10/11 March 2021
Following the Q&As on what data is required for sterilization processes of primary packaging (published in 2016) the European Medicines Agency, EMA, recently released the new Guideline on the sterilization of the medicinal product, active substance, excipient and primary container. The guideline comes into effect on October 1, 2019.
For containers required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site where sterilization of the containers takes place may not have undergone inspection by an EU authority. Consequently it may not hold an EU GMP certificate in relation to this activity. Sites located in the EU which perform sterilization of primary containers only are not required to hold a Manufacturer’s/Importer’s Authorization (MIA), whereas sites, which carry out sterilization of medicinal products, are required to hold a MIA in relation to these activities.
When a GMP certificate is not available, certification that the sterilization has been conducted and validated in accordance with the following ISO standards for Medical Devices/ Health Care Products would be considered sufficient to provide an acceptable level of sterility assurance for the empty container:
According to EMA, "it is the responsibility of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of containers". However, sterilization tasks are often outsourced or performed directly by the manufacturer/supplier of the packaging material. Therefore, the site where QP certification of the finished product takes place should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilization service. According to the guideline, this may be checked during audits performed by the manufacturer of the finished product. In addition, "the Competent Authorities may also decide to carry out their own inspections at the sites where such sterilization activities take place".
According to the guideline, the following details regarding the sterilization of the packaging components should be included in the quality dossier:
Where the container component is a CE-marked Class Is sterile device (e.g. sterile syringe), a declaration from the device manufacturer that the component is a Class Is sterile device together with a copy of the certificate of conformity from the Notified Body will suffice. In the absence of a GMP certificate or declaration that the component is a CE-marked Class Is medical device, the finished product manufacturer should provide a confirmation that the sterilization process has been conducted and validated in accordance with the relevant ISO standards.
Whenever possible, sterile containers should be packed before they are sterilized. When terminal sterilization by heat is not possible, the application of an alternative method of terminal sterilization, sterilizing filtration and/or aseptic processing may be considered.
If a sterilization process using principles other than those described in the Ph. Eur. is intended to be used for the sterilization of a container, the applicant may consider seeking scientific advice regarding the acceptability of the method and the documentation required. The guideline provides the principles for the choice of sterilization process for containers in form of a decision tree. In certain cases, the use of aseptic processing may be accepted, even if the final formulation itself can be terminally sterilized. Such cases could be justified by a user benefit, e.g.:
However, the choice to use a heat-labile container cannot in itself be the sole reason for not applying a terminal sterilization process and alternative materials should be investigated. Thus, a discussion regarding the efforts made to develop a container that may be terminally sterilized and a thorough benefit risk evaluation should be included.
Please see the EMA Guideline on the sterilization of the medicinal product, active substance, excipient and primary container for further information.