DOCUMENTATION ISSUES IN PRODUCTION AND THE LABORATORY LEAD TO UNIMARK REMEDIES LTD RECEIVING A WARNING LETTER FOR API ADULTERATION

During March 18-21, 2014 the FDA inspected the pharmaceutical manufacturing facility, Unimark Remedies Ltd., located at 337 Kerala Nalsarovar Road, Kerala Village, Bavla, Ahmedabad District, India. The FDA identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).

These deviations caused the APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).  The investigator observed specific CGMP deviations during the inspection, including, but not limited to, the following.

1.    Failure to document production and analytical testing activities at the time they are performed.

During our inspection, we found that test results and other entries in the production records were not entered while batches were in production.  For example,The investigator observed (b)(4) batch (b)(4) production on March 18, 2014. The start and stop times and (b)(4) for Step #(b)(4) were not recorded or signed in the batch record contemporaneously.

COMMENT: 

As noted above, start and stop times were not recorded or signed at the time of performance. A number of other Indian manufacturing operations have also been cited for a failure to enter information in a timely manner.

For your (b)(4) products returned due to the presence of extraneous threads, the investigator found many inconsistencies in your reprocessing batch records.  Specifically, operators signed batch records for periods when they were not in your facility, indicating these activities were documented by personnel who did not perform them.  During the inspection, and in your written responses, your managers admitted that the batch records were created after the manufacturing process.

COMMENT: 

Several lots were returned because of the presence of extraneous threads. By operators signing batch records when they were not in the facility, they were falsifying data. Again, there exists a history of this within Indian facilities (Click Here).

Water testing records for sampling point (b)(4) on March 19, 2014, were incomplete. Specifically, the analyst did not record observations at the time they were made on March 18, 2014.  Your microbiology records did not identify who prepared the samples, when they began incubation, who read the samples, or when the samples were read.

According to your responses to these FDA 483 observations, your manufacturing staff did not exhibit acceptable documentation practices, and your chemist or microbiologist each neglected his work. However, your management is responsible for routine oversight of manufacturing and testing operations, including the activities of operators and other personnel, and your responses do not address the failure of management and the flaws in your overall quality system.

COMMENT:

The Company was found to have incomplete microbiological testing records for their water. Both the chemist and microbiologist neglected their work and did not follow acceptable documentation practices. Interestingly, not only were the analysts blamed for the problems, but also management since they remain responsible for the overall Quality system. Often one finds that the individuals within a Department are blamed for the unacceptable practice. However, in this case, management is sharing in this blame (Click Here).

In response to this letter, (1) conduct and provide the results of a comprehensive investigation into your poor documentation practices. Your investigation should (2) address the flaws in your quality systems and management oversight that led to these serious deficiencies. (3) Provide your plans to revise your procedures so that all CGMP operations are documented at the time they occur.  Also (4) provide your plans to revise your procedures so that you preserve original or true copies of data in the batch records.  Also (5) provide your procedures for addressing deviations from acceptable documentation practices, (6) including training and oversight of personnel whose duties require preparation and review of API records.

COMMENTS: 

The above paragraph represents a very good summary of areas management should supervise and manage if they find themselves in a similar situation. The highlighted numbers in the previous paragraph have been inserted by the author to draw attention to these pertinent issues. 

2.   Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

Your laboratory systems lacked access controls to prevent raw data from being deleted or altered.  For example:

a.    During the inspection, we noted that you had no unique usernames, passwords, or user access levels for analysts on multiple laboratory systems.  All laboratory employees were granted full privileges to the computer systems. They could delete or alter chromatograms, methods, integration parameters, and data acquisition date and time stamps. You used data generated by these unprotected and uncontrolled systems to evaluate API quality.

b.    Multiple instruments had no audit trail functions to record data changes.

COMMENT: 

A lack of usernames, passwords, or user access levels for analysts as well as full privileges to the computer systems allow each individual to behave as an administrator. This particular citation is not unusual and has occurred with Sandoz .

We acknowledge your commitment to take corrective actions and preventive actions to ensure that your laboratory instruments and systems are fully compliant by January 15, 2015. In response to this letter, provide a copy of your system qualification to demonstrate that your electronic data systems prevent deletion and alteration of electronic data. Describe steps you will take (e.g., installing better systems or software) if your qualification efforts determine that the current system infrastructure does not assure adequate data integrity. Explain the archival process your firm has implemented to address these issues and how you will evaluate the effectiveness of these corrections. Provide a detailed summary of the steps taken to train your personnel on the proper use of computerized systems.