The initial draft of the EU Guidance for Process Validation was released for comment and the comment period closed in October. So what has the thoughts on the new guidance since it was released? Read the linked article in Master Control on line journal for some insights.
In February I published an article on the topic of Quality by Design as it applies to the Vaccines World. This was based on a presentation at an IBC conference on vaccine development. As you might imagine, QbD has been slow in development of biologics but even slower in Vaccines. Check out the article on the IBC website
Pharmaceuticals are notoriously heat labile; at least many of the new high tech ones. Many require cold temperature storage at 2-8C. While they can withstand higher temperature for short periods of time, the shelf life of the products is defined by the recommended storage temperature of 2-8C.
With that understanding, is it acceptable to routinely ship them at elevated temperatures eg. ambient? Think of the money we could save says your friendly distribution staff.
This was the question posed to me recently in a webinar hosted by The Tungsten Shield Group on Cold Chain Distribution.
The European regulations are clear. The transportation temperature must be the same as the recommended storage condition. Distribution is really moving storage. Thus, a product designed as requiring cold storage, also requires the same cold condition for distribution. It is clear.
However, the FDA is particularly silent on this in regulations at least. However, they do expect transportation conditions to equal the storage conditions. Thus even the FDA does no condone this practice.
Both regulatory bodies recognize that things go wrong. A shipment heats up due to delays beyond the validated time. Patients leave the drug on the dashboard of the car for hours. These things happen. And a robust stability program designed to explore the impact of elevated temperatures can come to the rescue to determine if the abnormal conditions have degraded the product or not.
However, these accelerated conditions hsould not be used to justify a save a buck program that puts product in jeopardy.
It has come to my attention in webinars I present, mostly through The Tungsten Shield Group, classes I teach at University of California and my consulting work, that many people have lost sight of what their goals should be. When we develop systems, put controls in place, monitor processes, we do it because it makes good business sense. Rather I am sensing a trend for people doing this activity to satisfy regulators. They ask the question
“what do the regulators expect?”
That is instead of developing a robust business process and fine tuning it to meet their needs.
I illustrated this point several months ago related to lot disposition in Designing your QMS post
But in a recent class, I unearthed another example. I was presenting a case for validating components of the cold chain – specifically, the ability of the insulated shipper to keep the product cold for the required time. I iterated that after the validation activity, I would ship certain prodcts with monitoring probes to track the temperature of the shipment for the duration. I indicated I would do it for the first x batches to confirm that the validation was indeed valid. Also it was a measure to assure product integrity if the shipping took longer than planned or the expternal temperature was outside anticipated range. I also indicated that there might be circumstances where I might continue this for a long period.
You might view this as belt and suspenders. But when the integrity of a product in shipment is critical, I think this is small price to pay. When would I do it? For clinical trial materials, where product integrity is critical is one example. I might also do it fr critical product lanuches where success needs to be assured.
The questioner followed up and stated.
If the regulators do not require it I won’t do it?
This in my mind is an example of putting the horse before the cart. and an unwise practice.
We should design processes that meet our business needs. I can assure you that they will meet 95% of regulatory requirements if they are designed well.
At a recent webinar presented by Tungsten Shield on the topic of the differences between Clinical Manufacturing and Commercial, one question perplexed me. It went something like this:
You advocate using less resources to release a commercial lot of material than a clinical lot and you point to Risk Management techniques. Surely, the commercial lot represents more value to the company and so shouldn’t you spend more resources?
My response went this way.
In the case of a commercial product where you are making the product round the clock, turning out perhaps a 100 lots a year, you expect operations or manufacturing to be highly experienced in making the product. They have tremendous experience. They should not be making mistakes. The QA department are seeing lot packages continuously and know the weak points and strengths of the process, departments testing etc so know where the risks are. Now the clinical lot, is probably very unique, maybe only made once and never the same twice since the process is changing. Similarly, the testing is evolving. The documentation is changing and evolving. So we do not have the history with the material. Add to that the lack of knowledge about the product particularly in early phase. All of these add up to a higher risk of issues especially to the patient. While the commercial lots do represent high value to the company, the clinical lots represent the future for the company where errors can result in products not making it through the clinic or causing delays in clinical programs and let’s not forget the impact on patients.
The questioner seemed fine with the response.