2014 proved to be another busy year for the FDA. We asked Barbara Unger, President of Unger Consulting and Editor-in-Chief of GMP Regulatory Intelligence, to summarize her key take-aways from the enforcement actions of the FDA and EU in 2014. Here’s Barbara:
This retrospective look at 2014 focuses on a few actions taken by regulators that have high impact to the pharmaceutical industry. It is not meant to be an all-encompassing analysis of actions taken in 2014. The actions we choose to address for 2014 are:
- Total FDA drug GMP warning letters were essentially flat in FY 2014, with compounding pharmacies and international sites hit hardest
- FDA drug recalls point to continued, growing focus on foreign particulates in parenteral products
- FDA prepares to launch the super-level Office of Pharmaceutical Quality to address all-things-quality in CDER
- Public availability of Eudra GMDP reports of non-compliance launches and highlights data integrity
- Changes to the EU GMP Guide include more specificity and continued incorporation of Risk Management and other ICH Quality Concepts
Total FDA drug GMP warning letters were essentially flat in FY 2014, with compounding pharmacies and international sites hit hardest.
First a disclaimer: every person and organization that tallies warning letters does so in a slightly different manner and thus absolute numbers rarely agree. That having been said, the general trends and conclusions aren’t generally impacted by the small differences in absolute number reported. In addition, the numbers here do not include the 12 warning letters issued to generic drug firms for failure to register and pay the required Generic Drug User Fee Act (GDUFA) fees.
The total number of GMP warning letters to pharma companies has remained reasonably constant over the last three fiscal years as shown in the table below.
|FY 2012||FY 2013||FY 2014|
|Pharma GMP warning letters||47||43||49|
The 49 warning letters from FY2014 are remarkable for the way in which they are divided among the areas FDA oversees within the pharmaceutical industry:
- 27 of the 49 (55%) warning letters were issued to compounding pharmacies. It is likely that this is because the Drug Supply Chain Security Act (DSCSA) became law in November 2013 and clarified the legal authority of FDA with regard to these types of business. The FDA ORA Reading room includes a detailed collection of forms 483, warning letters and related documents from both 2013 and 2014 inspections of these facilities. The recalls that have resulted from some of these inspections are generally based on the lack of sterility assurance for the parenteral products they manufacture. The warning letters to compounding pharmacies that manufacture parenteral products include a detailed description of FDA’s authority in the area, and markedly similar group of deficiencies in the areas of facility design and operation, testing, aseptic processing, and training.
- Amgen, Inc. received FDAs first warning letter to mention constituent parts of combination products in January, 2014. The deficiencies within the warning letter were assigned to 21 CFR Part 820 rather than 21 CFR Part 4. Note that although FDA classifies the subject of the warning letter as “CGMP/QSR/Medical Devices/Adulterated” I’ve counted it as being issued to a drug company.
- Only 4 of the 49 warning letters were issued to drug firm sites in the US, other than compounding pharmacies and include: Jubilant HollisterStier LLC, Ameriderm Laboratories Ltd., Greer Laboratories, and Amgen, Inc.
- Seventeen (17) 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 and Australia.
Regarding non-GMP drug warning letters, Eye on FDA reports that action letters from the Office of Prescription Drug Promotion decreased substantially in 2014. These action letters include both Warning Letters and Notice of Violation letters.
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FDA drug recalls point to continued, growing focus on foreign particulates in parenteral products
The number of recalls citing the presence of foreign particulates in parenteral products has increased in the past several years. Further, the number of companies who have been responsible for Class I recalls of this type has increased between 2011 through 2014. Data are taken from the weekly FDA enforcement reports.
The above figure shows a consistent increase in the Class I recalls for foreign particulates in parenteral products from 2011 through 2014. In addition, total number of such recalls has increased consistently from 2012 through 2014, more than doubling in number over that time period. Even considering that a single firm was responsible for twelve of the Class I recalls in a single week in 2014, the number of the events continues to increase.
The number of firms that performed Class I recalls between 2011 and 2014 has increased as well. The total number of firms involved increased from 2 in 2011 to 9 in 2014, with some of the firms responsible for multiple recalls.
Events that prompted these recalls include:
- A single customer complaint of a visible glass particulate in a vial,
- Evidence of glass delamination,
- The presence of fiber and plastic particulates from items intrinsic to the manufacturing process, and
- The presence of human or animal hair, insect parts, or visible mold
Clearly the presence of insect parts, hair and mold suggest breaches in GMP control over the manufacturing process. FDA is participating in discussion with industry groups to address the reason for the apparent increase in the frequency of recalls when the foreign particle comes from an intrinsic component used in the manufacturing process.
