CADILA (ZYFINE) RECEIVES SIGNIFICANT CGMP VIOLATIONS TO
INCLUDE RECORDING OF MICROBIOLOGICAL PLATES AS “NIL”
1. Your firm’s laboratory records fail to include complete data derived from all tests
necessary to assure compliance with established specifications and standards
[21 C.F.R. § 211.194].
For example,
a. Your microbiologists reported the MA 5 and MA 6 microbiological plates as “nil”
while each plate contained one (1) colony forming unit (CFU). On January 21, 2011, the FDA investigator observed the microbiological plates, MA 5 and MA 6, from air sampling locations in the Class 100/Grade A laminar air flow cabinet in the Microbiology Lab. Each microbiological plate contained one (1) CFU/m3. Your microbiologists reported these microbiological plates as “nil” on your form FM/QC/252-9 Quality Control Department Record of Environmental Monitoring of Microbiology Laboratory. However, the action limit for these sample locations is 1 CFU/m3 which requires an investigation per your procedure SOP/QC/049 entitled Environment Monitoring of Aseptic Area by Settle Plate, Air Sampling, Surface Sampling (RODAC Plate) and Personnel Hygiene for Viable
Count. The results as originally reported on your form FM/QC/252-9 would not have prompted an investigation.
Comment
Both the FDA’s Aseptic Processing Guidance from September 2004 and the EMA’s Annex 1, Revised, allow only one Colony Forming Unit (CFU) when using either Active Air Sampling or Settling Plates within an ISO Class 5 environment. To respond to the finding of a single CFU as “nil” should minimally require a Deviation and, in most cases, would create a CAPA.
b. The microbiological growth found on settle plate MS 4 was incorrectly
identified and reported as a typical microorganism when compared against your
firm’s library/photographs of typical environmental flora.
Your microbiologists identified the growth on the MS 4 plate as typical flora. However, the FDA investigator found that when compared with your normal environmental flora, the growth should have been reported as atypical since the microorganism identified is not
included in firm’s library/photographs of typical environmental flora.
Your written procedure SOP QC/049 requires further identification of microbial
growth not included in your firm’s library/photographs. The results
originally reported on your form FM/QC/252-9 (typical flora) would not have
prompted further identification.
Your response recognized that the microbiologists should have classified the MS 4 microorganism as atypical. Moreover, your response indicated that an investigation was
performed and microbiologists were retrained. You stated that as part of
your corrective actions two microbiologists will observe counts for three
months to “rule out any possibility of erroneous reporting.” However,
during the inspection, the FDA investigator observed two microbiologists
reading plates and recording data. Therefore, your corrective action plan
does not adequately address the observation, nor does it appear to improve on
current practices for reading plates and recording data. Additionally,
the revised form used to document the microbiologist observation lacks
appropriate identification of the microbiologist performing the task at the
time of the final reading of the plates.
Comment
Microorganisms should be identified correctly – especially
when they have been obtained from a Laminar Air Flow Hood. This requires that they be identified to both genus and species by the most accurate identification method possible, i.e., DNA Sequencing. To then indicate in a response “that as part of your corrective actions, two microbiologists will observe counts for three months to rule out any possibility of erroneous reporting” and then finding two microbiologists reading their own plates, rather than jointly reading plates, the FDA did not believe this to be an
improvement over the current practice observed. The FDA also found that the form used did not adequately identify the microbiologist performing the task.
You are responsible for the accuracy and integrity of the data generated by your firm. We are concerned that trained microbiologists employed by your firm were unable to accurately identify microbial growth on environmental monitoring plates. Additionally,
there is no assurance that such errors have not occurred previously (during the
manufacture of exhibit batches for application products pending with FDA). Provide a more comprehensive corrective action plan to ensure the integrity of all data used to assess the quality and purity of all drugs manufactured at your facility, including any registration lots.
Accurate and reliable microbiological data is essential to support the aseptic processing operations used during the manufacturing of sterile finished drug products intended for
distribution in the United States. Your response includes retraining documentation related to identifying environmental isolates as typical/atypical and observation of microbial growth, as well as retraining on SOP QC/049. According to information provided to the FDA investigators during the inspection, the Microbiology Laboratory is staffed by (b)(4) microbiologists. The training attendance sheets in your response do not
include the same individuals. For example, 10 QC personnel attended the
training on observation and counting of colonies on environmental monitoring
plates held on January 22, 2011; and, only 8 QC personnel attended the training
on identifying typical/atypical environmental isolates during environmental
monitoring plate observation. Explain this discrepancy and provide
documentation confirming that all employees have been retrained.
Additionally, provide documentation of specific training offered to all
employees regarding the importance of following CGMP, and ensuring that they
accurately report all required tests.
Comment
Training is often provided as a mode by which a Company that has been audited by the FDA states that they will become in compliance. In the case of this Client, they provided
information to the FDA following the receipt of their Form FDA 483 that they
have provided such training. However, as the FDA indicated above, the attendance sheets provided in the response differ between two sessions held to assure that the microbiologists at Zyfine had the required training. The FDA is seeking
additional information on this discrepancy. Issues of this type have surfaced at other Indian firms to include Ranbaxy.
2. Your firm has not established or followed appropriate written procedures designed to
prevent microbiological contamination of drug products purporting to be sterile
[21 C.F.R. §211.113(b)].
For example,
a. Your firm’s environmental monitoring is inadequate in relation to personnel
monitoring.
Our investigators found that gowns worn by operators working in the aseptic processing areas are only monitored (b)(4) per week. Additionally, gloves are only monitored at the (b)(4) the shift. We are concerned with the fact that operators performing
critical operations may not be adequately monitored. Therefore, there is
no assurance that your environmental monitoring program is capable of detecting
all microbiological contaminants.
Since personnel can significantly affect the quality of the environment, a robust personnel monitoring program should be in place in order to be compliant with CGMPs. Your response indicates that SOP/QC/049 was revised to require additional monitoring of
gloves after (b)(4) for personnel involved in aseptic connections on filling line and filtration activities apart from regular monitoring at the (b)(4) of the shift. It is your responsibility to ensure that all personnel involved in aseptic processing are properly monitored on a daily basis, or in association with each lot. We acknowledge that SOP/QC/049 has now been revised to require sampling of gowns per (b)(4)/per (b)(4).
Comment
Observation 2 (a) suggests that the Client did not fully understand the purpose for the monitoring of gloves for microorganisms – especially those involved in aseptic connections. Alcohol may be used to remove and kill vegetative cells when used on these gloves; however, this testing should also be used to determine the presence of spore forming microorganisms which may not be killed and require other environmental and use of glove methods to minimize any contamination.
b. The technician performing the air sampling held the probe close to the HEPA filter
face rather than (b)(4) as specified in section 4.5 of your written
procedure SOP/QC/049.
During the inspection, the investigators were provided with retraining records for technicians performing active air sampling.
Your responses and corrective actions related to items 2a and 2b of this letter failed to indicate the disposition of exhibit batches that were manufactured during the time when
personnel and air sampling monitoring was inadequate. Provide information
on the disposition of these batches.
Comment
The issue of air sampling with the probe suggested that the personnel were not following established SOPs at the site.
More importantly, the response to the FDA failed to indicate the disposition of exhibit batches manufactured during that period when personnel and air sampling monitoring was inadequate. When responding to an Observation, the Client cannot isolate the event, but must review what has occurred with the lot in question as well as batches previously made and distributed or being held in in-process inventory. Using a “silo” mentality will only create additional issues with the FDA.
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