| Title: Implementation of Real Time Release (RTR) Testing | |||||
| Guidance Number: 84 | |||||
| Prepared by: | Date: | Supersedes: | |||
| Checked by: | Date: | Date Issued: | |||
| Approved by: | Date: | Review Date: | |||
Implementation of Real Time Release (RTR) Testing
Introduction
Real Time Release Testing is defined in ICH Q8 (R1) part II as 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.
This document provides practical guidance on how to implement a Real Time Release (RTR) testing approach as part of a manufacturing control strategy to ensure product quality while enabling the rapid release of API, intermediate and/or finished products.
This document provides a framework for RTR projects. It serves to outline the important components that need to be considered in any RTR program. It provides guidance on the development of an underlying control strategy that will enable the adoption of an approach to release that relies on process understanding, monitoring and control rather than on end product testing.
The drivers for moving to RTR testing will be based on business benefits including the reduction in the cost of testing intermediates, API and finished product, enabling a “pull” supply chain, in support of Agile Operations and increasing the overall level of quality assurance through the introduction of real time monitoring and attribute based endpoints.
The scope of RTR testing applications can vary significantly ranging from specific attributes of individual unit operations to RTR for entire processes. Real Time Release testing can replace end product testing, but does not replace the review and quality control steps called for under GMP to release the product.
The overview presented in this guide is applicable to all manufacturing operations, batch and continuous, API, drug product, aseptic manufacturing and bioprocessing. The exact approach to RTR will vary from product to product.
Definitions
Control Strategy:
A planned set of controls, derived from current product and process understanding, that assures 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 Q8R1 and ICH Q10)
Critical Process Parameter (CPP):
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality (ICH Q8R1).
Critical Quality Attribute (CQA):
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. (ICHQ8R1)
Continuous Quality Verification (CQV):
An approach to process validation where manufacturing process (or supporting utility system) performance is continuously monitored, evaluated and adjusted as necessary. It is a science-based approach to verify that a process is capable and will consistently produce product meeting its pre-determined critical quality attributes. (ASTM E2537)
Design space:
The multidimensional combinations and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8 and ICH Q8R1) [NOTE: Q10 definition is limited to the first sentence above]
PAT
A system for designing, analyzing and controlling manufacturing through timely measurements (i.e during processing) of critical quality and performance attributes of raw materials and in-process materials and processes with the goal of ensuring final product quality (ICH Q8 R1/FDA definition)
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 R1).
General Guidance
Real Time Release encompasses more than just end product test replacement. It considers building a level of understanding of the manufacturing process that allows definition of the important parameters and attributes that need to be monitored and controlled to ensure quality. Real time release is a product of this requisite process understanding and an effective process control strategy.
The following graphic shows the key elements of any RTR strategy:
In any RTR testing strategy it will be key to demonstrate process understanding and to develop a process monitoring and control plan to assure the quality of critical quality attributes based on this process understanding and on knowledge of the process boundaries.
Additional guidance on each step can be found in section 4.0 of this guidance. The exact approach to implementing RTR testing will vary depending on a number of factors including manufacturing history, process variability, batch vs continuous operation, existing level of process capability data etc.
RTR testing can be readily applied to processes where a Continuous Quality Verification (CQV) approach has been implemented. CQV is an alternative approach to process validation where the process is continually monitored, evaluated and adjusted (when necessary) to achieve defined Critical Quality Attributes (CQAs).
CQV uses validated in-process measurements, tests, controls and process endpoints in lieu of the conventional 3 batch validation approach. The underlying control strategies to achieve either CQV or RTR may be very similar or identical. At the outset of any RTR project it is worth considering if CQV should also be a goal.
The scope of the RTR testing strategy should be clearly outlined to define whether the RTR testing is intended to be applied to individual unit operations or to the entire process. It should also be considered whether the alternate testing strategy will be filed for a single market or for multiple markets and whether CQV will be considered in conjunction. The scope should be defined before progressing through the key elements of the RTR testing strategy to ensure that the resulting RTR testing strategy fully addresses the desired RTR scope.
