Transcript dissolution - Society for Pharmaceutical Dissolution Science

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
General Strategy
• Focus on mean
• Variability
• IVIVC ?
• Quality problem
Degradation?
Stability?
Formulation?
Risk Based
Evaluation
• Assess and
manage risk
• Risk informed
decision
making
Problem Solving
Setting Specification
Adopted from John Duan/FDA presentation at USP on 3/25/2014
Current Practice
• Clinical and
biobatch
• Discriminating
dissolution
method
• Completeness
Risk Informed Decision Making
• Risk Assessment
– What can go wrong?
– What is the
likelihood it would
go wrong?
• Knowledge Inventory
– What information
will be most
useful
– What are the
consequences?
– What knowledge
is already
available
– What is the chance
to detect?
– 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-bycase basis
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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.
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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.
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• 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
Tools
GENERIC DRUGS
Optimizing Product Performance
Maintaining Product Quality
BE Studies
ANDA / BE
Dissolution
IR and MR
Biowaiver
BCS
Lower strengths
NDA / BA
In Vitro
Drug release
Ref: VP Shah
et.al., The
AAPS Journal,
16 (4): 621-624,
2014
Dissolution
Semisolids
Biowaiver
IR - Optimum
Bioavailability
Q1 , Q 2 , Q 3
Lower strengths
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
Thank You for
Your Attention