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Developing, Validating and Troubleshooting Dissolution Metho

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Transcript of Developing, Validating and Troubleshooting Dissolution Metho

Developing, Validating and Troubleshooting Dissolution Methods
Gregory P. Martin, President
Pharmaceutical Analytical Chemistry
greg.martin@complectors.com

© Complectors Consulting 2014

Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Life cycle

EXERCISE:
Method Development Decision Tree Based On Analytical Target Profile
Validation of Dissolution Methods Using a Phased Approach

EXERCISE
: Craft Guideline for Dissolution Method Validation
Method Troubleshooting

EXERCISE:
Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

Assessment of Attendees Needs
What experience do you have with dissolution method development?
Years of experience with dissolution development
Years of experience with dissolution
Type of company you work for
Education


What questions would you like to have answered today?
Please write at least 3 questions on the note cards provided

What is the Purpose of the Dissolution Method?
To enable formulation selection?
QC method?
To enable manufacturing changes?
Enable Formulation Selection
May use biorelevant media
Need knowledge of drug solubility vs pH
May need to know site of absorption

QC Method
Knowledge of clinical relevance of dissolution data?

Is the method discriminating? Over discriminating?

Enable Manufacturing Changes
SUPAC

Dissolution at pH 1, 4 and 7
Specialized Dosage Forms
Rapid release
Transdermal patches
Injections
Stents

Are There Solubility Challenges?
More than 70% of drugs being developed today are ‘poorly water soluble’

Regional Differences
Medium
Apparatuses
Use of Enzymes
Procedural differences

The Landscape is Complex
Make sure you know what the questions are before you start developing a dissolution method

1897-1950
1950-1980
1980-2000
2000-Present
1897-1950
Research in Chemical Engineering Science
1950-1980
Quality Control tool for pharmaceutical industry
1980-2000
Prediction tool for oral drug absorption: Bio-Relevant medium and dissolution
2000-Present
Dissolution in the framework of BCS: bio-waiver and IVIVC
*Dokoumetzidis, Aristides and Macheras, Panaos, “A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System”, International Journal of Pharmaceutics 321 (1 and 2), Sep 2006

1960's: Differences in dissolution linked to blood vessels
Large differences among brands and lot-to-lot
FDA investigated 44 lots from 32 manufacturers of 0.25mg digoxin tablets

2000-present: Biopharmaceutical Classification System
BCS Concept in 1995 by Amidon
Classified based on solubility and permeability

Effect of Intrinsic Dissolution Vs. Disintegration
Acceptable Analytical Practices for Dissolution of Poorly Soluble Compounds, Brown, Cynthia K., et al, Pharmaceutical Technology, Dec 2004.

Dissolution Apparatus
The most commonly used instruments include baskets and paddles
Apparatus 1 – Baskets
100 rpm most common
Apparatus 2 – Paddles
50 rpm most common
USP, EP and JP are harmonized on these devices

Apparatus 1 and 2
Apparatus 1: Basket
Apparatus 2: Paddle
Daily Apparatus Check
Condition of paddles or baskets
Centering of shafts in vessels
Temperature
37.0 +/- 0.5 deg C
May be maintained using a water bath or bathless heaters
Rotation speed +/- 4% (2 rpm at 50 rpm)
Sampling times are expected to be within +/- 2%
That’s 36 seconds at 30 min but only 12 seconds at 10 minutes.

Apparatus 3: Reciprocating Cylinder
Six sample holders
Select screen size
Each can use 6 different vessels
Select medium for each

USP IV- Flow Through
CE7 dissolution bath w/ 7 flow-through-cells
Pump
Medium selector
Fraction collector

Variety of flow cell design for
Tablets, Powders/granulates, Implants, SGC / Suppositories Pellets

USP Apparatus 5: Paddle Over Disk (Used with Apparatus 2)
USP Apparatus 6: Cylinder
(Used with Apparatus 1 and 2 Device)
TIM Gastrointestinal Model
Dynamic modeling of peristalsis, transit times, electrolytes, enzymes, bile salts
Continuous sampling of dissolved constituents through dialysis at jejunal and ileal compartments

USP Apparatus 7: Reciprocating Holder (Used with Apparatus 3)
Selection of Alternate Apparatus
Apparatus 3 Reciprocating Cylinder
Need for significant agitation and desire to change medium during test
Apparatus 4 Flow Through Cell
Low solubility, some extended release, stents
Apparatus 5 Paddle Over Disk
Transdermal patches
Apparatus 6 Cylinder
Transdermal patches
Apparatus 7 Reciprocating Holder
Extended release, transdermal patches, stents

