WARNING LETTER FEBRUARY 9, 2011
SANOFI AVENTIS DEUTSCHLAND GmbH (Part 2)
2. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R. § 211.42(c)]. For example,
a) The airflow velocity inside critical areas of the aseptic processing operations of Line (b)(4) was found unacceptable by FDA. The documentary evidence of in-situ air pattern analysis (e.g., smoke studies) reviewed during the inspection confirmed this condition.
With respect to aseptic processing in critical areas, you should be able to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Please note that proper design and control prevents turbulence and stagnant air in the critical areas. It is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination, and that any deficient conditions are addressed.
b) Your environmental monitoring program does not give assurance that environmental contaminants are reliably detected. Your practice of collecting samples from the gloves of operators, from left and right hands on alternate days is unacceptable. In addition, your SOP fails to include instructions for the location and duration of samples collected in the critical aseptic processing areas.
An adequate environmental monitoring program should be established by your firm. It should capture meaningful data and act as an early warning system to detect possible environmental contaminants that may impact the sterility of drug products manufactured at your facility that purport to be sterile.
Gloves from both hands should be sampled at the same time to provide a representative result. Personnel because of being left or right handed may favor the use of that hand and demonstrate a count on one day and none on the next because of this selective monitoring. Samples from the gloves should also be obtained on a periodic basis during aseptic processing as defined within the SOP and as the individuals are leaving the aseptic environment. Upon leaving the ISO Class 5 area, other areas of the gown should also be sampled on an on-going basis as defined within the SOP.
An Environmental Monitoring program should be developed during the commissioning of the facility. Following the commissioning, acceptance criteria should be provided that discusses how the sampling may be decreased based on Risk Management. Alert and Action Levels as well as specifications should assist with this. All of these data should be captured within a 21 CFR Part 11 compliant system, e.g., Novatek. Several references to include the FDA Guidance for Industry re: Aseptic Processing (Sept 2004) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070342.pdf and the revised Annex 1 (2009) http://tern-quay.com/Orange_Guide/Annexs/EU-GMP-Vol4_Annex1.pdf exist and discuss allowable levels of microorganisms as a function of the ISO class.
3. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. [21 C.F.R. § 211.25(a)]. For example,
On September 6 and 9, 2010, operators involved in the cleaning operations and aseptic connections during filling, were observed demonstrating incorrect aseptic techniques to prevent product contamination. We expect that operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper aseptic techniques are utilized during all operations.
The FDA will often during their tour of the Client’s facilities observe various activities throughout the site to assure that SOPs are being observed and followed. Even if the activity meets CGMPs, it must also meet the SOP. One cannot coexist without the other. 21 C.F.R. §211.25(a) also states “Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.” Annual GMP training conducted once a year is often not sufficient to meet the needs of the employees. Training on a daily basis may be required to meet FDA expectations.