Over the course of 2015, nearly a third of the warning letters issued by the FDA’s Center for Drug Evaluation and Research (CDER) were tied to violations of safe manufacturing practices in India-based facilities. Charged with ensuring drug safety, CDER sent a total of 12 manufacturing-related warnings to 11 different companies with facilities located in India.
While the violations differed in specifics, some themes emerged across the letters. Many of the manufacturing facilities struggled to maintain proper documentation of testing and sample data. Relatedly, at least nine facilities did not have appropriate controls in place to ensure electronic records and data were not manipulated. Others fell short in following up on out-of-specification results or complaints.
The range and contents of these letters tie into broader concerns over the quality of drug manufacturing in India. As the FDA’s Deputy Commissioner for Global Regulatory Operations and Policy, Howard Sklamberg, wrote in a March, 2015 blog post: “It’s no secret there have been challenges associated with the quality of generic drugs coming out of some facilities in India.”
Letters sent to wide range of drug suppliers
Some of the largest drug suppliers in India, including Sun Pharma, Dr. Reddy’s, and Cadila, were flagged for issues ranging from mishandling of key trial data to unsanitary conditions. CDER also reported violations at the Indian facilities of other global drug manufacturers like Novarti’s Sandoz unit or Canada-based Apotex. The Indian firm Cadila received two warnings over the course of the year related to issues in two different locations.
CDER typically issues the warning letters only to firms with manufacturing facilities located abroad. In 2015, it sent 38 such letters. A variety of violations can trigger a letter from CDER, such as failure to pay drug and facilities application fees, or shipping unapproved new drugs. In looking at the letters sent in 2015, BioPharma Dive focused on violations related to the breach of current good manufacturing practices (CGMP), the FDA’s primary standard for assuring up-to-date and safe manufacturing processes.
No controls over electronic records, improper documentation
A common thread among the violations committed by many of these facilities was a lack of sufficient controls placed on computer systems to prevent the alteration or deletion of electronic records. Nine letters concerning eight different firms noted violations tied to either non-existent electronic audit trails or improper user authorizations.
At facilities run by Dr. Reddy’s, Unimark Remedies, and Mahendra Chemicals, no usernames or passwords were required to gain access to some laboratory systems.
A letter to Dr. Reddy’s from November 2015 noted “anyone who accesses the system can use software administrator privileges, which means that there is no electronic or procedural control to prevent manipulation of data.” Nor was this a hypothetical concern. An analyst told an inspector that an unknown individual had logged on with the analyst’s credentials and performed injections and deletions without that analyst’s knowledge. Failure to implement this basic level of security leaves data and records open to manipulation, with no way of identifying the party involved.
Inspections at other facilities, including the most recent incident involving Cadila, found the audit controls used to track entries and changes either nonexistent or turned off.
Physical records also mishandled
The negligence presented in the letters also extended to the handling of physical data and records. At the Ahmedabad facility of Mahendra Chemical, lab operators used unbound, loose notepaper to record “critical manufacturing data.” After transcribing the notes, operators destroyed the originals. The technical director of the facility also signed off on and backdated reviews of batch records despite not being present on those dates.
At one of Cadila’s plants, a plastic bag was found in the scrapyard containing notebooks of deficiencies recorded during a review of batch records. A follow-up investigation by the manufacturer was inadequate as it “did not include a comprehensive review of all records in the waste area or a thorough review of your firm’s practice of destroying CGMP records.”
Firms failing to follow up on complaints, OOS results
Sun Pharmaceuticals, Dr. Reddy’s, Cadila, and Sipra Labs were all flagged by the FDA for a failure to follow up on “unexplained discrepancies or failure of a batch or any of its of its components to meet any of its specifications.”
The letter sent to Sun described an out-of-specification (OOS) report documenting impurities found in a six-month stability test for an injection manufactured for Europe and the U.S. However, Sun did not identify the cause of identity of the impurities, nor did it include batches sent to the U.S. in its investigation. The FDA also made sure to point out Sun neglected to inform the FDA of this incident.
Five 2014 OOS reports prepared by Cadila related to the potency and uniformity of warfarin sodium tablets did not name a cause or describe corrective actions. Cadila told the FDA it would suspend manufacture of the tablets in September, 2014 and then resumed production two months later.
However, in June 2015, Cadila informed the FDA more lots of warfarin tablets had failed. The FDA slammed Cadila in the subsequent warning letter saying, “These persistent failures indicate that your manufacturing process is not in a state of control. Nevertheless, at this time, drugs from this facility are being released to the market.”
Heightened concerns over manufacturing quality
On top of these warning letters, concerns have mounted over the quality of drug manufacturing in India and China. Combined, the two countries produce roughly 80% of the active pharmaceutical ingredients in the world’s drugs. However, the FDA’s resources to inspect the hundreds of sites involved are stretched very thin. Bloomberg reports there are only 2 inspectors for 700 Chinese facilities, while three are located in India full time.
In part citing these figures, the U.S. House Energy and Commerce Committee in December, 2015 requested the Government Accountability Office assess the capability of the FDA to properly inspect foreign manufacturing facilities. Separately, the European Medicines Agency last year banned the importation of 700 drugs from India, which led to a broader trade spat between Europe and India.
For the FDA’s part, Deputy Commissioner Sklamberg notes the agency can’t solve all these issues only through inspections. Rather, firms’ “quality culture” has to improve. It will be worth keeping an eye on new reports of violations as 2016 unfolds.