Inspections, Compliance, Enforcement, and Criminal Investigations
Marck Biosciences Ltd. 7/8/14
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring, MD 20993|
RETURN RECEIPT REQUESTED
RETURN RECEIPT REQUESTED
July 8, 2014
Mr. Bhavesh Patel
Mr. Bhavesh Patel
Marck Biosciences Limited
Plot No. 876, N.H. – 8
Village Hariyala, Tal Matar
Kheda 387411, India
During our October 29-November 1, 2013 inspection of your pharmaceutical manufacturing facility, Marck Biosciences Ltd. located at Plot. No. 876, N.H. – 8, Village Hariyala, Tal Matar, Kheda, India, investigators from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. These violations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have conducted a detailed review of your firm’s response dated November 20, 2013, and note that it lacks sufficient corrective actions.
Our inspection revealed specific violations during the inspection, including, but not limited to, the following:
1. Your firm failed to prepare batch production and control records for each batch of drug product that include documentation of each significant step in the manufacture, processing, packaging, or holding of the batch (21 CFR 211.188(b)).
a. Our inspection revealed “unofficial” visual inspection records, signed by production personnel, with data that is different from the official batch records reviewed by your firm’s quality unit. In many of the cases reviewed, the unofficial records showed significantly more quality defects than the official batch records. For example, for (b)(4) injection ((b)(4)%), IP batch #(b)(4), the unofficial record completed by production personnel showed 200 units failing to meet specifications. Production personnel later completed the official batch record for this batch, showing only 18 units as having been rejected. During the inspection, your firm was unable to demonstrate that all units with quality defects were in fact rejected.
Your firm’s response states that, in many cases, your production personnel add extra units into the (b)(4) unit and lower the number of rejected units on the official paperwork to account for these extra units. This explanation is unacceptable for several reasons, including that this practice does not accurately represent the number of units with quality defects present in each batch in the official batch records, it obscures the number of rejected units in any given batch, and it misrepresents the number of units sterilized during each batch. Given that your unofficial and official records are discrepant, there is no assurance that your firm rejected all units that did not meet your acceptance criteria. Your firm’s response states that you have audited a random selection of 848 batch records and found a difference between unofficial and official records in 2.5% of instances. However, during the inspection, our investigators found discrepancies between official and unofficial records in 76 of 156 batches reviewed. Your response does not include an explanation as to the differences between your internal audit results and our inspectional findings.
In response to this letter, provide an updated assessment of the extent of the differences between unofficial and official records used at your facility. Provide documentation showing whether you exceeded the maximum validated number of units in the (b)(4), and explain the significance of that unvalidated condition. Describe controls in place to prevent data manipulation by your operators and supervisors.
b. The inspection revealed your firm’s use of scratch paper containing critical manufacturing data. The data on these scratch paper records did not always match the data on the corresponding official batch records, as in the case for the amount of raw materials added to (b)(4) Suspension USP (b)(4)% Batch (b)(4). Although your firm stated that this batch was destroyed on October 18, 2013, the investigators observed that your records showed that the batch was removed from quarantine on October 25, 2013.
Your response to this finding does not explain why your production personnel used scratch paper for documenting CGMP-relevant data. In addition, the discrepancy between your destruction records and your quarantine records provide further evidence that your documentation is not accurate and reliable.
The use of unofficial and scratch paper records is not acceptable CGMP. In your response, provide assurance that the use of unofficial and scratch paper records has been discontinued and describe how your firm will prevent this practice in the future. Also describe your procedure to assure that all CGMP-related operations are documented at the time of occurrence.
c. Employees interviewed during the inspection admitted that your firm recorded activities in batch records that were not performed. Specifically, your head of production reported to our investigator that he completes “in process quality assurance check” fields in the batch record but does not actually perform the listed operations. In response to this letter, describe your investigation into this situation, outlining your efforts to determine the scope of data falsification within batch records and your corrective and preventive actions.
