Dissolution Data in New and Generic Drug Regulatory Submissions: US FDA Perspective Vinod P. Shah, Ph. D. Pharmaceutical Consultant (Formerly with US FDA) International Annual Symposium on Dissolution Science Disso India 2015 Society for Pharmaceutical Dissolution Science Goa, India, Aug 31 – Sep 1, 2015

Dissolution Data Dissolution information is very pivotal for assuring product quality and performance Should be based on QbD principles and design space Dissolution profile comparison – f2 criteria Dissolution data are required - For drug approval To set specifications for batch to batch release It must meet compendial (USP) tests For biowaiver based on dissolution (lower strength, BCS 1 and 3, SUPAC related changes)

Dissolution Data Immediate Release Dosage Form Apparatus, dissolution medium, agitation Single time point, Profile Capsules, use of enzyme Sparingly water soluble drugs, use of surfactant Quantitative rupture test for liquid filled capsules Extended Release Dosage Form Profiles, multi-media, multi-agitation Specifications – 3 or more time points Dissolution studies in alcohol

Dissolution of Capsules Soft Gelatin and Hard Gelatin Capsules

Dissolution – Gelatin Capsules Capsules – Pellicle formation due to cross linking Use and selection of enzyme (2nd tier) based on pH of the dissolution medium (dm) Dissolution medium with pH equal or below 4.0 Enzyme pepsin – activity of NMT 750,000 U/L of the dm. Dissolution medium with pH above 4.0 and below 6.8. Enzyme papain – activity of NMT 550,000 U/L of the dm or bromelain – activity of NMT 30 GDU/L of dm. Dissolution medium with pH equal or above 6.8. Enzyme: pancreatin – activity of NMT 2000 U/L of the dm. 2-step Tier II method for poorly soluble drugs using surfactant media . Pre-soaking with enzyme – if surfactant is in the dm.

Dissolution in Alcohol Media

ER Products - Dissolution Studies in Alcohol Due to concerns of dose dumping when taken with alcohol, additional dissolution testing using various concentrations of ethanol in the dissolution medium is required: - T and R product, 12 units in each case, data collected every 15 minutes for 2 hours Proposed method (without alcohol) 5% (v/v) alcohol 20% (v/v) alcohol 40% (v/v) alcohol (e.g., Morphine, Cyclobenzaprine, Methylphenidate HCl, Dexmethylphenidate HCl, Oxycodone, Trazodone, Bupropion, Venlafaxine, Lamotrigine, Quetiapine Fumarate, Ropinirole)

FDA: New Drugs Setting Dissolution Specifications Current Practice Clinical and biobatch Discriminating dissolution method Completeness Focus on mean Variability IVIVC ? Quality problem Degradation? Stability? Formulation? Risk Based Evaluation Assess and manage risk Risk informed decision making Setting Specification Problem Solving General Strategy Adopted from John Duan/FDA presentation at USP on 3/25/2014

Risk Informed Decision Making Risk Assessment What can go wrong? What is the likelihood it would go wrong? What are the consequences? What is the chance to detect? Knowledge Inventory What information will be most useful What knowledge is already available What information is not available Adopted from John Duan/FDA presentation at USP on 3/25/2014

Generic Drugs: Regulatory Dissolution Method Immediate release and Delayed Release Products Generally USP method, which is most of the time same as NDA method. FDA recommended method published in FDA data-base Extended Release Products Based on Biobatch It can be different from manufactuerer to manufacturer. OGD tries to achieve consistency in selecting dissolution methods for generic extended-release (ER) products In Quality by Design (QbD) paradigm, it may be necessary to develop dissolution method for ER products case-by-case basis

Root Causes of Dissolution Changes Stability Slow down, Increase in variability Quality problem Chemical degradation, Formulation change, Manufacturing process, Gelatin cross linking Nature of the drug, Excipients (corn starch contains stabilizer), Storage conditions Heat and humidity

Biopharmaceutics Classification System (BCS)

Biopharmaceutics Classification System* It is a framework for classifying drug substance based on its solubility and permeability Drug Substance (API) classified into 4 classes: Class 1: Highly Soluble / Highly Permeable (HS/HP) Class 2: Low Solubility / Highly Permeable (LS/HP) Class 3: Highly Soluble / Low Permeability (HS/LP) Class 4: Low Solubility / Low Permeability (LS/LP) It is a drug development tool to justify ‘biowaiver’ in conjunction with the dissolution of the drug product. *GL Amidon, H Lennernas, VP Shah, JR Crison. A theoretical basis for a biopharmaceutics classification system: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 12: 413-420, 1995 FDA Guidance - Waiver for Class 1 and Class 3 Drugs

Similarity Factor f2 Rt = % drug dissolved of reference product at time t Tt = % drug dissolved of test product at time t n = number of time points Minimum of 3 time points (zero excluded) Dissolution of R and T under same conditions 12 units (one / vessel) for each batch Only one measurement should be considered after the comparator product has reached 85 % dissolution (or asymptote is reached) RSD: ≤ 20% at early time point & ≤ 10% at higher time points Ref: VP Shah. Dissolution Technologies: 6(3), Aug1999.

