Delay, Denial, or Limiting of Inspections Since 2008
by Barbara Unger, GMP Quality Expert and GMP Regulatory Intelligence Editor-in-Chief
In October 2014, the FDA published a final Guidance for Industry, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection. Publishing this guidance was a requirement of section 707 of the Food and Drug Administration Safety and Innovation Act (FDASIA). Section 707 of FDASIA adds 501(j) to the Food, Drug, and Cosmetic Act (FD&C Act) to deem a drug adulterated if it “has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.” Before that time and since, the FDA cited instances where firms have delayed inspections or denied investigators access to areas or documents that they should be able to view.
Because this seemed to be increasing in frequency in 2016, I searched GMP warning letters starting in 2008 to document this claim. Table 1 shows this began as early as 2008, continued through 2012 – 2015, and eight firms were cited for this in 2016. Sites in China were the most frequent recipients with 7 of the 12 warning letters. Sites in India were next with 3 of the 12. And one site in Japan and the US received a warning letter with this deficiency.
Table 1. Warning Letters Citing ‘Delay, Deny, Or Limit’ Of Inspections
|YEAR||COUNTRY||COMPANY||IMPORT ALERT 99-321||IMPORT ALERT 66-402|
|2008||Japan||Tomita Pharmaceutical Co. Ltd
|2012||China||Shanghai Huhui Daily Use Chemical Products Co., Ltd.
|No||5/22/2013 (2), 11/26/2013|
|2013||India||Fresenius Kabi Oncology
|2014||China||Beijing Shunxin Meihua Biotechnical Co. Ltd.
|2015||China||Zhejiang Hisun Pharmaceutical Co., Ltd.
|2016||China||Beijing Taiyang Pharmaceutical Industry Co Ltd
|2016||China||Zhejiang Hisoar Pharmaceutical Co
|2016||US||Frontida BioPharm Inc||N/A||N/A|
|2016||China||Xiamen Origin Biotech Co Ltd
|2016||China||Baoying County Fukang Medical Applications Co., Ltd.
|2016||India||Pan Drugs Limited
- “Detention Without Physical Examination Of Products From Firms Refusing FDA Foreign Establishment Inspection”
- “Detention Without Physical Examination of Unapproved New Drugs Promoted in the U.S”
Table 2 addresses imposition of import alerts, either 99-32 for refusal of inspection or 66-40 for failure to comply with GMPs. It’s far more common for firms to have import alerts put in place for failure to comply with GMPs than for refusal of inspection. In the three instances that used import alert 99-32, the firms were also put on import alert for failure to comply with GMPs. In some cases, a warning letter is associated with import alerts put in place for multiple sites.
Table 2. Sites of Warning letters and Import Alerts
|COUNTRY||Warning Letters Citing Delay, Deny, or Limit||IMPORT ALERT 99-32||IMPORT ALERT 66-40|
The following pages provide the text from each of the warning letters. This provides a view to how the inspection was delayed, denied, or limited. I would expect this to continue in the future in the areas with less developed regulatory authorities, though by now it should be evident that denying an inspection can have severe financial impact because the firm will likely be placed on import alert.
|Year||Country||Company||Text of Compliance|
|2008||Japan||Tomita Pharmaceutical Co., Ltd||COMMENT:
During the inspection, your firm refused to provide copies of production records, laboratory records, and written procedures requested by the FDA Investigator and Analyst for their later review. Your refusal to provide documents during the inspection, your firm refused to provide copies of production records, laboratory records, and written procedures requested by the FDA Investigator and Analyst for their later review. Your refusal to provide documents hinders FDA’s ability to perform an inspection and determine your firm’s compliance with CGMP requirements. Thus, FDA considers your refusal to provide documents as a refusal to allow inspection. APIs manufactured by your firm may be refused entry into the U.S. pursuant to Section 801(a)(3) of the FD&C Act in that the methods and controls used in their manufacture do not appear to conform to current good manufacturing practice within the meaning of Section 501(a)(2)(B) of the FD&C Act, if documents necessary for an inspection and CGMP assessment are not provided it hinders FDA’s ability to perform an inspection and determine your firm’s compliance with CGMP requirements. Thus, FDA considers your refusal to provide documents as a refusal to allow inspection. APIs manufactured by your firm may be refused entry into the U.S. pursuant to Section 801(a)(3) of the FD&C Act in that the methods and controls used in their manufacture do not appear to conform to current good manufacturing practice within the meaning of Section 501(a)(2)(B) of the FD&C Act, if documents necessary for an inspection and CGMP assessment are not provided.
