Elizabeth (Liz) Csaszar is a development manager for the BridGE team at CCRM. Her areas of interest are cell manufacturing, clinical translation of cell based therapies, and blood cell technologies. Liz obtained her PhD at the University of Toronto, focusing on the strategies to expand and self-renew hematopoietic stem cells in vitro. Liz is interested in STEM outreach and education. Follow her on twitter at @lizcsaszar
The essay tells the tale of how a cure for scurvy was well established by the mid 1700s and yet, 150 years later, Antarctic explorers were dying of scurvy, despite thinking that they were diligently taking all precautions to prevent it.
As Ceglowski writes, “Somehow a highly-trained group of scientists at the start of the 20th century knew less about scurvy than the average sea captain in Napoleonic times.” A series of poor decisions, bad luck, technological changes, and shifting medical paradigms all contributed to the cure being lost to the medical community during the 1800s. Reading this account as a process development scientist, it stood out to me that the whole debacle began because the Royal Navy made a single terrible process development decision: swapping out lemons for concentrated lime juice.
The discovery of the cure for scurvy started out on a clinical science high note when James Lind, a physician with the Royal Navy, performed what is regarded as one of the first controlled clinical trials in 1747 to show that oranges and lemons could cure scurvy. Groups of sick sailors were provided with various treatments, with one group receiving two oranges and one lemon per day. The sailors who received the citrus rapidly recovered and the study was considered a success.
The reason that the fruit prevented scurvy (or the scientific mode of action (MoA) of the drug product) was unknown, but was hypothesized to be due to the acidic nature of the citrus. Today, we know that scurvy actually results from a vitamin C deficiency and oranges and lemons happen to be great sources. By 1799, Royal Navy sailors were prescribed 1 oz of lemon juice a day as a prophylactic measure. All was good on the scurvy front and if explorers had simply continued to consume lemons on their travels, scurvy would not have been a problem again.
However, in the 1800s, the Navy made what can only be described as a massive process change to their scurvy drug product. They replaced lemons with limes. Furthermore, they began processing the limes into a concentrated juice using copper equipment. The change was made for economical and political reasons as colonization of the West Indies had made Britain rich in lime plantations.
Since the limes were even more acidic than lemons, it was assumed they would be at least as effective. However, with this assumption, the Navy had inadvertently created an almost completely ineffective scurvy prevention. Limes, in fact, have much less vitamin C than lemons and what was present was largely obliterated by the processing steps.
There is no record that they performed a study with the lime juice prior to implementing it on the Navy’s ships.
This sort of manufacturing change is the stuff of process development scientists’ nightmares, and seems terrifyingly naive when considered from our modern viewpoint full of regulatory approvals and rigid post-approval management of drug products. And yet, these are the very same issues and decisions that we continue to be vexed by: raw material management; supplier changes; drug product shelf life; container material choices.
Today we know that rigorous management of process changes require a potency assay linked to the drug product’s MoA. However, particularly in our world of cell-based therapies, MoAs are frequently multifaceted and unclear, and potency assays are often underdeveloped.
In other words, we sometimes make our process decisions based on information that is the modern equivalent of the irrelevant fact that limes taste just as sour as lemons.
The tale of scurvy’s cure may be a historical process development failure but, more importantly, it is a poignant cautionary tale for modern medical science.
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