A Regulatory Perspective on EmergingAnalytical Technologies

Yan Wang, Ph.D.Office of Biotechnology Products

OPQ/CDER/FDA

CMC Strategy Forum

July 17, 2018-Gaithersburg, MD

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Disclaimer

• The views and opinions expressed in this presentation represent my own best judgment, and should not be used in place of regulations, published FDA guidances, or discussions with the Agency.

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Outline

• Analytical method lifecycle and product lifecycle• Expectations of using various analytical methods for different uses• Expectations of using emerging analytical technologies• Challenges of using emerging analytical technologies in quality control

environment • Conclusions

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Analytical Method Lifecycle and Product Lifecycle

Pre-clinical Phase 1 and 2

Phase 3 and BLA

submission

Post-licensure

Method development

Method qualification

Methodverification, validation (transfer?)

Method transfer,

validation,re-validation, replacement

Product and process understanding

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The Current Analytical Tool Box

Source: Marjorie Shapiro, CASSS WCBP 2018

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Different Uses of Analytical Methods

• Raw materials • In-process controls• Lot release• Stability• Characterization• Comparability• Reference standard qualification• Analytical similarity assessments• Trending analysis during development and post-licensure• Deviation investigation

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A list of Essential Information for Analytical Methods to Be Used for Quality Control

• Principle/Scope • Apparatus/Equipment• Operating Parameters• Reagents/Standards• Sample Preparation• Standards Control Solution Preparation• Procedure• System Suitability• Calculations• Data Reporting

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Expectations for Analytical Method Validation

• Validation protocol: Validation studies are run according to an established validation protocol Method validation acceptance criteria are pre-established and documented

• Validation report:Validation characteristics typically include specificity, linearity, accuracy,

precision, range, quantitation limit, detection limit and robustness depending on the nature of the methods

Validation samples should be representative of the routine samples to be tested, and allow evaluation stability indicating properties (e.g., all peaks that could form during shelf life, if possible and applicable)

Pre-established method validation acceptance criteria must be met to support validation; If a method fails validation, root causes for the failure must be investigated, resolved, and the assay re-validated

Validation site and laboratory should be specified

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Expectations for Analytical Method Transfer

• Method transfer studies are run according to a method transfer protocol with predefined acceptance criteria for selected method performance parameters involved in both sending and receiving laboratories

• Same representative samples should be run in both sending and receiving laboratories

• For stability indicating analytical method, the same force degradation samples or the same samples reflecting the stability indicating properties should be run in both sending and receiving laboratories

• At minimum, accuracy and precision should be evaluated during method transfer (if a quantitative method)

• Characteristics of analytical methods should remain consistent across all the quality control laboratories for the transferred methods

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Expectations for Analytical Method Replacement

• Essential information of new analytical methods should be sufficient

• Method replacement should not be proposed until full validation results are available

• Analytical method comparability studies should be performed demonstrating that

the new method is ideally equivalent or superior to the original method and suitable for its intended purpose

The new method is not more susceptible to matrix effects than the original method

• Retention samples from pivotal clinical batches should be used to evaluate the new process-related or product-related variants or any new impurities discovered with new method

• Stability indicating properties should be evaluated if applicable

• Appropriate statistical analysis can be used to determine the equivalence of two methods

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Applications of Using Emerging Analytical Technologies

Characterization (CE, MS, UPLC etc.)

Lot release/Stability(CE, MS etc.)

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Theoretical Example of Using MS Analysis in Product Characterization

• Product: an IgG1 mAB, for IV injection• Charge heterogeneity is determined by CEX• Acidic peaks are characterized by MS containing a specific Met-oxidation which

impacts the potency (i.e., 8% Met oxidation at X corresponds to 90% potency); other PMTs have no impact on the potency; the level of Met oxidation at X is consistent (i.e., 4- 6%) in all drug substance batches

• A tighter acceptance criterion might be established for the acidic peaks or for the potency at drug substance lot release

Charge variants MS results

Acidic peaks Met –oxidation at X with 5%, Glin1, deamidation at Y

Main peaks Glin1, deamidation at Z

Basic peaks C-terminal lysine

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Theoretical Example of Using HILIC-UPLC-MS Analysis in Lot Release

• Product: an IgG4 mAB, for SC injection

• N-linked oligosaccharides released by PNGase-F are determined by HILIC-UPLC-MS

• The level of high mannose is around 12.3% which may impact the PK

• An acceptance criterion for high mannose determined by HILIC-UPLC-MS should be established for drug substance lot release

Oligosaccharide Relative amountG0F 42.6%G1F 33.4%G2F 8.0%G0 2.0%G2F+1NeuAc 1.7%High Mannose 12.3%

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Expectations of Using Emerging Analytical Technologies

• Method qualification study is expected for all the emerging analytical technologies to be used in product characterization

• The more complicated and new technology, more data are expected

• Method validation activities (e.g., full method validation, method transfer, method comparability study etc.) are expected for all the emerging analytical technologies to be used in lot release and stability

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Challenges of Using Emerging Analytical Technologies for Quality Control

• CE (Capillary Electrophoresis)

• MS (Mass Spectrometry)

• UPLC (Ultra Performance Liquid Chromatography)

• MAM (Multi-Attribute Method )

• More......

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Multi-Attribute Method (MAM)

• MAM is an attribute-specific LC-MS based peptide mapping method to identify and quantify multiple product-specific quality attributes at the amino acid level

• MAM workflow

Rogers, R. et al., The AAPS Journal (2018)

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Can MAM Replace Some Quality Control Methods?

• How equivalent is MAM to other quality control methods (e.g., CEX, CE etc.)?

• What quality attributes could be controlled at lot release and stability by MAM when replacing some quality control methods (e.g., CEX, CE, etc.)?

CEX MAM Non-reducing CE-SDS

Image source: Public available at internet

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Use of MAM for Quality Control

• Tremendous interest exists in transitioning this technology to routine use• Questions of using MAM for quality control: Is there sufficient accuracy and precision (e.g., various level of

artificial modifications due to sample preparation)? Is there a question of method sensitivity (e.g., lower sequence

coverage due to peptide separation method limitation)? What is the potential ability to determine unexpected variants (e.g.,

issues of software threshold setting up for data analysis)? Will it require frequent re-validation (e.g., new instrument, modified

method etc.)?

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Conclusions

• Analytical methods are key for product and process understanding

• It is critical to understand the limitations and uses of analytical methods during analytical method lifecycle management

• The expectations of using emerging analytical technologies are same as any other methods used for biotechnology products

• The newer technology, and the larger the role it plays in the control strategy, the more data that may be potentially necessary

• Communication is essential

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Acknowledgments

Cristina Ausin

Joslyn Brunelle

Shen Luo

Marjorie Shapiro

Joel Welch

Haoheng Yan