Biopharmaceutical Manufacturing – A CMO Perspective with Case Studies

By Laureate Pharma

The biopharmaceuticals market:

Biopharmaceuticals have the potential to cure diseases rather than merely treat symptoms, and have fewer side effects because of their specificity. The increasing number of new diseases treatable with biopharmaceuticals is driving the demand for these drugs worldwide. Biologics, representing nearly 30% of all therapeutic compounds under development are popular with Pharma companies. The U.S. Protein therapeutics market size is projected to grow to $90B by 2010. Among biotherapeutics, the hottest area is monoclonal antibodies with 160 monoclonals in development. The Global antibody therapeutics market is estimated to be $16.7 billion in 2008 with 400 drugs in clinical trials and 700 in pre-clinical development targeting more than 100 diseases.

Why companies outsource biopharmaceutical manufacturing:

Companies need to manufacture their product candidate under current Good Manufacturing Practice (cGMP) conditions to conduct clinical trials. Biologics manufacturing is technologically complex and is highly regulated by the FDA. It requires significant experience and specialized skills to produce the large complex protein structures in large scale. Even small deviations can have deleterious effects on the production process, and stability and efficacy of the end product. cGMP compliance warrants that the manufacturing staff has technical expertise in specific areas including upstream and downstream operations, process development, project management, process engineering, quality assurance, analytical development, quality control, regulatory compliance, and many other highly specialized functions.

Significant investment capital is needed to construct a manufacturing facility. It costs $10 million to construct, equip and launch a 100L traditional pilot plant facility. The cost goes up to $40 million for a 1000L pilot plant and for a 10,000 to 20,000L facility, the cost becomes prohibitive ranging in several $100 millions. Outsourcing biomanufacturing also reduces time-to-market as constructing a new, fully validated facility takes several years.

Large pharmaceutical companies have their own manufacturing facilities and have experience, expertise and capacity to produce clinical trial materials. Most small or medium size Pharma/biopharmaceutical companies do not have the capital to build cGMP compliant manufacturing facilities, nor the expertise needed to produce large-scale clinical trial materials. Added to this mix are virtual companies, which outsource almost everything, including manufacturing. As the biopharmaceutical industry matures, outsourcing is becoming an integral part of production strategies. Using contract-manufacturing organizations (CMOs) for cell line development, upstream and downstream process development, analytical testing, formulations and fill/finish to produce complex biopharmaceuticals is an attractive high-quality and economical alternative for companies of all sizes – from ‘virtual’ biotechnology companies to large Pharma with commercial manufacturing and analytical infrastructure.

Outsourcing manufacturing provides companies an opportunity to place greater focus on their own core competencies. We have seen this scenario in several of Laureate Pharma’s client companies, who have adopted a business model focused exclusively on discovery research and early development. They never intend to develop their own manufacturing capabilities, relying instead on outsourcing to an experienced CMO. This strategy can lower production costs, improve manufacturing efficiency and have a positive impact on the balance sheet. By handing over the responsibility and complexity of daily production to CMOs, these companies can significantly minimize their risk and decrease their development timelines. Their time and resources can be better spent in drug discovery and lead optimization.

CMOs can offer services ranging from cell-line development, cell banking, bioreactor production, process development, protein purification, scale-up, pilot scale production, cGMP production, analytical and testing services, validation, quality control testing, protein conjugation, modification and radiolabelling, to final formulation, lyophilisation, fill and finish. This essentially covers the entire drug development and manufacturing process.

How Laureate Pharma as a CMO adds value to the Pharma industry:

Striving for innovation and continuous improvement has become ever more important in biopharmaceutical manufacturing. As the industry evolved, Laureate as a contract manufacturer has grown by acquiring newer technologies such as single-use bioreactors and other disposable technologies and has adapted them for use in the manufacturing operations.

We use disposable components and single-use bioreactor systems to provide a number of quality, operational and economic advantages. These disposable components arrive pre-cleaned and sterilized, thereby eliminating the need for cleaning and sterilization process steps. A fully disposable option means elimination of cross contamination, cleaning and subsequent validation resulting in less usage of Water For Injection (WFI). The reduced operating costs, smaller footprint of disposables, increased productivity and rapid turn-around time are some of the major benefits that are driving us and others in the biopharmaceutical industry towards single-use technology in manufacturing. As a dedicated contract bio manufacturer (CMO), we understand the value of single use systems and where, when and how the disposable technology option works for us throughout the biopharmaceutical production process.

