This has always been a question people ask.  As a consultant i see a slice of the industry that interacts and works with me, so I have my opinions.  However, a company that employs me may not represent the average company.  So a colleague of mine, Peiyi Ko, and I decided to conduct a survey asking these questions.  we used Survey Gizmo as the survey tool and LinkedIn Groups as the interface.  These 40 questions were posed and because of the interesting answers we got, we are publishing them in two parts.  This post has the first part published in Pharmaceuticalonline.  In this part, we examine the implementation of various guidances and regulations.  The second will feature how ell they have impacted the company Quality Management System.

The second part will be published in a couple of months.  Bookmark my website so you will see it when the next is posted.

Happy reading

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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.

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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.

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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.

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At a recent webinar I presented for Tungsten Shield on the topic of Lot Disposition, I had an interesting question.  It occurred when I was discussing review of investigation reports and it went like this:

What regulation calls for the Lot Disposition group in the US to review the technical content of an investigation before dispositioning a lot for the clinic or commerce?

And this question was prompted because of the following comments I made.

We all know that the QP in Europe examines all the information, he deems necessary prior to dispotioning a lot – it’s what he is obligated to do by law.  That includes review of the investigation reports related to deviations.  It includes a review for completeness and also a technical review to assure he agrees with the conclusions and the content.  He further assures he understands and agrees with the logic behind the decision.  I contend that in the US, the equivalent person responsible for lot disposition should also review the content to understand the decision to release the material or not and if the investigation is not complete or to his liking, should send it back before moving forward to release the lot.  After all by signing the release, you have made a decision that the lot is acceptable.  Part is to assure the investigation is complete but another part is that the decision is logical and supported by the report.  It is not simply a compliance agreement but a techncial one as well.  During an inspection, he would be asked why he released the lot. And an answer of “the investigation was complete and said so, does not wash”.

The questioner did not get it and responded that no regulation actually required it so why do it.  I responded that when I sign something eg lot release, I am putting my name on the line and am assuring the decision is right.  It is just a good business process.

I sense many people just do not buy into that concept but rather look to the regualtory bodies to tell them what to do rather than develop good business processes.

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