aaps small molecule view of ich m10 draft guideline · •fda perspective of m10 conveyed as...

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AAPS Small Molecule View of ICH M10 draft Guideline

Steve Lowes – Q2 Solutions, Bioanalytical and ADME Labs COMPANY CONFIDENTIAL

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• Accommodating comments and perspectives from Industry and Regulators

– Typically blended comments throughout this presentation - lot of synergy with FDA regulators at the Silver Spring

workshop

• FDA perspective of M10 conveyed as setting minimal requirements expected – “you may choose/need to

do more or you may defend doing the minimum”

• Appeal for common interpretation :

– When education of guidance language lags the ‘in-effect regulatory language’ we can expect observations and

citations with the consequential actions and results

IntroductionSilver Spring AAPS Workshop ICH M10 (10th-13th June, 2019)

Company Confidential

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• General consensus is that the M10 draft Guideline is well written and represents current thinking around

regulated bioanalysis topics

– Guideline does not purport to be a Best Practice or an Academic Treatise

– Latitude exists to do appropriate, good science

– “Let’s refrain from getting bogged down in the details”

• Scope of M10 draft continues to generate discussion and warrants consideration of edits for finalization of

the Guideline

– i.e. Scope may be considered overly broad

• Applicable to pivotal nonclinical TK/PK studies – including those falling under the scope of the GLPs

– However, other nonclinical studies can be used for regulatory decision making around safety and efficacy :

• E.g. ‘The Animal Rule’ – animal model used as a surrogate for human studies (e.g. Anthrax tolerance studies)

• Recommend In-Vitro studies be clarified as Out of Scope

• Can full-validation be truly possible for non-liquid matrices?

• Recommendations on clarifying and revising the scope were frequently referenced and are expected to be

a consistent point in public comment feedback

Scope & General


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• Proposed for Lines 102-107: This guideline describes the method validation that is

expected for bioanalytical assays that are submitted to support regulatory submissions.

The guideline is applicable to the validation of bioanalytical methods used to measure

concentrations of chemical and biological drug(s) and their metabolite(s) in biological

samples (e.g., blood, plasma, serum, other body fluids, or tissue) obtained in nonclinical

TK studies falling under the scope of the GLPs that are used to make regulatory

decisions, nonclinical PK studies that are conducted as surrogates for clinical studies

when no human efficacy trials can be conducted, and all phases of clinical trials in

regulatory submissions for which a primary objective of the study is to assess,

compare or characterize drug exposure.

ScopeRecommended language


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• Emphasis on the fundamentals:

– Applicant (Bioanalyst) should understand the analyte(s) of interest

– Develop an assay that is suitable for validation

• “…. optimizing the procedures and conditions involved with extracting and detecting the analyte.”

– Where are we going with the word “optimization” as it applies to development of an assay?

– Sensitivity optimization was of particular note

• Extraction recovery

• Instrumentation

– Correlate to intended use of the assay or “the method is ready for validation”

• Regulatory value in understanding the background and life cycle of the assay

– Changes in procedures

– Unusual aspects of the assay

– Resolution of issues

Method Development


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• Method Development reports are not proposed

– Auditable documentation should support the methodology that is validated

– Want to be able to capture the life-cycle of the assay

• Especially for problematic assays

• Any special precautions/conditions/difficulties

– However concern around overly-broad language such as

• “consider aspects of any prior analytical methods that may be applicable.” (Line 130)

• Clarification in Scope may be appropriate around method development expectations

Method Development(Continued)


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• Matrix Effects

– Need to demonstrate that matrix effects are understood

• I.e. The potential to have a quantitative impact upon the assay

• Show transparency of the assay to different matrix lots

– Demonstrate in 6 independent lots of matrix

• Doing so at LQC and HQC – why conduct in triplicate? Proposed: Use of singlet analysis in each lot.

• What if 1 (or more) lots fail?

