Current Trends in Manufacturing Philosophy

Test methodologies have certainly been influenced by the latest manufacturing philosophy. The US Food and Drug Administration (FDA) has stated, "Quality cannot be tested into products; it should be built-in or should be by design."² This concept of building quality into a medicinal product is reliant upon having a thorough understanding of the manufacturing process, as from this, greater control may be achieved. Process analytical technology (PAT) is a system that enables greater understanding of the manufacturing process by providing a mechanism to design, analyze, and control manufacturing through taking measurements of critical quality parameters during processing. This in turn provides a procedure to ensure acceptable end-product quality at processing completion.

The PAT system offers substantial benefits, yet several challenges and threats must be overcome if it is to be successful in biomanufacturing. These include:

• Innovation to develop analytical tools that assess critical attributes presently unmonitored
• Investment required to implement novel technologies
• Increased complexity of required data-retention for huge data volumes generated by continuous monitoring
• Likelihood of stringent acceptance specifications due to increased data
• Regulatory uncertainty and need for more guidance

Regulatory authorities are debating the extent to which product similarity can be trusted for biogeneric products, and they have indicated that new testing regimes will eventually be required on a case-by-case basis. This will undoubtedly influence the development of new and improved analytical methods.

In the key US market, all drugs are governed by the Federal Food, Drug, and Cosmetic Act (FDCA). To gain FDCA approval for generic pharmaceuticals, an applicant must file an Abbreviated New Drug Application (ANDA) scientifically demonstrating that the product is bioequivalent and that it is comparable to an innovator drug in dosage form, strength, route of administration, quality, performance, and intended use. The approval process for generics in Europe is similar to that in the US. There, the procedure is overseen by the European Agency for the Evaluation of Medicinal Products (EMEA), is rapid, and does not require clinical trials if bioequivalence is demonstrated.

By comparison, there is presently no similar pathway for biogenerics either in the US or Europe. In the US, most protein therapeutics are classified as biologics and are governed by the Public Health Service Act (PHSA). The PHSA provides a Biologics License Application (BLA) for new biologic marketing approval, but it lacks an abbreviated pathway for generic biologics. In Europe the process for biologics has not been finalized, but the EMEA recognizes the complexity of such molecules; therefore, under proposed changes, biosimilar products may, or may not, be molecular copies of the original product. The products must, however, depend on the same mechanism of action and be intended for use in the same therapeutic indication. It is still unclear if in Europe a biogeneric should be registered through the abbreviated procedure applicable for well-defined traditional generics or undergo a full registration process.³

The EMEA has recently issued guidelines (currently under consultation)^{4,5, 6,7,8,9} for producing biogeneric medicines (referred to as "biosimilar"). FDA, meanwhile, is continuing to discuss its position on biogenerics, and draft guidelines are expected later this year. The debate on biosimilar products is still continuing; however, it is clear that the analytical tools need to be available to prove that a generic product is essentially similar to the reference product. Discussions with regulatory agencies can lead to new state-of-the-art methods being adopted, or conversely, to a retrenchment to more traditional methods, as illustrated in the following examples.

An Example in Which State of the Art is Clearly Better

State-of-the-art polymerase chain reaction (PCR) has gradually replaced Southern blotting because Southern blotting is too slow and cumbersome. During the late development phase of a complex recombinant protein vaccine in the late 1990s, it was noted that the stability of one of the genetic elements of the cell line was questionable during production. Rather than redefine the production method it was agreed that the company would provide a routine analysis for gene copy number. The classical method for detection of the genes was Southern blotting.¹⁰ However, it became apparent that this method had serious problems as a quality control test: it was very time-consuming, variable, and cumbersome.