The Calcott Consulting Blog:

   Articles on Warning Letter:


You thought the Indian companies were taking a hammering. Better look to the US Pharmacies

April 26th, 2014 by

In the first quarter of 2014, 3 Indian companies were issued warning letter (see my posting on the blog) whereas 7 pharmacies were hit.  Statistically significant?  Perhaps.

After the debacle of the New England Compounding Center about a year ago, the FDA has been on a rampage in the Pharmacy world.  I am no lawyer but the way I read it is the pharmacies are using a loophole in the law centered around the  issues of FDA jurisdiction.  FDA basically regulates interstate distribution of drugs, so make a drug in state X and “export” it to state Y – yep FDA has jurisdiction. So the manufacturers of drugs are under FDA rule.

Now, pharmacies are allowed to take these drugs and dispense prescriptions.  So when you go to your corner pharmacist, you can see them dispensing.  Counting out pills and putting them into bottles.  Hardly much risk here so long as they don’t muddle them up, get them cross contaminated  etc.  But they can also do further dispensing.  For instance, they can take a sterile vial or bottle of a drug and dispense it to another sterile container.  Now this is another matter.  What we are describing is aseptic processing.  As we all know that’s a risky business.  How many manufacturers fall foul of the regulations in industry?  The number of warning letters are numerous.

But it seems that FDA can not step in unless there is a demonstrated safety calamity.  But we don’t want to wait for that each and every time.  So what can the FDA do?  Their tack is to inspect these operations when they suspect that the Pharmacy has overstepped their authority.  It seems that in a majority of the 7 letter this quarter they have seen that the pharmacies have been dispensing these aseptically prepared drugs without prescriptions and compounding several drugs together.  Some of these drugs have different regimes of taking the drug.  Ergo, they are no longer dispensing, but manufacturing.

Now when they go in and inspect they cite for lack of GMP adherences and the story goes on.  Call me naive, but if I go to a pharmacy, I want an assurance that the drugs I am receiving are not adulterated.  I don’t care who regulates them but I want it done properly.  Clearly the Boards of Pharmacy have not been doing a good job (they are the ones who regulate at a state level rather than FDA).  What we have here is a standard clash between Federal and state control – we see it every day in other matters but in this case they are using our health as a pawn in the game.

 

Keep up the good work FDA.

He is the link to the 7 warning letters

Nora Apothecary Services ,  Lowlite Investments DBA Olympia PharmacyPallimed SolutionsWedgewood Village PharmacyTotal Pharmacy Services ,Avella of Deer ValleyVillage Fertility Pharmacy

 

Indian Companies get hammered in Q1 2014

April 1st, 2014 by

In the first quarter of 2014, there are 3 warning letters for Indian Companies.  Add to that the travails of Wockhardt and Ranbaxy over the last couple of years and it looks bleak for Indian Companies in general.  I regularly read LinkedIn Groups and I noticed a thread related the question of reliability of Indian Medicines.

Can We trust Indian  Drug Companies?

It created a firestorm of responses, many of which were from India.  The responses fell into three categories which I will paraphrase

1. The FDA is picking on us – EU and US companies have the same problems

2. I would never take an Indian medicine again

3. Indan regulators find no problem who is the FDA to tell us what our standard should be

1. Of course some US and EU and other country companies have run foul of the law. Actually there are over twice the number of warning letters directed to Pharmacies than Indian companies in Q1.  So maybe the FDA is picking on a broader range of companies.  Or putting it another way – they are doing their job and hard one it is.

2. Are all Indian companies bad?  Of course not.  I do not know the statistics but I have heard that 50% (and it could be higher or lower) of the US generics is from India and undoubtedly the major are fine (at least I hope so).

3. I am sorry but if you want to sell drugs on the US market you have to play by the rules here.  On paper, the Indian regulations are as tough as the FDAs but the question is detection of issues and enforcement that will separate the theory from the reality.

So what are the issues that are found

UVS issues appear to relate to data integrity.  Check my  previous posting on the blog .  The link to the warning letter is here

Smruthi Organics Ltd has a Warning Letter with only 3 observations.  One centered on data deletion, record destruction and inadequate investigations.  The link is here

Canton Laboratories Private LTD has a warning letter with 4 observations.  The essence is failure to keep data from testing, failure to actually test, failure to adequately clean equipment and failure to manufacture according to instructions and keep adequate records..  The link to the Warning Letter is here

In reality there is a lot of similarity in all these observations.  It does make one wonder about the quality of medicines.  Is this the tip of the iceberg?  Should I be worried?

 

Not just telling you your faults but how to rectify

March 30th, 2014 by

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.

A new FDA Paradigm? Citing Guidances

February 28th, 2014 by

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.

Finally, the FDA enforces some post approval commitments

March 23rd, 2012 by

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.