Data Preparation for Regulatory Purposes
Tempris offers for data preparation for regulatory purposes the possibility to directly compare ’21 CFR Part 11 compliant’ data obtained using the identical process analytical technology method throughout the development process. Product temperature data generated by the Tempris system can form an integral part of the regulatory strategy for submission of new product applications or substantiation of change requests to the regulatory authorities, especially in Section 32P of the Common Technical Document (CTD) relating to manufacturing. With the introduction of the ICH Guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System) and corresponding national legislation (e.g., the Quality by Design Initiative in the US), the expectations for scientific understanding of product properties and manufacturing processes have dramatically increased. An essential aspect of this scientific and risk-based approach is applying process analytical technology (PAT) throughout the product life cycle. Product and process attributes previously identified as critical for pharmaceutical quality need to be routinely monitored, preferably in real-time.
An example of this approach can be found in this article by Dr. Andrea Weiland-Waibel of Explicat Pharma, GmbH: Wireless Temperature Measurement in Lyo Process Development, Validation and Production.
Definition of the Design Space with PAT Methods
In addition to process monitoring, PAT methods are also essential for the definition of a Design Space, i.e., a range of process control parameters, especially for the primary drying step, that result in acceptable product quality. Within this Design Space (submitted in CTD section 32P3), the process conditions can be varied without needing to submit a change notification, which grants more flexibility to the manufacturer. For freeze-drying processes, the approach for the definition of a Design Space is not yet uniform or standardized. The most straightforward approach is to determine specific ranges and combinations for shelf temperature and chamber pressure over the process time and to verify the acceptability of the process by robustness testing. Other more complex approaches have been presented that define the mass flow rate vs. the chamber pressure under consideration of critical formulation temperature and equipment limitations. These require more effort but claim to achieve a truly optimized primary drying process.
Process Robustness Testing
Process robustness testing typically entails the performance of “hot cycles” with elevated shelf temperature and chamber pressure (resulting in higher product temperature and shorter drying time) as well as “cold cycles” with reduced shelf temperature and chamber pressure (resulting in lower product temperature and extended drying time). During these experiments, rigorous monitoring of critical product and process attributes (with the most important product quality attribute: product temperature) is performed, followed by thorough characterization of the product, including stability studies. To allow scientifically sound interpretation of the results, information about the critical product attributes during the process needs to be available.
Tempris – for all Lyo Scales
Due to the applicability of the identical Tempris technology on all freeze-dryer sizes from laboratory to routine manufacture, the user is provided with consistent product temperature data from early development up to the registration batches and subsequent production. The comparability of the processing conditions can be directly assessed, and the evolution of the processing conditions can be documented. As the data provided by Tempris complies with 21 CFR Part 11 (Electronic Records, Electronic Signatures), it is globally suitable for use in pivotal batches and regulatory submissions.