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Nagesh Bandi, Ph.D. Executive Director, GRACS-CMCMSD

Overview of Clinically Relevant Dissolution Specifications: Technical Considerations & Regulatory Expectations

Jun 13, 2018

New Pharmaceutical Frontiers; SINDUSFARMA - IPS / FIP - ANVISA

We Have a Shared Goal

Patient Risks

Development & manufacturing efficiency

Availability of high quality medicine to the patient

Achieved through science and risk-based methods and specifications

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Apply Good Science to Achieve Desired State

Link Good Manufacturing Practices (GMPs) to Clinical Performance

• Scientific basis for rational cGMP decision-making• Evaluate linkage between critical quality attributes vs. clinical outcomes

(safety/efficacy)• Manufacture a product at commercial scale with consistent high quality

Ultimately, good science leads to enhanced understanding of a given product & process and helps to link quality with clinical performance

Clinical performance = efficacy and safety as described in the label and derived from the

clinical trials

“Fit for use” cGMP products meet established

quality attributes (Purity, Strength, Identity,

Bioavailability/delivery, etc.)

Strong Public Health

Protection

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Science & Risk-based Development Approaches –Linking Process/Product /Patient

Product

Patient

Process

Clinical

Outcome

Critical Quality

Attributes

Material Attributes &

Process Parameters

Moore C, 2011 DIA-AAPS Workshop

Consider clinical relevance

how do CQAs impact performance and safety?

• Utilize knowledge gained from pharmaceutical and clinical development

• Develop specifications focusing on critical quality attributes

• Minimize risks through process design, process controls, and control strategy

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What is Clinical Relevance?Correlation between product quality attributes and clinical performance (i.e., safety and efficacy)• Biomarkers (as surrogates for clinical outcomes)• Models (e.g., PK/PD model)• Allows some quality attributes to function as surrogate markers for clinical

performance• IVIVC/R

Considerations• Indication and Use –Acute vs. chronic dosing–Narrow vs. non-narrow therapeutic index drugs–Patient population – pediatric, elderly–Immediate Release (IR) vs. Modified Release (MR)–Drug delivery system

Dissolution can help us define clinical relevance6

Relating CMC Variables to Clinical Performance

• Establishing boundaries based on the clinical impact of the product design and manufacturing process is a challenge for biopharmaceutical scientists, as links need

to be established from formulation/process variables to product clinical performance.

Clinical Outcome

Manufacturing process

Formulation Composition

Dissolution Bioavailability/ Pharmacokinetics

Pharmacology/ Toxicology

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EfficacySafety

Phase 3

Commercial

How Can Dissolution Act as a Surrogate Marker for Clinical Performance?

• Clinically relevant dissolution specifications are a set of in vitro dissolution testing conditions (method) and acceptance criterion, that can identify and reject drug product batches that are not expected to be bioequivalent to clinical pivotal batches

Meeting the specification ensures that the product will result in similar safety and efficacy relative to formulation(s) used in pivotal trials.

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Specification may or may not indicate acceptable performance (limited batch data): Resulting in tighter specifications• Specifications may differ for different

health authorities

Specification is based on limited batch data so not accounting for variability in product, process, and method (regardless of clinical relevance)

• Example: batches that fail approved specification may still be equivalent (safety & efficacy)

In vitro performance not reflective of in vivo behavior leading to • variable bio performance • Stock out issues for critical drugs

(with no generics)

Dissolution Specification: Reasons for Getting it Right

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Robust Products & Submissions

Risk based approaches to change management based on development data.

Comprehensive dissolution development presentation in the dossiers

Align in-vitro quality standards with identified risk

Low risk products (e.g. BCS 1 and 3): Explore disintegration methods and specs

High risk products (e.g. MR) : Explore clinically relevant dissolution methods and specs

Identify high and low risk Products (immediate release/modified release

Early Read out of Biopharm Risks with cross functional input

(clinical, CMC, Biopharm)

Framework for a Risk-Based Dissolution Strategy

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CRS Road-Map ties it all Together!

Hermans, et al., The AAPS Journal, November 2017, Volume 19, Issue 6, pp 1537–154911

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Approach 1 Approach 2

• Clinical relevance of the dissolution specification is not always assured

• Specification is set only based on in vitro considerations and pivotal clinical batches

• This scenario, may result in a tighter specification limiting regulatory flexibility

Approach 2a Approach 2b

• Predictive and robust in vivo in vitro correlations attained

• Permits the setting of dissolution specifications based on targeted clinically relevant plasma concentrations

• Enables future flexibility for process and product changes

• Established range of release characteristics resulting in bioequivalence

• Clinical relevance is assured within established range,possibly with a wider dissolution criteria

• If adopted, could result in a safe space with appropriate regulatory flexibility