Where do we use disposables in a biomanufacturing process?
Single-use filters, single-use tangential-flow filtration (TFF) membranes, flexible tubing, sterile liquid containment bags, disposable bioreactors, mixing systems for media preparation, sterile bags with normal-flow filter manifolds and aseptic connectors are all used in appropriate steps during the process, optimizing and accelerating the production time during biomanufacturing. In downstream processing, we use disposable formats for cell removal, harvest clarification, membrane absorption chromatography steps, viral filtration, ultra filtration and diafiltration.

To demonstrate how we use single-use technology at various steps and add value throughout the bio manufacturing process, we cite below a case study on the usage of disposable bioreactors.

Case Study #1

A biotechnology company with a focus on development of monoclonal antibody-based therapies for treatment of various diseases approached us to produce pre-clinical material for toxicology studies as well as cGMP material for Phase I studies.

The Challenge: Our client company had a well-developed process that was ready for technology transfer. They had completed cell line development and media development and were successful in scaling up to small-scale (5L) bench-top bioreactors. However, they had no capability for large-scale production of their biotherapeutics. The client wanted us to complete tech transfer and generate toxicology materials within 6 months, followed by production of Phase I materials within 9 months.

The Solution: The amount of cGMP therapeutic material required for Phase I stipulated that we use a 2000L stirred tank bioreactor. We developed a successful process flow starting with a vial of Master Cell Bank cells and scaled them up in sequence in Wave 20L, 50L, 200L and 1000L bioreactors to inoculate our 2000L stirred tank bioreactor for production of product. One of our challenges in the process was to scale-up the high density and high antibody yielding CHO cells in the 1000L Wave bioreactor® to generate inoculum for the 2000L stirred tank bioreactor. To sustain the maximum viability of the cells in this large vessel, we developed optimal mixing speed by adjusting both the angle of rocking and the rock rate. Using this model we prepared the entire seed train using Wave disposable bioreactors and generated inoculum for the 2000L production reactor. The scale-up was successful and the process yielded the desired amount for phase I clinical study for our client. By using single-use technologies such as Wave bioreactor we were able to eliminate time and resource consuming clean-in-place procedures and streamline the entire manufacturing process. We completed the optimized scale up process within the time frame and the budget as stipulated by our client.

Case Study # 2

Downstream process development solutions for unique proteins:
The challenge: Not all proteins are amenable to purification using platform processes. Some of the uniquely engineered fusion molecules could prove to be tricky and could lead to unexpected results. One of our client companies had engineered a unique fusion molecule as a target drug candidate and wanted us to develop and design the manufacturing process to produce Phase I clinical materials.

The solution: This unique, bioengineered protein had three components, an active enzyme sequence, an antibody Fc sequence and an acidic peptide sequence tag. Each site separately could be purified using standard existing platform processes. However, the three sites in combination, located on a single protein, posed certain challenges in the purification process and did not behave as predicted. After several trials with different techniques and different conditions we were able to design a process that proved to be scalable and robust. The final purification process comprised eight unit operations starting with Concentration/Diafiltration followed by Solvent/Detergent Virus Inactivation, Protein A Chromatography, Butyl HP Sepharose Hydrophobic Interaction Chromatography (HIC), Diafiltration, Capto Adhere Chromatography, Nanofilter Virus Removal and ending with Concentration/Diafiltration. The process was successfully implemented at 200 L and 2000 L bioreactor scale to produce material for toxicology and clinical studies.

Summary:

Contract Manufacturing Organizations play an important role in the biopharmaceutical industry and help create value to their clients. Starting from the initial clone selection and cell-line development through cGMP bioreactor production and purification, CMOs optimize the process and product yields at every step. Whether it is a standard template or custom process, CMOs have the resources and skills to design the appropriate process suitable for every unique situation. The rapid growth of biopharmaceutical products has provided numerous opportunities for Contract Manufacturing Organizations such as Laureate Pharma with specialty skills. Laureate has been successful in providing superior bioprocessing services from clinical to commercial scale to a variety of drug development firms, capitalizing on its expertise and experience and at the same time building on its own service offerings.