Then the light came on
Quality rejected the lot of injectable product because of a color change between the time of filling and the visual inspection,
and I was told to find out what caused the color change. We had been making the product for 35 years and no one could remember
such a problem before.
The visual inspection department supervisor told me that not all vials were affected, and that the effect seemed to be all
related to one side of the pallet. So the path of that pallet of product was traced through the plant, where it was discovered
it had been stored near a window for some weeks! It was a light-induced change. We immediately began a series of experiments
to determine whether light could create the change, and it quickly became clear that sunlight or other strong lights such
as sodium vapor lamps could cause the color change. One ingredient in the product was established as the causative agent in
the color change.
The corrective action turned out to be quite simple: Don't put the product near a light source, and cover it with an opaque
material before storage.
Dim ... but long lasting
Hey, he wasn't the brightest bulb in the box, but he was persistent. Back in the 1970s, the company evaluated medicinal drug
product-release test results against statistical process control (SPC) limits. Although we'd never think of doing this today,
at the time it was a common practice to reduce the shelf life of batches that had release test results outside the SPC limits
but within the NDA-approved specifications.
So, in his duty as release officer, our dim bulb would notice the out-of-limits result and come to our stability group for
a calculated shelf life. On this occasion, the lot was not only outside the SPC limits, but outside the NDA-approved specifications.
He wasn't too happy when we just laughed at him for even suggesting it had a shelf life. Try as we could, we never got him
to understand that the lot had already expired as far as the government was concerned, even when we showed him the math (way
beyond him, but hey, we tried), which gave a negative number for a shelf life! The batch never was released.
I had moved to a new company and was given responsibility for the stability program. An injectable multivitamin product showed
signs of instability in vitamin D, so we reduced the expiration dating period for future batches. But the stability profile
kept getting worse, and we realized that it would be hard to sell the product with a shelf life of less than 12 months.
An investigation team was set up, and during our shotgun investigation*, we noted that we had purchased the vitamin D in quantities
sufficient for 50 finished product batches. For each batch, the bulk vitamin D was removed from the storage freezer, thawed,
opened, and weighed in room-temperature and ambient-humidity weigh rooms. Analysis of the bulk confirmed that it was degrading
despite the storage temperatures, apparently becaue of the numerous freeze–thaw cycles and the uptake of moisture during the
thawing and opening.
Although a recall was never necessary, we did change the way the vitamin D raw material was weighed. The entire bulk lot into
was divided into finished batch-sized quantities using glass vials that were deemed less likely to react immediately upon
receipt and release. This division was performed in a glove box under dry conditions. The glass vials were then frozen and
stored until needed for a batch, when only one at a time would be removed from the freezer and thawed for use.
*shotgun investigation: investigate a wide variety of possibilities at once, no matter how unlikely.
Pharmaceutical Technology's monthly "Agent-in-Place" column distills true-life cautionary tales from the secret files of Control, a senior compliance
officer. If you have a story of clueless operators, oblivious management, inopportune lapses of judgment, or Murphy's Law
in action, please send it to Control at AgentinPlace@advanstar.com
. We won't use any names, but if we do use your tale of disaster, courage, or just plain weirdness, Control will send you
a coveted Pharmaceutical Technology t-shirt.