MERCK KGaA RECEIVES WARNING LETTER (12/15/11)
FDA INCLUDES THREE EUROPEAN FACILITIES TO INCLUDE MERCK SERONO S.A., AUBONNE, SWITZERLAND WITH MEDIA FILL ISSUES
The FDA released on Wednesday, February 17, 2012 a Warning Letter that was sent to Merck KGaA on December 15, 2011. Within the Warning Letter the FDA advised Merck KGaA management of deficiencies at three separate facilities, two in Switzerland and one in Rome, Italy. The focus of this Blog is upon Merck Serono S.A., Aubonne, Switzerland and referenced as MS-Aubonne. While each of the other sites had two Warning Letter Observations, MS-Aubonne incurred a total of five. Emphasis is being placed on the first of the five.
MS-Aubonne
1. Your firm has not established or followed appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile [21 C.F.R. § 211.113 (b)].
COMMENT
21CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” In addition, FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION, A. Process Simulations, 1. Study Design states that “Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments)” and lyophilization, when applicable be used to include the “requisite manual interventions.
For example, the media fill program does not include all major contamination risk factors in your aseptic process and consequently does not sufficiently demonstrate the state of process control. There is no assurance that your media fill studies are sufficient to establish that the aseptic process is in control. Specifically, your current media fill procedure is deficient in that:
a. Not all personnel involved in the aseptic manufacturing and filling of sterile drug products have participated in a media fill. Please note that media fill is a critical evaluation of the process uses ability of aseptic processing personnel to perform aseptic interventions, and their participation is essential.
Comment
Each individual participating in aseptic manufacturing and filling should participate in at least one of three media fills required for a validation.
b. Your firm lacks records to establish that aseptic processing personnel performed interventions that are representative of the operation.
For example, during the inspection, the investigator noted that your firm’s media fill, conducted February 24, 2011 on Line, (b)(4) failed to require performance of interventions, document these interventions, or document when the individuals performing aseptic processing operations entered and exited the room.
Comment
Interventions to include their documentation should be noted as being performed. While each individual is not required to perform each intervention, all required interventions should nevertheless be performed to assure that all are completed. In addition, documenting when personnel performing aseptic processing operations both enter and leave the ISO Class 5 environment is essential to assure that all required monitoring is achieved, to assure that the consequences (total number of personnel within the clean room) is known and to demonstrate that the gowning performs as intended.
Your response indicates corrective actions by November 2011 including training and revision of standard operating procedures (SOPs) to include specific instructions for operations in the aseptic areas. Your response was inadequate because it did not address the following issues:
- major interventions
- instituting (b)(4) plate monitoring of the aseptic line personnel who participate in a media fill
- total number of personnel and their activities (only three technicians were mentioned)
- a risk assessment for previously manufactured products
- an interim plan for manufacturing on an appropriately qualified line
Extraido do blog http://barryafriedmanphdllc.wordpress.com/2012/03/03/merck-kgaa-receives-warning-letter-121511/
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