MICRO LABS LIMITED, VERNA, INDIA RECEIVES WARNING LETTER (01/09/15)

The FDA inspected Micro Labs Limited, located at Plot No. S-155 to S-159, Phase III, Verna Industrial Estate, Verna, India, between May 5-10 and 12-13, 2014. 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, Parts 210 and 211. In September 2014, the FDA subsequently issued an Import Alert banning the shipment of all products from this firm into the United States. This Warning Letter is a follow-up to all of the previous activities between Micro Labs Limited and the FDA.

A series of four Observations were presented within the Warning Letter.  One of the most substantial Observations (#1) indicated that the firm:

“…firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a))”. 

The FDA’s inspection identified laboratory test records that Micro Labs did not review and evaluate in making batch release decisions.  These records contained uninvestigated, out of specification (OOS) data.  Your firm did not include the data described below when calculating test results that was used to release finished product. Your firm also failed to identify, investigate, and determine the significance of the OOS results discussed below until the FDA investigators identified the excluded records during our inspection.

Your response states that you have initiated investigations into such extra data, together with data integrity audits. The FDA note that your response does not address the testing you have performed on active pharmaceutical ingredients, in-process goods, and validation samples tested by your QC laboratories.  In addition, your response does not include a complete review of all “trial” data (including samples and standards) generated by your firm to ensure that all of the OOS results have been identified and investigated.  As part of your response discussed below under “Summary,” please include the results of such a review, including steps taken to fully understand the scope and significance of this practice.

Observation #2 stated:

Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). 

“FDA investigators discovered a lack of basic laboratory controls to prevent changes to electronically stored data. The following examples show that you (Micro Labs) lack effective control of the integrity of instrument output data:

1. a)    The ten Shimadzu HPLC instruments in the QC “commercial” laboratory were configured to send acquired injection data to PCs without audit trails.
2. b)    There was a lack of controls to prevent substitution or overwriting of data. The (b)(4) audit trail dated January 6, 2014, for HPLC MLG/QC/12/026 and the (b)(4) audit trail dated January 15, 2014, for HPLCs MLG/QC/12/031 and MLG/QC/12/027 each showed sample injections marked with the same small graphic symbol.  For each of these entries, you replaced the original injection sequence data with data from a single manual injection and failed to save the original sequence data.”

COMMENT 

Audit trails represent a very basic element of Good Manufacturing Practice (GMP). 21 CFR Part 11 speaks to the issue of being able within the laboratory to track all data. Forwarding data to PCs without audit trails suggests a deliberate manipulation and ability to falsify data.  

In addition, the substitution or overwriting of data with data from manual injections and the failure to save the original sequence again suggests data falsification.

3. Your firm failed to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).  

According to your management, a new standard operating procedure (SOP) was approved in February 2014, in order to eliminate your “trial” sample injection practices. However, during our inspection, we observed that your analysts continued these “trial” injection practices after the approval of your new SOP, and that your quality system and your management failed to detect and correct these deviations from the new procedure (see, e.g., Example 1(a)(5) above).

COMMENT

When new Standard Operating Procedures (SOPs) are implemented, aside from providing training on the SOPs, management needs to assure that the users are following the amended SOPs.  To have the FDA become the Quality Unit and find that the analysts continued to use “trial” injections, strongly suggests that the Micro Labs need to determine the capabilities of that Quality Unit and what kinds of management and oversight skills be implemented.