Discussion?
Why do you think we perform Dissolution Testing?
Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Lifecycle
EXERCISE: Method Development Decision Tree Based On Analytical Target Profile
Validation of Dissolution Methods Using a Phased Approach
EXERCISE: Craft Guideline for Dissolution Method Validation
Method Troubleshooting
EXERCISE: Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

General Approach to Dissolution Method Development
Identify the purpose of the method and the stage of development (ATP)
Learn about drug
Understand solubility
Type of dosage form
Informs Analytical Target Profile
Select dissolution conditions
Medium, apparatus, speed, sampling times
Technique for analysis
Validation
Acceptance criteria

Life cycle Approach to Dissolution Methods
Stage I
Design/Analytical Target Profile
Development
Method Understanding

Stage II
Method Qualification/Validation
[Change Control and Continual Improvement]

Stage III
Procedure Performance Verification

Method Design: ATP
Analytical Target Profile (ATP)
Address method requirements (this is not necessarily the same as instrument capability)

Identify critical analytical performance characteristics (may include some or all of the characteristics described in ICH Q2/USP <1225>)
Establish acceptance criteria for requirements and characteristics, as appropriate

ATP establishes criteria which then facilitate a QbD approach: what changes can be made to the method (medium, rotation speed) or product without affecting the established criteria?

Questions for the ATP
Conventional apparatus?
Constraints on medium?
Full dissolution necessary?
Duration of the test?
Reproducibility requirements?
Mode of analysis?
Discrimination necessary?

ATP Example: Immediate Release Tablet
Uses standard apparatus (USP 2 or 1)
Uses standard medium (pH 1 – 7.5)
Immediate Release, e.g. > 80% within 45-60 min.
Replicate analyses are ‘similar’ (f2 > 50); RSD at Q < 5%
Method is robust over normal lab variability
Simple analysis (e.g. UV or HPLC)
Solution stability >24 H; 72 H preferred
Likely to differentiate unacceptable batches (e.g. different composition, hardness, significant stress) or batches showing clinical differences

Method Design: Additional Considerations
Method requirements may vary based on stage of development or intent of method
May need to revisit if something changes (life cycle approach)
Change in potencies
Toxic degradant identified
Regional differences in regulations (e.g. Japan prefers to avoid 0.1N HCl for dissolution)
Change in location (e.g. method t ransfer)

Selection of Medium Parallels the Evolution of Dissolution Methods
Method Development And Understanding
Method Development
H
aving identified method requirements and critical analytical performance characteristics, these can now be used to drive method development and to evaluate outcomes from the method development process
Using a QbD approach should result in improved methods which will be suitable for their intended use, while saving time, money and resources in the method development process
Method Understanding
An iterative process with Method Development, this incorporates traditional robustness and ruggedness evaluation as well as Risk Analysis, e.g. Fishbone Diagram and/or FMEA
Output should be an understanding of which key input variables impact the ATP

Discussion
Discuss Analytical Target Profile For a Challenging Project

Method Development Type of Dosage Form
Solid, oral, ‘immediate release’: tablets and capsules
Liquid filled capsules
Sustained (extended) release tablets and capsules
Delayed release tablets and capsules
Rapid Release dosage forms
Suspensions
Transdermal patches
Injections
Stents

Method Development: Solubility Evaluation
Determine solubility in water and appropriate buffers (typically in the physiological range of 1-7)
Recognize the difference between dynamic and equilibrium solubility
Consider pKa’s
Evaluate the impact of buffer concentration and salts/counter ions
Evaluate surfactants if compound is poorly soluble (and consider pH modification)
Evaluate solubility in bio-relevant media (SGF, SIF, FaSSIF, FeSSIF)
Evaluate solution stability

Method Development: Medium Selection
Typically, water or buffers in the pH range of the GI tract (pH 1-7)
Wider pH range or surfactants may be used if necessary
For surfactants, evaluate concentration necessary and impact of pH
Biorelevant media
Evaluate solubility of the drug substance
Select medium with ‘sink’ conditions of at least 3
‘Sink’ is the ratio of the amount of drug substance which could be dissolved in the medium to the amount in the drug product


Are sink conditions always necessary?

