Process Development

The delivery of a new biopharmaceutical to the marketplace requires an extensive and extended period ofpro-cess development involving the application of advanced techniques in molecular biology, cell culture, separation technology, and formulation science, taking several years to complete. Prior to regulatory approval, development of the manufacturing process consumes considerable resources in terms of equipment and material as well as the people that are needed to prepare and characterise the clinical trial material. Once the manufacturing process is finalised, the process details are transferred to the manufacturing facility where the material is to be made. Details of the manufacturing process and the characterisation of the material produced are provided to the regulatory agencies to provide evidence of a stable and reproducible process, molecule, and product. Process changes after regulatory approval require additional process and molecular analyses as well as additional filings in many cases.

The creation of the Master Cell Bank (MCB) is a critical milestone in biopharmaceutical process development. The MCB is a cryopreserved, long-term store of recombinant cells, either bacterial or mammalian, containing the gene that encodes the desired protein. Following transfection of host cells with a DNA plasmid containing the desired gene, the cells are subjected to a cloning procedure to ensure genetic uniformity and then are screened to identify clones that have a stable, high-level expression of the desired protein. Once identified, the desired clone is expanded and cryopreserved in vials, creating the MCB. The MCB is the source of all cells used to manufacture the medicinal product, either directly by thawing MCB vials or via an intermediate working cell bank (WCB) derived from the MCB. Cell banks are usually laid down as hundreds of vials and stored at multiple redundant locations to ensure security of supply. These cell banks are extensively tested and characterised to ensure that they are fit for purpose, stably express the desired protein over the manufacturing period, and do not contain microbiological contaminants.

Another major component of process development is defining the cell culture process that expands the small number of cells in the MCB or WCB vials into the large volumes of cells required to produce economically viable amounts of proteins in a production facility. For example, the process may require expanding 3 million cells in a 1-millilitre vial to a 20,000-litre volume in a stainless steel bioreactor to achieve 10 million cells per millilitre. The cell culture development process establishes the appropriate nutrient media and specific physiological conditions for cell growth including O2 and CO2 levels and the pH of the medium, as well as any specific manipulations required to achieve high levels of protein production. Processes may be separated into

7.5 Biopharmaceutical Manufacturing 63

Fig. 7.1. Overview of the production process for a biopharmaceutical product. [Reprinted with permission from Walsh, G (ed) (2003) Biophar-maceuticals: Biochemistry and biotechnology, 2nd edn. John Wiley & Sons, Chichester]

two phases including an early rapid cell growth phase to maximise the number of cells available to make protein and a second production phase to maximise protein output. The phase transition can be triggered by changes in bioreactor conditions or by the addition of certain induction molecules to the cell culture medium.

The cell culture process ("upstream process") presents the expressed protein to the "downstream process" for further processing to a pure active ingredient (Fig. 7.1). This downstream processing is usually composed of a harvest step that separates the cells from the protein product as well as a number of further separation steps that purify the protein product from the remaining cell culture-derived impurities. The process development team evaluates a wide range of separation technologies and experimental conditions to determine the optimal conditions for separating the protein product from the process impurities to ensure that all products made using the process will meet predetermined quality specifications.

An important activity in most process development projects is the definition of the formulation in which the protein is delivered to the clinic or marketplace. Chemical solutions are assessed for their ability to maintain stable, intact, and biologically active protein for the desired shelf life of the biopharmaceutical. Biopharma-ceuticals generally are relatively fragile at room temperature and require cold chain transport and storage. Long-term stability studies (several years in duration) are carried out on the protein using a range of temperatures followed by detailed characterisation to detect any changes in chemical structure or biological activity.

Biopharmaceutical Manufacturing

Over the past 2 decades, the manufacture of biophar-maceuticals has progressed dramatically to the highly complex, state-of-the-art operations that epitomise the industry today. Modern biopharmaceutical production facilities comprise multiple departments that function together to produce, test, and assure the quality of the biological drug (usually called the drug substance) before release to a fill/finish facility for drug product manufacture. Drug product manufacturing involves the preparation of the final, sterile presentation of the biological drug substance and can include lyophilised or liquid products in vials or syringes. The drug product is packaged before ultimate delivery to the patient.

Biopharmaceutical manufacturing is carried out under the philosophy and approach of good manufacturing practice (GMP). GMP is an aspect of quality assurance that ensures that the biological drug is consistently produced and controlled to a standard appropriate for its intended use. The tight controls present in modern biopharmaceutical manufacturing plants ensure consistency in the manufacture of the biological drug. Raw materials such as media, water, and gases are tested against multiple specifications before being released for use in the process. Cleaning procedures are validated to ensure that process residues or by-products are removed from equipment between successive batches. Sterilisation procedures are verified for all equipment, such as bioreactors and automated process equipment, governed by a central or distributed con trol system, which helps to remove human error in the process step execution. Air quality is regulated by environmental control systems to maintain pressure differentials and high-quality, low-particulate air in processing zones that require clean operations such as late-stage purification operations. Taken together, these steps assure that all aspects of manufacture are tightly controlled to deliver a biological drug that meets a predefined series of pharmaceutical biochemical and functional specifications.

No aspect of the manufacturing process may be changed without proper technical assessment of its impact by authorised groups within the manufacturing organisation, and where relevant, regulatory authorities. This process, known as change control, is overseen by the quality organisation. During its manufacture, the biological drug is transferred between stages of the manufacturing process (e.g., drug substance to drug product manufacturing) only after all quality control test criteria are met and a quality assurance-led batch release process is executed.

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