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New draft guideline on the sterilization with regards to the manufacturing of Medicinal Products, APIs, Excipients and Primary Containers released by EMA

EMA has released a new draft guideline entitled "Guideline on the sterilization of the medicinal product, active substance, excipient and primary container" which contains clear provisions with regard to the acceptance of alternative sterilization processes by the European authorization authorities. The document describes the requirements on sterilization of medicinal products, APIs, excipients and primary containers, as well as on the choice of the method of sterilization.

According to the document following conditions and physical parameters with regards to manufacturing of sterile medicinal products have been described in detail:


• Steam sterilization
• Dry heat sterilization
• Ionization radiation sterilization
• Gas sterilization (with ethylene oxide, ethylene chlorohydrins, etc.)
• Sterile filtration
• Aseptic processing
According to the document, the following processes should be described in detail with respect to the manufacturing of sterile medicinal products:
• The choice of the sterilization method has to be justified.
• The method must be validated.
• The method described in the corresponding general monograph of the European Pharmacopoeia has to be used. All deviations have to be justified.
• The procedures for all sites (including outsourced activities) where sterilization is performed have to be documented (CTD module 3, chapters 3.2.P.2 and 3.2.P.3).


The document clarifies that the requirements laid down in Part II of the EU GMP Guide are only applicable for the manufacture beginning with the starting material up to the finished API, immediately prior to sterilization. The document describes the following selection criteria for the sterilization method of APIs and excipients:
• The terminal sterilization step should be made in the final container whenever possible.
• When sterilization by heat is not possible because of temperature sensitivity of the product, alternative methods or aseptic processing may be used if they are properly validated. Terminal steps for the reduction of the microbial level are also possible as long as they are not used to compensate for poor aseptic manufacturing practice.
• A change (shortening) in shelf-life or storage conditions caused by the terminal sterilization step is not in itself a reason to allow aseptic processing unless the new storage conditions or shelf-life would cause problems or restrictions in the use of the product.
• The risks induced by an increased level of impurities should be balanced with the risks induced with an aseptic manufacturing method (e.g. characteristics of the degradation products vs. posology of the medicinal product). Attempts performed to determine sterilization conditions to give acceptable impurity levels and to simultaneously achieve a microbial reduction of at least 10-6 have to be described in the quality dossier.
• Under specific conditions, aseptic processing may be accepted even if terminal sterilization of the product itself would be possible, e.g. in the case of eye drops in polyethylene containers enabling administration of single drops or pre-filled pens.
• The considerations for the choice of the container should be described in the dossier also in the case of heat-sensitive final containers.


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