FDA and the EU have taken serious enforcement actions against several firms in the others geographic jurisdiction in calendar year 2016. Perhaps this flurry of my-inspectors-are-more-rigorous-than-yours type represents an unofficial test of sorts as these two agencies move to rely more on each other’s inspections. These inspections may test the limits and validity of the underlying assumption that would permit this mutual recognition. Also interesting is that the European inspections specifically evaluate investigational product manufacture, something FDA does not generally do except on a for-cause basis. Below we cover the three EU reports of GMP non-compliance issued regarding sites in the US and three FDA warning letters, one FDA import alert, and one untitled letter issued regarding sites in the EU.

Three of the twelve posted reports of Eudra GMP non-compliance for inspections conducted in 2016 were issued to sites in the US:

  • Two (2) Pharmaceutics International Inc. sites, both in MD
  • Bend Research Inc. in Bend, OR

All three were inspected by the FDA since mid-2015.

Similarly, FDA has taken the following enforcement actions against firms in the EU in calendar year 2016, specifically:

The eight enforcement actions focused on similar deficiencies primarily in the area of data governance / data integrity, potential for cross contamination of products and inadequate controls over aseptic processing of parenteral products. These deficiencies are summarized in and more detail is provided following.

TABLE 1:  Summary of GMP Deficiencies

CompanyUS Identified DeficienciesEU Identified Deficiencies
Pharmaceutics International Inc.(Hunt Valley MD)· Failure to minimize potential for cross-contamination in a multi-product facility with shared equipment.· Data governance failures including generation and checking of data from electronic systems, and failure to investigate previous data integrity shortcomings
Pharmaceutics International Inc.(Cockeysville, MD)· Failure to minimize potential for cross-contamination · Data governance failures including generation and checking of data from electronic systems, and failure to investigate previous data integrity shortcomings
Bend Research(Bend, OR)· Repeated failure to correct deficiencies from previous inspections (2015 and 2012) · Failure to provide ‘requested and reliable information’. Also, 2 critical data integrity deficiencies and 1 major data integrity deficiency · Deficiencies in identification of mobile equipment in multipurpose facilities
Teva Pharmaceuticals(Godollo, Hungary)The form 483 that preceded the import alert by 4 months identified: deficiencies in aseptic processing, environmental monitoring and media fills · Lack of controls over computer systems with 9 examples · Lack of facility repair including white powder evident on surfaces above the barrier for a filling line.
BBT Biotech(Baesweiler, Germany)· Deletion of electronic data, shared passwords, lack of audit trail capabilities · Lack of adequate change management and stability data
Corden Pharma Latina S.p.A.(Sermoneta, Italy)· “Black grime and filth” in the aseptic processing area. · Media plates used in EM were of a poor quality that could have resulted in underestimation of microbial counts. · Floor drains in sterile API rooms
SmithKlein Beecham Limited(Worthington, UK)· Penicillin contamination in areas where non-penicillin products are manufactured·         Presence of foreign particles in API
ALK-Abello A/S(Horsholm, Denmark)· Failure to requalify lyophilizer in ~ 15 years · No action on ~80 action limit excursions for bioburden in WFI used in aseptic manufacture · Use of expired agar plates in aseptic facility

EUROPEAN ENFORCEMENT ACTIONS AGAINST SITES IN THE US 

MHRA inspections resulted in reports of GMP non-compliance issued to two Pharmaceutics International Inc. sites in Maryland. These  inspections were conducted at the end of February, 2016. The reports include the always serious combination of data integrity and risk of cross contamination and/or deficiencies in aseptic processing. This combination rarely ends without enforcement action of some type. Each of the two sites is addressed separately below but common deficiencies were identified at both sites.

  • Hunt Valley, MD Site: Products of concern at this site are non-sterile products. Specific commercial products identified as being manufactured at this site include Ammonaps tablets, Ammonaps oral powder, Lutigest vaginal tablets, and investigational products that were not specifically identified. Two critical deficiencies were identified including, 1) failure to minimize the risk of cross contamination between hazardous and non-hazardous products manufactured in the same facility on shared equipment. I assume by ‘hazardous’ the MHRA means high potency medicinal products rather than non-pharmaceutical products and, 2) Failure of the Quality Unit to perform their responsibilities, particularly ‘gross failure of change management’ that permitted use of an ‘unqualified HPLC system’ and quality investigation that were not based on QRM principles. Three major deficiencies were identified including: ‘1) organisational data governance failures, particularly relating to generation and checking of analytical data obtained from electronic systems, and inadequate investigation into previous data integrity failures. 2) deficiencies in sterilisation and depyrogenation processes, and 3) insufficient control of aseptic operations to provide the required level of sterility assurance.’

