerging model: manufacturing-capacity sharing arrangements

Achieving a good return on assets through manufacturing-capacity utilization is an ongoing challenge for biopharmaceutical/pharmaceutical companies. Pharmaceutical companies need manufacturing capacity on hand to produce commercial products and also to launch new products as they come through their drug-development pipelines. The inherent uncertainty of drug development, however, makes it difficult to balance the need for timely access to manufacturing capacity with the interest of avoiding underutilizing capacity and a resulting reduction on a return on assets. One strategy taken by some companies has been to enter manufacturing capacity-sharing agreements, which allows one partner to monetize underutilized capacity and another partner to secure access to manufacturing capacity.

In December 2012, Biogen Idec and Eisai formed such a strategic alliance to strengthen the manufacturing capabilities of both companies' facilities in Research Triangle Park (RTP), North Carolina. Under the terms of the agreement, Biogen Idec will lease a portion of the Eisai facility to manufacture oral solid dose products for both companies. Eisai will provide Biogen Idec with vial-filling services for biologic therapies and packaging services for oral solid-dose products. The 10-year lease agreement gives Biogen Idec the option to purchase the Eisai oral solid-dose facility.

Approximately 50 Eisai personnel are expected to become Biogen Idec employees in early 2013, building on the company's RTP workforce, which exceeded 1000 in 2012. Eisai currently employs approximately 225 full-time employees at its RTP site. Biogen Idec and Eisai have both operated manufacturing facilities in RTP since the mid-1990s.

Merck & Co. and MedImmune, the biologics arm of AstraZeneca, also have a capacity-sharing arrangement in biologics, an arrangement the companies formed in September 2011. The relationship emerged to address underutilized capacity on behalf of MedImmune and a need for Merck to secure biologics capacity for its biologics program.

In 2007, AstraZeneca completed the acquisition of MedImmune, which became the biologics arm of AstraZeneca, incorporating the MedImmune assets, legacy AstraZeneca biologics assets, and Cambridge Antibody Technology, which AstraZeneca had acquired in 2006. A key manufacturing asset for MedImmune, which is headquartered in Gaithersburg, Maryland, is the company's large-scale monoclonal antibody (mAb) manufacturing facility in Frederick, Maryland. Prior to its acquisition by AstraZeneca in 2005, MedImmune committed to support 500 kg of production per year through the addition of two 15,000-L bioreactors, which would replace an original 2 x 2500 L plant. The additional capacity was intended to meet the mid-range product demand of MedImmune through 2013.

In acquiring MedImmune in 2007, AstraZeneca further authorized an additional 500 kg of capacity to include a total of four 15,000-L bioreactor trains at the new Frederick facility. When the MedImmune product for which the initial capacity was intended did not proceed through clinical development, MedImmune realized that existing products would not fill the site. The combination of a pipeline-delivery gap and the subsequent improvement in titers or grams-per-liter yields required an alternative solution to fill capacity (1). The companies formed a 15-year manufacturing capacity-sharing agreement in September 2011 with Merck utilizing MedImmune's Frederick, Maryland facility for Merck bulk-product manufacturing. The companies also are exploring the suitability of Merck's facilities in the production of microbial-based compounds in MedImmune's pipeline and other potential manufacturing opportunities where business strategies intersect.

Reference

1. P. Van Arnum, "Outsourcing Resources supplement to Pharm. Technol. 36 (8), s28–s32 (2012).