Recommendations and Rationale
This guidance sets out to recommend a number of practical steps that should be considered in the development of any RTR testing strategy.
Step 1: Compile process understanding
Process understanding is the foundation of any process control strategy to enable RTR. Process understanding should be based on sound science and quality risk management. CQAs should be defined and sources of variability (input material attributes and process parameters) that can impact product quality should be identified and appropriately understood.
Understanding of the functional relationship between CQAs, material attributes and process parameters may be based on experimental studies, knowledge of similar processes and/or historical manufacturing data. It is also important that the boundaries of the process are well understood.
Step 2: Define process monitoring and control requirements
A control strategy incorporating RTR testing should enable a move from an approach reliant exclusively on end product testing and offline assessment of product quality to an approach that facilitates release based on process controls and/or real time monitoring and control of attributes and parameters that are critical to quality.
“ ICH Q10 and Q8 (R1) 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 Q8(R1): Understanding sources of variability and their impact on downstream processes or processing, in-process materials, and drug product quality can provide an opportunity to shift controls upstream and minimise the need for end product testing.”
The process control strategy, which is predicated on the functional relationships between input material attributes, process parameters and quality attributes, will demonstrate that the process produces product complying with predefined acceptance criteria.
Based on process understanding, the outlined process boundaries and the use of a quality risk management approach, it should be possible to develop an effective control strategy that supports the product specification. This control strategy should ensure that final product quality is acceptable by control of raw material attributes, CPPs and CQAs.
Rationale should be provided to support the proposed control strategy and any amendments to the analytical procedures and acceptance criteria in the specification. Process understanding can also be used to provide rationale for exclusion of parameters or tests previously applied. When real time / near real time monitoring is employed, careful consideration should be applied to the sampling location and frequency to ensure adequate control of the CQA’s and CPP’s. The sampling strategy will differ for different operations particularly with regards to continuous versus batch processes.
A typical RTR control strategy could include (but is not limited to) any of the following elements:
- Control of raw material attributes.
- Control of process parameters.
- On line or at-line monitoring (close to the source of variability) to control key unit operations that have an impact on downstream processing or product quality.
- Process capability based test elimination
- Rapid on-line/ at-line testing of finished product
- Surrogate testing (e.g. replacement of dissolution with disintegration when correlation has been demonstrated)
- Multivariate assessment of attributes and parameters from entire, or elements of the manufacturing operation
- Appropriate off line testing
- Acceptance criteria that are ‘met if tested’ and alternate specification tests to achieve the CQA requirements.
The control elements incorporated in any RTR testing strategy would be subject to regulatory consideration and approval. Examples of RTR control strategies from two products are provided in later section.
Step 3: Define approach for process adjustment
It may be possible to introduce control mechanisms for some processes that can automatically effect mid course adjustments to process parameters within the required range and/or design space based on measurements of output attributes of a unit operation. Such control is commonly termed Advanced Process Control (APC).
Advanced Process Control is not essential to achieve real time release but it can add significant benefits in terms of reducing product variability as well as business gains, such as yield, operational effectiveness, and reduced processing costs. Simple control and adjustment methods such as diversion of non-conforming material should also be considered.
Step 4: Define end product release strategy
The end product release strategy should be defined. End of process off line testing can be revised and often minimized or eliminated through the introduction of upstream in-process measurements of CQAs, coupled with control of CPPs. It may also be possible to replace individual tests based on control of CPPs where measurement has demonstrated a consistently high process capability (e.g. Cpk) for that attribute and that test replacement is also supported by a solid understanding of the factors that impact the attribute.
For example, a high Cpk is calculated for impurities currently tested at the end of drug product manufacturing and it is known that impurities are controlled during the API manufacture. If studies have shown that additional degradent impurities can only form under certain DP manufacturing conditions which are controlled, it may be possible to replace the off line DP impurity test.
