LACK OF ENVIRONMENTAL MONITORING DURING 23 MONTHS ATTRACTS FDA ATTENTION
Approximately one year ago (March 12 – 20, 2012), the FDA audited the Novo Nordisk A/S facility located at Novo Alle, Bagsvaerd, Denmark. During the audit the FDA encountered significant deviations that lead to the following Warning Letter.
Observation 1 states that “your firm has not established or followed the appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR §211.113(b)].
- Approximately 846 environmental monitoring (EM) samples were not collected in the Class 100 (Grade A) and the Class 10,000 (Grade C) areas from March 2010 to February 2012 during the manufacture of sterile (b)(4) products.”
Novo Nordisk indicated in their response that several of the “missed” samples were actually ”samples for which the exposure time for the plate had been exceed or delayed, which suggests that you may have rejected or invalidated some results. Your response did not address why the ongoing actions implemented as early as December 2010 have not been effective at eliminating missed environmental monitoring samples”.
COMMENT
Observation 1 brings to the fore several elements to include 1) how were so many samples ignored, 2) what were the Quality personnel (Quality Assurance, Quality Control, Regulatory Compliance) doing to review the data on an ongoing basis, 3) how was product released without a complete batch record review, 4) were deviations being written, 5) if so, by whom, 6) when this number of deviations occur, why did they not become a CAPA, 7 ) why did internal audits not “catch” this issue, 8) were metrics not developed that tracked deviations on an ongoing basis, and 9) the Observation suggests a total breakdown of management control.
Further, since each released product requires a completed batch record – even though the environmental records need not be attached, a document to that effect must be a part of the completed batch record. Thus, the FDA’s question re: “how release of the products during this period was justified by your firm” is entirely valid. It appears that the Client may not have even been aware of the lack of sample testing until the investigators arrived. (Note date of FDA regulatory audit vs. time frame of non-collection.)
- Operators working inside the aseptic core during the manufacture of (b)(4) batches were observed wearing goggles that had not been adequately sterilized and had two openings on the top.
The FDA comments that the “goggles currently worn in the Class 100 area are not sterilized, but rather sanitized. Your disinfectant qualification document “Validation of in-use efficacy of (b)(4) of production surfaces” does not describe specific studies to demonstrate effective recovery of organisms from the goggles. The qualification study’s acceptance criteria following disinfection are <(b)(4) cfu/contact plate of Asepergillus brasiliensis and <(b)(4) cfu/contact plate for all other organisms. Our expectations is that gowning components, including goggles, be sterilized before use in an aseptic processing area. However, disinfection may be appropriate if your firm demonstrates full decontamination”
The investigators also noticed that the goggles used in the aseptic core were observed with two openings of approximately (b)(4) cm x (b)(4) cm. Your firm’s response indicated that you are evaluating a redesign of the goggles; however, your redesign does not appear to consider the use of goggles with more protective venting mechanism for operators working in the aseptic core.
COMMENT
The FDA, in today’s aseptic processing environment requires that all gowning materials used within an ISO Class 5 environment be sterile. Disinfectants to include sporicides do not provide the Sterility Assurance Level provided by steam or other terminal sterilization methods. To permit the presence of A. brasiliensis or other microorganisms suggests that the disinfectants currently in use in their facility are inadequate and minimally should be replaced by sporicides. However, with goggles available that do not contain openings in the top and that can be terminally sterilized, there exists no need to use any chemicals of any type. One would need to have an adequate steam sterilization cycle as well as a satisfactory number of pairs of goggles to satisfy each operator’s requirements.
- The environmental monitoring for non-viable particulates is performed a substantial distance away from the filling station on the aseptic fill line (b)(4).
“Your response indicates that the (b)(4) location is more critical than the filling needles for the non-viable particles monitoring. However, your response fails to provide scientific data and justification to support your conclusion.
In your response to this letter, provide a diagram describing the positioning of each non-viable particle monitoring probe on the filling line and a justification for each position. Please explain if the (b)(4) which you have deemed a critical position, will continue to be monitored in lieu of a position sufficiently closer to the point of fill.”
COMMENT
The FDA’s Guidance for Industry for Aseptic Processing (September 2004) discusses the need to perform non-viable airborne sampling in close proximity in three particular locations within an ISO 5 environment to include 1) close proximity to sterile open vials, 2) at filling needle station, and 3) where stoppers are being applied. A number of companies are now providing such equipment that is minimally invasive and can obtain data at a variety of micron sizes, be in the immediate vicinity of the area to be sampled, and at a frequency that will provide adequate data.
Additionally, ICH Q9 which discusses Risk Management, should be reviewed to assure that scientific data and regulatory risk are appropriate if the (b)(4) location is truly more “critical” than the filling needles
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