PAN DRUGS LTD, INDIA, RECEIVES WARNING LETTER (090215) FOLLOWING THE RECEIPT OF AN IMPORT ALERT

An inspection of Pan Drugs LTD, Gujarat, India from July 14-18, 2014 lead to serious deviations that caused their APIs to be adulterated 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.

COMMENT:

Pan Drugs was placed on Import Alert by the FDA earlier in 2015.  Whenever a Company is placed on an “Alert” such as this, there is a very high probability that the Company will be receiving a Warning Letter in several months.  In this situation, the Company indicated (see below) that “we have decided to divert the referred batches” to the domestic (India) market. It should, however be noted, that the Indian government, in response to popular criticism, has begun to crack down on companies that historically have diverted APIs or final product to their own markets because of what foreign regulatory agencies have deemed to be “adulterated”. 

CGMP Violations

During the investigation, the following cGMP violations were noted.

1. Failure to properly maintain, repair, and keep clean buildings used in the manufacture of APIs in a manner that prevents contamination where open equipment is used. For example,

1. a)    Our investigator observed holes in the walls and roof which allowed pigeons access near production equipment in multiple manufacturing areas.

1. b)    Gaps and holes in outside walls for piping and air ducts which allow contaminants to enter the building.

2. Failure to properly maintain equipment used in the manufacture of APIs and minimize the risk of contamination, where open equipment is used. For example,

1. a)    Our investigator observed rust, dirt, lubrication leaks, and exposed insulation material on and around open drug manufacturing equipment.

We note that you continued to manufacture product intended for the U.S. market even after you recognized that your facility and equipment were in disrepair and not compliant with CGMP requirements.  Your June 6, 2014, change control (CC14/001) stated, “Warehouse and Facility to be upgraded to achieve GMP standards.”  However, in July 2014, you manufactured (b)(4) API batches (b)(4).

In your response, you state, “we have decided to divert the referred batches” to the domestic (India) market.

We acknowledge that you ceased manufacturing operations, on July 12, 2014, upon notice of FDA to inspect your facility. We also acknowledge that you have committed to complete various repair and renovation activities within 60 to 90 days, with the intention to assure a suitable facility.  However, your facility was also under renovation during the previous FDA inspection in May 2011, when you made similar statements about ongoing renovations.

In response to this violation, provide photographic evidence that you have fulfilled your commitment to fully renovate the facility, and demonstrate that the entire facility meets CGMP requirements.  Your response should also include your plan to ensure your facility and equipment will be proactively maintained in such a way that your product is continually manufactured under CGMP conditions.

COMMENT: 

Issues observed within Observations 1 and 2 listed above represent basic issues within 21 CFR 210/211 and areas that even the least season regulatory investigator should perceive when performing an audit.  In 2011 and again prior to the FDA’s visit in 2014, Pan Drugs shut down their facilities – purporting for the purpose of fixing the problems that were twice observed.  The FDA determined that they would not lift the Import Alert unitl the firm could provide photographic evidence that they have fulfilled their commitment to fully renovate the facility, and demonstrate that the entire facility meets cGMP requirements.  The FDA also wanted Pan to provide a plan to ensure that the facility with its equipment will be proactively maintained and that the APIs would be produced under cGMP conditions.

3. Failure to maintain complete data derived from all testing and to ensure conformance with established specifications and standards.

For (b)(4) USP, lot number (b)(4), manufactured in June of 2012, the “ANALYTICAL TESTING PROTOCOL” used to record the results of testing contained fillable sections for heavy metals analysis, residual solvent analysis, the names of analysts performing those tests, and the names of a second person to review the results. The document provided to the investigator for the lot indicated that:

1. No heavy metals analysis was performed
2. The name of the analyst who performed the residual solvents analysis was not included
3. No second person reviewed the documents for accuracy, completeness, and compliance with established standards

In your response, you provided subsequent test results on lot number (b)(4), and stated that you are retraining personnel involved in analytical testing. You also stated that you “will check all analytical records till current batch and take corrective action for all such types of oversight errors.”  Your response failed to specify whether any lots were released that lacked complete analytical testing information, either because the test was not performed or the data was not recorded. You also did not indicate if any lot was released without a secondary review of results to ensure compliance with established standards.

Until we receive adequate confirmation that you have made global corrections, we will not schedule a follow-up FDA inspection and your firm will remain on Import Alert 66-40.

COMMENT: 

The FDA advised that Pan Drugs “failed to specify whether any lots were released that lacked complete analytical testing information, either because the test was not performed or the data was not recorded. You also did not indicate if any lot was released without a secondary review of results to ensure compliance with established standards.”  The FDA has often cited other firms and Indian firms, in particular, where “oversight errors” were deemed not to be errors, but fraud on the part of those drug companies.  There have been a number of cases, especially within India, where the FDA, through their investigations, have found the various companies to be knowingly not following their SOPs.