Bioassays for Establishing Equivalence Linking API and Formulation to their Biological Effect

Sid Bhoopathy, PhD Chief Operating Officer

Limited Access; Limited Success

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IMS Report: Declining Medicine Use and Costs: For Better or Worse? May 2013 and AAPS Local BE Workshop, November 2016 API | RLD | PD Specific

In Vitro Based BE

Attributed to lack of generic- Topicals

Ophthalmics

Locally Acting GI + additional CDPs

Slow down of unique generic drug product approvals PK Clinical End Point Studies In Vitro

Complex Ophthalmic

Complex Topical

Locally Acting GI

In Vitro Characterization Based Equivalence

Drug Substance

Drug Product

Active Ingredient & Excipient Attributes

Formulation Variables

Optimization

Formulation Function Characterization

Characterization of CPPs

DOE for Process Variables

Controlled Reproducible

Process

Target Product Profile

Q1/Q2 Similarity

Critical Quality Attributes

Input Process

Output Q3

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Characterization Based Equivalence

Which attributes to measure? Identifying key factors that impact BA

How to perform?

Outcome can be methodology dependent

Open-ended process optimization Interpretation of differences observed; do they matter?

No insights on site of action vs. formulation interaction Complex, multifactorial and layered biology API molecular diversity or multiphasic formulations

Q1/Q2 not possible

Unable to use approach; Constraint

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Deg

ree of C

om

plexity

Limitations

API | Formulation

Opportunity for Innovation

www.absorption.com

In Vitro CBE API | Excipients | Physicochemical Characterization

Therapeutic Equivalence

PK Assays: - Interaction - Accumulation

Effect Assays: - Enzyme

upregulation - Healing biomarkers

Site of Action ↔ Formulation | Bio-relevant

Integrated Assays

Augmented Q3 - Bioassays

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Characterization of CPPs

DOE for Process Variables

Controlled Reproducible

Process

Q1/Q2 Similarity

Input Process

Assays to Support Postulated Mechanism of Action

Formulation Function Characterization

Augmented Q3 Q3 Bio-relevant Tools

Accurate | Sensitive | Reproducible

Output

Drug Substance

Drug Product

Formulation Variables

Optimization

Target Product Profile

Critical Quality Attributes

Active Ingredient & Excipient Attributes

Bioassay Development

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Strategy Endpoint, methodology and mode of measurement

Optimization Various assay parameters Physiologically relevant conditions

Qualification Validation feasible Sensitive over a range of concentrations Reproducible Discriminatory

Validation Comply with relevant guidelines

Pivotal Performance assessment Multiple lots of RLD and Test formulations Quantitative Comparison

Bioassays - Integrated Effect

Local GI Dissolution, pH, viscosity, acid neutralizing capacity, re-dispersibility, specific gravity, PSD

Ophthalmic

pH, rheology, crystalline habit, re-dispersibility, surface tension, osmolality, buffer capacity, PSD

Topical

Crystal habit, rheology, PSD, pH specific gravity, water activity

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Inhibition Bioassay

Combined effect of changes to viscosity, dissolution, and specific gravity

Formulation Variant

Sensitive Selective Specific

Comparative Physicochemical Characterization

Bioassays - Orthogonal Measures

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Assay outcomes are complementary

Combined selectivity strengthens assurance of overall conclusions

API

TEST_43

TEST_75

TEST_06

RLD_72

RLD_66

RLD_63

RLD_23

RLD_10

RLD_02

0

5

10

15

20

25

Error bars are the standard deviation of the mean (SD);dotted lines bracket the range of the RLDs.

Formulations

Rate

of T

rans

fer

Test_79

Test_43

TEST_06

RLD_72

RLD_02

0

50

100

150

200

250

300

Error bars are the standard deviation of the mean (SD);dotted lines bracket the range of the RLDs.

Formulations

Capa

city

Con

stan

t

Confirmation of the same endpoint using a different assay or methodology

Closer to the targeted in vivo effect

Bioassay 1-Association Bioassay 2-Diffusion

Bioassays – Greater Relevance

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Quantify a single formulation property Evaluate multi-faceted formulation-related effect mechanisms Assess relevant interactions between doses

Bioassays – Mitigate Q2 Differences

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Early Action Bioassay Intermediate Action Bioassay Extended Action Bioassay

-20

-6.18

0

6.18

20

HQ vs OQ LQ vs. OQ API vs. OQ HV vs. OQ -6

-4

-3.24

-2

0

2

3.24

4

API vs OQ HQ vs OQ LQ vs OQ LV vs OQ

LB..UB

-80

-60

-38.2

-20

0

20

38.2

60

80

API vs OQ HQ vs OQ LQ vs OQ

LB..UB

Bioassays represent product effect via multiple mechanisms between doses

Selective to compositional differences

May be used to construct a zone of “no bio-impact" with Q2 differences

12

Pathways to Approval In Vitro CBE

Bioassays- Integrated Approach that links API to

Formulation Clinical Studies

Approach

Product Specific Guidance is required

Q1/Q2/Q3 IVRT comparison for

test and RLD formulations

Independent of Product Specific Guidance availability

Q1 Similarity Q2/Q3 differences may be

justifiable Orthogonal bioassays with in

vivo relevance that complement physicochemical characterization

Clinical Endpoint Site of Action PK

Risks & Probability of Success

Knowledge, capability and experience under progress

Frequent revisions to

guidance based on new knowledge

Product guidance is a

recommendation/guide not a roadmap

Success based on

Q1/Q2/Q3 being achieved limits utility

In vitro CBE risks mitigated with a “totality of evidence” approach

Knowledge, bioexemption

capabilities and experiences are growing

Wider product development

applicability Possible to overcome Q2 and

Q3 differences

Time consuming, expensive, potentially inconclusive

FDA Guidances

acknowledge difficulty in approach and requests Sponsors to propose alternative reproducible methods

Opportunity to innovate

to enhance patient access