Guest Column | October 6, 2016

What Recent FDA Enforcement Actions In The EU Mean For FDA/EMA Cooperation

By Barbara Unger, Unger Consulting Inc.

FDA Healthcare

FDA and the EU have taken serious enforcement actions against firms in the other’s geographic jurisdiction during the calendar year 2016. In the preceding article, we looked at European inspectorate actions against sites in the U.S.  Issues identified as problematic included deficiencies in aseptic processing of parenteral drugs, data integrity concerns, lack of controls to prevent cross-contamination, and failure to adequately address observations from previous inspections. FDA had inspected each of the three facilities within the past year.

Now, we turn our attention to enforcement actions that FDA has taken against sites in the EU in 2016, including an import alert, three warning letters, and an untitled letter. Note that FDA findings focused on similar areas as the Europeans: aseptic processing, data integrity, and the potential for cross-contamination. It is impossible to determine whether these sites were recently inspected by EU authorities and deemed acceptable.

FDA Actions Against Sites In The EU

FDA imposed an import alert against products manufactured at a Teva Pharmaceuticals site in Hungary in May 2016.   The 12-page form 483 from January 29, 2016, identifies observations in multiple areas including aseptic processing, media simulations, environmental monitoring, and lack of appropriate controls over computers or related systems. Justin Boyd, who is often an investigator where serious data integrity issues are identified, was one of the FDA investigators in this inspection.

The three warning letters issued to European sites are addressed individually in the following sections.

BBT Biotech GmbH – Baesweiler, Germany

BBT Biotech received a warning letter dated May 16, 2016 based on the outcome of an inspection ending May 7, 2015.  The firm manufactures APIs. Deficiencies include but are not limited to:

  • The firm does not have stability data to support the expiration date assigned to the API.The firm responded that they would now follow their SOP and perform stability testing but their response was deemed inadequate because they did not include any retesting of the APIs already distributed.
  • The firm does not have a change management system.In the specific example cited, a crude raw material supplier was not adequately evaluated nor was the change adequately documented.
  • The firm documented an OOS result that was possibly due to the change in supplier, but other lots made with the material from the new supplier were not evaluated.Thus, the data do not support the conclusions as to root cause of the OOS.
  • Computer systems shared passwords and did not have audit trail capabilities.Thus, actions could not be attributed to a unique individual nor was it possible to determine whether data have been altered or deleted.All analysts had ADMIN privileges. Thus, electronic data could be deleted or manipulated without being able to trace the action to a single individual.Data from instrument were copied to a CD and then deleted from the instrument system to free up space on the hard drive.There was no demonstration that all data were accurately transcribed to the CD.

In addition, the firm was required to: “In your response to this letter, investigate your retention and review of CGMP data and provide the results. Focus on your firm’s review and retention of laboratory raw data. In addition, provide your interim plan for reviewing and retaining data while your firm is in the process of implementing access controls and audit trail capabilities.”

CordenPharma - Sermoneta, Italy

CordenPharma received a warning letter dated May 20, 2016, based on the outcome of an inspection ending May 29, 2015. The firm manufactures both APIs and sterile drug product. (In a 2015 press release, CordenPharma announced it had received approval to manufacture clinical product at the site. It did not specify which agency gave the approval, but FDA does not “approve” facilities for manufacture of clinical product.) Deficiencies include but are not limited to:

  • “Black grime and filth” were visible on the tiles in the aseptic processing area. In the warning letter, FDA reminds them that floors in an aseptic processing area should be smooth hard surfaces, and the agency asked for photographic evidence of the “floor replacement” as well as requalification of the environmental monitoring and a media fill strategy.These are not the types of remediation that will happen quickly.
  • Cleaning procedures in the aseptic area involved spraying of water that left standing water pools, which could be a source of microbial contamination.
  • Bulk drug product samples were not taken and tested for sterility.
  • Sixty-one media plates used in environmental monitoring for API production were damaged or in a condition where they may have resulted in an underestimation of microbial contamination.
  • The sterile API rooms had floor drains that FDA stated were not consistent with ISO 5 / Grade A area facility design and operation.The firm was provided a link to the FDA’s guidance on aseptic processing.

All these observations raise the question of why these deficiencies were not identified during the pre-approval inspection (PAI), assuming one was conducted.

