Real Time Release Testing

In 2004, FDA published a final guidance for industry introducing the concept of Process Analytical Technology (PAT) – A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality – and redefining pharmaceutical manufacturing and quality assurance for the future. That guidance also addressed a concept known as "real time release," defined as "the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data". The PAT component includes, according to the guidance, "a valid combination of assessed material attributes and process controls," and builds upon the 1985 guidance on parametric release, which is used primarily in heat-based sterilization of drugs. A few years later, in August 2009, the parties to the International Conference on Harmonization (ICH) adopted ICH Q8(R2) Pharmaceutical Development, which used the term "Real Time Release Testing" (on-line or in-line testing) – RTRT. The definition of this term in ICH Q8(R2) shifted the emphasis from the decision to release a batch to the measurements themselves, as follows: "the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls". There are many benefits to be gained from RTRT applications: The outcome of a high level of process understanding Controlling the process Adjust for variability in raw and in-process materials Increase yield, reduce waste, scrap Reduce the risk of losing a batch Reduced QC test Increased control activity on the manufacturing shop floor Reduced cycle time Real time monitoring of Critical Process Paranetrs and Critical Quality Attributes (CQAs -A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8(R2)) for free (must also be included in continuous process verification and Annual Product Review) Quality of the finished product can be measured during manufacturing – no surprises! Regulators might be more interested in the beginning but this will fade as process understanding has been demonstrated –reduced inspection frequency Despite the potential gains that can be realized from RTRT, industry still is trying to work out the practicalities of implementing the approach, and therefore, is not yet fully benefitting from its promises. Many questions remain regarding the instrumentation to use, when and where on the manufacturing line to conduct tests, how to evaluate on- or in-line analyzers during manufacture, and what regulatory authorities expect. Challenges by introducing Real Time Release Testing New –not familiar to many PAT tools in place (in-line analysers, PAT data management, multivariate data analysis, process control) Require new skills and reorganisation of work Risk associated with implementing PAT –Installation of probes, representative sampling, failure of instrument, failure of multivariate models, failure in feed forward & backward controls, etc Backup strategy must be in place Models needs frequent update If RTRT fails it cannot be replaced by end-product testing Regulators might be very interested in the beginning Industry's hesitation toward applying RTRT was abundantly clear during the October 2010 ICH Quality Implementation Working Group (IWG) workshop, held in North Bethesda, Maryland. A breakout session on control strategy addressed RTRT controls and brought up even more questions about its application, such as: • How is batch release affected by employing RTRT? • Does RTRT mean elimination of end product testing? • Is a product specification still necessary in the case of RTRT? • When using RTRT, is there a need for stability test methods? • What is the relationship between Control Strategy and RTRT? • Do traditional sampling approaches apply to RTRT? • If RTRT results fail or trending toward failure, can end-product testing be used to release the batch? • What us the relationship between in-process testing and RTRT? • What is the difference between RTR and RTRT? • Can surrogate measurement be used for RTRT? The European Medicines Agency (EMA) published a guideline on RTRT in 2012 to replace its former guideline on parametric release. The new document is meant to align better with the ICH terminology and to allow for real time release tests beyond that of sterility testing, which is the most common real time release practice. Under RTRT, a combination of in-process monitoring and controls may provide, when authorized, substitute for end-product testing as part of the batch release decision. Interaction with all relevant regulatory authorities prior and during the assessment process preceding regulatory approval is required. The level of interaction will depend on the level of complexity of the RTRT control procedure applied on site. When designing the RTRT strategy, the following minimum criteria are expected to be established and met: I. Real time measurement and control of relevant in-process material attributes and process parameters should be accurate predictors of the corresponding finished product attributes. II. The valid combination of relevant assessed material attributes and process controls to replace finished product attributes should be established with scientific evidence based on material, product and process knowledge. III. The combined process measurements (process parameters and material attributes) and any other test data generated during the manufacturing process should provide a robust foundation for RTRT and the batch release decision. A RTRT strategy should be integrated and controlled through the PQS. This should include or reference information at least of the following: quality risk management, including a full process related risk assessment, in accordance with the principles described in EudraLex, Volume 4, Part I Chapter 1 and Part II Chapter 2, 43 change control program, control strategy, specific personnel training program, qualification and validation policy, deviation/CAPA system, contingency procedure in case of a process sensor/equipment failure, periodic review/assessment program to measure the effectiveness of the RTRT plan for continued assurance of product quality. Relationships between RTRT, Control Strategy, PAT and QbD • RTRT, when used, is part of the Control Strategy (A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control (ICH Q10)) – Can include some or all of the final product CQAs • Quality by Design (QbD - A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8(R2)) is not directly correlated to RTRT – You can have QbD approaches without RTRT – However, it would be difficult to justify RTRT without a science and risk based approach • Not all Process Analytical Technology (PAT) leads to RTRT – PAT systems can be designed to control CQAs of raw materials or in-process materials and not contribute to RTRT • A design space is not required for RTRT – Having a design space can increase operational flexibility, without additional regulatory approval RTRT examples For illustrative purposes some examples are given, which are not intended in any way to limit the scope of the application of RTRT. A combination of in-process tablet weight, blend content uniformity measurement e.g. by NIR, drug substance purity and particle size could serve as a control strategy for drug content of a tablet if the relationship has been demonstrated. Core tablet weight, blend uniformity, drug substance purity and particle size in this example are the RTR tests. The production batches are released by the Qualified Person based on the outcome of the RTR tests, any other required tests and GMP compliance. Attributes relating to the properties of a tablet granule such as porosity, particle size, surface area, bulk/tapped density etc. if shown to have a predictive relationship with dissolution behavior could serve as RTR testing surrogates for dissolution testing. These dependencies would have to be confirmed on a product-by-product basis. RTRT for impurities for an active substance may be achieved through control of starting materials and process parameters which directly impact impurity levels, supported by empirical and mechanistic knowledge of impurity formation and purging during processing. References EudraLex – The Rules Governing Medicinal Products in the European Union – Volume 4 – EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use – Annex 17: Real Time Release Testing and Parametric Release FDA, Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004). EMA, Guideline on Real Time Release Testing (formerly Guideline on Parametric Release), final, March 2012. ICH, Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers (Nov. 11, 2010), http://www.ich.org/. FDA, Draft Guidance for Industry, Process Validation: General Principles and Practices (Rockville, MD, November 2008). http://www.pharmtech.com/real-time-release-testing?id=&sk=&date=&%0A%09%09%09&pageID=4 http://www.pharmtech.com/moving-toward-real-time-release-testing By Afandiyev R.