In order to assure success of GMP campaigns, manufacturing plants often produce one or more batches prior to the actual campaign. These batches are called by various names: “practice runs,” “demonstration runs,” and often “engineering batches.” This practice serves multiple purposes, including testing the production equipment (hence, “engineering batch”), finalizing batch production records, training operations staff, and finalizing a process control strategy. Since the batches are not necessarily intended for disposition to either the clinic or the market, they may or may not be run using all of a plant’s cGMP systems. Batch production records, for instance, may be marked-up, red-lined, and hand-corrected, while deviations may not necessarily be treated in the same manner as a full production run. You have the liberty to adjust the process and equipment in real-time, to tweak settings, automation and parameters as necessary. They are, in some ways, off the books.

The batch may utilize live cell banks and all of the materials that would be used in production, or may be run with simply media, buffer and other components, often called a “water batch.” In small molecule production, these are often “solvent runs.” In one instance, I know of a plant where we planned nine various batches prior to starting the final process validation (PV) runs, which virtually assured success of the PV runs. Conversely, we started another plant once with only one engineering batch, and never ran another one for at least six years, with many campaigns of different processes and compounds. We had that much confidence in our facility, staff, equipment and processes, and they were ours: we owned and operated them. We could adjust for potential lot failures and deviations, so long as we met our overall goals.

This best practice becomes a more controversial situation, however, when a biopharmaceutical company is using a CMO to produce its material. An engineering run, for the client, has little practical value, as it takes time, costs money, and produces material that cannot (usually) be used in humans. For the CMO, however, the engineering run has all of the value ascribed above; namely, it is an opportunity to warm up prior to the actual race. Without it, there is a heightened risk of batch failure, or at least significant deviations and a complicated (read: “messy”) batch history.

Biopharma Sponsor Perspective

A client is virtually always on an aggressive timeline, having a need for material in short order. There are always cost considerations, and engineering batches appear to be a very expensive insurance policy. Senior management will often encourage aggressive risk-taking, and the risk of skipping an engineering batch would appear to be low. So what if it fails? If it succeeds, you are that much closer to your goals. You have saved both money and time. If you are working with a CMO that you believe is capable, you assume they already know their equipment very well, so why should they need to practice on your dime? If they are running your process, you usually have a lot of confidence in the process development work leading up to this point, and you may already have experience with this process in other plants and at other scales. So why not skip the engineering batch and run a full GMP batch? If the CMO is charging you for time in the facility, you want the maximum return on that investment. It is, very much, on the books. You’ll live with the deviations, as long as you get your material on time.

CMO Perspective

For the CMO, your first order of business is to make your client successful. You want to assure success, avoid deviations, and get the high-quality material to your client on time. You often do not know this process well at all, and each step is critical to the success of the campaign. Your operations staff has not trained on these batch records, your QC group is not familiar with these new methods, and your development team has provided you with little data to build confidence. It is likely you had a rapid tech transfer, so your confidence isn’t as high as you’d like. Your second order of business is to make money, and you cannot afford to run your facility for an extended length of time without being paid at fair market value for your efforts. You need a way to discharge risk without losing your shirt. What if your competitors claim to run without engineering runs? Is it worth losing clients over the issue?

When negotiating contracts and supply agreements, the issue of defining success is critical. If the two parties can agree on what success looks like, the partnership is more likely to be productive. If success for the client means potential failure for the CMO, the project is less attractive and most likely burdensome. If the CMO’s success would cost the client dearly, then the partnership is on a similarly shaky foundation.

This is one of those situations where there is no clear, right answer. I was at a conference this year where a director of outsourcing for a company said in a seminar, “I’d do six engineering batches for every campaign, if I could afford to!” Although she was exaggerating for effect (I think?), she clearly understood the pros and cons. The cost of a lot may be paid back many times if it assures success of a campaign. By contrast, being aggressive and sharing risk can build a very strong partnership if the effort is ultimately successful for both parties. CMOs and their clients need to find an intelligent way to share and discharge risk. Engineering batches may serve a useful purpose, but each partner will need to come to the table with a good understanding of the other party’s perspective. Ask yourself, if you were running this ­process in your plant, would you do an engineering lot?  

E. Morrey Atkinson, Ph.D. is chief scientific officer and vice president of R&D at Cook Pharmica, a bio-CDMO based in Bloomington, IN. Prior to joining Cook Pharmica, he spent nine years at Eli Lilly & Co., as both head of Biotechnology Manufacturing Sciences and Technology in Kinsale, Ireland and director of Bioprocess R&D in Indianapolis, IN. Having experience in both of the sponsor and provider areas, he has a unique perspective on the challenges that drug companies face, as well as the outsourcing services that support them. Morrey will occasionally discuss biopharma issues in this space from both of these viewpoints. To comment on this article or suggest a topic of interest, please contact him at morrey.atkinson@cookpharmica.com.