Dies haben wir zum Anlass genommen und die Warning Letters der letzten Jahre der FDA etwas genauer angeschaut. Die am häufigsten erwähnten Punkte haben wir Ihnen als Originalzitate nachfolgend aufgelistet:

• Dead legs were observed in the …system and there is no temperature control on the storage tank located outside of the building.
• Failure to ensure that equipment used in the manufacture, processing, packing or holding of drug products is of appropriate design, adequate size, and suitably located for its intended use [211.63]. For example, you have not validated the performance of manufacturing equipment, including a lack of installation qualification, operation qualification and performance qualification of your purified water system. Our investigator observed 4 dead legs associated with this water system.
• In addition, cross connections and dead legs were observed with the plumbing for the alfalfa soak tanks, the chlorinator for the spray, water holding tanks is not maintained, specifically, the filter was noted to be completely encrusted and the chlorinator was not working, mold was observed on shelves and walls in the alfalfa grow room, there is no pest control program in place, and product is packed and held under unshielded fluorescent lights.
• The plumbing system included defects that could contribute contamination to the drug product. For example:

• There were multiple significant design deficiencies such as dead legs of various lengths, throughout the WFI system.
• There were no piping and instrumental diagrams for the WFI or purified water system.
• WFI frequently fails conductivity due to system shut down.

• The purified water system was observed to have sagging lines and dead legs, is inadequately maintained, and use points are insufficiently tested and controlled.
• The following deviations relating to the watering point were observed during the inspection:

• No backflow preventer device on the water piping system.
• The potable water hose was not capped.
• There was an accumulation of dust on the floor of the potable water cabinet.

• Lack of any piping or instrument drawings of the deionized water or the recently modified water system for the purposes of system maintenance, monitoring and operation.

• There was insufficient data to demonstrate that the purified water system was capable of providing water which consistently met chemical and microbiological specifications. Critical attributes of the system and sampling and testing schedules were not outlined; daily sampling after each phase of the system was never conducted; and there were no written sampling procedures. In addition, grooved, flexible piping was used to transfer purified water from the DI beds to the holding tank. There was no data to show that this piping could be adequately sanitized.
• The recirculating loop description provided via diagram fails to document any temperature considerations or flow rates for the loop.
• Written procedures do not include passivation of the water system in the event that additional welding or modifications are performed.

• Water for Injection (WFI) is not sampled in the same manner as it is used in production

• The current Piping and Instrumentation Diagram for the equipment could never be located during the inspection. The piping configuration for the rinse Water for Injection (WFI) included a large dead leg due to the presence of an inverted filter housing which is not drained after use. Several valves and the sampling port were not physically labeled. In addition, several leaking valves and fittings were noted on the WFI piping. These valves were not part of the preventative maintenance program at the firm.
• Thermometers which are used to monitor the temperature of the WI system are not calibrated.

• Failure to ensure that equipment used in the manufacture, processing, packing, or holding of a drug product is of appropriate design and adequate size to facilitate operations for its intended use [21 CFR 211.63], in that the Water for Injection (WFI) system is inadequately designed. For example:

• sections of copper piping and flexible silicon tubing are not sloped in a fashion to facilitate adequate draining
• piping and equipment couplings used in the WFI system have threaded unions.

• Failure to adequately monitor, investigate and take action on utility design features and utility malfunctions which could have an adverse effect on the purity and quality of sterile or non-pyrogenic bulk pharmaceuticals. For example:

• Ball valves, which are not considered to be sanitary, were used in the connectors to attach hoses from the Low- Endotoxin Water System to the equipment used to manufacture Piperacillin Monohydrate.
• Incidents of failures of the resistivity meters, leaks and low pressure in the Low Endotoxin Water System were not investigated to determine their effect on the bacteriological quality of the water used for production of Piperacillin Monohydrate.

• Containers used to hold sterile water for injection (WFI) for final rinsing of vials are not sterilized or monitored for presence of microbes.

Im Rahmen des Seminars Rohrleitungen für Pharma-Wasser und Reindampf (PT 8), welches am 17./18. Februar 2004 in Marburg stattfindet, werden u.a. diese wichtigen Punkte und auch eine Vielzahl von Details zu diesem Thema diskutiert.

Am zweiten Seminartag haben Sie die Möglichkeit, an einer Besichtigung bei Dade Behring teilzunehmen.

Bei Dade Behring in Marburg wurden in den letzten Jahren GMP-gerechte Systeme für gereinigtes Wasser in Betrieb genommen. Besichtigt werden können verschiedene Erzeugungs- und Verteilungssysteme, wobei die Rohrleitungen sowohl im Werkstoff PVDF als auch in Edelstahl realisiert wurden.