USP Tests

Drug Product Quality Tests and Drug Product Performance Test Drug product tests are divided into two categories (1) Those that assess general quality attributes and (2) Those that assess product performance, i.e., in vitro release of the drug substance from the drug product. Quality tests assess the integrity of the dosage form, whereas performance test assess drug release and other attributes that relate to in vivo drug performance. Taken together, quality and performance tests assure identity, strength, quality and purity of the drug product.

Drug Products – USP Tests Quality Tests and Performance Test Compendial requirements Monographs Product Quality Tests Identity, quality, purity, strength, assay, potency, content uniformity Product Performance Test Dissolution IR dosage forms; S1, S2, S3 MR dosage forms 12 Units – Ranges; L1, L2, L3

USP Dissolution Tests USP Apparatus 1 and Apparatus 2 FDA – Mechanical Calibration USP – Mechanical calibration + Performance Verification Test (calibrator, Prednisone tablet) <711> Dissolution <724> Drug release <1092> The dissolution procedure: Development and Validation <1094> Capsules – Dissolution Testing and Related Quality Attributes USP Apparatus 3, 4, 5, 6, 7

Quality by Design (QbD) FDA is encouraging the use of QbD as an approach to speedup product development As of January 2013 FDA requires all new ANDA filings to be based on QbD principles. ------------------------------------------------------------- Lack of understanding and misconception

Quality by Design (QbD) Use of QbD concept Demonstrates knowledge of the product Identifies possible sources of variability and risk Allows assessment of product quality attributes Forms the basis of continuous improvement

Product Lifecycle and QbD – Pharmaceutical Quality Assessment System for the 21st Century, FDA, December 2009

Principles in QbD Design space Process control strategy Process understanding Experimental strategies Design of experiments (DOE) Risk management Process and product robustness

QbD Guiding Principles Drug Release Rate Dissolution testing is a tool for Product development and optimization Product characterization Establishing performance test A clear distinction of the purpose for which this tool is to be used is necessary QC tool vs. waiver of in vivo studies

Product Specifications Specifications are chosen to confirm the quality of the drug product. It should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug product. Specifications are binding quality standards. Specifications should refer to relevant development data, pharmacopeial standards, test data of batches used in toxicology and clinical studies, accelerated and long term stability studies, reasonable range of expected analytical and manufacturing variability.

Drug Product - Safety, Efficacy, Quality The safety and efficacy of new drug product is established thru toxicity and clinical studies. The drug product safety and efficacy for the generic product is established by it being pharmaceutically equivalent and bioequivalent, and thus therapeutically equivalent. The quality of the product is ensured thru product identity, strength, purity, assay, potency, content uniformity, dissolution (for solid oral dosage forms) and being manufactured under FDA’s good manufacturing practice. The approved drug product should also conform to the drug product performance criteria.

Dissolution Progressive Applications … Reducing Regulatory Burden …

Ref: VP Shah. J Pharm Sci. 102: 2895-2897, 2013.

Progressively Reducing Regulatory Burden GENERIC DRUGS Optimizing Product Performance Maintaining Product Quality Tools BE Studies ANDA / BE Dissolution BCS Lower strengths IR and MR Biowaiver NDA / BA In Vitro Drug release Q1, Q2, Q3 Lower strengths Semisolids Biowaiver Ref: VP Shah et.al., The AAPS Journal, 16 (4): 621-624, 2014 Dissolution IR - Optimum Bioavailability Medicines Compendium

Role of Dissolution Testing in Regulating Pharmaceuticals Increasingly, in vitro dissolution testing is relied on to assure product performance. An appropriate dissolution test procedure is a simple and economical method that can be utilized effectively to assure acceptable drug product quality. Appropriate dissolution test can be used as a surrogate marker for Bioequivalence.

Conclusions Dissolution data should be based on QbD principles and design space Dissolution data in NDA and ANDA regulatory submissions are used for drug approval to set product specifications Regulatory changes are recommended to assure its intended purpose of product quality should reflect (your) product characteristics and performance

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