Smoke Study Findings Contribute to Mylan Laboratories Warning Letter (8/06/2015)

The following is the second Blog in an on-going series of Blogs obtained from a Warning Letter about Mylan Laboratories, Bangalore, India as well as other Mylan (Agila Specialties Private Ltd.) facilities in India. This second Blog continues the review of the Mylan facilities which were audited February 6-13, 2015 and are located at Plot No. 284-B (19A) Bommasandra Jigani Link Road, Ind. Area, Anekal Taluk, Bangalore, 560 105. 

Warning Letters that discuss “Smoke Studies” may be found in my Blog by clicking on Apotex,  and Hospira

OBSERVATION

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

You do not have a scientific rationale for the environmental monitoring sampling locations in aseptic filling Suites (b)(4). You did not include factors such as smoke study findings, number and location of operators, and historical microbial data in your assessment of hazardous points.

For example, we found that settling plates are not appropriately placed in critical areas. Your smoke study showed that during set-up and filling, air flows toward the front (when the (b)(4) is open) or back of the RABS. However, two relevant sampling points were recently eliminated. As a result, these points of increased risk are not monitored.

COMMENT 

ICH Q9 discusses in detail the necessity for “scientific rationale” and “risk management” whenever determining sampling points and their use within ISO Class 5 environments. The elimination of two “relevant sampling points” illustrates how the FDA’s client, Mylan Laboratories, did not understand this concept.

During our inspection, we noted that you have no justification for two different action levels for finger dab results. While you have an ISO 5 action level of (b)(4) CFU for set-up personnel, you use an ISO 6 action level of (b)(4) CFU for operators who do not routinely participate in aseptic processing operations using the RABS.

However, the inspection found that these “ISO 6 operators” made ISO 5 interventions, including within the (b)(4) laminar airflow hood (LAF) and the RABS. Notably, when >(b)(4) CFU was recovered from an “ISO 6 operator” who had accessed the RABS during an intervention, your firm did not consider the result to be outside the action limit.

COMMENT

Consistency in results is critical to ISO 5/6 operations. Using ISO 6 operators to make ISO 5 interventions requires operators to meet ISO 5 microbiological standards. Management also needs to understand this concept (click here) for FDA Guidance for Industry, Aseptic Processing, Sept 2004.

Detecting sources of contamination during aseptic processing operations is critical to safeguard product sterility. In response to our inspection, you followed a Product Quality Assessment (PQA) protocol and found visible foreign particulate matter within your examined lots. In March and April, 2015, you voluntarily recalled seven “for Injection” lots of Gemcitabine 200 mg/vial, Gemcitabine 2g, Gemcitabine 1 g, Carboplatin 10 mg/mL, Methotrexate 25 mg/mL, and Cytarabine 20 mg/mL. In June, 2015, you expanded your recall to an additional eight lots of Gemcitabine and Methotrexate. However, other lots released into distribution may have been compromised by this manufacturing issue.

In response to this letter, send a progress report on your search for the root cause of this particulate contamination problem.  Describe your product quality assessment protocol, including analysis of retain samples, corrective actions and preventive actions, and risk assessments to evaluate the product quality effects of your inadequate aseptic processing activities and inadequate environmental monitoring program.

COMMENT

21 CFR 211.192 discusses issues with recalling lots as well as quarantining lots which remain within the facility. This Observation (192) specifically “shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy”. While the FDA did not specifically mention 21 CFR 211.192, the terminology within the Warning Letter clearly implies a lack of understanding of this section of the CFR.