The first attempts to use monoclonals (Mabs) as antitumor agents in the 1980s did not live up to expectations. The recent success of improved therapeutic Mabs, such as Rituxan for cancer and Remicade for arthritis, are proving clinically effective and financially attractive. This resurgent interest in Mabs creates opportunities for contract manufacturing organizations (CMOs) that produce Mabs and other biologics.
Stephanie Finnegan, CEO and founder of Goodwin Biotechnology (www.goodwinbio.com), a former consultant to the pharmaceutical industry, reasoned that just as many drug companies contract out the manufacturing of pills and tablets, the same paradigm could apply to Mabs and recombinant proteins.
It makes financial sense to outsource production of biologics for preclinical, Phase I, Phase II, and even Phase III trials, Finnegan says. Not only are biotherapeutics more difficult to make than chemical drugs, but most biotechnology companies do not have the capital to build their own manufacturing facility.
Moreover, investors dont want to invest in bricks and mortar, she states. Unless a company has at least two drugs on the market, building a manufacturing plant is not financially sound, Finnegan maintains.
Goodwin Biotechnology built a niche serving bench-to-clinic clients with products in preclinical through Phase II development. The company grew 400% in the past year and increased its staff from 25 to 50 people. In January, Goodwin Biotechnology decided to double its GMP-manufacturing space to better serve clients entering late-stage development. When clients reach Phase III trials, they have to leave us because we arent large enough, explains Finnegan.
Finding a Niche
The pharmaceutial technologies and services group of Cardinal Health (www.cardinalhealth.com/pts) uses a patented gene product expression technology, GPEx, to insert genes and create stable mammalian cell lines with high gene copy numbers.
GPEx employs retroviral vectors to deliver genes coded as RNA that are reverse-transcribed to DNA and integrated into host cell genomes. It enhances protein yields to permit efficient pilot plant and large-scale production of Mabs and other therapeutic proteins. By inserting multiple copies of genes of interest, Cardinal Health can reportedly create cell lines that express as much protein as traditional gene transfection methods in half the time.
The GPEx technology originally was developed by Gala Biotech to make transgenic cows using retroviral vectors discovered by the late Nobel laureate Howard Temin at the University of Wisconsin-Madison. Cardinal Health acquired the company in 2003.
We noticed that the cultured cells used to make the retroviral particles express high levels of proteins, especially antibodies, says Paul Weiss, president of Cardinals biopharmaceutical development center.
Weiss describes Cardinal Health as a CMO plus because the GPEx technology optimizes cell lines for clients so that clients can then either remain with Cardinal Health or take the improved cell lines elsewhere. Because of its diversified capabilities, Cardinal Health can take a clients gene for an antibody, create or optimize a cell line, produce bulk protein, perform FDA biosafety testing, develop a stable formulation, and fill and finish the final product in vials, ready for dosing of patients.
Cambrex Bio Science Walkersville (www.cambrex.com) recently signed an agreement for the manufacture of Gerons (www.geron.com) GRNVAC1 telomerase vaccine (see GEN, March 1, 2006, p. 46). Gerons production process is being transferred to Cambrex, which will carry out the cGMP manufacture of the product, a therapeutic cancer vaccine composed of autologous dendritic cells, loaded ex vivo with telomerase mRNA.
We will leverage our cell therapy expertise and cGMP-manufacturing capabilities to enable Geron to advance the development of GRNVAC1 in the clinic, adds Shawn Cavanagh, Cambrex senior vp and general manager, bioproducts.
According to Cambrex officials, the companys manufacturing facilities provide a number of support services that might be required to produce human cells for therapeutic use, including autologous cells of varying shelf life for shipment to the U.S. and Europe; allogeneic cells, including sourcing, production of cell banks, and expansion to product quantities; and stem cell production via both master and feeder cell-banks.
Cambrex is equipped for and has experience with flasks, roller bottles, beads, and cell factories, including tissue engineered formats to meet specific customer requirements, says a company spokesperson. U.S.-based suites currently comply with ISO Class 7 (Class 10,000) classification to meet U.S. requirements, and suites with ISO Class 5 (Class B) compliance for European needs are expected to be available shortly. European suites meet all current European GMP regulatory standards, according to the firm.
The CMO team at Avid Bioservices (www.avidbio.com) is flexible to accommodate each client, says Richard Richieri, senior vp of bioprocess development and manufacturing.
In addition to standard batch and fed-batch processes, Avid offers perfusions (continuous cultures) that maintain high cell densities. Depending on the cell line, perfusions can generate as much material in a day as a fed-batch process produces in two weeks. When perfusion works, it has tremendous process economics, explains Richieri.
Avid Bioservices started in 2002 as a wholly owned subsidiary of Peregrine Pharmaceuticals (www.peregrineinc.com) to perform in-house biomanufacturing, then expanded to serve outside clients. One client recently received API approval for Avid to manufacture its commercial materials. Ever since we passed that inspection, weve been getting more Phase III clients, says Richieri.
U.S. Biologics Market
Patheon (www.patheon.com) provides contract development and manufacturing services from 14 sites worldwide. The company has two facilities in Italy and one in the U.K. that handle biologics, ranging from preclinical development through Phase III and commercial manufacturing.
All three facilities are FDA-approved, and they offer sterile and lyophilized manufacturing services. Obtaining FDA approval is paramount to our business development and investment strategy because the largest biologics market is the United States, says Jonathan Arnold, director of business management for European operations.
Patheon has invested heavily in liquid filling, vial filling, and lyophilization operations at its European facilities. A key challenge of freeze drying in biologics is scaling up, says Mathew Cherian, director of pharmaceutical development services in Italy. The equipment used creates lyophilized products in quantities suitable for preclinical to late-clinical stage testing. We have taken peptides, proteins, and monocolonal antibodies from small-scale, 0.2-meter-square freeze driers through commercial-scale, 33-meter-square driers, he says.
