REAL TIME RELEASE TESTING AND PARAMETRIC RELEASE
ANNEX IXSupplementary provisions
ANNEX IX REAL TIME RELEASE TESTING AND PARAMETRIC RELEASE I. REAL TIME RELEASE TESTING I.1. Under a real time release testing approach, a combination of in-process monitoring and controls may replace end-product testing in the context of the batch release. This approach may only be implemented if it is authorised in the marketing authorisation. I.2. When designing the real time release testing strategy, the following minimum criteria shall be considered: — the proposed real time measurement and control of the relevant in-process material attributes and process parameters shall be accurate predictors of the corresponding finished product attributes; — the suitability of the combination of the relevant assessed material attributes and process controls to replace end-product testing shall be scientifically demonstrated; — the combined process measurements (process parameters and material attributes) and any other test data generated during the manufacturing process shall provide a robust basis for the batch release decision. I.3. A real time release testing strategy shall be integrated and controlled as part of the pharmaceutical quality system, in particular with respect to: (a) personnel: the implementation of real time release testing requires input from a cross-functional/multi-disciplinary team with relevant experience on topics, such as engineering, analytics, chemometric modelling or statistics; (b) control strategy: when implementing real time release testing, it is paramount to ensure the robustness of controls applied during the manufacturing process and their suitability to ensure the quality of the product and consistent production. The control strategy shall be adapted through the life-cycle in light of acquired knowledge and in accordance with quality risk management principles; (c) management of changes: requirements set forth in Article 26(3) are particularly relevant when implementing real time release testing; (d) validation and qualification policy: the qualification and validation of in-line ( 1 ) and on-line ( 2 ) analytical methods is particularly relevant when real time release testing is implemented, especially when advanced analytical methods are used. Particular attention shall be paid to the location where the sampling probe is placed within the manufacturing equipment; (e) any deviation or process failure shall be thoroughly investigated and any adverse trending indicating a change in the state of control of the process, equipment or facilities shall be followed up appropriately; (f) continuous learning through data collection and analysis over the life cycle of a product is important. Manufacturers shall scientifically evaluate data (including data trends), to assess opportunities to improve quality and/or consistency. For the implementation of changes, Article 26(3) applies. I.4. When real time release testing has been approved in the marketing authorisation, this approach shall be routinely used for batch release and may not be replaced by end-product testing (unless the terms of the marketing authorisation are amended). In the event that the results from real time release testing fail or are trending toward failure, there shall be a thorough investigation. The results of the investigation shall be duly considered for a decision on batch release (release may only take place if it is ascertained that the product complies with the terms of the marketing authorisation and good manufacturing practice). Trends shall be followed up appropriately. I.5. Attributes (e.g. uniformity of content) that are indirectly controlled by approved real time release testing shall appear in the certificate of analysis for batches. The approved method for end-product testing shall be mentioned and the results given as ‘Complies if tested’ with a footnote: ‘Controlled by approved real time release testing’. II. PARAMETRIC RELEASE II.1. Parametric release for terminally sterilised products is the release of a batch based on a review of critical process control parameters instead of relying on end-product testing for sterility. Requirements set forth in Annex I regarding terminal sterilisation shall apply. II.2. An end-product test for sterility is limited in its ability to detect contamination as it utilises only a small number of samples in relation to the overall batch size, and also because culture media may only stimulate growth of some, but not all, microorganisms. Therefore, an end-product testing for sterility only provides an opportunity to detect major failures in the sterility assurance system (i.e. a failure that results in the contamination of a large number of product units or that result in contamination by the specific microorganisms whose growth is supported by the prescribed media). In contrast, data derived from in-process controls (e.g. pre-sterilisation product bioburden or environmental monitoring) and by monitoring relevant sterilisation parameters can provide more accurate and relevant information to support sterility assurance of the product. II.3. Parametric release may only be applied to products sterilised in their final container using either moist heat, dry heat or ionising radiation (dosimetric release), according to European Pharmacopoeial requirements. Additionally, it is required that the manufacturer has a good record of compliance with good manufacturing practice and a robust sterility assurance programme in place to demonstrate a consistent process control and process understanding. II.4. The sterility assurance programme shall be documented and include, at least, the identification and monitoring of the critical process parameters, the steriliser cycle development and the validation thereof, the container/packaging integrity validation, the bioburden control, the environmental monitoring programme and relevant aspects concerning personnel, premises, equipment and utilities. II.5. Risk management is an essential aspect of parametric release and shall focus on mitigating the factors that increase the risk of failure to achieve and maintain sterility in each unit of every batch. If a new product or process is being considered for parametric release, a risk assessment shall be conducted during the process development, including an evaluation of production data from existing products if applicable. If an existing product or process is being considered, the risk assessment shall include an evaluation of historical data. II.6. Personnel involved in the parametric release process shall have experience in the following areas: microbiology, sterility assurance, engineering, production and sterilisation. The qualifications, experience and training of personnel involved in parametric release shall be documented. II.7. Any proposed change that may impact on sterility assurance shall be handled in accordance with Article 26(3) by appropriate personnel who are qualified and experienced in sterility assurance. II.8. A pre-sterilisation bio-burden monitoring programme for the product and primary packaging material shall be developed to support parametric release. The monitoring shall be performed for each batch and the sampling locations of filled units before sterilisation shall be based on a worst-case scenario and be representative of the batch. Any organisms found shall be identified to confirm that they are not spore forming, which may be more resistant to the sterilising process. II.9. Appropriate measurement of critical process parameters during sterilisation is a critical requirement in a parametric release programme. The standards used for process measuring devices shall be specified and the calibration shall be traceable to national or international standards. II.10. Critical process parameters shall be established, defined and undergo periodic re-evaluation. The operating ranges shall be developed based on the sterilisation process, the process capability, the calibration tolerance limits and parameter criticality. II.11. Routine monitoring of the steriliser shall demonstrate that the validated conditions necessary to achieve the specified process is achieved in each cycle. Critical processes shall be specifically monitored during the sterilisation phase. II.12. A sterilisation record shall be kept which shall include all the critical process parameters. Sterilisation records shall be checked for compliance with the specifications by at least two independent systems. These systems may consist of two people or a validated computer system plus a person. II.13. Once parametric release has been approved as part of the marketing authorisation, decisions for release or rejection of a batch shall be based on the approved specifications and the review of critical process control data. Routine checks of the steriliser, changes, deviations, unplanned and routine planned maintenance activities shall be recorded, assessed and approved before releasing the products to the market. Non-compliance with the specification for parametric release may not be overruled by a sterility test. ( 1 ) The testing equipment is integrated into the process line, where the analysis is implemented under the process conditions. After the measurement, the sample moves forward continuously along the flow. This was the original method for real-time analysis. ( 2 ) The sample is extracted from the process line in a statistically representative way and introduced to the measurement zone. The measurement conditions are similar to those of the process line. After the measurement, the sample may be drained as waste or introduced back to the process line.