Analytical Elements of Module 3 for Biopharmaceutical ... · 4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy, specificity, etc…) 5. Validation

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Analytical Elements of Module 3 for Biopharmaceutical Products: Beyond S.4 and P.5

Nadine M. Ritter, Ph.D.President and Sr. Analytical Advisor

Global Biotech Experts, [email protected]

To do this, their control strategy is based on:

ICH Q6B: Specifications; Test Procedures and Acceptance Criteria or Biotechnological/Biological Products (August 1999)

Capabilities of the analytical methods

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Capabilities of the manufacturing process

Stability of the bulk substance and final product

Nature of pre‐clinical and clinical batches

Biopharmaceutics are molecularly complex and heterogeneous

Their heterogeneity must be characterized and controlled

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ONE Process, MANY Methods!

MULTIPLE ORTHOGONAL analytical methods are needed to measure all critical physical and functional characteristics

of a biological Drug Substance or Drug Product

© 2018 N. Ritter, Ph.D. © N.M. Ritter, Ph.D. 2019 3

Albrecht Dürer, “Rhinoceros” (1514)

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11 (12) CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino

1. Compositional, Conformational and Functional Characterization of Target Protein


CMC Analytical Data Packages =The Biomolecular “Story” of Each Rhino

1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)


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1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards



1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterization of Impurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,

specificity, etc…)


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specificity, etc…)5. Validation of cGMP Test Methods (e.g. confirmation of above parameters, plus

addition of data for method robustness and stability‐indicating capability)





addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)

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addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)

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addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)

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addition of data for method robustness and stability‐indicating capability)6. DP Formulation development (excipient selection, formulation stability)7. DS and DP Batch release data (manufacturing consistency and product quality)8. Extractable and Leachable Studies (risk assessment for DS; confirmation for DP)9. Degradation evaluation (establishment of stability profile, validate stability

methods, characterize degradants, assess comparability/similarity)

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methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)

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methods, characterize degradants, assess comparability/similarity)10. ICH Stability testing (accelerated and ongoing real‐time/real conditions)11. DS and DP Comparability assessment (during clinical development and post‐

approval)

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ProcessA

ProcessB

ProcessC


1. Compositional, Conformational and Functional Characterization of Target Protein2. Characterizatiompurities (Product Impurities and Process Residuals)3. Establishment and Bridging of Product Reference Standards4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy,




approval)BIOSIMILAR PRODUCTS ONLY:12. Analytical Similarity – Comparison of Biosimilar product to Originator Product

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ProductA

ProductB

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approval)BIOSIMILAR PRODUCTS ONLY:12. Analytical Similarity – Comparison of Biosimilar product to Originator Product

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The Harmonized CMC “Story Board”

• ICH Guidance M4Q(R1) (September 2002)

– Module 3 Quality (CMC)

– 3.2.S. Drug Substance

– 3.2.P. Drug Product

– 3.2.A. Appendices

– 3.2.R. Regional Information

• ICH M4Q Q&A (July 2003)

– The majority of clarifications and additions were on analytical issues associated with 3.2.S. and 3.2.P. sections

– Some Q&As add substantial details to the analytical ‘story’

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3.2.S. Drug Substance 1. General Information

1.1 Nomenclature

1.2 Structure

1.3 General Properties

2. Manufacture

2.1 Manufacturer

2.2 Manufacturing Process and Controls

2.3 Control of Materials

2.4 Control of Critical Steps and Inter.

2.5 Process Validation

2.6 Process Development

3. Characterization

3.1 Structure and Characteristics

3.2 Product and Process Impurities

4. Control of Drug Substance

4.1 Specifications

4.2 Analytical Procedures

4.3 Validation of Analytical Procedures

4.4 Batch Analyses

4.5 Justification of Specification

5. Reference Standards

6. Container Closure System

7. Stability

7.1 Summary and Conclusions

7.2 Post Approval Commitment

7.3 Stability Data

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My name is Rhino

I am big and the analytical data say that overall I look like this:


1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical labs that do QC release and stability testing of my DS

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1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer



2.4 Control of Critical Steps and Intermed.



3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytics used to control my DS raw materials and US/DS intermediates


1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical comparability studies done to check my DS process changes

ProcessA

ProcessB

ProcessC

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1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical data that prove my structure and function


1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical data that prove which degradants and impurities I could have

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1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical controls to keep my DS consistent


1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here how the QC methods used to measure my DS are conducted

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1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here is proof of how they can perform reliably and accurately


1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here is the gold standard rhino against which other rhinos are analytically compared

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1.1 Nomenclature

1.2 Structure


2. Manufacture

2.1 Manufacturer






3. Characterization




4.1 Specifications



4.4 Batch Analyses




7. Stability



7.3 Stability Data

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Here are the analytical data showing I am stable over time

1. Description and Composition2. Pharmaceutical Development

2.1 Components2.2 Drug Product2.3 Manufacturing Process Development2.4 Container Closure System2.5 Microbiological Attributes2.6 Compatibility

3. Manufacture3.1 Manufacturer3.2 Batch Formula3.3 Descr of Process and Process Controls3.4 Control of Critical Steps and Ints3.5 Process Validation

4. Control of Excipients5. Control of Drug Product

5.1 Specifications5.2 Analytical Procedures5.3 Validation of Analytical Procedures5.4 Batch Analyses5.5 Characterization of Impurities5.6 Justification of Specification

6. Reference Standards7. Container Closure System8. Stability

8.1 Summary and Conclusions8.2 Post Approval Commitment8.3 Stability Data

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3.2.P. Drug Product

Here is my DP form

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3.2.P. Drug Product

Here are the analytical comparability studies done to check my DP process changes