– Recommend establishing a priori procedures to defend the assay selectivity for the intended use

• Multiple lots of matrix (i.e. 6 independent lots) from nonclinical species was questioned

– Quantitative matrix factor (and/or normalized matrix factor) experiments are not required

• Consider whether such experiments would be appropriate for a particular assay

Full ValidationSelectivity


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• Regression model language (Lines 294-295) refers to simple regression model that is selected according to

written procedures

– Consensus that a standard operating procedure is overly burdensome for selection of a LC-MS calibration curve fit

• Specific to cases of using replicates to establish calibration curves (Lines 309-316) the draft calls for

rejection of calibrator levels if <50% of replicates meet acceptance criteria followed by re-evaluation of the

curve, including regression analysis.

– This causes some confusion on how to handle analytical runs where there are calibrator failures

– Proposed that this section is clarified, deleted or additional training material with examples be provided.

Full ValidationCalibration Curve and Range


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• Quality Control (QC) levels

– Continued debate around the medium QC level

• Arithmetic mean QC (Mid-QC) vs geometric mean QC (GM-QC)

• Considering a 1st order PK profile, by definition, most sampling points will generate concentrations below the arithmetic mean

• Therefore, the GM-QC can be expected to be more representative of study samples

– Proposed language that reflects LBA language for defining the mid-QC

• “…around the geometric mean of the calibration curve range (medium QC) and …”

• Evaluation of Accuracy and Precision (A&P)

– The objective of understanding the true A&P inclusive of data that fails a priori +/-15% criteria

– Confusion arises “if the within-run A&P criteria is not met in all runs.”

– Followed by calculate “an overall estimate of within-run A&P for each QC level”

– i.e. how does this differ from between run A&P?

– Proposed: Clarify the intent and objective here

Full ValidationAccuracy and Precision


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• Minimal discussion on Carryover language:

– Well established practice of evaluating carryover with a blank/zero sample after a ULOQ injection

– Only discussion was regarding number times carryover is evaluated in a validation

– Proposed: Conduct 3 times:

• 1 x each A&P run

Full ValidationCarryover


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• Dilution QCs received significant discussion

• Debate around whether dilution factors demonstrated in validation need to be repeated as a QC check in

sample analysis

• M10 language states “Dilution ratio(s) applied during sample analysis should be within the range of the

dilution ratios evaluated during validation.” (Line 377)

• Reminded of FDA statement – “M10 sets a minimal guidance”

– AAPS wrap up point: “If you prefer an internal control of QC dilution factor in sample analysis then OK, but lets not

force that into Guidance language.”

• The QC discussion extended to calibration range (Lines 553 – 567) and changing this to reflect the

concentrations of study samples … ‘where possible’

Full ValidationDilution Integrity


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• Co-medication impact on stability was one of the most concerning topics

– Lines 403-405 “If multiple analytes are present in the study samples (e.g., studies with a fixed combination, or due to a

specific drug regimen) the stability test of an analyte in matrix should be conducted with the matrix containing all of the

analytes.”

• Discussion conclusions:

– Co-med stability should be a separate section and be independent of modality (i.e. NOT small molecule specific).

– Provide options for a paper argument in lieu of actual matrix stability measurement.

– Consider a tiered approach for stability, including bench top assessment before long term stability measurement is

performed.

– For co-formulated combination, provide options to use other in-vitro or CMC data to support matrix stability.

– Don’t interchange ‘analyte’ with ‘dosed compound’ terminology

Full ValidationStability


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• Proposed language for co-medication stability experiments:

For fixed dose combination and specific drug regimen where

primary objective is PK assessment, the stability test of an

analyte in matrix should be conducted with the matrix

containing all of the dosed compounds.

Full ValidationStability


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• Good agreement that -20°C stability should cover -70°C stability

• Recommend to not include whole blood stability for serum. (Line 463)

• Recommend to delete the section pertaining “process stability” (section 3.2.8 part(4)). No additional data is

provided by this experiment. I.E. Reinjection reproducibility suffices the practical need.

• The current interpretation from the industry does not recognize the need for using three separate tubes for

matrix stability. It is recommend 3 aliquots from a single tube per concentration per time point be used in

matrix stability testing.

• Proposed: Stability of the analyte in the studied matrix is evaluated using low and high concentration

stability QCs. Aliquots of the low and high stability QCs are analysed at time zero and after the applied

storage conditions that are to be evaluated. A minimum of three stability QCs should be prepared and

analysed per concentration level/storage condition/timepoint.

