New ZLG-Aide Mémoire for the supervision of sterile manufacturers

The ZLG in Germany (Central Authority of the German Federal Länder for Health Protection Regarding Medicinal Products and Medical Devices) expert group 3 has published a new Aide Mémoire (AiM) recently that provides inspectors in Germany with a guideline for the GMP supervision of sterile manufacturers. It can be compared to the FDA "Guides to Inspection". The Aide Mémoire now available complements the AiM "Supervision of manufacturers of medicinal products" with specific requirements for the manufacturers of sterile/aseptically produced medicinal products. The division into chapters and numbering corresponds to the structure of Annex 1. The AiM is interesting also for pharmaceutical manufacturers as it gives information on the authorities' expectations in GMP inspections concerning the state of the art and on the areas in which questions have to be expected.

In many parts the AiM is much more detailed than the underlying Annex 1. This is especially remarkable in the chapter on the classification, qualification and re-qualification of clean rooms. Whereas Annex 1 only refers to the EN/ISO 14644 series (sheets 1-4) the AiM contains concrete requirements and instructions. For example, it lists the test parameters expected in a qualification:

  • Tightness and leakage in ventilation ducts 
  • Measurement of the high and low pressure in the clean room 
  • Determination of the number of air exchanges 
  • Leakage tests of the incorporated terminal filters 
  • Flow direction and flow velocity measurement in rooms with TMF 
  • Measurement of recovery times in rooms with LTF 
  • Determination of the clean room class 
  • Smoke studies for the visualization of the flow conditions  
  • Temperature 
  • Humidity

Even the points expected in the measurement report of the particle test are listed individually. The extent of testing for the re-qualification as well as the expected frequencies are also described. Basis is again the 14644 series (including the annex!) but also the PIC/S-document PI 032-2 which also interpretes the requirements of Annex 1 more closely.

Chapter 20 (Alert and action limits for particle and bacterial count) is another example. Annex 1 only talks about "appropriate limits". The AiM on the other hand gives concrete information for example on the standard deviation for particle measurement and it contains formulas for the limits of bacterial counts without normal distribution.

Another example is chapter 37 (Training). Here, Annex 1 only talks about a regular training in the correct manufacture of sterile medicinal products of the personnel employed in clean areas. The AiM however, is much more concrete and requires for personnel in Grade A and Grade B zones a triple successful entering of clean rooms under supervision including a microbiological monitoring of the personnel. Additionally it is expected that a re-qualification of the process of entering a clean room is carried out at least once a year.

Please see the (only in German language available) document "Überwachung von Steril-Herstellern" for further information.

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