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FDA prepares to launch the super-level Office of Pharmaceutical Quality to address all-things-quality in CDER
FDA announced implementation of a reorganization at the end 2014 that was initially described in 2012. The CDER super Office of Pharmaceutical Quality (OPQ) became effective January, 2015 and consolidates drug quality efforts throughout the lifecycle of the product. It will include “all non-enforcement related drug quality work” according to the FDA web page describing the Office. Dr. Woodcock will be the Acting Director of the super office until a permanent Director is identified. “OPQ creates a uniform drug quality program across all sites of manufacture, whether domestic or foreign, and across all drug product areas.” Announced changes include:
- The Office of Pharmaceutical Sciences will move to OPQ. This group oversees CMC submissions for drugs and biologics.
- Both pre-approval and routine inspection activities will move from the Office of Compliance to OPQ, and
- Bioequivalence/bioavailability, and non-clinical study inspections will move from the Office of Compliance (Office of Scientific Investigations) to the Office of Translational Sciences within the Office of Regulatory Policy.
Consolidation of these activities into a single office will affect all drug firms and represents a significantly different way for FDA to provide oversight. We may begin to see the early impact of this reorganization during the year, but significant impact likely will not be felt for a few years. Publication of draft guidance on “Quality Metrics” is anticipated in 2015 and will be key for implementation of changes in GMP inspection planning and management.
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Public availability of Eudra GMDP reports of non-compliance launches and focuses additional visibility on data integrity
The public section of the Eudra GMDP database was modified to include reports of non-compliance in December 2013. The first full year of its availability was 2014, though earlier reports are included in the collection. The database does not necessarily include all such reports, but is a welcome level of transparency from the EU regulators on the specifics of inspection outcomes. The non-compliance reports identify specific firms and locations, provide a high level overview of critical and major departures from EU GMPs, and identify actions that are taken or to be considered by the national authorities.
Many of the reports include data integrity related issues and cross contamination concerns among products made in multi-product facilities. FDA forms-483 and warning letters over the past decade have included increasing numbers of observations and deficiencies in the broad category of data integrity. With the publication of the EU reports of non-compliance including a focus on data integrity, manufacturers should not consider this topic is addressed only by FDA, and should prepare for GMP, GCP and GLP inspections accordingly.
In addition, selected regulatory agencies periodically publish a list of common observations identified during GXP inspections. Among the regulators publishing this information on a periodic basis are: EMA ( for both GCP and GMP), HPRA, MHRA, and Health Canada. FDA also routinely publishes the list of regulations associated with the most common inspection observations. None of these summary publications, however, link the observations to an identified manufacturer and location.
Firms with GMP Regulatory Intelligence programs should monitor these reports, FDA forms 483 and warning letters to support inspection preparation, selection of business partners and supplier qualification for services and products.
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Changes to the EU GMP Guide include more specificity and continued incorporation of Risk Management and other ICH Quality concepts:
Chapters and Annexes of the EU GMP Guide continue to be revised to provide both additional detail and formal incorporation of risk analysis and risk based decision justification. Firms would be prudent to evaluate whether their SOPs and processes covered by these revised Chapters and guidance may need to be modified. Following are a few of the revised documents finalized and published in 2014:
- Chapter 3, Premises and Equipment. Section 3.6 has been added to this chapter and addresses avoidance of cross contamination and detail on when dedicated facilities might be appropriate. The chapter becomes effective March 1, 2015. Reference is made to Chapter 5 (see below) and Annexes 2, 3, 4, 5 and 6 of the GMP Guide. The reader should also read the Guideline on Setting Health Based Exposure Limits in the guidance section below.
- Chapter 5, Production. This chapter was substantially revised, increasing the length of the document from 6 pages in the current version to 10 pages of text in the revised version. The chapter becomes effective March 1, 2015.
- Chapter 6, Quality Control. This chapter includes an entirely new section on “Technical Transfer of Analytical Methods” along with details on the requirements for laboratory documents, and a reminder that sampling must ensure that test results are representative of the lot or batch. The chapter became effective October 1, 2014.
- Chapter 8, Complaints and Product Recall. This is another chapter that has been substantially expanded, from 1 ½ pages to 4 ½ pages with additional granularity in requirements. Sections include requirements for both commercial and investigational products. The chapter becomes effective March 1, 2015.
Other guidance with potential broad based impact include
- Guideline for Process Validation for Finished Products – Information to be provided in Regulatory Submissions. The guideline was dated February 27, 2014 and became effective 6 months after publication.
- Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities. This guideline is to be read in conjunction with EU GMP revisions to Chapters 3 and 5 above. It calls for a “structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data” to address carry over limits between products in multi-product equipment and facilities. The Guideline becomes effective June 1, 2015.
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