Last week, the US Food and Drug Administration (FDA) placed Divi’s Labs Unit II, located in Visakhapatnam (in Andhra Pradesh, India), on its import alert list for “refusing FDA foreign establishment inspection” and also for “not meeting drug GMPs” (good manufacturing practices).
The news came as a surprise, as it added an additional dimension to the known news about the cGMP problems the FDA had encountered at Divi’s facilities.
FDAZilla.com shared the Form 483 issued to Divi’s Labs Unit II. This week, PharmaCompass shares the observations made by FDA investigators — Latorie S. Jones and Massoud Motamed — during their inspection from November 29 to December 6, 2016.
Concerns over Divi’s product quality
Unlike other sites where concerns in the quality control department have been related to disabled audit trails or deleted test results, at Divi’s the investigators uncovered an “extensive use of inhibit integration” and other anomalous integration techniques for assessing US APIs.
‘Inhibit integration’ is a capability to disable detection of certain peaks/compounds which in turn can drive more favorable results from the testing equipment. At Divi’s, the FDA investigators concluded that the technique was used to mask unknown impurities.
In addition, Divi’s product quality was questioned when a “known impurity was integrated as part of a desired peak and not considered in the calculation of total impurities.”
The FDA also uncovered that the last 30 batches of an API had displayed an ‘unknown peak’ that was integrated as part of the desired peak.
An unknown peak usually refers to an unknown impurity.
Impurity commingled with the
During the inspection, investigators observed colored residue commingled with the product. Divi's could not explain how the cross contamination of the colored residue with the API was avoided.
As Divi's had received complaints associated with abnormal colored/stained material along with dark particles in product supplied by the company, the observation by the investigators once again raised concerns over Divi’s product quality.
The FDA also noted that equipment deficiencies were observed throughout the inspection.
A failure to conduct investigations was also a cause of concern as Divi's had received a customer complaint related to product contamination. And, it could not determine the root cause of the problem.
Subsequent interoffice memorandums (IOMs) highlighted that the issue “has/could not be resolved” and the fact that Divi’s “failed to suggest removing product from the market or conducting a comprehensive assessment for detecting” the contamination was also highlighted by the investigators.
Divi’s chromatographic systems at R&D become a cause of concern
FDA also raised concerns over Divi’s use of the chromatographic systems in its R&D department. The chromatographic systems in Divi’s R&D did not have the audit trail functions enabled (a mandatory requirement these days to address concerns related to data-integrity) and were utilized for cGMP functions which included providing data to address Drug Master File (DMF) deficiencies and performing investigations.
The R&D division was found to guide the quality and production functions to commence cGMP activities. For example, when the product failed to meet specifications, R&D instructed onward processing.
In another example, when a sample generated an OOS (out of specification) and no laboratory error was evident, the Quality Assurance (QA) at Divi’s, in consultation with R&D, determined there should be a re-sampling and re-testing. Quality Control then followed R&D’s advice, and passing results were obtained and reported.
The investigators also found the product (drug) from production in the R&D area.
So how did Divi’s refuse the FDA inspection?
The FDA website states if there is “refusal to permit inspection of a foreign facility or provide reasonable access to FDA’s inspectional personnel, combined with other evidence,” this provides “an appearance that the firm’s products are manufactured, processed, or packed under insanitary conditions”. This way, the firm is considered to have refused the FDA inspection.
According to the Form 483, a 2014 IOM was falsified . The photocopy given to the investigators was inconsistent with the copy received during the inspection.
In addition, a customer complaint log was not accurate — a 2015 complaint from a customer about unknown solvents was not included and the incinerator at Divi’s contained several intact documents intermingled with other documents, including IOMs.
All these would have led to a failure by the FDA investigators to conduct a thorough inspection.
If Divi’s is on import alert, what will happen to Hetero Labs?
After the inspection at Divi’s, the same FDA investigators (Jones and Motamed), spent the next 10 days at the finished formulations facility of Hetero Labs Ltd, where they uncovered document shredding through a review of the CCTV camera footage.
At Hetero, a document shredder had been introduced into the firm’s document storage area around four days before the FDA inspection. The documents being shredded were of a color consistent with batch packaging records and batch manufacturing records.
In addition, data derived from the company’s programmable logic controller (PLC) for compression machines was found to be inconsistent with batch records and validation reports in support of applications to the FDA.
Like Divi’s, Hetero’s failure to remove defective product from the market was also cited as a concern.
Hetero Labs received a complaint as “one tablet in bottle was twice the thickness” of others, with the same markings and color as the other tablets.
The firm then conducted an investigation and confirmed this weight disparity, following which it concluded that if the patient inadvertently consumes the tablet (which was twice the thickness/weight), there would be “no impact” on the patient’s health or safety. The firm failed to remove the defective product from the market.
Deficiencies in the quality of equipment and utensils used at the site were also mentioned in the Form 483 issued as investigators found residue on equipment which was stated to have been “cleaned”. The product transfer lines were soiled and had a mold like appearance.
Unlike other companies where data-integrity violations are an outcome of disabled audit trails or deleted test results, at Hetero the audit trail was enabled and there was no mention of deleted results on the Quality Control’s high performance liquid chromatography (HPLC) system.
However, the FDA investigators did find over 400 occurrences of a user abort since September 23, 2016. Majority of these user aborts were during data acquisition. On further investigation, investigators uncovered that “a sub-set of these user abort events demonstrated a time gap between the last injection (analytical testing) and the user abort event.”
The concerns raised at these two major Indian pharmaceutical companies indicate a shifting focus on part of the FDA investigators — there is greater depth in the nature of their observations.
While inspections continue to depend on the investigator, FDAZilla’s database shows Motamed having inspected Interquim, CTX Life Sciences and Pan Drugs. And all these companies have received warning letters recently.
A recurring trend in all these warning letters have been concerns over the quality department’s decisions made to release API to the US market, the lack of depth in investigations as well as the quality of the equipment used to manufacture drugs.
While it remains to be seen whether Hetero will be next on an import alert or not, it is clear that organizations need to increase their focus beyond enabling audit trails in quality control equipment while preparing for FDA investigations.
Now, deviations and equipment quality can also become serious issues.
As far as Divi’s is concerned, with 10 APIs being exempt from the import alert and Divi’s expecting the impact on revenues to be less than 5 percent, it remains to be seen how quickly it can resolve the FDA’s concerns and get off the Import Alert List.