When I read FDA Warning Letters and I do often, most take the format of telling you the observations and then indicating that this is not a complete list. However, about 10% go one step further and basically read you the riot act suggesting that you need to hire a consultant to “educate you” on the errors of your ways. These are quite common.
But I believe they went to the next level for USV Limited of Mumbai. In the 2/6/2014 WL, they even listed out 7 steps for remediation. View this as reading the riot act 7 times over. Basically there was suspicion of fraud in the data.

The link is Warning Letter

They went on as follows
Get a consultant specialising in data fraud to do the following
1.) Identify the time period when the issue occurred
2.) Identify and interview employees involved in that period
3.) Identify and interview employees who have left who were employed during the period
4.) Gather data to support what comes out of the interview
5.) Trace issues to specific managers including senior management
6.) Determine if any other offending managers are in a position to influence data integrity decisions and expand your oversight
7.) Put into place procedures to prevent recurrence and assure there are no discrepancies between what was filed and reality. Create CAPAs to remedy issues. This does not apply simply to what we found but everything in essence.
Nothing revolutionary just common sense.

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Just when you thought you had it straight, the FDA throws you a fast ball – or is it a slider, a spit ball. Not being a baseball fan, never quite certain what the saying is. Had I used the cricket analogy, I would have said a googly. But I digress.

Reading the new batch of FDA warning letters before my morning coffee, I came across an interesting paradigm breaker.

We all know FDA issues guidances and agrees to the ICH guidances. However, being guidances they are not law. That means that these documents and their contents are “suggestions” of practices they agree with. If you follow them they will give you no grief. They are really the path of least resistance. You can perform other practices and if satisfactory, you are OK. Just it might take more discussion during an inspection.

Now to the warning letter. It was issued to CBSCHEM Ltd of Hong Kong. In observation 1, they find fault in the traceability of the APIs. And which source of “regulation”?. The guidance ICH Q7 together with a hyperlink to the FDA website.

IS this the beginning of a new paradigm where they will cite Guidances?

Time will tell.

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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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Earlier in my career, as head of global quality in a well known company that will remain anonymous, we had experienced a regulatory inspection that had gone quite well.  Although it was a full week with two inspectors, we had survived with 2 citations (note I do not say 483’s – so you do not know what agency it was doing the inspection).  These citations were relatively minor and very clearly, “one offs”.  There were absolutely no repeat violations from previous inspections with the observations being isolated in that no question of systemic issues were involved.  Answering the observations were easy even including broad based CAPA’s.

In the debriefing that followed, after the inspectors left, I did my normal congratulations to the team assembled.  I indicated that although we had received two citations, these were minor and easily correctable.  I continued that we should not rest on our laurels but continue the continuous improvement program taking heed from some of the non-citation comments the inspectors had left us with.

The team was ready to leave when the new head of operations asked to say a few words.  He was in his first two weeks on the job and so, I guess wanted to take charge, launched into a monologue that left the whole team cold.  He indicated he was embarrassed by the inspection since we had received citations and that the performance was unacceptable.  In future, any citation received would bear directly on all employees.  Needless to say, that speech went over like a lead balloon.  Over the next few months the plant was handed goals that were draconian in nature which brings us to the topic of this blog for this week.

Bad Metrics!!!!

In the world of continuous improvement, I always remember a quote of Demings (or at least I always attribute it to him – but I could be wrong) and it goes something like this.

If you can not measure it, it can’t improve it 

So in order to improve performance we set up metrics to measure our operations.  Metrics should be measurable, objective (or at least relatively immune to subjective interpretation) and easily collected.  So observations or citations from an inspection are a clear item that fits into the category. So how do you formulate the metric?

The naive answer is simply to set a goal of say,

No citations, 483 points or observations

And that is an admirable goal.  But does it  set the right standard?  Compare these two observations and ask whether they are equally serious.

Operator training records are inadequate, in that operator X has not been trained on procedure y

versus

The Quality unit is ineffective in that they fail to follow their procedures.  Examples include

a.)  Lot disposition procedures were not followed for the following lots……….which were released before QC data were approved.

b.)  Annual product reviews were not carried out for years 2001………..2010.

c.)  ……………………………….

d.)  ……………………………….

e.)  ……………………………….

f.)  ……………………………….

g.)  ………………………………

h.) Complaints were not investigated for the following products……

In the first case, while it may not be fully clear what the importance of procedure y is, there is no indication that training records were inadequate in any other employee.  And you know that they would have looked and cited them if they had found any.

