Dr Joachim Ermer, Sanofi, Germany
Patrick Jackson, GSK, United Kingdom
The aim of this two day course is to provide guidance to apply the principles of the modern concept of lifecycle management to analytical methods, as initiated by the PhRMA/EFPIA Position Paper [QbD Analytics. Implications and Opportunities of Applying QbD Principles to Analytical Measurements, Pharmaceutical Technology, Feb. 2010, 2-8] and further elaborated by USP’s Validation and Verification Expert Panel in a Stimuli Article for a proposed USP General Information Chapter [1220 The Analytical Procedure Lifecycle. Pharm. Forum 43(1)]. The application of Quality-by-Design principles during the whole analytical lifecycle provides opportunities, not only for new development products, but also for drugs already marketed. This course will deal among others with the following questions:
- What is the content of the three stages of analytical lifecycle aligned current process validation concepts?
- What are the opportunities of applying QbD principles to analytical lifecycle management?
- How can the Analytical Target Profile (ATP) help to define the measurement requirements and increase regulatory flexibility?
- Why is it important to have a clear understanding and expectation of method performance?
- What is the benefit of a risk-based method development and establishment of an appropriate Method Control Strategy?
- What is the impact and benefit of an integrated lifecycle approach on method verification, transfer, and changes?
- Why is a continued method performance monitoring important, and how can it be achieved?
Five interactive workshops will be provided throughout the two days which will enable delegates to understand and discuss the concepts in more detail, and to be able to apply what they have learned. Delegates will have the opportunity to work through the whole analytical lifecycle by gaining “hands-on experience” using several case studies.
During the course an overview of the PhRMA/EFPIA Position Paper and the Stimuli Article for a proposed USP General Information Chapter <1210> will be provided which are based on the Analytical Target Profile (ATP) concept. The ATP defines the objective of the test and quality requirements for the reportable value. It therefore aligns with the ICH definition of QbD as “a systematic approach that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [ICH Q8]. Besides serving as focal point throughout the analytical lifecycle, the ATP has the potential to facilitate continuous improvement if regulatory authorities would approve the requirement-based ATP instead of specific methods. Each method conforming to the ATP requirements could be implemented by the company’s internal change control management system, thus providing regulatory flexibility.
The three stages of the analytical lifecycle align with current process validation concepts. In Stage 1, the ATP is used to drive method design and development activities. Risk assessment tools and statistical methods used to facilitate understanding of the method (e.g. robustness, design of experiments) and its performance characteristics (e.g. accuracy and precision) and their acceptance criteria will be discussed in the course.
Stage 2, Method Performance Qualification, confirms that the analytical procedure, operated in the routine
environment is capable of delivering reproducible data which consistently meet the ATP. This includes the finalisation of the Method Control Strategy, e.g. a science-based definition of the replication level of the reportable value. This stage includes also holistically analytical transfer and implementation of compendial procedures.
An important aspect in the lifecycle approach is Stage 3, the Continued Method Performance Verification, i.e. the ongoing assurance that the analytical procedure remains continuously in a state of control. This includes an ongoing program for routine monitoring of analytical performance data, as discussed in the FDA Method Validation Guideline from July 2015, and the systematic evaluation of changes.
Note: In order to fully benefit from the workshops, attendees should preferably bring a notebook with Excel®.
This course is designed for analytical managers and scientists who are responsible for performing or reviewing activities like method development, validation, transfer, operation of methods in a QC environment, statistical evaluation of method performance, analytical change control etc.
In addition, QA and regulatory affairs professionals will benefit from this course by gaining an understanding in future CMC trends. This will aid more effective multifunctional discussions on these topics within industry.
The three Stages of Analytical Lifecycle Management
Analytical Target Profile
- Overview on EFPIA/PhRMA Paper and the proposed USP Chapter <1220>
- Analytical Target Profile: To Reportable value, Types of ATP (point estimate, statistical), - As focal point during the lifecycle, Potential regulatory flexibility, Regulatory situation, ICH Q12
- Stage 1 – Method Design
- Stage 2 – Method Performance Qualification
- Stage 3 – Continued Method Performance Verification
ATP Performance Attributes
- Design intent of the analytical measurement
- Linkage with process control strategy (critical quality attributes)
- Reportable value
- Definition of ATP Types
- Decision rules
- Business requirements of method
Method Performance Attributes
- Accuracy and precision, error types
- Expected random difference between means
- Point estimates and statistical approaches (USP <1210>)
- Simultaneous evaluation of accuracy and precision
- How to establish Target measurement uncertainty
- Acceptable impurity precision and accuracy
- “Translation” of general performance attributes into method-specific attributes
- Precision levels & variance contributions
- Linearity: Justification of the calibration model
- General and intermediate Quantitation Limit
Stage 1: Method Design
- Application of statistical simulations
- Gain experience (“feeling”) for the consequences of variability
- Variability of RSD determinations
- Probability of OOS results
Workshop Risk Assessment
- Method design and understanding
- Method selection
- Risk assessment
- Analytical Method Control Strategy
- Knowledge management
- “Translation” of ATP into specific method requirements
Stage 1: Robustness Investigations
- Use of fishbone diagrams
- Identification of controllable factors, noise factors and experimental parameters (CNX)
- Use of priority matrix and failure mode and effects analysis (FMEA)
- Design of experiments
- Identification of experimental parameters
- Establishment of the Method Operable Design Region (MODR
Stage 2: Method Performance Qualification
Workshop Replication Strategy
- Precision of the reportable value
- Precision study for the definition of a science-based replication strategy: to average or not to average?
- Experimental confirmation of performance or reference to stage 1 investigations?
- Establishment of appropriate acceptance criteria
Stage 3: Continued Method Performance Verification - Change Control
- Optimisation of precision of the reportable value
Workshop Method Selection, Lifecycle and Change Management
- Knowledge management system
- Analytical Method Transfer
- Method equivalency, significance and equivalence tests
Stage 3: Continued Method Performance Verification - Routine Monitoring
- Selection of a method/technique likely to meet the ATP requirements for example attributes
- Consideration of business needs
- Examples for Methods and Changes
- Evaluation of impact
- Risk assessment
- Definition of appropriate actions
Workshop Routine Monitoring
- FDA Method Validation Guidance
- Evaluation of ongoing performance, suitable parameter and data
- Program for routine monitoring, control charts
Wrap up & Final Discussion
- Identification of suitable performance parameters for example methods
- Establishment of a monitoring program
The concepts and tools used over the two days will be summarised and future implications and opportunities of the analytical lifecycle approach will be discussed. Delegates will be given time to ask questions on how they can apply what they have learned to their own analytical methods.