Discussion on Poorly Water Soluble Drugs
Choice of surfactant
Anionic/cationic/neutral
Effect of concentration
CMC, surface tension
Impact of source
Purity, composition, interference

Some Surfaces Used for Dissolution of Poorly Water Soluble Drugs
Discussion of Biorelevant Media
Typical Hierarchy of Data

Human data >
Animal data >
Biorelevant dissolution >
Quality Control Dissolution


(Note that the data considered more valuable is also more expensive)

QC Dissolution vs. Biorelevant Dissolution
For traditional quality control dissolution tests, the criteria have been:
Sink conditions (generally 3X or 10X)
Apparatus 1 or 2
Standard buffers or surfactant solutions
> 80% dissolved within 60 min. for immediate release products
Biorelevant dissolution may involve:
Non-sink conditions
Alternative apparatus or multi-stage dissolution
Media mimicking the human GI tract
Sometimes, significantly less than 80% dissolv
ed

What are the Conditions in the Human GI Tract?
How can we
best
mimic these conditions?

Early attempts at Biorelevant Media (USP)
Simulated Gastric Fluid
0.08N HCl
NaCl
Pepsin (optional enzyme)
Simulated Intestinal Fluid
Phosphate Buffer (pH 7.5 to 6.8)
Pancreatin (optional enzyme)

Limitations of SIF
For water insoluble compounds, solubility in SIF was inadequate, and not representative of the GI tract

For some drug products, there are noticeable differences between fed and fasted humans, and SIF has no way to differentiate

FaSSIF and FeSSIF
There has been much work done to address these issues
The presence of endogenous surfactants (e.g. sodium taurocholate) and fats (e.g. lecithin) aid in the dissolution of poorly soluble compounds
Varying the proportions may help to address fasted vs. fed states

FaSSIF, One Liter
pH 6.5
Osmolality--270+10 mOsmol
Sodium taurocholate--3 mM
Lecithin--0.75 mM
KH2PO4 --(Monobasic)3.9 g
KCl--7.7 g
NaOH-- Qs pH 6.5

Be Aware of the Limitations
Despite the intuitive implication, biorelevant dissolution results do not always correlate with in vivo results

It is important to challenge in vitro – in vivo correlations, even when using biorelevant dissolution testing

When is Bio-relevant Dissolution Appropriate?
Potentially – all the time
Probably not as valuable when the drug is soluble and the dosage form is immediate release
More likely to be valuable when the drug is BCS Class II and dissolution is rate limiting
Can be very useful for formulation screening in early development
Can be useful for understanding likely impact of dissolution slow down (e.g. on stability)

Future Directions for Bio-relevant Dissolution
Continued growth in use – particularly for formulation selection or changes
Convergence between Bio-relevant dissolution and QC dissolution
Move towards clinically relevant specifications
Better understanding of how and when to use
For example, classes of compounds
Continued advances in technology
Including advances in media, including less expensive and easier to prepare

Method Development: Apparatus Selection
USP Apparatus 2 (Paddles) and 1 (Baskets) are used most frequently
Typical volume is 900 ml (could be 100 to 4000 mL)
Typical temperature is 37ºC (32ºC for transdermal patches)
Typical agitation rates are 50-100 rpm (paddles) or 50-150 rpm (baskets)
Another Apparatus may be selected, usually for a particular reason
In some cases, disintegration can be used in lieu of dissolution
Early Phase studies
BCS Class I with >85% released in 15 minutes

Sinkers may be used with Apparatus 2
Sinkers come in a variety of shapes and sizes
They can address a number of issues:
floating, stick, etc.
Selection of other Apparatus
Apparatus 3 Reciprocating Cylinder
need for significant agitation and desire to change medium during test; generally non-disintegrating dosage form
Apparatus 4 Flow Through Cell
low solubility, some extended release
Apparatus 5 Paddle Over Disk

transdermal patches
Apparatus 6 Cylinder
transdermal patches
Apparatus 7 Reciprocating Holder
extended release, transdermal patches, stents

Method Development: Sampling Times
Typical Immediate Release Product
15, 30, 45, 60 min
10, 20 min may be of interest
5 min if rapid dosage form
Delayed release
2 hours in 0.1N HCl
Adjust pH to 6.8, then additional 45 min (or as specified in monograph)
Extended release
At least one early time point (to demonstrate lack of dumping), an intermediate time point and a later time point (to demonstrate the plateau)

Do you prefer to replace medium or use calculations to address the impact of taking multiple samples?

Sampling Techniques
Manual
Cylinder filter
Membrane filter
Centrifugation (not recommended)
Autosampler
Cylinder filter
Membrane filter
Autosampler with determination
e.g. UV determination, HPLC
In situ testing (fiber optics)
Full automation

Manual Sampling
Does sampling location matter?
U
SP <711> states: withdraw a specimen from a zone midway between the surface of the Dissolution Medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall.
How much variation in time is allowed?
Specimens are to be withdrawn only at the stated times within a tolerance of ±2%.