Laureate Pharma (www.laureatepharma.com)specializes in bioproduction, in particular antibodies and other recombinant proteins produced in mammalian cells, says Mike Cavanaugh, vp of business development. The company offers services ranging from initial process development and cell-line optimization to final filling and finishing. Most of their clients are in clinical-stage development, but Laureates facility also is approved for commercial manufacturing.
The majority of the contract manufacturing of biologics at Baxter's Biopharma Solutions (www.baxterbiopharmasolutions.com) takes place in Bloomington, IN. In general, Baxter manufactures injectable and intravenous drugs, says Joe Mase, group market manager for contract services. That expertise readily transfers to the manufacturing of biologics, such as cold manufacturing requirements or aseptic formulations. Most of the volume at Baxter is for Phase III and commercial-scale production.
Challenges and Trends
CMOs have to take care of each clients individual concerns from cross contamination of their product at the earliest stages to understanding the regulatory issues at the Phase III stage, as well as dealing with the eventual cost concerns surrounding bringing biotherapeutics to the patient.
Managers of CMOs typically juggle 10 to 20 clients in a year. Just as each cell line requires different media, growth conditions, and purification processes, each client comes with different time lines, expectations, and past experiences. The project they bring to us is their livelihood, says Finnegan. We try to make each client feel like they are our only client.
Avoiding the Empty Tank
According to Weiss, in the CMO business, an empty tank is a bad thing. Good project management skills help to schedule different projects in different departments. CMOs encounter high fixed costs. You cant attract a well-educated work force, then lay them off if youre not busy, says Finnegan. Staggering stages of production for several clients keeps bioreactors fully utilized, and fixed costs can be leveraged across several clients to benefit everyone.
Advantages of Disposables
The chief concern of clients is cross contamination of products made at CMOs. Avid uses disposable equipment and supplies, including filters, tubing, bags, and tank liners, to prevent cross contamination. Disposable items reduce labor time that is spent cleaning equipment and they speed up change. In our facility, the only stainless steel equipment are the bioreactors, says Richieri.
Clients even ask for disposables, says Cavanaugh, as an assurance that no cross contamination will occur. Cross contamination and disposables are hot topics right now, he adds. Laureate also segregates products so that multiple commodities are never manufactured in the same area. Additionally, disposable equipment offers flexible manufacturing platforms for small batches. Laureate Pharma uses disposable bioreactors for development work and seeding stainless steel bioreactors.
Patheon also uses disposable supplies for small-scale development projects. The use of disposable, one-use compounding vessels is now a common and routine practice, says Cherian. For commercial production, however, Patheon dedicates bioreactors, pipes, and filling equipment to prevent cross contamination. The materials used to make biologics are so expensive, says Arnold, that the cost of investing in dedicated equipment is comparatively small.
Another way to reduce the chance of cross contamination, according to Mase, is to replace vials with prefilled syringes. Since most biologics must be injected or infused, prefilled syringes also save time and eliminate errors. The syringe market is growing 15% a year, says Mase, as ready-to-use products increase market share. Moreover, vials must be overfilled up to 18% to insure that patients receive a correct drug dose, whereas syringes need only about 3% overfill. Therefore, prefilled syringes reduce the high cost of manufacturing biologics.
Validation issues become more challenging as products progress toward Phase III trials. About half of Goodwins clients are Canadian or European, so we have to know about regulations from other countries, says Finnegan.
More CMOs are offering one-stop shops that do everything from cell line development to final fill, says Richieri. Clients benefit from one-stop shops because they only have to worry about one facility and one management team.
According to Weiss, CMOs would benefit from innovations in downstream processing methods to purify proteins. Engineered cells can express greater than a gram of protein per liter, but the same old downstream purification methods cant handle that effectively, says Weiss. The industry needs improved downstream purification techniques capable of processing as much as five grams of protein per liter.
A future concern is how to make biologics affordable to patients. Chemical drugs are fairly inexpensive compared to biotherapeutics, says Finnegan. She foresees outsourcing production to Asian countries, once a cookbook process is standardized in the U.S.
Faster Process Development
Richard Hetrick, director of business development at QSV Biologics (www.qsvbiologics.com), talks about a major trend that he believes will impact multiproduct manufacturing over the next five years: faster process development/optimization.
According to Hetrick, technologies are now available for speeding up process development and optimization. This could shave months from the process development cycles and save hundreds of thousands of dollars immediately, with huge productivity improvements recognized in the early stages of clinical production.
In a nutshell, here is the current dilemma: sponsors usually want to get to early trials with GMP product ASAP at the lowest cost. This is understood since 80% of the candidate products will eventually fail, explains Hetrick.
However some processes come to the CMOs directly from the lab bench with extremely poor yields and processes that can neither be scaled up directly or meet GMP requirements. So how much process development is enough, and what is a reasonable cost in dollars and time?
The result, in most situations, he notes, is that there is never a good time from the sponsors perspective to spend the additional money or absorb the time delay to implement process improvement programs.
Some CMOs see process development as substantial sources of revenue with development projects consuming six months to a year at costs upwards of $1 million. To them, shortening the time and lowering the cost hurdle represent lost revenue, he maintains.
We have the opposite view. The faster we can complete the development and the higher the process yield we can achieve, the quicker we can get the sponsor into the GMP suite and move on to another client.
This is not so strange when one considers a recent study completed by Sandra Fox of High Tech Business Decisions. It shows that most of the CMOs business comes from former clients. Our focus is working with as many clients as possible, since this appears to be the path to long-term success in this industry, says Hetrick.