Lets take a Closer Look at the Approaches…

Low Risk Candidates (from a Biopharm Perspective): BCS class 1 & 3

API PropertiesBCS Class I/III

FormulationTablets/capsules with standard

Pharmaceutical Ingredients

ProcessWet Granulation/Roller

Compaction/Direct Compression

followed by compression or

encapsulation

Dissolution MechanismTablet disintegration or capsule rupture followed by

rapid solubilization of drug particles

Critical Quality

AttributeTablet disintegration/ Capsule

rupture time

BCS Class I/III IR products –potential opportunity to eliminate dissolution testing and replace with disintegration testing

Granule hardness

Granule particle size

Granule porosity

Development data includes impact of granule

properties on tablet disintegration or capsule

rupture time

Prior Knowledge Risk Assessment

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BCS Class 2 and 4 Drugs

Conduct Quality risk assessment

Understand Impact of manufacturing variables on clinical quality based on: prior knowledge+ dissolution data +

any available clinical data

Establish dissolution limit to ensure clinical quality

Define safe space based on dissolution limits

High Risk Candidates (from a Biopharm Perspective): BCS class 2 & 4

Safe Space is established by evaluating the clinical impact of the most relevant process variables and material Attributes.

For a BCS Class 2 (and 4) it is not possible to test all the potential tablet variants generated during the establishment of the manufacturing design space in the clinic.

Therefore need to establish a link between an in vitro test (dissolution) and safety and efficacy (volunteer PK).

The link serves as a surrogate for clinical performance and helps in defining the clinical impact of all variants (process and formulation). PBPK modeling and other modeling approaches also will provide directional input.

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Clinical Quality risk analysis

Pharmacokinetics (Safety and Efficacy)

API Physical Properties

Particle size

Crystal form

Formulation

Binder concentration

Disintegrant Concentration

Lubricant concentration

Granulation

Over granulation

Milling

Over milling

Under milling

Mixing

Speed

Order

Compression

Force

Speed

Narrow down list of parameters

Establish surrogate in-vitro method-Dissolution?

Establish link with Clinical efficacy

Understand impact of selected parameters on Dissolution

Link results to Clinical Effect

API Design Space Formulation Design Space

Process Design Space

Development Approach for BCS Class 2/4 Drugs

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Approach 2 - Examples

• Several examples are in the open literature and they follow more or less the proposed CRS road map including:

• Dickinson PA, Lee WW, Stott PW, Townsend AI, Smart JP, Ghahramani P, et al. Clinical relevance of dissolution testing in quality by design. Aaps J. 2008 Jun;10(2):380-90

• Kesisoglou F, Hermans A, Neu C, Yee KL, Palcza J, Miller J. Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In -Process Controls. Journal of pharmaceutical sciences. 2015 Sep;104(9):2913-22.

• These approaches differ when CRS is established

–AZ: as part of formulation and process understanding/development

–MSD: as part of process understanding

–Both strategies lead to CRS!

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Clinical Relevance is a Well Established Concept: Immediate Release

….. “determining the relationship between critical manufacturing variables and a response surface derived from an in vitro dissolution profile and an in vivo bioavailability data set”. …….

…. “To ensure continuous batch-to-batch equivalence of the product after scale-up and postapproval changes in the marketplace, dissolution profiles should remain comparable to those of the approved biobatch or pivotal clinical trial batch(es)”.

..”the dissolution specification should ensure batch to batch consistency and, ideally, signal potential problems with in vivo bioavailability”.

..”In an optimal case the in vitro results can mimic the in vivo situation”.

…”From a quality assurance point of view, a morediscriminative dissolution method is preferred, because the test will indicate possible changes in the quality of the product before in vivo performance is affected”.

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What are the Challenges?

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Approach for Clinically Relevant Specs (CRS) should align with

product risk attributes

Establishment of CRS on limited data (i.e., only the ranges covered in in-vivo studies) could result in

conservative specifications

Lack of aligned tools for biorelevant in-vitro evaluation

(“one size fits all”?)

Mutual (industry and regulators) agreement of an aligned approach to risk-based dissolution methods

and specifications

Challenges

Navigating the Global Regulatory Landscape: Registration Challenges for Dissolution

Acceptance CriteriaDissolution Media

Similarity Factor IVIVC/IVIVRGlobal Dissolution Package

Method

Statistics

Current State: One Product; multiple specs; multiple dossiers

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https://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLjvseW3pMgCFUk8PgodNosFpg&url=https://en.wikipedia.org/wiki/Tablet_(pharmacy)&psig=AFQjCNFUSD56oI1UeeHQnMm76Ex-sMUuXA&ust=1443897553873930

Next Steps

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• How can industry and regulatory agencies collaborate to facilitate implementation of science and risk-based approaches to setting dissolution specifications?

• Agreement to update regulatory policies and guidance to align with science and risk-based approaches to dissolution strategy

• Increase efficiency of submissions and meetings through understanding and alignment of expectations and achieve consistency across submissions

• Opportunities for convergence?

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