|2012||China||Shanghai Huhui Daily Use Chemical Products Co.,Ltd||1. Component test records specifically associated with batches of drug product manufactured at your facility were not readily available for an authorized inspection during their retention period. [21 C.F.R. § 211.180(c)]
a. Your firm refused to provide the test records of (b)(4), an active pharmaceutical ingredient (API) used to manufacture the drug products, (b)(4) Skin Protectant and (b)(4) Skin Protectant. Your firm refused to provide the results of tests performed on (b)(4) and instead redacted the test methods and acceptance criteria in your (b)(4) raw material specification sheet prior to providing a copy of this document to the investigator.
b. Your firm also refused to provide the test records for (b)(4), an API used in your (b)(4) Skin Protectant Cream, by redacting this data before providing a copy of (b)(4) raw material specification sheet to the investigator.
|2013||India||Wockhardt Limited||1. Your firm repeatedly delayed, denied, limited an inspection or refused to permit the FDA inspection.
Examples are as follows:
a. On March 18, 2013, an FDA investigator identified the presence of torn raw data records in the waste area and asked one of your firm’s QA Officers to remove these torn raw data records for the investigator’s review. This QA Officer presented the FDA investigator with approximately 20 paper records, none of which included raw data entries identified in the waste area earlier during the inspection. The FDA investigator asked three times if there were any more records found in the waste area, and the QA Officer responded to each question, “no, this is all of the records”. The FDA investigator then re-visited the waste area and found that the raw data records had been removed and placed in a different holding bag. These records included raw data testing worksheets from anti-microbial effectiveness studies, controlled Master Batch Records for (b)(4) ((b)(4))”, equipment calibration records, and stability protocol records. Because you provided some, but not all, of the records requested by the investigator that FDA had the authority to inspect, you limited access to or copying of records for the FDA inspection. Because you directed FDA investigators away from the requested documents, and because the FDA investigator was impeded by having to locate and reassemble torn records that FDA had requested and had the authority to inspect, you delayed the inspection.
b. On March 18, 2013, an FDA investigator identified the presence of unlabeled and partially labeled vials in the laboratory glassware washing area. When the investigator asked a QC Analyst to describe the contents of these vials, the QC Analyst immediately began dumping the contents of the vials into the drainage sink. The QC Analyst stated that the content of the vials could not be determined. Because you limited the direct observation by the FDA investigator and prevented any determination of the contents of the unlabeled vials, you limited the inspection.
c. On March 19, 2013, an FDA investigator interviewed the Production Head regarding his knowledge of the unofficial batch record forms being used to record the results for the visual inspection of drug products. The Production Head stated that he had only seen this unofficial defect data for “1 to 2 batches”. The FDA investigator had an earlier conversation with two manufacturing operators, who stated that the Production Head had directed this practice throughout the manufacturing facility and regularly requested and reviewed the unofficial BMR visual inspection results. On March 21, 2013, the Production Head stated that he was fully aware of the practice of using unofficial batch record copies during the course of manufacturing operations. The Production Head acknowledged that he had provided inaccurate information in the previous instances. By stating that the data that existed was limited to one or two batches and that no other data existed, you provided some, but not all, of the records requested by the investigator that FDA had the authority to inspect. Additionally, you limited access to or copying of records for the FDA inspection. Because you denied the existence of records that FDA had requested and had the authority to inspect in order to obstruct the direct observation of the requested documents, you delayed the inspection.
d. On March 18, 2013, your Vice President of Manufacturing stated on three different occasions that the facility inspected (b)(4) aseptic filling line for all products (vials and pre-filled syringes) produced for the U.S. market. However, the FDA investigators later identified (b)(4) aseptic filling line for pre-filled syringes manufactured for export to the U.S. market, in use since at least September 2009. The area was operational and was an area of the inspection site that FDA has authority to inspect. The FDA investigator was impeded at the inspection site from properly performing the inspection in a reasonable manner. Because you directed the FDA investigator away from this production area, you obstructed the direct observation of the manufacturing process to an unreasonably short amount of time, and you limited the inspection. Because the investigator only later discovered the existence of the area, you delayed the inspection.