The number of tests to be completed at the end of processing can be significantly reduced with an effective “upstream” monitoring and control strategy.
“ICH Q8 (R1) Enhanced understanding of product performance can justify the use of alternative approaches to determine that the material is meeting its quality attributes. The use of such alternatives could support real time release testing. For example, disintegration could serve as a surrogate for dissolution for fast-disintegrating solid forms with highly soluble drug substances. Unit dose uniformity performed in-process (e.g., using weight variation coupled with near infrared (NIR) assay) can enable real time release testing and provide an increased level of quality assurance compared to the traditional end-product testing using compendial content uniformity standards.”
“FDA PAT Framework: ‘The combined process measurements and other test data gathered during the manufacturing process can serve as the basis for RTR of the final product and would demonstrate that each batch conforms to established regulatory quality attributes”.
Where end product testing of the finished product is required, and cannot be replaced with upstream monitoring, it may also be possible to replace conventional off line test methods with rapid in-line/at-line test methods for certain CQAs.
The final quality expectations for the product will not change. However the approach to demonstrating that the product meets the quality expectations will move from testing of end product to an approach that utilizes known correlations between raw material attributes, process parameters and upstream monitoring.
The RTR approach should be designed to ensure that the required CQAs are achieved. Product release specifications include a list of tests, references to analytical procedures, and appropriate acceptance criteria to ensure acceptable quality. Real time release testing may require a move to alternative analytical procedures and/or modifications to the acceptance criteria, where allowed by pharmacopoeia. However, the quality expectations for the product remain the same.
How the manufacturer justifies and complies with the release specification will need to be detailed in the regulatory submission. The submission will need to describe how the data to confirm that the product meets specification will be generated to take account of revised sampling and testing strategies. It should be noted that eliminating the need to perform a specific test (based on scientific justification) does not necessarily justify removal of the test listing from the product specification (eg if a compendial requirement exists). In this case, the submission should explain why the testing is not performed and sufficiently justify how real time release testing and the control strategy will provide assurance of acceptable quality and support the statement “will meet if tested”.
Off line testing with conventional methods is still required for end stability testing (i.e. shelf life testing / stability testing) as well as post market surveillance ((e.g. complaints), where appropriate. Therefore a second specification may be required outlining Shelf Life / Stability specification requirements. Offline release testing may still be required routinely for attributes not covered by the RTR strategy.
Conventional testing may also be used to support evaluation of process changes, where relevant. For example, dissolution testing may be more discriminatory than disintegration testing in assessing the impact of a change.
Table 1 below illustrates a number of different approaches that can be taken as part of the end product release strategy. It shows how the conventional end product attribute testing can be eliminated or replaced by using an alternative process control approach.
Note that this table does not represent a recommended release approach for a single process, but serves to illustrate a number of different options and examples for RTR testing of individual attributes.
Incorporating RTR into existing quality systems
RTR will be implemented on a product basis while other products manufactured at the manufacturing facility will remain released based on traditional approaches. Quality systems at a manufacturing site such as SOP’s, Deviations, Change control, Process Validation, personnel roles and approval workflows, which cover, traditional approaches to GMP compliance and product release may need modification to facilitate parallel RTR and traditional release approaches operating at the manufacturing facilities. Careful consideration should be given to change control for RTR processes.
It is likely that the greater process understanding, mechanistic knowledge of process boundaries and presence of monitoring and control systems will allow more efficient and effective deviation investigation, change management and validation. Assessment of current quality systems and documentation (Policies, Master Plans, SOPs) should be part of the scope of the implementation of new RTR approaches.
Examples
Two examples of RTR projects are presented in this section. One example is included for a continuous process and one example for a batch process. In each case the appropriate work was completed to develop process understanding based on risk assessment, define process boundaries and develop effective process control strategies. The tables below show the output of the RTR strategies by highlighting the difference in conventional vs RTR testing requirements.