Full ValidationStability Cont. : Processed Sample Stability, -20 °C vs -70 °C and multi-tube stability testing


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• (Line 974): If stability is established at one facility it does not necessarily need to be repeated at another

facility.

– However: Risk of transferring stability data between CRO/Pharma (what happens if the stability data is deficient, who

gets the 483?). A company/CRO may consider stability data owned by another company as not shareable.

• A change from one matrix within a species or changes to the species within the matrix = Partial

Val?…hardly!

– Maybe not stock solution stability but does need everything else

Partial and Cross ValidationsPartial Validations


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• Of significant concern was reference to cross validation across studies:

Data are obtained from different fully validated methods across studies that are going to be combined or compared to

support special dosing regimens, or regulatory decisions regarding safety, efficacy and labelling.

• Cross validation is not generally required to compare data obtained across studies from different

laboratories using the same or different validated method at each site.

• Propose: Include why cross validation is needed e.g. “Cross validation is conducted to evaluate the bias

between methods (or laboratories) such that the results from studies using them can be appropriately

interpreted. Cross validation allows the comparison of two methods (labs) and informs us how they are

related”.

• Additional comments around Lines 1013-1015:

– Are incurred samples always required for cross validations? Concern over generating secondary results on clinical

samples. Exclude non-clinical samples from requirement to use incurred (study) samples.

• Suggest language change to “use QCs and/or study samples”

Partial and Cross ValidationsCross Validations


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• Most significant discussion around repeat analysis was specific to Incurred Sample Reanalysis (ISR)

– ISR is not a method validation activity. Therefore edit lines 923-925 to read:

“Therefore, ISR is a necessary component of bioanalytical method validation. is needed to provide necessary confidence

that the validated bioanalytical method is delivering reliable data for the study samples. It is intended to verify the

reliability of the reported sample analyte concentrations and to critically support the precision and accuracy

measurements established with spiked QCs.”

• Additional recommendations:

– ISR should be limited to specific studies listed in M10 (Lines 927-930)

– The extent of ISR depends upon the analyte and the study samples and should be based upon an in-depth

understanding of the analytical method and analyte. For ISR, reanalyze about 10% of the number of samples, with a

minimum of 20 and a maximum of 100 samples.

Study Sample AnalysisReanalysis of Study Samples


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• Other repeat analysis discussion regarding specific case of a value needing to be confirmed (e.g. pre-dose

sample with measurable concentrations):

– Currently M10 calls for replicate determinations (if sample volume allows) – Line 599

– Proposal: Specify with “minimum of duplicate determinations”

Study Sample AnalysisReanalysis of Study Samples


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• Concern that recommended documentation (Table 1) is excessive and impractical

– Reference to logs, run sheets and other specific types of documentation

– Specific storage locations/conditions of reagents, solutions and matrix should be considered lab specific meta data

and not appropriate for validation and bioanalytical reports

– Chain of custody information is important but may not be appropriate to include in bioanalytical report and submission

documents

– Remove requirement for granular data including blank matrix lot #s, and instrument ID #s

• Chromatograms and associated data

– Standardize on 20% chromatograms for BA/BE and 5% others with additional chromatograms when requested

– Integrated chromatograms consistent with final data – original/raw chromatograms retained at bioanalytical site

– Correspondence pertaining to study conduct should be available with study records and don’t need a separate file.

– Clarity should be provided what type of documentation is needed for inspection audit reporting.

Documentation


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• Key items that AAPS Workshop concluded deserve attention (for small molecule bioanalytical assays):

1. Scope of the Guideline

2. Clarification on Method Development expectations (e.g. in the Scope)

3. Clean up the mid-QC confusion (e.g. use a geometric mean QC)

4. Fine tune requirements language around co-medication stability experiments

5. Remove requirement for multiple tubes in conducting stability experiments

6. Clarify expectations on when cross validation assessments should be conducted (i.e. not

across studies)

7. Appeal to limit the ISR experiment (e.g. in Scope and how executed)

8. Documentation requirements

Conclusions


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• Faye Vazvaei and rest of Silver Spring workshop organizing committee

• Speakers, Panelists and Moderators

• AAPS Staff

Acknowledgments


aaps small molecule view of ich m10 draft guideline · •fda perspective of m10 conveyed as...

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