1. 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

2. 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)

5. 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

6. Dissolution of Capsules Soft Gelatin and Hard Gelatin Capsules

7. 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 Enzyme pepsin – activity of NMT 750,000 U/L of the dm.
Dissolution medium with pH above 4.0 and below 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 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.

8. Dissolution in Alcohol Media

9. 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)

10. 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

11. 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

12. 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

13. 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

14. Biopharmaceutics Classification System (BCS)

15. 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: , 1995
FDA Guidance - Waiver for Class 1 and Class 3 Drugs

16. 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.

17. USP Tests

18. 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.

19. 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

20. 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

21. 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

22. 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

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

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

25. 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

26. 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.

27. 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.

28. Dissolution Progressive Applications … Reducing Regulatory Burden …

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

30. 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): , 2014
Dissolution
IR - Optimum Bioavailability
Medicines Compendium

31. 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.

32. 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

33. Thank You for Your Attention