FDA and USP Perspectives on
Dissolution Testing from Regulatory
Filing Point of View
Vinod P. Shah, Ph. D.
Pharmaceutical Consultant
(Formerly with US FDA)
Disso Asia 2014
Society for Pharmaceutical Dissolution Science
Mumbai, India, May 5-6, 2014
FDA: Drug Safety, Efficacy, Quality
- BA/BE Studies - NDA
- BE studies - ANDA
- Biowaivers
- Dissolution
USP: Public Standards
- Quality, purity, strength, consistency
- Compendial requirements
- Monographs
- IR dosage forms; S1, S2, S3
- MR dosage forms 12 Units - Ranges; L1, L2, L3
Product Quality and Product Performance Test
Assure that safe and effective drugs are marketed in the
country and are available to the American people.
To improve the health of the people around the world
through public standards and related programs that
help ensure the quality, safety and benefit of
medicines and foods.
USP sets standards for the quality, purity, strength, and
consistency of these products - critical to public
Dissolution Test
• It is the most useful physicochemical test for
assessment of drug product quality
• To assess batch to batch quality
• The release specifications (QC test) allows
batch release into the market place
• Functions as a signal of BioInequivalence
Application in granting Biowaiver
Immediate Release Drug Products
- Apparatus 1 (Basket), 50/120 rpm
- Apparatus 2 (Paddle), 50-75 rpm
- Aqueous Medium, pH 1.2 - 6.8
- For sparingly water soluble drugs - use
surfactant - must be justified, lowest amount
must be used
- 500-1000 ml at 37 + 0.5oC
Sampling Times
- 15 minute intervals until 85 % dissolution
Extended Release Drug Products Dissolution Data
- In multimedia, different pHs
- Influence of agitation
- Profiles with at least 3 to 4 points
- Range of dissolution at all points
- Time: 1 or 2 Hrs, around 50 % dissolution and
around 80% dissolution
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.
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
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., Oxycodone, Trazodone, Bupropion, Venlafaxine, Lamotrigine,
Quetiapine Fumarate, Ropinirole)
FDA: New Drugs
Setting Dissolution Specifications
Risk Based
• Assess and
manage risk
General Strategy
• Risk informed
• Focus on mean
• Variability
• Quality problem
Problem Solving
Current Practice
• Clinical and
• Discriminating
Setting Specification
• Completeness
Adopted from John Duan/FDA presentation at USP on 3/25/2014
Risk Informed Decision Making
Risk Assessment
• Knowledge Inventory
- What can go wrong?
- What information
will be most
- What is the
likelihood it would
go wrong?
- What knowledge
is already
- What are the
- What information
- What is the chance
is not available
to detect?
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 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
Biopharmaceutics Classification System
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
Waiver of in vivo BA & BE for
IR drug products based on BCS
Criteria for biowaiver
- Highly soluble: Highest dose soluble in 250 ml in pH 1.2 - 6.8
- Highly permeable: extent of absorption greater than 85%
- Very rapidly dissolving: 85% in 15 minutes or
- Rapidly dissolving: 85% or greater
by basket method 100 rpm or paddle method 50 rpm in 900
ml in pH 1.2, 4.5 and 6.8
For a waiver of BE, T and R products should exhibit
similar dissolution profile
FDA Guidance - Waiver for Class 1 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
- 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
<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
Allows assessment of product quality
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
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.
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
• Appropriate dissolution test can be used as a
surrogate marker for BA/BE.
Thank You for
Your Attention