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EAS 2015 Disso Presentation_JHH_final
- 2. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 2 • Dissolution Testing – a Review – General Expectations – Role of Dissolution – General Considerations – In Vitro • Applications of Dissolution Testing • Expectations – Biorelevant Dissolution Testing – Clinical‐Relevant Dissolution Specification • Collaborative Efforts during Development • Phase Dependent Strategy for Method Development • Dissolution Testing ‐ Limitation • Concept of Curve Matching • Robust Product • Think Outside the Box & Summary Outlines
- 3. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 3 A Dissolution Test is Expected to be: • Appropriately Discriminatory – Formulation – Materials & Compositions (CMA*) – Manufacturing Parameters (CPP*) – Lubrication – Blending Time – Compression Force, …, etc. – Stability – Temperature, Humidity, Photosensitivity, and other Stresses • Rugged/Robust • Reproducible (Reliable) CMA: Critical Material Attribute CPP: Critical Process Parameters Review – General Expectations
- 5. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 5 • Any in vitro dissolution method can be utilized • The method once defined should be the same for all formulations tested (within a project/product) • The preferred dissolution apparatus is USP apparatus I or II used at compendially recognized speeds • An aqueous medium either water or buffered solutions not exceeding pH 6.8 is recommended • The coefficient of variation (% CV) for mean dissolution of a single batch should be less than 10 % (Tighter %CV is expected for a good spec setting.) • At least 80 % dissolution should be achieved with the proposed test Review – General Considerations ‐ In Vitro Dissolution Testing (Source: Dr. Patrick Marroum with slight modification.)
- 6. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 6 • Quality control test to assure batch to batch consistency (Be able to discriminate formulation/process differences.) • Surrogate for bioavailability – When different in vivo drug release characteristics are observed, the dissolution method is expected to be sensitive to pick up the differences even in the absence of a predictive IVIVC test • Use for Justification of Biowaiver – Demonstration of Bioequivalency (for BCS 1 and BCS 3 products) Applications of Dissolution Testing
- 7. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 7 Expectations – Biorelevant Dissolution Methods? Biorelevant Dissolution Testing* Predictive? In Vitro In Vivo It is desirable to have a method (any method) which is able to predict the in vivo drug performance! Biorelevant Media: • FaSSIF • FeSSIF • Carbonate media Equipment: • TIM/TNO • Artificial Stomach‐ Duodenum Model Methods: • Artificial Stomach− Duodenum Model • Biphasic Dissolution • pH Dilution Method Knowledge obtained with in vitro tools aids understanding of DP in vivo performance However, for dissolution testing, there is NO biorelevant method until we can prove the clinical relevancy.
- 8. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 8 Expectations – Clinical‐Relevant Dissolution Specification (Biorelevant) Dissolution Method Clinical Relevant Dissolution Spec Reflect Performance In Vitro In Vivo (Matching the profiles! ‐ Deconvolution & Convolution) Analytical Deliverable: Dissolution method to support Clinical‐relevant Dissolution Specifications!
- 10. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 10 Phase Dependent Strategy – FIH (Pilot) Activities Goal Needs • Physical/Chemical properties of API • Compatibility of Excipient • Identify BCS Classification of the drug if possible Formulation: Suitable Formulation Disso: Full Drug Release PK: Basic Info (e.g. Tmax, Cmax, and AUC) Formulation Design /Operation principle For BCS 1 and 3 drugs, follow the FDA new guidance using the standard apparatus and conditions. For BCS 2 and 4 drugs, Standard Apparatus and Conditions with minimal modifications Responsibilities: • Formulation – Pilot Samples • Analytical – Assay • PK – Clinical Results
- 11. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 11 Phase Dependent Strategy – Phase 1b – 2b (Development) Activities Goal Needs 1. Explore in vitro drug release behaviors under different disso method conditions. 2. Formulation screening by disso method and compare disso data to clinical results. 3. Select the most relevant disso method according to formulation/process understanding and clinical results. •Material/process Variability CMA’s & CPP’s •Minimize method variability Formulation: • Formulation variability • Process sensitivity Dissolution: • Reliable/Reproducible Method • Clinical relevance may not be established at this time but should be evaluated as early as possible PK: • Animal studies may be used during early development • Deconvolution Absorption Profiles • Establish Target Dissolution Profile • Building the knowledge around Formulation and Process • Design Space – Explore extreme conditions • Clinical study to evaluate key formulation/process attributes on the drug release characteristics? ($$$ Cost & When to do it?) • QbD: Decision whether in‐vitro drug release (disso) be used as end point to define design space and control strategy • BCS Classification defined (or earlier!)
- 12. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 12 Phase Dependent Strategy – Phase 1b – 2b (Development) – continued Responsibilities: • Formulation – To prepare samples with different key attributes (i.e. formulation/process variables) to evaluate the impact on dissolution profile • Analytical – Fully understand method variables, i.e. pH impact, RPM, addition of surfactants, and Apparatus differences. Select the appropriate method which can discriminate the formulation/process variables. Minimize the method variability. • PK – Deconvolution absorption profiles. Define BCS classification. (Animal studies may be used during early development.)
- 13. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 13 Phase Dependent Strategy – Phase 2b ‐ 3 (Final Stage) Activities Goal Needs 1. Process Validation. 2. Stage II (Final Stage) Method Validation. 3. IVIVC, as feasible Formulation: • Process control – Design Space Control Strategy Dissolution: • Method is sensitive to CMA’s and CPP’s • Method is capable to reject non‐bioequivalent batches PK: • Identify BE or non‐BE batches • Sound product knowledge with fully understood formulation/process • Identify CMA’s/CPP’s and set up control strategy to assure product quality • Dissolution method is discriminating, robust and reproducible which can be used for QC purpose • Clinical data with non‐BE samples to support dissolution specification
- 14. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 14 Dissolution Testing ‐ Limitation • Using biorelevant media and specially designed equipment for dissolution testing do NOT guarantee clinically relevant results! • Drug substance and formulation properties should be considered in the in vitro method development, and the process is a case‐by‐case activity.
- 19. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 19 Think Outside the Box! • How much has HPLC been improved over the last 30 years? • How much has Dissolution Testing changed over the last 30 years? Could we bring more freedom in operating Dissolution Apparatus? USP App 1 and App 2 are the most QC friendly apparatus! How about: • pH Changes √ • Temperature ≠ 37⁰ C (?) • RPM Ramping (?) • Other Controls (?)
- 20. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 20 • A Dissolution Test to support clinically relevant acceptance criterion/criteria can not be developed by Analytical/Disso group alone. It has to be a strong collaboration among Analytical, Formulation, and PK groups. • Formulation has to specially prepare some “unordinary samples” to see the impact from CMA’s/CPP’s to the drug release for both in vivo and in vitro. • PK group to design biostudies and collect clinical data. Establish the target profile for studied product. Collect in vivo data for those “unordinary samples” for information. • Analytical to select the most appropriate dissolution testing conditions to match the “target dissolution file”. Compare the dissolution profiles of those “unordinary samples”, and set up the relevant specification. • The teams working together to consolidate all the findings and define the “control space” for manufacturing process (control strategy) to assure the quality of the product. Summary
- 21. Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 21 Thanks to the following providers for the pictures used in this presentation: • David Tan, AbbVie Singapore – Slide 14 • www.drug‐dissolution‐testing.com ‐ Slide 14 • Electrolab India P. Ltd. – Slide 19 • Wikimedia Commons, the free media repository – Slides 14 & 19 Acknowledge