Batch success rates have been generally in the mid-90 percentile for a decade, and as with many things you put an economic lens to, the marginal cost of inching ever-upward towards 100% success rate becomes very expensive. In fact, as with safety incidents across organizations, success rate in batch production is something that can never be 100% anyway. There will always be failure modes that with some probability will occur. Certain companies, and within certain boundarized time intervals, could indeed try to lay claim to “100% batch success rate,” but when we see that published in an advertisement in the future, we’ll all know better and can quietly chuckle to ourselves.

Even still, we keep innovating. There have been incredible gains within our industry in terms of design and development of disposable/single-use technologies—to the extent that our past-selves from 10 or 15 years ago would have thought that our current state today of integration of single-use consumables would have been unlikely. Clearly, many so-called ‘sterility’ issues arise due to external penetration of the process for additions of supplements as well as process sampling, and better use of process analytical technologies (PAT) and further momentum towards continuous manufacturing reduces the probabilities of contamination by decrementing the overall number of bioreactor infiltrations. But in order to help us face hard realities and better appraise our marginal costs as we continue into the future of this topic, read the following header:

It’s never sterile
As an industry, we haven’t done ourselves any favors by subverting science and putting resources in patently falsifiable goals, and one of these is pursuit-at-all-costs of “sterile” manufacturing. Sterility is a theoretical construct that doesn’t exist in practice. Sterility is a probabilistic unicorn, and like reducing workplace safety incidents to “zero”—so long as humans are employed in the processes—is an impossible goal. Such is the world of risk assessments, where we can reduce the theoretical occurrence of an outcome, such as an infiltrating microbe, to very, very low numbers approaching zero—as with safety defects—but they won’t be zero for more than small snapshots of time or progressively-small spatial integrals within a bioprocess. For example, if you swab a surface to test for microbes, there calls into question the initial ‘sterility’ of the swab instrument, the accuracy of the lab testing to identify a single microorganism, or its residues, and the surface area ‘slice’ of the vessel or piping that you exposed to testing because it surely wasn’t all of the process-contact surface area. Results are then extrapolated to potentially suggest that sterility exists.

I’ve been in silicon wafer microprocessor cleanrooms—entire vertical laminar flow rooms, not just BSCs—as well as cleanrooms in biopharma and BSL-2, 3, and 4 facilities. Sterility exists in none of them. But most cases of single-organism presence will not lead to an abject contamination because very small numbers of microbes in isolated cases can have very difficult times persisting, even in mesophilic environments.

The null hypothesis
Are CIPd/SIPd hard piping sections sterile? No. There we use F0 calculus to give us a probability that there would be organisms existing after a particular sterilization cycle. How about single-use disposables that are gamma-irradiated? It’s great technology, both on the side of the durable good, as well as on the side of the radiation physics. But it’s still not a guarantee of sterility. In fact, radioactive half-lives themselves are based on underlying probabilities discovered by George Gamow, and it’s not possible to say with certainty in a radioactively-decaying sample of an element whether “this” atom will decay to its isotope or if “this other one” will instead.

We never test every infinitesimally-small section of each system over long enough timelines to empirically say that they’re “sterile.” But what we can (and do) do a good job of is having systems which we can maintain as aseptic. That is, endeavoring to make them free from foreign organisms, or what my medical dictionary lists as “restricting microorganisms in the environment and preventing contamination of the surgical wound.” Philosophically and semantically, this difference between “sterile” and “aseptic” is like the difference between the proper phrasing of null hypothesis significance testing. If you were to perform a statistical test on two groups to test if they are different from each other, the null hypothesis isn’t that the two groups “are the same,” it’s that the two groups “are not different.” And this is a big difference.

But what we don’t have in pharma manufacturing is an epidemic of sterility problems leading to patient illness or damage. In fact, during a review of end-user (patient) complications due to improper practices or lack of asepticity, issues at the pharma manufacturing level are ultra-rare. The British Medical Journal published in 2013 a treatise (Makary, author) on how ‘medical error’ is the third leading cause of death in the U.S. These are patient-facing practices that are directly causing or leading attributably to death. Upon statistical evaluation of the impact that defects in drug production, including aseptic issues, have on patients via a rare events statistical process control chart, there isn’t even a detectable signal. Not so in actual patient care centers.

The state of affairs at the patient-treatment level
I’ve spent a lot of time at cancer centers recently reviewing their protocols and practices. One thing I can tell you is that I have more than 42 pages documenting improper aseptic procedures undertaken by care staff, cleaners, facility design, and visitor requirements. And to further add gravity to this measure, each page has more than 12 observations with notes for each. Why does this matter? Well, principally, those inpatients at cancer centers are among the most susceptible of healthcare populations because they are significantly immunocompromised while undergoing chemotherapy, radiation treatment, experimental CAR-T, and any other modality. If we look at the patient-centric goal of these treatments, they’re to make people better. But in many cases, the practices extrinsic to the actual invasive treatments themselves produce more risk than they prevent. 8 ½ x 11” pieces of paper printed with an admonishment to “make sure you clean your hands… Clean hands prevent infections” hanging on hallway bulletin boards and elevator walls doesn’t do anything to encourage staff to better adhere to aseptic practices, and it gives visitors a point to pause and reflect on: “You mean to tell me that trained medical staff need to be assaulted by homemade signs in a multi-million-dollar cancer center because they don’t do it properly?” And I can also tell you that there was no visible protocol or procedure, no trainer available, and no oversight of visitors when they were told in critical care areas to don nitrile gloves and facemasks, including one instance observed of a visitor putting the surgical mask on backwards.

We do the best we can in industry given all the moving parts we are working with. We capture deviations to investigate as an industry where things are going awry, and we help each other by cross-pollination of ideas, vendors, and technologies, to continue the drive to make things better. But we should still probably call it ‘aseptic manufacturing,’ because that’s more accurate. And frankly, it’s more catchy than “aspirationally-sterile manufacturing.”

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Ben Locwin

Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com