Sample Clarification
Post-sampling dissolution can cause serious problems with the accuracy of dissolution data
It is usually necessary to remove undissolved materials
Tablet fragments
Excipients
Drug particles
Filtration
Cylinder filter
Membrane filter
Centrifugation
Ultracentrifugation

With poorly soluble compounds, use of very small particle size (nanoparticles) or other approaches to improve solubility may necessitate more stringent means of sample clarification, such as ultracentrifugation.

Filters
Cylinder filter
Nominal 10 micron and 35 micron
Easy to use
Fit on end of cannula
May not remove all undissolved material
Membrane filters
Various materials of construction and pore size
May not work with some automated techniques
Qualification
All filters should be qualified to assure they do not adsorb dissolved drug

Automation
Automation (e.g. autosampler or fully automated system) can be valuable in conserving resources and/or reducing cycle times

There is an expectation that results from an automated method would be comparable to the corresponding manual method
Typical requirements are mean within 5% at each time point where >85% dissolved or curves are similar (f2)



What requirements do you think are appropriate for comparing automated results to manual results?

Validation vs. Sampling
Automation (e.g. autosampler or fully automated system) can be valuable in conserving resources and/or reducing cycle times

There is an expectation that results from an automated method would be comparable to the corresponding manual method
T
ypical requirements are mean within 5% at each time point where >85% dissolved or curves are similar (f2)

Method Development: Type of Analysis
Spectrophotometric, Fluorimetric
Rapid
Need to demonstrate specificity
Potential for in-situ analysis
Chromatographic (HPLC, GC)
Requires more time, expensive equipment
Wider dynamic range
Automated analysis and data handling
Others as appropriate

Method Development: Observations
Observations can be very valuable
Noting disintegration time, variability
Coning
Sticking
Capsules collapsing
Dosage units behaving differently from one another

Discrimination
Can the method distinguish between formulations which have different clinical characteristics?

Can the method distinguish between batches which are different?
DS particle size or morphology?
Physical differences (hardness, disintegration)?
Composition differences?
Manufacturing differences?

Exercise
Method Development Decision Tree Based on Analytical Target Profile
Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Lifecycle
EXERCISE: Method Development Decision Tree Based On Analytical Target Profile
Validation of Dissolution Methods Using a Phased Approach
EXERCISE: Craft Guideline for Dissolution Method Validation
Method Troubleshooting
EXERCISE: Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

Method Validation: Demonstrating Procedure Performance
Primary criteria
V
ariability is satisfactory and profiles are similar
No significant analytical solution stability problems
Appropriate discriminatory ability

Method Validation
Use good science
Refer to ICH Q2 and USP <1225>, <1092>
Typical elements to be validated:
Accuracy
Precision
Specificity
Linearity/Range
Robustness
May depend on Phase of the project

Method Validation
Accuracy
Recovery of drug from the dissolution medium
Precision
Repeatability
Intermediate precision
Specificity
Freedom from interference from the placebo and filters
Linearity and range
Need to cover the range of expected results
Robustness
Impact of small, deliberate changes

Method Validation:
Additional Considerations
Filter qualification
Demonstrate no loss of active
Carryover
Between pots or sampling times
Solution stability
During and after the test
Validation of automation
Manual versus automated sampling
Ruggedness/Intermediate Precision
Impact of “noise” factors likely to be encountered during use of the metho
d

Intermediate Precision
Performance of a method on different equipment, by different chemist, in different laboratory, etc.
Design an experiment considering different “noise” factors
FMEA may be useful
Statistical analysis of the results may help to identify the major sources of variability

Robustness
Evaluate the impact of small, deliberate changes in parameters on results from the dissolution test
Deaeration
Medium concentration
80%, 100%, 120%
Medium pH
+/- 0.1 pH unit
Temperature
Rotation speed
Determinative step (all the usual parameters)

Discussion?
Have you developed a template for validation of dissolution methods? How does it vary by stage of development?
Specification
A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. - ICH Q6A

Acceptance Criteria
Acceptance criteria are generally based on critical quality attributes of the drug product and on historical data
The customer needs must be met
The drug product should perform in a manner consistent with prior lots
Influenced by the compendial form of the Acceptance Criteria
Normally increments of 5%
Economic preference to minimize second stage testing
Ultimately decided by the Regulatory Agency

Compendial Acceptance Criteria for Immediate Release Products
Traditional Approach vs. QbD
The traditional approach to setting dissolution specifications has included review of available data and analysis of the data to generate one or more acceptance criteria and associated time points
The QbD approach starts with an understanding of patient needs, builds based on an understanding of the drug product and the manufacturing design space and uses these to identify a critical quality parameter and an associated acceptance range.