SmithKline Beecham Limited - Worthington, UK

SmithKline received a warning letter on June 30, 2016, based on the outcome of an inspection ending July 10, 2015.  This site manufactures APIs.  The deficiencies focused on potential cross-contamination with penicillin, as well as inadequate investigations. Deficiencies include but are not limited to:

  • The firm identified the presence of penicillin in non-penicillin areas over 187 times since 2012.FDA commented that, “Your facility and controls to prevent contamination of non-penicillin drugs with penicillin are wholly inadequate.”
  • The analytical method used to detect penicillin was not validated to detect all types of penicillin made in the facility.The method validation raw data could not be located, and the method itself has been modified since the original validation.
  • The firm could not demonstrate that the current cleaning validation was adequate to remove the penicillin currently manufactured at the site.The FDA gave the firm two choices:either dedicate the facility to production of penicillin or fully decontaminate the facility.If the firm decides on the later, the firm should not provide any non-penicillin products to the U.S. market from this site until the FDA verifies the adequacy of this decontamination.Further, FDA stated, “It is profoundly difficult to completely decontaminate a facility of beta-lactam residues.” FDA’s statement that an activity is “profoundly difficult” strongly suggests that their preference is for the firm to dedicate the facility to penicillin operations.
  • The cited deficiencies addressed exceeding bioburden alert level or action level in the water system, out-of-specification (OOS) events for APIs, and the presence of foreign particles in APIs.Sampling errors were identified as a root cause in many of the water system bioburden excursions, but no data was provided to support the conclusion.The OOS for the API included an opportunistic pathogen that was identified in the water used to manufacture the batch.Investigation into the foreign particles did not include a root cause identification, nor was the investigation and analysis extended to other products made using the same equipment.

ALK-Abello A/S – Horsholm, Denmark

ALK-Abello received an untitled letter based on the outcome of an inspection ending March 14, 2016.  The firm manufactures licensed biologicals and intermediates.  This is the first GMP untitled letter in 2016 issued from FDA’s Center for Biologics Evaluation and Research (CBER). Deficiencies include but are not limited to:

  • Water for injection (WFI) points of use in aseptic manufacture were not monitored at appropriate intervals for endotoxin and total organic carbon (TOC).Further, there was no procedure to address actions that should be taken when consecutive action-level bioburden excursions occur.There have been approximately 80 excursions from the bioburden action level since the FDA inspection in 2014. No corrective actions were initiated until January 2016.
  • Environmental isolates were not used in growth promotion studies supporting media simulations. This is identified as a repeat observation.
  • Expired agar plates were used for environmental monitoring in the aseptic facility.
  • The lyophilizer had not been requalified since March 2000. Further, no requalification occurred after temperature mapping failures.In addition, lots have been aborted due to problems with the lyophilizer.
  • The firm did not have a procedure to specify when stability samples are selected for testing.Approximately 125 samples had not been tested at the required stability time points since 2014.


The actions taken by both EMA and FDA in 2016 against firms in each other’s jurisdictions have common areas of focus, including aseptic processing, cross contamination, and data governance / data integrity.  EMA took actions against firms in the U.S. that had been inspected by the FDA within 12 months of the European authority inspections, so it is likely that either the EMA deficiencies were not identified by FDA or were not deemed to be as serious as the Europeans determined them to be.  For the EU firms against which FDA took action, it is impossible to determine when they were last inspected by a European authority or the nature of the observations.

Meanwhile, in a July 2016 cooperative inspection event, FDA, MHRA, TGA, and Health Canada conducted inspection of the Hospira Healthcare India Private Limited site in Irungattukottai, India. MHRA posted a report of non-compliance for the site on the EudraGMDP web page. MHRA also withdrew the existing GMP certificate only for sterile products, not for solid orals.  Also, no sterile products are to be supplied to the EU while the statement of non-compliance remains in effect. The site is not subject to FDA import alert (#66-40), nor is it listed as such on the Health Canada website as being subject to import action. It did, however, receive an FDA warning letter (May 2013) and two form 483s (December 2013 and February 2015).

As FDA and EMA move to rely on each other’s inspection outcomes, both want to ensure parity in issues identified to ensure they continue to protect the public health of their citizens. The authorities continue to inch closer to mutual acceptance of inspection results, but as this data shows, room for improvement and areas of concern remain.   The cooperative inspections, such as the one conducted this year of the Hospira site in India, work to build confidence among a group of regulatory authorities about the scope and manner of each other’s inspections.

About The Author

Barbara Unger formed Unger Consulting, Inc. in December 2014 to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry. She has extensive expertise in this area having developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen Inc. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Barbara was the first chairperson of the Rx-360 Monitoring and Reporting work group (2009 to 2014) that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. She also served as the chairperson of the Midwest Discussion Group GMP-Intelligence sub-group from 2010 to 2014.

Before Amgen, Barbara worked for the consulting firm Don Hill and Associates, providing regulatory and quality services to the pharmaceutical industry, and for Eli Lilly and Company in quality and CMC regulatory affairs positions. She began her career in the pharmaceutical / device industry with Hybritech Inc. and received a bachelor's degree in chemistry from the University of Illinois at Urbana-Champaign.