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
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
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.