ProcessA

ProcessB

ProcessC








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3.2.P. Drug Product

Here are the analytical data showing the potential for leachablesforming in the DP

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3.2.P. Drug Product

Here are the analytical labs that do QC release and stability testing of my DP








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3.2.P. Drug Product

Here are the analytics used to control my DP formulation and filling steps

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3.2.P. Drug Product

Here are the analytics used to control my DP excipients








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3.2.P. Drug Product

Here are the analytical controls to keep my DP consistent

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3.2.P. Drug Product

Here how the QC methods used to measure my DP are conducted








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3.2.P. Drug Product

Here is proof of how they can perform reliably and accurately

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3.2.P. Drug Product

Here are analytical data on the DP degradants and impurities that I could have








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3.2.P. Drug Product

Here is the analytical gold standard DP rhino (if different from DS gold standard)

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3.2.P. Drug Product

Here are the analytical data proving I am stable over time

Any additional drug substance and/or drug product information specific to each region should be provided. Consult the appropriate regional guidance and/or regulatory authorities for additional guidance.

BIOSIMILAR PRODUCTSAnalytical data packages comparing Biosimilar Product to Reference Product

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3.2.R. Regional Information

Here are the analytical similarity data comparing a biosimilar rhino product to the reference rhino product

PRODUCTA

PRODUCTB

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Phase 1 CommercialPre‐ClinicalQUALIFY R&DMETHODS

QUALIFIED R&DMETHODS



PH 1 VALIDATEMETHODS

INITIAL PRODUCTCHARACTERIZATION

1ST REFERENCE STDCHARACTERIZATION

NEW REFERENCE LOTQUALIFICATIONS

PROCESS CHANGECOMPARABILITY



LOT RELEASE –DP LOTS




PRELIMINARYFORMULA TOX LOTS

STABILITY – INITIALFORMULATION

STABILITY – LEAD FORMULATIONS

STABILITY – FINALFORMULATION

STABILITY ‐ DP1 ANNUAL LOT

LOT RELEASE –DS LOTS

LOT RELEASE ‐ DSPHASE II LOTS



DS STABILITYTOX LOTS

STABILITY –DS CLIN LOTS



STABILITY ‐ DS1 ANNUAL LOT

PRIMARY/WORKNGREFERENCE LOTS

NEW REFERENCE LOTQUALIFICATION

PH 3 VALIDATEMETHODS

PH 2 VALIDATE METHODS

RE‐VALIDATEMETHODS

FORMULATIONSCREENING STUDY

DP STABILITYTOX LOTS

FORMULATIONSELECTION STUDY


SELECT QCDS and DP METHODS

EXT & LEACHSTUDY

FORM or C/C CHANGERE‐DO E&L

SELECT R&DDS and DP METHODS

Phase 2 Phase 3

COMMERCIALSPECIFICATIONS

PHASE 3 CLIN LOTSPECIFICATIONS



PRECLIN LOTSPECIFICATIONS

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LOT RELEASE –DP TOX LOTS

LOT RELEASE –DS TOX LOTS

ICH ACCELERATEDSTABILITY DATA

VALIDATESTABILITY METHODS

FORCED DEGRADATIONSTUDY DATA

RE‐VALIDATESTABILITY METHODS

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Initial Clinical CommercialPre‐Clinical

VALIDATEMETHODS

VALIDATE QCMETHODS

RE‐VALIDATEQC METHODS

ICH ACCELERATEDSTABILITY DATA

1ST REFERENCE STDCHARACTERIZATION

REFERENCE STDBRIDGING

NEW REFERENCE LOTQUALIFICATIONS






STABILITY – INITIALFORMULATION

STABILITY – FINALFORMULATION

STABILITY ‐ DP1 ANNUAL LOT




DS STABILITYTOX LOTS



STABILITY ‐ DS1 ANNUAL LOT

PRIMARY/WORKNGREFERENCE LOTS

FORCED DEGSTABILITY METHODS

RE‐VALIDATESTABILITY METHODS

FORMULATIONOPTIMIZATION STUDY

DP STABILITYPRECLIN LOTS


EXT & LEACHSTUDY

FORM or C/C CHANGERE‐DO E&L

SELECT QCDS and DP METHODS

Add’l Clinical

COMMERCIALSPECIFICATIONS

ADD’L CLIN LOTSPECIFICATIONS

INITIAL CLIN LOTSPECIFICATIONS

PRECLIN LOTSPECIFICATIONS

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LOT RELEASE –DP TOX LOTS

LOT RELEASE –DS TOX LOTS

BIOSIMILARITY

ANALYITCALSIMILARITYSTUDIES:• PRIMARY• SECONDARY• TERTIARY• HOS• FUNCTIONAL

ANALYSES• ACCELERATED

STABILITY• SIDE BY SIDE

FORCED DEGRADED

SIMILARITYSPECIFICATIONS

QUALIFY R&DMETHODS

CHARACTERIZEREFERENCE PRODUCT


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The CMC dossier should tell each Rhino’s complete analytical story:

“Here is evidence proving my complexity and heterogeneity*, and here is how it is controlled

and maintained consistently over time”


*Each biosimilar Rhino’s analytical story includes:“Here is evidence of how my complexity and heterogeneity compares to their complexity

and heterogeneity”

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THANK YOU!


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Documents

Analytical Elements of Module 3 for Biopharmaceutical ... · 4. Qualification of All Test Methods (e.g. establish linearity, precision, accuracy, specificity, etc…) 5. Validation