GMP Requirements for Ready to Sterilize (RTS) and Ready to Use (RTU) Containers

Currently, there is a growing interest in the supply of GMP pre-sterilized packaging material (e.g. ready-to-sterilize (RTS), ready-to use (RTU) products). However, suppliers are facing new GMP requirements (e.g. regarding validation of the sterilization procedure) which apply with the revised EU GMP Annex 1 entitled “Manufacture of Sterile Medicinal Products”, which provides guidance on the approaches to sterilization of products, equipment and packaging components. The manufacture of sterile products covers a wide range of sterile product types, like the following:

• Active substances (APIs),
• Excipients,
• Primary packaging material,
• Finished dosage forms.

Validation of the Sterilization Procedure

According to EU GMP Annex 1, all sterilization processes should be validated. Validated loading patterns should be established for all sterilization processes and load patterns should be subject to periodic revalidation. Maximum and minimum loads should also be considered as part of the overall load validation strategy. The validity of the sterilizing process should be reviewed and verified at scheduled intervals based on risk. Recently, the European Directorate for the Quality of Medicines & HealthCare (EDQM) issued a draft guideline on "Content of the dossier for sterile substances". According to the EDQM, details are required for the methods used to sterilize the packaging components. If the reference conditions of Ph. Eur. chapter 5.1.1. Methods of preparation of sterile products are not used, validation data for the sterilization process of the packaging material should be provided.

How to demonstrate GMP Compliance?

The requirements of the EMA Guideline on the sterilization of the medicinal product, active substance, excipient and primary container should be considered to determine the most appropriate sterilization method. According to the agency, "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".