e. On March 20, 2013, an FDA investigator requested the QC data package and raw data testing documentation for (b)(4) tablets Batch # (b)(4) , (b)(4) and (b)(4) batch # (b)(4) , and (b)(4) tablets batch # (b)(4) . The investigator repeated the request no less than six times on March 20, 2013, and again multiple times on March 21, 2013. The data was provided to the FDA investigator during the close-out meeting of the inspection on March 22, 2013. You failed to produce the requested records within the timeframe requested by the investigator without adequate justification. By delaying the provision of requested data and documents until the last scheduled day of the inspection without reasonable explanation, you limited the ability of the investigator to review and analyze the documents to an unreasonably short amount of time and you delayed the
|2013||India||Fresenius Kabi Oncology Ltd||COMMENT:
During the inspection your firm also repeatedly delayed, denied, limited or refused to provide information to the FDA investigators. Please be reminded that the Food and Drug Administration Safety and Innovation Act (FDASIA) § 707, also deems a product to be adulterated if drugs have been manufactured, processed, packed or held in an establishment by an owner or operator who has delayed, denied, or limited an inspection. Examples of instances where the inspection was either delayed or information denied are as follows:
You have also recently informed us that High Pressure Liquid Chromatography units and PCs were removed from the facility for the duration of the inspection to conceal data manipulations. This action, which apparently also occurred in association with past inspections, is very worrisome to us and should be explained in your response to this letter. Please provide a list of all manufacturing and laboratory equipment in your facility used to produce and test products intended for the US market.
You failed to establish an effective corporate and local system for managing quality which would include the appropriate organizational structure, procedures, processes and resources, as well as activities to ensure confidence that all APIs produced by your facility will meet the intended specifications for quality and purity. We highly recommend that you hire an independent third party auditor, with experience in detecting data integrity problems, to assist you with the evaluation of your overall compliance with CGMP and assessing if data submitted to applications was impacted. If a third party is to be hired, please provide the FDA with a copy of their assessment. Also provide a copy of your assessment and investigation into the deficiencies presented in this letter describing the specific findings.
|2014||China||Beijing Shunxin Meihua Bio-technical Co., Ltd.||1. Your site produces crude heparin for purification into finished API. On February 19, 2014, FDA investigators explained the purpose of the inspection to you as the most responsible official at Beijing Shunxin Meihua Bio-technical Co., Ltd, (hereafter Shunxin). You barred the investigators access to the production area and other parts of the manufacturing facility. In several instances, the investigators requested to inspect the facility, but were repeatedly denied access to the production area. Your firm also limited FDA access to certain requested records. For example, the FDA investigators requested batch production records for review, but were refused access to these records repeatedly.
Furthermore, during the review of a list of your suppliers, one of the few documents you did provide, we noted that you are supplied by (b)(4), which research indicates has the same physical address as, and is thus an alias of, the (b)(4), a firm that is currently on FDA Import Alert 55-03, “Detention Without Physical Examination of Different Forms of Heparin and Heparin-Related Products.”Import Alert 55-03 includes firms for which there is information indicating that their heparin and/or heparin-related products appear to be adulterated. One basis for detention without physical examination under Import Alert 55-03 is that the firm’s quality system is inadequate for the prevention of contamination (including oversulfated chondroitin sulfate (OSCS))or otherwise does not conform with CGMP. If your firm is being directly or indirectly supplied by establishments that are associated with historical OSCS contamination or that otherwise lack adequate CGMP, your firm could be manufacturing heparin and heparin-related drugs that could be subject to import alert. FDA recommends that you ensure that you properly evaluate and qualify all your suppliers (e.g., suppliers of crude heparin or heparin API), as required by CGMP, and change the source of your supply, where appropriate. Consequently, your use of this supplier on Import Alert 55-03 led to the appearance of adulteration of your heparin drugs.
|2015||China||Zhejiang Hisun Pharmaceutical Co., Ltd.||Access to information during inspectionWe note that some records we requested during the inspection were not provided in a timely manner.
During the inspection, an analyst removed a USB thumb drive from a computer controlling an HPLC. When asked to provide the drive, the analyst instead exited the room with the thumb drive. After approximately 15 minutes, management provided our investigator with what they asserted was the USB thumb drive in question. It is impossible to know whether management provided the same USB thumb drive that the analyst had removed.