The second case really points to not just a systemic issue of problems but also to a system that is failing – the Quality Management System – the cornerstone of GMP operations.

So how should we develop metrics around citations?

Numbers have a place, but the nature, seriousness and depth of the observation are more important.

A good metric might read

No systemic citation pointing to a major system in the plant. No repeat violations from previous inspections. No citation identified and corrected in internal audits. No citation that is likely to have an impact on patient safety.

These are not perfect metrics but they do point to the important elements of compliance and good operation.

The same metrics might also be used for internal audits that are carried out more frequently than inspections.

While shooting for zero – an admirable goal – a more pragmatic goal is more reasonable.

Is an inspection with zero observations possible?  Yes it does happen.  Sometimes it is because the plant is well managed and it was a fair inspection.  In some cases the inspection was so light weight the inspector did not check anything (and it has happened to me at least on one occasion).  In other cases, the inspector did a conscientious job but just never spotted the issues areas.

As with audits, inspections are run by humans and, in consequence, variability in inspections and audits is large.  I always think of inspections as biological assays with their large standard deviations.

In fact, getting a zero observation inspection is often dreaded by Quality staff because it tends to lull the naive operation person into a false sense of security.

Oh!  By the way, the draconian operations guy did not last long at the company before being asked to leave.  But until he left, morale at that plant was not the best.

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I am intrigued by certain webinar companies that appear to spend a fortune on advertising.  You’ve seen their emails and half page ads. They go like this.

What’s the one thing that you can control that is a disaster waiting to happen?  Those piles  of SOP’s fresh off the press that nobody knows what to do with.  Bullet proof your procedures.

You’ve seen the adverts. If only life were that simple.

Actually, writing SOP’s is a relatively easy job if you go about it the right way.

Rolling them out is also simple, again if you do it the right way.  We will talk about these two parts later.

It’s not as if perfect SOP’s are needed and that rolling them out must be done perfectly.

I have audited organisations that had pretty poor but acceptable SOP’s with training programs that are uninspiring and yet these organisation operate in compliance.  Are they efficient  – NO?  Do you want to use their SOP’s and training programs – NO?  But they work and the companies stay out of trouble.

Actually the 800-pound gorilla in the room is really management involvement and support for the principles of compliance which includes following SOP’s and actively training staff.

How can you detect this problem?  It is often detected by looking at regulatory citations and/or audit findings.  Look for those observations that are made with CAPA’s that never seem to prevent recurrences.  Look for repeat observations.  Now look at the CAPA’s.  How many call for a rewrite of one or more SOP’s?  How many call for retraining?

As I always say in my class, if SOP rewrite was the right solution, how come we are so bad at doing it that we have to keep rewriting them?   Time and time again. And the problem does not go away.  Are these rewrites so bad or are we tying to correct the wrong thing?

If training and its roll out was the key issue, how many times do you retrain Bill on the procedure and he just does not seem to get it, before you say that there must be another issue here?

At some point, step back and ask the question, how come these rewrites and retraining do not solve the problem?  The answer is closer than you think.  It is the culture in your organisation.  It is a difficult message to deliver and to receive.  But, as my father used to say, understanding you have a problem is half way to solving it.

Do you allow non-compliance with your SOP’s?  Are they optional in your programs?

The answer to all these issues is to do the following:

1.) Before you write an SOP or review it for rewrite, ask the question of whether the effort is worth your time.  Is there an SOP already in place?  If not, do you really need another?  Only then consider rewriting or producing an SOP.

2.) Make sure you get subject matter experts involved in the writing or at least defining content.

3.) Make sure all stakeholders are involved in reviewing the draft SOP.  Does that mean they all approve it?  NO.  There is an owner and QA who need to approve an SOP.  Perhaps 1 or 2 others, but rarely more, are required.  Too many approvers mean things get log jammed.

4.)  Communicate the new SOP before it goes live so that involved parties can assess and train as appropriate.

5.)   Training does not have to be complicated.  It may mean simply reading and  acknowledging you understand it.

6.)  Give the organisation enough time between issuance and go live.

7.)  Document all activities.

Now the biggy.  Make following SOP’s a requirement for continued employment.  Follow them yourself.  Nothing spells disaster more than a boss that is above SOP’s.  If you do not set an example for following them, you are setting an example that they are optional.

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