The emergence of influenza A (H1N1) and the efforts to provide vaccines to the vulnerable are timely examples of biopharmaceuticals’ continuing importance. These medicines pose unique challenges to drug manufacturers, however, mainly because the molecules of their active ingredients can be quite big. The size of a biopharmaceutical is partly attributed to its complex molecular structure: essentially a polymer of many amino acids onto which additional large molecules such as carbohydrates might be attached.

Large-molecule drugs also exhibit great variation. Living cells do not create homogeneous sets of molecules, but rather generate products that contain sequence diversity. And biological cells’ sensitivity to manufacturing-process parameters also contributes to variations in the end product. The growth and purification conditions in biopharmaceutical production processes yield preparations that are roughly 95% pure, according to Jim Green, senior vice-president of preclinical and clinical development sciences at Biogen Idec (Cambridge, MA).

Not only can the basic amino-acid sequence differ between proteins, but the number, type, and placement of attached carbohydrates can also differ between otherwise similar proteins. The combination of sequence variation and variations in carbohydrate-attachment sites can produce similar molecules that the immune system perceives in dramatically different ways.

In recent years, the US Food and Drug Administration has been emphasizing that greater process understanding and control helps manufacturers create products of consistent quality. But biopharmaceuticals’ size, heterogeneity, and sensitivity to process parameters make it difficult for even innovator companies to produce them exactly the same way every time, says Jeffrey R. Mazzeo, biopharmaceutical business director at Waters (Milford, MA).

Time and technological advances, however, have increased manufacturers’ ability to control their processes and products. During the past 10 years, new equipment has greatly improved the manufacture, and characterization of monoclonal antibodies, says Bill Haddad, CEO of Biogenerics (Brewster, NY). Technological advances have made it easier to perform analytical testing and create master and working cell banks. New technologies also have allowed manufacturers to control their processes within tighter specifications and produce recombinant proteins with highly specific, predefined quality characteristics.

In addition, scientists have developed platform technologies that enable antibodies and fusion proteins to be manufactured consistently. Platform technologies are standardized manufacturing methods that allow streamlined protein production, says Green. They ensure that the major operating principles used to manufacture different antibodies within one facility or company are maintained.

A process that incorporates platform technology could include the following steps:

1. Protein expression in CHO cells
2. Production in a fed-batch bioreactor
3. Cell removal
4. Protein A affinity chromatography
5. One or two additional chromatography steps
6. Virus inactivation and removal steps
7. Ultrafiltration or diafiltration
8. Drug substance storage.

“To the extent that platform technologies become part of standard manufacturing practice and can be used by any company,” Green adds, “some degree of consistency may be obtained in product quality.”

Regulatory initiatives can also aid biopharmaceutical production. FDA’s quality-by-design initiative is meant to be a way for manufacturers to control variability, says Mazzeo. The maker of a follow-on glycoprotein biologic, for example, must study key parameters such as glycosylation (i.e., the attachment of carbohydrates) to determine the specifications that will yield a high-quality product. Performing design of experiments and refining the manufacturing process helps manufacturers ensure that their products’ characteristics stay within the appropriate range.

An in-process surveillance program that incorporates process analytical technology (PAT) would also help ensure process understanding and control. PAT would allow operators to observe trends and predict when products will be outside specifications. But establishing in-process quality control can be much more difficult for biologics than for small molecules because of biological systems’ greater inherent complexity, says Marc Goshko, executive director of legal affairs at Teva Pharmaceuticals (North Wales, PA).

Although the complexity of large-molecule drugs presents difficulties for manufacturers, recent scientific and technological advances have given the industry greater control over product variability than before. As the industry’s understanding improves, it will be able to provide high-quality biopharmaceuticals such as vaccines more efficiently and reliably.