2. Your firm failed to maintain adequate written records of major equipment maintenance (21 CFR 211.182).
FDA investigators identified two maintenance logbooks that included multiple entries describing significant equipment malfunctions, but for which no investigation into the potential effect on product quality was performed. In addition, your records do not always include information on repairs following these malfunctions. For instance, no maintenance actions or product impact investigations were recorded for out-of-limit findings during equipment calibration. In other cases, your firm determined that there was no product impact without justification. In addition, we note that ten serialized entries had been torn out of the logbooks. Your staff could not locate these records during the inspection and reported to our investigator that the entries had likely been destroyed.
Your response does not address this issue in a comprehensive manner and instead only addresses the five entries specifically discussed on the Form FDA-483 issued at the close of the inspection. For these five entries, your response does not discuss your investigations into the potential impact on product quality. In addition, your response does not discuss any investigation into the missing records or address the root cause or extent of these deficient practices throughout your facility. In your response to this letter, include your plan for systemic improvements to be made to address these deficiencies.
3. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).
a. At the time of our inspection, your (b)(4) contract employees had not received any training on CGMP. These contract employees performed critical manufacturing operations, such as sterilizing operations. Your response states that general CGMP training would be given to contract employees, but you do not address why contractors were not trained prior to our inspection or the effect of this deficiency on product quality.
b. The inspection revealed that your firm falsified documents designed to demonstrate the effectiveness of CGMP training. Your production head admitted to pre-filling out the answers to post-training comprehension assessment questions and entering the names of employees on these documents. Your company policies require personnel to demonstrate understanding of training through evaluation.
That a senior manager was engaged in the falsification of documents is troubling and raises questions about validity of documents generated by your firm. Furthermore, your response to the FDA Form-483 is deficient in that it fails to address the root cause or the extent of the falsification of training documents. In response to this letter, provide this information and also indicate how your systems will be changed to address these fundamental issues. Provide a summary of your investigation into the training status of all employees participating in CGMP activities at your facility. As part of this overall training summary, include an update on the training of all contract employees. Also include your current curriculum for general CGMP training.
4. Your firm did not follow written procedures regarding storage and warehousing of drug products (21 CFR 211.142).
During the inspection, your firm was unable to locate approximately (b)(4) units of (b)(4) injection from Batch #(b)(4) that had been manufactured several weeks earlier. In a bound notebook that contained torn records, our investigators found a single intact record dated October 25, 2013, requesting the materials to package these units. Your firm’s personnel failed to produce packaging records for these units during the inspection. Both your staff members and our investigators carefully examined the entire warehouse in an attempt to locate the missing units, but the units were not found during the inspection. We have concerns that your firm may have released and distributed these units outside of the quality system. In response to this observation, you state that you found the missing units in (b)(4) boxes after the investigators left, in the same warehouse that they thoroughly checked during the inspection. However, you did not provide any photographic evidence of this discovery.
In response to this letter, provide evidence that these units were released by your quality unit prior to being distributed. Also describe any new procedures intended to achieve full accountability and control over all products in your facility, and describe any controls in place to prevent unauthorized product shipments. In addition, provide an explanation for the torn records found by the investigator, describe your document retention policies, and include details of any corrective and preventive measures you are implementing to address FDA’s discovery of these destroyed records.
5. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and keep them free of infestation by rodents, birds, insects, and other vermin (21 CFR 211.56(a)).
a. During the inspection, investigators noted significant mold growth in the washroom located at the entry to the sterile manufacturing area. The ceiling of this room had been allowed to deteriorate to such an extent that it caved in. This room shares a common mezzanine with the adjacent sterile processing rooms.
Your response does not identify any efforts to identify the mold growth or relate it to environmental monitoring data from the neighboring sterile suite, nor does it discuss the potential effect on the microbial quality of products made in your facility. Your response also does not discuss why this deterioration was permitted by your management until our inspection of the facility. In response to this letter, describe your investigation into the extent of mold within your facility, including within your HVAC system. Describe any additional findings of mold, corrective measures, and your investigation into the effect of any findings on product quality.
