ICH Q8 (R2) Pharmaceutical Development makes a number of references to real-time testing as a result of an enhanced quality by design (QbD) approach to development and a control strategy that includes real-time testing. When used in conjunction with release real-time testing (RTRT) is defined 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. RTRT allows for the measurement of on-line measurements in lieu of end-product testing.
In conventional testing samples are collected, analyzed and test results reported via a Certificate of Analysis (CoA) that provides documentation of the sample ID, processing point the sample represents (could be a purification step in a batch, or sample point in a continuous process), analysis conducted, analysis results and certification provided attesting to the results.
The answer to address the CoA requirements for a real-time test was partially address in a joint Industry Working Group and later published by the FDA in July 2012 through guidance entitled Q8, Q9 &Q10 Questions and Answers. The purpose of the document was not to adopt the ICH guidelines but to provide clarification on the ICH guidelines at they relate to cGMP. In Section III entitled What are the Points to Consider for Control Strategy the following clarification is provided in Subsection C Specifications and Certificate of Analysis (CoA) for Real-time Release Testing (RTRT).
The purpose of specifications and CoAs remains the same in the case of RTRT, but the way to develop them is different. Real-time release tests(RTRT) are considered to be specification testing methods and follow the established regional regulatory requirements for release specifications (as interpreted in e.g., ICH Q6A and ICH Q6B) together with other regional regulatory requirements (e.g., formats, GMP, batch acceptance decisions).
The use of RTRT has been addressed (see ICH Q8(R2), section II.E (2.5); ICH Q8, Q9, and Q10 Q&As, section II.B (2.2)). The following points should be considered when developing a specification and CoA for RTRT:
• Quality attributes:
• Not all CQAs need to be included in the specification.• The attribute to be measured (e.g., surrogate for a CQA) can depend on the point of testing and/or control (e.g., materials, process steps, process parameters).• Linking of the measured attribute to CQA and QTPP
• Methods of control:
• The type of control used (e.g., models, process analytical technology (PAT), test of isolated material, end product test, stability and regulatory test)• Reference to the testing method used, if relevant• Validation of control method
• Acceptance criteria:
• Acceptance criteria at control point• Criteria for stability and regulatory testing
• CoA elements:
• Reported results (e.g., values calculated from models, established calibrations, and actual test results)• Acceptance criteria related to the method used• Method references
In essence I’m treating an on-line measurement result like an on-line measurement result, which makes sense since the on-line method needs to be validated just the same. The CoA reporting however is another question. If I was running an electronic batch record that interfaced with a PAT method could the resultant CoA be created automatically in a work instruction? How would I want to show this to an inspector? Would I still need to report and maintain the result in LIMS?