The UK GMP certificate was withdrawn. The MHR recommends recall of product where alternative medicines exist, no future batches of non-critical product may be supplied to the EU while the report of non-compliance remains in effect. Regarding investigational products produced at the site, ‘The proposal to continue supply individual batches of investigational medicinal product should be submitted as a substantial amendment, supported by a risk assessment and demonstrating a positive benefit risk ratio for trial subjects. This should be authorised by the National Competent Authority.’

This is similar to the conditions imposed on Bend Research Inc. in Bend, OR after a recent inspection and report of GMP non-compliance by the competent authorities of Sweden

  • Cockeysville, MD Site: The products deemed to be non-compliant with EU GMPS include investigational products, both sterile and non-sterile. MHRA includes the ‘clarifying remark’ as follows: ‘The scope of this statement of non-compliance is limited to medicinal products considered non-critical to public health. Where manufacture and/or testing is continued for critical products, this should be supported by a documented risk assessment containing sufficient information to support activity on a risk management basis. The statement of non-compliance also applies to all investigational medicinal products (IMPs) manufactured by PII and the manufacture and supply of these products should cease. The only exemption to this is where a trial sponsor can demonstrate that the benefit risk ratio remains positive and supports the continuation of a particular trial. PII is required to carry out a risk assessment, in conjunction with the sponsor of each trial for which they manufacture IMP, to discuss such continuation of supply on a batch by batch basis.’

The deficiencies identified are the same as those identified at the Hunt Valley, MD site.

Recall of product is recommended where alternatives exist for medically necessary products. Further no additional batches of product are to be imported into the EU while the statement of non-compliance remains in force.

The MHRA provides insight into how they view continued use of clinical trial materials made at these sites. ‘The proposal to continue supply individual batches of investigational medicinal product should be submitted as a substantial amendment, supported by a risk assessment and demonstrating a positive benefit risk ratio for trial subjects. This should be authorised by the National Competent Authority.’

Recently the EMA began a review of medicines manufactured at these two sites. According to an announcement on the EMA website “EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.”

Finally, FDAzilla’s STORE identifies several recent FDA inspections at both Maryland sites. The most recent for the Cockeysville, MD site occurred in April, 2016. I think that was likely in response to information provided to FDA by the MHRA because the previous inspection at the site was just under a year ago, in May, 2015. The most recent inspection at the Hunt Valley, MD site also occurred in May 2015. I would expect FDA to re-inspect them shortly, if they haven’t done so already. It’s unlikely that the MHRA identified deficiencies appeared only in the past year, so it might be that FDA did not identify them in the most recent inspections or did not deem them so critical as did MHRA.

  • The competent authority of Sweden (MPA) inspected Bend Research Inc. in Bend, OR on February 24, 216. The firm manufactures human medicinal products and human investigational medicinal products. The report of non-compliance includes failure to correct deficiencies noted during inspections in August – September 2015 and August 2012. They also identified two critical deficiencies in data integrity and one major deficiency in data integrity, and major deficiencies in the area of identification of mobile equipment in multipurpose facilities. The authorities also identified “Repeated failures to … provide requested and reliable information.” 

The GMP certificate for manufacture of investigational medicinal products is withdrawn. Further, “It is recommended that, unless exceptionally justified, any pending Clinical Trial Applications in the EEA, listing Bend Research Inc. (BRI) as a manufacturer, are not approved until a new GMP certificate has been issued. No new EEA marketing authorisation applications, line extensions or variations to existing EU marketing authorisation applications where BRI is involved as a manufacturer can be supported until a new GMP certificate has been issued. These recommendations are not meant to interfere with the possibility of making exceptions for critical supply of a medically essential product (whether as a marketed product or as part of an ongoing clinical trial). If there is a significant patient risk connected to discontinuation of a treatment and no alternative treatment exists, the supply may be regarded as medically essential but this should be verified with the competent authority in the country concerned.”

