March 31, 2015 marked the end of the first half of FY2015 for the FDA, and we take this opportunity to look at GMP warning letters issued to pharmaceutical firms. The data come from drug GMP warning letters that issued between October 1, 2014 and April 1, 2015 that are posted on the FDA website. A few warning letters issued prior to April 1 may yet be posted, but this update provides an early view of how the year is shaping up. As a starting point, it’s useful to look back at the number and distribution of warning letters issued in FY2014.
FDA issued 49 GMP warning letters to pharmaceutical companies in FY2014 by my count. This number does not include the 12 warning letters that were issued to generic companies for failure to register and pay the required Generic Drug User Fee Act (GDUFA) fees. FY 2014 was unique because 27 of the 49 warning letters issued in FY2014 were issued to compounding pharmacies including those that registered with FDA as outsourcing facilities. The Drug Supply Chain Security Act became law in November 2013 and clarified FDA’s authority in regulating these entities. For those interested in additional detail, the FDA ORA Reading room includes the collection of enforcement actions for manufacturers of these products including forms 483, warning letters, and recalls. Note that all compounding pharmacies are located in the US and are also regulated by the States Board of Pharmacy.
|FY2012||FY2013||FY2014||1st Half FY2015|
|Drug GMP Warning Letters||47||43||49||18|
FY2014 also reinforced FDA’s move in expanding the scope of their inspections to more closely reflect the source of both APIs and dosage forms for drugs used in the United States. When the warning letters to compounding pharmacies are excluded, only 4 of the 49 letters were issued to pharmaceutical companies in the US. These included warning letters to Jubilant HollisterStier LLC, Ameriderm Laboratories Ltd., Greer Laboratories and Amgen, Inc. The warning letter to Amgen classifies the subject as “CGMP / QSR / Medical Devices / Adulterated and addressed combination products though I include it here as a pharma GMP warning letter for two reasons: Amgen is primarily considered a biopharmaceutical company and this is the first warning letter to mention combination products after 21CFR4 (GMPs for Combination Products) published in January 2013. Eighteen warning letters were issued for inspection of sites outside the United States including China (4), India (7) and one each for sites in Hong Kong, Ireland, Germany, Mexico, Italy, Canada and Australia. Again, after excluding warning letters issued to compounding pharmacies, 82% of the remaining warning letters were issued for sites located outside the United States.
The Table below shows the distribution of warning letters so far in FY2015. The total number of GMP warning letters is lagging behind FY2014 though their overall distribution is similar. More than fifty percent of them have been issued to compounding pharmacies, all located in the US. Only one has been issued to a firm in the US that is not a compounding pharmacy. Similar to FY2014, after the warning letters to compounding pharmacies are excluded, sites outside the US received 89% of the warning letters.
|Compounding Pharmacies||US Sites||OUS Sites|
|First Half FY2015||10||1||8|
The countries outside the US with facilities that were the subject of a warning letter in FY2015 include: India (4), Thailand (1), China (1), Italy (1) and Portugal (1). Note that one of the firms in China and the site in Thailand are part of the same international company, the Novacap group, headquartered in France. Deficiencies in these two letters are similar, including shortcomings in providing assurance of data integrity. Warning letters issued in FY2015 are shaping up similar to FY2014 regarding the type of firms involved and countries where the inspected sites are located. The tabulation is provided in the APPENDIX identifying the firm’s name and type of manufacture, date of the warning letter, number of deficiencies and links to the letters on the FDA website.
A more in depth discussion and history of FDA’s enforcement actions in the area of data integrity over more than the past decade may be found HERE. The collection of FDA form-483 specific data integrity observations and warning letter data integrity deficiencies over this extended time period are also available. Information on the inspections, inspectors and full forms 483 that resulted in these warning letters may be found HERE.
In conclusion, for drug GMP warning letters issued in the first half of FY2015:
- Numbers are on track to be lower than for FY2014;
- Compounding pharmacies continue to be the lead category in FDA’s drug warning letters as they were in FY2014;
- Drug GMP warning letters that are not issued to compounding pharmacies are issued mostly to sites outside the US;
- Data integrity continues to be a focus in warning letters issued to sites other than compounding pharmacies.
NOTE: This BLOG is an abbreviated version of an article I wrote that appeared in the weekly subscription based GMP Regulatory Intelligence newsletter published by FDAzilla.