We note that a recent MHRA report of a December 2013 audit conducted at your facility discussed the findings of fungus growth within a large volume parenteral product manufactured at your facility. Please provide a full accounting of this incident and a copy of your investigation into the matter, along with corrective and preventive actions taken.
b. The investigators noted numerous dead insects in the “Sample Pass Through” Room, located approximately (b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility. In addition, dead and decaying frogs were found next to the product exit dock. Your response states that these pest infestation issues would be corrected. It also includes a commitment to remove the manufacturing waste near the entrance to the facility and to fill in the swamp-like perimeter that appeared to be serving as a harborage for vermin. Your response does not address why the observed conditions were permitted to exist in and around the manufacturing facility. In response to this letter, discuss this issue and provide details of your pest prevention program.
6. Your firm failed to exercise strict control over labeling issued for use in drug product labeling operations (21 CFR 211.125(a)).
Our investigators found numerous loose and uncontrolled labels for multiple products in the open office area adjacent to the packaging lines. Unused labels were not stored in a manner to prevent mix-ups or mislabeling.
Your response to this observation does not include any explanation as to why your firm allowed unused labels to remain in the production area, and lacks adequate explanation of whether this deviation has affected any production lots and led to mislabeling deviations or complaints regarding in-date marketed products.
You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each manufacturing run. These records should be properly identified to demonstrate that each released batch was manufactured appropriately, tested, and found to meet release specifications. Appropriate record retention policies should also be in place. Our inspection discovered that your firm could not provide basic records for your products.
When destruction of documents is appropriate, you should follow a document destruction procedure that ensures documents are destroyed in a controlled manner. This would include, at a minimum, identification of the appropriate documents and retention timelines, documentation of what was destroyed, and the names and signatures of those who witnessed the destruction.
Please provide your corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity. This plan should include the corrective actions implemented to ensure that all managers, supervisors, and quality unit personnel are properly trained in ensuring data integrity and detecting data manipulation. The investigation undertaken in response to FDA’s inspection should provide detailed descriptions of other incidents where your quality unit failed to ensure proper manufacturing or testing of materials and include a retrospective review of all manufacturing and testing records generated by your firm’s personnel. If other instances of missing, inaccurate, or unreliable data are found, your investigation should assess the effect of these discrepancies on the quality of the drug products manufactured at your facility.
We expect that you hire a third party auditor, with experience in detecting data integrity problems, to assist you with this evaluation and assist with your overall compliance with CGMP. It is your responsibility to ensure that data generated during operations is accurate and that the results reported are a true representation of the quality of your drug products.
Your data integrity expert should:
1. Identify all instances in which unofficial and scratch paper records have been used in your manufacturing and laboratory facilities and assess the possibility of misrepresentation of data on official records in each case.
2. Interview current and former employees to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting in CGMP records.
3. Identify the specific managers in place who participated in, facilitated, encouraged, or failed to stop subordinates from falsifying data in CGMP records, and determine the extent of top and middle management’s involvement in or awareness of data manipulation.
4. Determine whether any managers identified in item (3) above are still in a position to influence data integrity with respect to CGMP requirements or the submission of applications to FDA.
5. Audit past distribution practices and complete a detailed accounting of the distribution of all batches of product manufactured within the past two years to determine under what circumstances batches were distributed prior to release by the Quality Unit.
6. Perform a comprehensive data integrity audit of all data submitted to FDA supporting drug applications and describe any discrepancies between data or information submitted to FDA and any “unofficial” accounting of actual data or practices onsite. This audit should include both manufacturing data and laboratory data, including data used in process validation studies and analytical method validation studies.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at firstname.lastname@example.org so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA continuing to refuse admission of articles manufactured at Marck Biosciences in Kheda, India, into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may be subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. In addition, if you no longer manufacture or distribute the drug products at issue, provide the dates and reasons you ceased production. Please identify your response with FEI # 3006257565.
Please send your reply to: Mary E. Farbman, Ph.D., Compliance Officer; White Oak Building 51 Room 4234; 10903 New Hampshire Avenue; Silver Spring, MD 20993-0002.
Thomas J. Cosgrove, J.D.
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research