by
Stephan O. Krause, PhD, MedImmune/AstraZeneca | Jul 07, 2014
In February 2014, the U.S. FDA published the draft guidance, <em>Analytical Procedures and Methods Validation for Drugs and Biologics.</em> Once finalized, this 2014 draft guidance will replace the 2000 FDA draft guidance, <em>Analytical Procedures and Methods Validation.</em> I want to highlight the development of PDA Technical Report 57: Analytical Method Validation and Transfer for Biotechnology Products, and its influence on the content of the new FDA draft guidance.
In February 2014, the U.S. FDA published the draft guidance, Analytical Procedures and Methods Validation for Drugs and Biologics. Once finalized, this 2014 draft guidance will replace the 2000 FDA draft guidance, Analytical Procedures and Methods Validation. I want to highlight the development of PDA Technical Report 57: Analytical Method Validation and Transfer for Biotechnology Products, and its influence on the content of the new FDA draft guidance.
After PDA’s Science Advisory Board (SAB) accepted the need for TR-57 following my presentation in 2006, I assembled a team of both PDA member and nonmember volunteers. Drafting of the document kicked off in 2007. We wanted to provide more practical guidance to readers, so we focused on topics where ICH, FDA, and/or industry guidance was missing. Later, TR-57 was well received by reviewers from U.S. and EU regulatory agencies (FDA/CDER and the Paul-Ehrlich-Institute in Germany) along with industry representatives. Ultimately, TR-57 influenced the content of the FDA draft guidance.
Reviewers from the FDA and Paul-Ehrlich-Institute provided positive feedback on the guidance in 2011. Siegfried Giess, PhD, Head, Section of Immunochemistry with the Paul-Ehrlich-Institute, said: “…From my point of view the advantage of this report is that it covers not only the classical validation process but also method transfer, comparability and maintenance. Another advantage is that the report gives a lot of guidance regarding the details of the different validation steps. I think you have developed a very helpful document not only for lab people but also for assessors. I hope that many companies will use this document in the future.”
Rashmi Rawat, PhD, Acting Team Leader, Regulatory Science and Policy, CDER, U.S. FDA, also expressed support for TR-57: “I wanted to thank you for coming to us and giving an excellent presentation. It was very useful for us to know the industry perspective. Your talk provided a better understanding for the method validation and comparability issues. It was the first talk in many years that focused on these topics, so everybody here appreciated the talk. Lately, this topic has gained more importance as the companies are increasingly replacing old method technologies with new ones and transferring methods globally. Lots of people are now waiting for this PDA technical report to be published.”
A summary of those TR-57 topics, covered in the new FDA draft guidance, and aligned with the published technical report, is given in the table below.
PDA technical reports have served our industry well and TR-57 is no exception. We, as PDA volunteers and authors, take pride in making valuable documents available to industry and regulators, and with that, improving industry standards. The results speak for themselves here and the experience and recognition gained for us authors is more than worth the effort and time it takes. I wrote this short article to reflect on the value of PDA technical reports and my positive experience writing TR-57. Maybe it will convince some of you to do the same?
| Alignment of TR-57 and FDA Draft Guidance |
| PDA TR-57 topics presented (in blue) to FDA CMC Product Quality Reviewer Teams, or, otherwise covered in PDA TR-57 | FDA Product Quality Reviewers’ questions/comments during June 2012 presentation | Alignment of PDA TR-57 with current FDA draft guidance content |
| Risk-Based Validation Studies (Categories) and AMV studies completed prior to PV Stage 2 | When are the method validation studies completed? | Similar risk-based method validation strategies and completion timing (clinical phase 3) |
| Compendial Method Verification Studies for each Method Type | Are compendial methods always (formally) verified? | Both clarify the performance characteristics to focus on |
| Analytical Method Transfer (AMT) comparison of variability and bias. AMT case study shown | How exactly does a comparison/equivalence study fail in AMT? | Both clarify the performance characteristics to focus on. Both are based on USP <1224> |
Analytical Method Comparability (AMC)
- Use of ICH E9 models
- Representative sample types and sizes for AMC studies
- Justification of above
| Why is ICH E9 used for AMC models? Can AMC models be switched once data becomes available? Are justifications used for E9 model, acceptance criteria, and sample sizes? | Same use of noninferiority, superiority, and equivalence models for AMC and how comparison studies are to be set up and justified |
| Use of confidence interval (CI) limits for the E9 models and the treatment of bias | How were CI limits justified? What to do if 90% CI overlaps or 90% CI out of limit(s)? | Same use of CIs, acceptance criteria setting and justification, and treatment of bias. |
| Analytical Method Maintenance (AMM): Periodic method performance and validation status reviews | How often should AMV status be reviewed and validity of AMQ/AMV studies reassessed when specifications change? | Both encourage the use of the concept of AMM (continuous validation) |
AMV failures and protocol deviations
- Investigation process similar to OOS
| No questions/comments. | Not covered in FDA draft guidance |
| Method characteristics to be evaluated | N/A | Same performance characteristics to be evaluated |
| Method robustness studies—timing, use of data, DOE concept | N/A | Both suggest DOE for robustness |
| Use of method development data in method validation (report) | N/A | Both provide this option |
| Use of ASTM E29-02 for significant digits | N/A | Both suggest E-29-02 |
| Validation of stability-indicating methods | N/A | Similar validation considerations |
| FDA approved methods can be verified (instead of validation) | N/A | Both allow for this option |
| Use of recommended statistics for method validation studies | N/A | Both suggest the same statistics |
| Use of retains for method comparability studies | N/A | Similar use of retains for method comparability studies |
| Revalidation triggers and characteristics to be studied | N/A | Similar risk-based revalidation requirements to be confirmed |
Editor’s Note: Technical Report No. 57 can be purchased at the PDA Bookstore. Members can also access it for free by accessing the PDA Technical Report Portal.
About the Author
Stephan O. Krause is a Principal Scientist at MedImmune/AstraZeneca. He has over fifteen years of management experience in QA/QC. He is the PCMO L01 Task Force Leader and a member of PDA’s Biotech Advisory Board.