EMA’s new Draft Guideline on the Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers
For medicinal products administrated in sterile form, the process to reduce the microbial level is a critical manufacturing step with regard to quality. The EMA has recently published the draft of a guideline on that topic which contains a range of clarifications. Read more about the coming requirements on sterilisation of medicinal products, APIs, excipients and final containers
As referred to in the European Pharmacopoeia, the procedure for terminal sterilisation of a medicinal product, an API, or an excipient is generally the method of choice. Yet, this might be difficult in many cases for product stability reasons. That’s why other microbial reduction processes can be used like sterilising filtration or aseptic processing. So far, there has been some uncertainty about these methods and their acceptance in a marketing authorisation procedure or a variation application, and about which data have to be submitted.
EMA’s new draft guideline entitled “Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container” from April 2016 contains clear provisions with regard to the acceptance of alternative sterilisation processes by the European authorisation authorities. Those provisions apply to chemical and biological medicinal products for human and veterinary use as well as the respective APIs and excipients, but aren’t applicable for immunological veterinary medicinal products.
The document describes the requirements on sterilisation of medicinal products, APIs, excipients and primary containers, as well as on the choice of the method of sterilisation. Besides, the document contains two decision trees for the selection of the sterilisation method for products in diverse galenic forms.
Please find hereafter a summary of most important aspects in this chapter:
Manufacturing of sterile medicinal products
The conditions and physical parameters for the following processes are described in detail:
- Steam sterilisation
- Dry heat sterilisation
- Ionisation radiation sterilisation (here reference is made to the Note for Guidance “The use of Radiation in the Manufacture for Medicinal Products“, ISO 11137 and Ph. Eur. Chapter 5.1.1)
- Gas sterilisation (with ethylene oxide, ethylene chlorhydrin, etc.)
- Sterile filtration
- Aseptic processing
Basically, the following rules apply to all processes:
- The choice of the sterilisation 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 sterilisation is performed have to be documented (CTD module 3, chapters 3.2.P.2 and 3.2.P.3).
Manufacturing of sterile APIs and excipients
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 sterilisation. The sterilisation step performed on the API is considered to be a step in the manufacture of the medicinal product. As a consequence, each manufacturing establishment which performs sterilisation of an API requires a manufacturing authorisation, a GMP certificate and thus aQualified Person too. This also applies to establishments which manufacture sterile excipients. APIs and excipients with a Certificate of Suitability (CEP) are also covered by this regulation.
Selection of the sterilisation method
The following principles apply:
- According to Ph. Eur., general chapter 5.1.1, the terminal sterilisation step should be made in the final container whenever possible.
- When sterilisation 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 sterilisation 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.
- An increase in impurity levels or degradation products upon terminal sterilisation doesn’t directly lead to the acceptation of aseptic processing. 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 sterilisation 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 sterilisation 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. Here, terminal sterilisation of the product would destroy the final container.
- The considerations for the choice of the container should be described in the dossier also in the case of heat-sensitive final containers. Here, the search for materials which come through terminal sterilisation has priority. For example, polypropylene is more resistant than polyethylene. The choice for the final container has to be justified.
- Large volume parenterals should be terminally sterilised whenever possible.
In general, the regulatory authorities will expect a detailed justification for the selection of the sterilisation method or the aseptic processing in the form of a benefit/risk analysis.
The essence of the requirements described in the chapters of this guideline can be found in the two decision trees for sterilisation of products in diverse administration forms (aqueous liquid; non-aqueous liquid, semi-solid, dry powder).
The deadline for comments on this Draft Guideline Sterilisation of the medicinal product, active substance, excipient and primary container ends on October, 13th 2016.
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