The language specifies that an investigational product may be used when “verified with the competent authority in the country concerned.” This is similar to the terms in the reports issued regarding investigational products manufactured by Pharmaceutical International Inc.

The most recent FDA inspection of Bend Research Inc. was September 2015 according to information provided at FDAzilla.com.

FDA ACTIONS AGAINST SITES IN THE EU

FDA imposed an import alert against products manufactured at a Teva Pharmaceuticals site[ii] 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 often is an investigator along with Peter Baker, was one of the investigators in this inspection.

The three warning letters issued to European sites are addressed individually below.

  • BBT Biotech Gmbh (Baesweiler, Germany) 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) 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. Fierce Pharma reports that “CordenPharma last year got FDA approval to produce sterile products at a plant in Italy. Now, it has gotten an FDA warning letter for a host of issues for its aseptic filling, including the fact the FDA doesn’t like the plant’s design when it comes to sterile production.” It seems odd that a facility with inadequate design and the problems described in the warning letter would have been approved in the first place. Deficiencies include but are not limited to:
    • “Black grime and filth” were visible on the tiles in the aseptic processing area. FDA reminds them that floors in an aseptic processing area should be smooth hard surfaces, and they ask for photographic evidence of the “floor replacement” as well as requalification of the environmental monitoring and a media fill strategy. These are not the type of remediation that will happen quickly.
    • Cleaning procedures in the aseptic area involved spraying of water that left standing water pools that could be a source of microbial contamination.
    • Bulk drug product samples are not taken and tested for sterility.
    • (API) Sixty-one media plates used in environmental monitoring were damaged or in a condition where they may have resulted in an under estimation of microbial contamination.
    • The sterile API rooms had floor drains which FDA states are not consistent with ISO5/ Grade A area facility design and operation. The firm is provided a link to the FDA’s Guidance on Aseptic Processing.

All these observations beg the question of why these deficiencies were not identified during the PAI, assuming one was conducted.

  • SmithKline Beecham Limited (Worthington, UK) 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 and inadequate investigations. The form 483 may be purchased at the FDAzilla STORE. Deficiencies include but are not limited to:
    • The firm identified the presence of penicillin in non-penicillin areas over 187 times since 2012. FDA comments that ‘Your facility and controls to prevent contamination of non-penicillin drugs with penicillin are wholly inadequate’.
    • The analytical method used to detect penicillins 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 cannot demonstrate that the current cleaning validation is adequate to remove the penicillins currently manufactured at the site. The FDA gives the firm two choices: either dedicate the facility to production of penicillins or fully decontaminate the facility. If the firm decides on the later, until the FDA verifies the adequacy of this decontamination, the firm should not provide any non-penicillin products to the US market from this site. Further, FDA states ‘It is profoundly difficult to completely decontaminate a facility of beta-lactam residues.’ More than a hint in that last sentence.
    • The investigations that were cited as deficient addressed exceeding bioburden alert level or action level in the water system, 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 were 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 in the same equipment.
  • ALK-Abello A/S (Horsholm, Denmark) received an untitled letter based on 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 CBER. Deficiencies include but are not limited to:
    • WFI points of use in aseptic manufacture are not monitored at appropriate intervals for endotoxin and TOC. Further, there is 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 has 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 does not have a procedure to specify when stability samples are selected for testing. Approximately 125 samples have not been tested at the required stability time points since 2014. 

CONCLUSION:

In conclusion, 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 US which had been inspected by the FDA within 12 months of the European authority inspections so it is likely that either the deficiencies were not identified by FDA or were not deemed to be as serious as the Europeans determined them to be. For the firms that FDA took action against in the EU it is not possible to determine when they were last inspected by a European authority or the nature of the observations. 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 move closer to the mutual acceptance of inspection results, but as these data show, room for improvement and areas of concern remain.

[i]  The associated form 483 issued to Teva Pharmaceuticals at the end of the inspection on January 29, 2016 may be purchase from FDAzilla STORE, http://fdazilla.com/store/form483/3002875215-20160129

[ii]  The associated form 483 issued to Teva Pharmaceuticals at the end of the inspection on January 29, 2016 may be purchase from FDAzilla STORE, http://fdazilla.com/store/form483/3002875215-20160129