SISTER COMPANY OF NECC RECEIVES TWENTY PAGE 483 CONTAINING SEVERAL REPEAT OBSERVATIONS
COMMENT
The FDA conducted an inspection of Ameridose, LLC, Westborough, MA from October 10 through November 9, 2012. The investigation, involved fourteen Investigators and three microbiologists including one microbiologist from CDER. A total of fifteen Observations including several repeat Observations within this twenty page document denote a variety of issues to include sterility, sterility testing and microbial identifications. Several of the Observations along with Comments are listed below.
OBSERVATION 2
Each batch of drug product purporting to be sterile is not laboratory tested to determine conformance to such requirements.
“…Your firm does not test final units of finished product lots for sterility and the presence of bacterial endotoxin in finished sterile drug product lots after aseptic manual filling operations before release.” NOTE: This represents a repeat Observation to the FDA 483 issued on August 6, 2008.
COMMENT
Testing of “finished product lots for sterility” is required by USP<71>. Both sterility and endotoxin USP<85> testing should be part of each final lot release criteria.
OBSERVATION 3
There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. (NOTE: From 21CFR 211)
- Your firm failed to investigate microbiological contamination observed at least fifty three (53) times noted during (b)(4) sterility testing of sterile stock solutions intended to be used in the manufacture of sterile injectable drug products… In approximately eighteen (18) instances your firm retested the affected stock solutions and microbiological contamination was also observed in a least one of the retest samples.
2. There is no data to support your firm’s claims that all of the sterility failures were attributed to contamination during the performance of the (b)(4) sterility method.
- There is no documented evidence that your firm implemented permanent corrective actions to prevent these sterility events from recurring.
COMMENT
Retesting of stock solutions for sterility (see USP<71>) should not be performed unless there exist knowledge of a definite error in the testing protocol. If contamination is arising from the performance of the sterility testing, extensive training should occur to demonstrate the competency of the involved technicians.
- 3. Sterility test positive results were routinely considered questionable by the laboratory, and re-testing was done without justification. More specifically, when a positive result is obtained using the (b)(4) sterility testing method, your firm considers the initial positive to be an “inconclusive” or “suspect” result and performs re-testing. This is done although no laboratory cause of contamination has been identified. It is noteworthy that when further (b)(4) testing was done, the testing often revealed additional non-sterile units. This includes but not limited to all lots that are named in this observation.
COMMENT
Investigations to include deviations, Out of Specification and CAPAs should routinely occur prior to the performance of “re-testing”. As noted above, the finding of additional non-sterile units does not bode well for either aseptic conditions or the sterility of the final filled product.
- 4. Your firm did not adequately differentiate or subculture microbes found in sterility test positives. Both lots that failed sterility were assumed to be cocci based on observation under microscope. However, despite multiple findings of contaminated units, no attempts were made to subculture the bacteria and further differentiate the microbe to determine its identity (e.g., gram stain, use of the (b)(4) available in your microbiology lab).
COMMENT
Several various FDA, USP and EP documents exist discussing the requirements for identification of microorganisms to the species level. These include the recently revised USP<1116> (May 2012) and Annex 1 (March 2009) as well as the FDA Guidance for Industry, Aseptic Processing (2004). Identification provides a “roadmap” and often a root cause to the source of contamination.
B. 5. Insufficient relevant EM/personnel monitoring data was available from the production operations to correlate possible contamination sources in the environment with microbes found in sterility test. Without knowledge of identity of microbes found during environmental monitoring, your firm lacked critical information to investigate possible root causes of the sterility failures.
COMMENT
Please view the previous comment.
- The Quality Unit failed to adequately investigate, and implement permanent corrective actions after 45 environmental microbiological excursions (bacterial and mold) were isolated from critical areas such as personnel fingers inside class 100 hoods and controlled manufacturing areas (surfaces and air) during the manufacture of sterile injectable drug products in 2012. There is no documented evidence that suggests that a health hazard evaluation was initiated nor conducted in order to assess the potential quality impact of isolates present during the manufacture of sterile drug products. Furthermore, your firm does not perform identification of the observed microbiological isolates.
COMMENT
A “health hazard” impact represents an excellent mode to help assess the root cause of microbiological contamination as well as the potential impact of any microorganisms present during sterile drug product manufacturing. This remains a difficult task if the various “bugs” present have not been identified.
The entire Form FDA 483 may be found at:
http://www.fda.gov/downloads/AboutFDA/CentersOffices/
OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/UCM327729.pdf
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