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 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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There has been a lot of discussion at conferences and on LinkedIn as to whether QbD is just for big Pharma and Biotech and whether smaller companies are being discriminated against.  This triggered me to write an article for Metric Streams, GXP Lifeline.  Enjoy

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Over the last several years I have read in the trade press reports on post approval commitments of companies with respect to clinical studies and the frequency at which they have been initiated.  The reports vary but they appear to be in the 20-30% range.  What does that mean?

We all know the situation.  We make our submission and in the negotiations in the last several weeks we deal with

1. Label approval.  We wrestle with the inclusion of efficacy, wanting as broader claim as possible, and reduced or minimised safety warnings.  Often we just accept what we are goven.
2. Manufacturing inspections.  We negotiate the various responses to the inevitable observations at the pre-approval inspection.  We make some illogical commitments just to get the license.
3. CMC submission.  We argue for adequacy of the submission, often agreeing to outlandish requests because we are so close to approval.
4. Clinical data.  After the advisory panel recommendation for approval, we negotiate with the agency with respect to the adequacy of the efficacy and safety package. We often commit to Phase 4 studies to further gather data to demonstrate safety in  a larger patient pool and other studies.

Then we get approval and we are off to the market.  But in the years following approval, we are supposed to perform these post approval studies mentioned in point 4 above.  The reports I mentioned earlier are that only 20-30% of these commitments are actually acted upon after about 2 years.  I do not mean completed since these studies may take much longer but actually initiated.  This sounds like an abysmal record.

But up until now I have not seen any report of action by the agency against these recalcitrant companies.  That is until now.  On February 17 of 2012, FDA issued a warning letter to Merck, Sharp and Dohme on the lack of follow through for some animal studies that were committed to as part of the approval for Januvia® and Janumet®.  The complete response letter was issued late in 2009 with an observation that the post marketing Pharmacovigilance studies were not sufficient to assure safety of the product.  They required a further animal study to be performed post approval.  A timetable was agreed to with protocol approvals and study report completion dates.  These were to be completed by June 2011.  As of February 2012, the studies had not been submitted.  Thus the FDA has labeled the product as misbranded and required response with data or further action will occur.

The Warning Letter describes the details of the rationale and the commitment and then goes on to document the events that lead up to the situation.  It presents interesting reading.

This does represent another facet of Commissioner Hamburg’s tougher enforcement.

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At a recent IBC conference on Product and Process Validation, I moderated a panel discussion on this topic with four panelists in addition to myself.  They included two from Pfizer, and one each from Genentech/Roche and Shire Pharmaceuticals.  What were the conclusions:

1. All companies were finding the efforts of QbD painful and laborious and were only just beginning to touch on the new PV guidance.  This was true for the larger companies and especially so for the smaller ones.
2. Some were seeing a back pedalling by the regulators on what benefits the companies might reap for this added work.
3. All recognised that the very small company might find it exceedingly painful if not impossible.

The panel discussion was published in Pharma QbD and I have included a link so you can read more.

Stay tuned, I will be writing more on the topic.

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