When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be adulterated under section 501(j) of the FD&C Act.
|2016||China||Beijing Taiyang Pharmaceutical Industry Co Ltd||1. Your firm delayed, denied, or limited an inspection, or refused to permit the FDA inspection.
On November 16, 2015, our investigators observed through a window a warehouse containing numerous drums bearing your company’s label. When our investigators requested access to this warehouse, you barred them from entering the warehouse to examine the containers or the material in them without giving a reasonable explanation.
The following day, you gave our investigators access to the warehouse. However, upon entry they observed that a significant number of drums had been removed and were not available for inspection. When they asked about the drums they had observed the previous day, you provided no explanation of the whereabouts or contents of the drums.
You delayed FDA’s access to the warehouse and limited FDA’s inspection by removing the drums before our investigators could inspect them.
|2016||China||Zhejiang Hisoar Pharmaceutical Co||1. Failure to record activities at the time they are performed.
During the inspection, we observed that you did not have worksheets for recording microbial test results and that you failed to contemporaneously document microbial limits test results for (b)(4) API batch (b)(4).
In your response, you stated that tests for microbial limits were not routine for (b)(4). The microbiologist documented test methods and results “when she had time,” and “there was a possibility that our QC microbiologist documents results by memory instead of document (sic) at time of operation.” Your response did not demonstrate the reliability of any data recorded and reported in the past.
In your response to this letter, provide:
|2016||US||Frontida BioPharm Inc||Access to Information During the Inspection
During the inspection, there were numerous instances where your firm failed to provide our investigators with information regarding investigations, corrective actions, and preventive actions in a manner that would allow the investigators to fully understand and evaluate your firm’s internal processes and compliance with CGMP requirements. Your vice president of quality repeatedly denied any knowledge of your clonidine HCl API supplier’s recall, even though e-mail evidence collected during the inspection showed that this individual had been notified of the recall as early as July 16, 2014. During the inspection, your firm removed this individual from his position.In your response, you stated, “Mutual recognizes that the manner in which it provided information about this issue to the investigators during the inspection did not effectively convey Mutual’s process for product disposition or the rationale for its decisions throughout the handling of the batch of Clonidine HCl API.”When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be adulterated under section 501(j) of the FD&C Act. We recommend that you review FDA’s guidance for industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf
|2016||China||Xiamen Origin Biotech Co Ltd||2. Failure to keep buildings used in the manufacture of API in a clean condition.
During the inspection, the investigator recorded dirty warehousing spaces and
Access to information during inspection
During the inspection, your firm also made misleading or deceptive statements and delayed the investigator’s access to accurate and truthful information. For example:
• During the inspection, an employee told the investigator that there were no drugs on site. The investigator observed a room adjacent to the conference room that was being used as a warehouse for relabeled drugs.
• The same employee told the investigator that your firm stopped relabeling drugs in January, 2015. However, during the inspection, the investigator reviewed an exported drugs list that showed that your firm distributed drugs after January 2015 and into January 2016.
When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be adulterated under section 501(j) of the FD&C Act.
|2016||China||Baoying County Fukang Medical Applications Co., Ltd.||1. Your firm delayed, denied, or limited an inspection, or refused to permit the FDA inspection.
On June 6, 2016, during the inspectional walk through of the laboratory testing area of your facility, our investigator asked you to explain the microbiological testing processes used on the (b)(4) that you manufacture and distribute to the United States. Your firm’s representative stated he would not disclose the firm’s trade secrets. Our investigator explained that as part of the inspection, FDA needs to know the details of the operations, and that FDA does not disclose details of the information. Nonetheless, without reasonable explanation, the full test procedure was never provided.
Your firm limited the inspection by refusing to disclose the manufacturing process you use in your facility to conduct microbiological testing on (b)(4). You may wish to review FDA’s guidance document, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, at http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm360484.pdf
|2016||India||Pan Drugs Limited||Access to Information during Inspection
Your firm attempted to delay the start of the inspection, and some records we requested during the inspection were not provided.On November 30, 2015, our investigator observed your warehouse supervisor tearing out pages from your firm’s annual report and placing the pages into his pocket. Eventually, the supervisor provided the pages to our investigator.On December 1, 2015, our investigator requested printed chromatograms from you HPLC and GC. You failed to provide them.When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be adulterated under section 501(j) of the FD&C Act. We recommend that you review FDA’s guidance for industry, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf
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