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With Start-Up Biotechs, First-in-Human Trumps Quality by Design (QbD)

According to the 2011 FDA Guidance for Industry on process validation and 2012 EMA process validation guideline, process design and understanding should begin as soon as a lead molecule is identified and process development begins. However, is this always the best strategy?

The product’s critical quality attributes (CQA), those features of the product that impact clinical safety or efficacy, should be defined and controlled. To do so requires understanding which process parameters are essential to producing a product with the intended CQA. Contrast these recommended approaches with the reality of a start-up biotechnology company developing a potentially life-saving, disease-ameliorating biopharmaceutical product that may or may not actually succeed in the clinic. Let’s look at the reality of a hypothetical biopharmaceutical company, BioX. BioX is developing a cutting-edge product with potential for treating an aggressive and incurable cancer. Undoubtedly, they will be competing with other companies for access to physicians and centers to enroll patients in their trials. If successful, BioX will encounter competition in the market.

BioX has raised money to move their product from the conceptual stage to the IND/IMPD or equivalent stage, and has promised investors that the initial human trials will commence within 12 – 18 months following program initiation. BioX and its investors are highly motivated to manufacture a product that meets all safety requirements so patient safety is not compromised. However, BioX is not very motivated to define CQA or to invest time and resources into understand the manufacturing process at the level specified in the guidance documents at this initial stage. In my experience, speed to clinic trumps extra time in early process development for these small companies every time. So what process design and development activities should BioX invest in prior to first in human trials? Also, what steps can be taken to reduce future process risk without adding unnecessary delays in the product development timeline?

An obvious choice in my opinion, is investing in an MAA/BLA enabling production cell line. By using current technologies coupled with robust, well-characterized parental cell lines, it is feasible to obtain multiple stable, high producing microbial or mammalian cell lines within relatively short timeframes. A strategy of using Multiple Master Cell Banks (MMCB) allows more than one clone can be pushed through the initial development activities. The final testing to ensure that the selected production cell line meets commercial requirements is postponed until later. This approach reduces the risk of cell line failure during lengthy stability testing. Multiple Master Cell Banks can be produced at relatively low cost if the testing is deferred until final clone selection so that only one MCB needs to be tested. By moving 3 to 4 clones forward at this stage, reduces the risk of failure due to clonality or genetic stability issues. Without “back-up” cell lines, companies like BioX lose precious time to clinic, a situation that can be fatal to a small company.

Product produced at a smaller scale than the intended cGMP process, even product produced in a development laboratory, can supply IND-enabling GLP toxicology studies, enabling completion of these studies well in advance of the availability of full scale GMP material. These time-saving, low-risk approaches to initial development are often applied by companies such as BioX. Further, such approaches are routinely meet with regulatory approval provided sufficient data supporting the comparability of the GMP clinical trial material to the product used for the toxicology studies is provided. Upon successful completion of early clinical trials and an indication of efficacy that warrants further development, BioX can then turn its attention towards full process understanding, defining CQA and critical process parameters, and entering into the activities that are expected and anticipated per the guidance documents mentioned above. This paradigm is the reality for many companies and provides BioX and others with a route to the clinic and, hopefully, the market in a manner that is beneficial to patients, physicians, and the market.


Blog article by: Susan Dana Jones