Recently the FDA has started referring to Clinically Relevant Specifications for dissolution, which embraces the QbD approach.

Traditional Approach: Data to be evaluated
Data should be associated with a specific drug product and dissolution method
If the drug product or dissolution method changes, prior data would not normally be included
Specification should be based on all available data
Release data from all clinical and stability lots, and other lots if appropriate
Stability data at proposed storage conditions
Stability data at accelerated conditions may be included if not significantly different
Dissolution data are considered an important link to the performance of the pivotal biobatch

Proposing the Specification
The time point(s) should be carefully selected: typically on or near the plateau for immediate release products. For sustained release products, early, mid and late time points are selected.
The acceptance criteria are customarily a multiple of 5
It is helpful to create a histogram of the dissolution data to visualize the distribution of data
Statistical analysis will aid in the selection of the acceptance criteria

Histogram of Dissolution Data
Some Guidelines for Setting Specifications
Immediate Release Oral Dosage Form (includes suspensions)
Single time point with lower limit
Increments of 5%; frequency of S2 testing
May be able to use disintegration, IF:
Soluble across physiological pH range AND
Correlat
ion between dissolution and disintegration
Probably not required for true oral solution
Delayed Release Oral Dosage Form
Two stages, parallel or sequential
Extended Release
Typically 3 time points
Ranges generally not more than 20% at each time point

Specifications for Generic Products
Usually, firms developing generic products will consider using the compendial or filed methods and acceptance criteria

It is not necessary to use either the same method or same acceptance criteria, and there are many examples of this in the USP
Theophylline Extended Release Capsules list 10 tests

Clinically Relevant Specifications
Recently, there have been significant efforts by FDA to have sponsors use a ‘clinically relevant’ approach to evaluation of discriminating power of a dissolution method.
In the best case, multiple formulations with differences in bio performance are evaluated in vivo. Results are then used to identify an appropriate ‘dissolution space’.
There is a potential for wider acceptance criteria using this approach.

What are "clinically relevant specifications"
Specifications which take into consideration the clinical impact of variations in the critical quality attributes and process parameters assuring a consistent safety and efficacy profile.


Abstracted from presentation by Susan Sharp, FDA, at AAPS Annual Meeting, Nov 2012

Approaches for Establishing CRS
Approach 1:
Range established based on batches tested in pivotal phase 3 clinical trials

Approach 2:
Range established based on a range of release characteristics resulting in bioequivalence

Approach 3:
Range established based on predictive and robust in vivo in vitro correlations

Abstracted from presentation by Susan Sharp, FDA, at AAPS Annual Meeting, Nov 2012

How Can You Compare Performance Between Formulations?
This question occurs in various situations
Between lots
Formulation changes (e.g. scale up, post approval changes)
Innovator vs generic
The definitive approach is to demonstrate bioequivalence
Due to cost and time requirements, it is desirable to use dissolution as a surrogate, and obtain a waiver for bioequivalence studies.

FDA Has a Guidance For That
Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. CDER August 2000

Related Guidelines: SUPAC IR/MR
Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation CDER November 1995

SUPAC-MR: Modified Release Solid Oral Dosage Forms CDER September 1997

Situations Addressed
Changes to INDs, NDAs, ANDAs and Post-approval Changes
Types of Changes
Components and Composition
Site
Manufacturing
Significance of change
Level 1- unlikely to have detectable impact
Level 2 – could have a significant impact
Case A, B, C
Level 3 – likely to have a significant impact

Biowaivers may be possible
Rapid (for IR, 85% in 30 min) and similar (f2 > 50) in vitro behavior
BCS Class I (highly soluble and highly permeable)
Pharmaceutical equivalents (same dosage form and active, including salt and polymorph)
May require dissolution using compendial procedure, pH 1, 4.5, 6.5, 7.5 or 6.8
May require established IVIVC for composition or manufacturing changes

Use of f2 for Dissolution Comparison
Method must be appropriately discriminating
Value of observations
Need to meet the requirements
12 units
Enough time points to characterize dissolution
CV earlier timepoints NMT 20%; others NMT 10%
Only one measurement after 85% for both products
Consider whether multiple media (different pH or surfactant conc.) are appropriate
Plot of Typical Data
Plot of data with 10% difference at each timepoint
Plot with 15% difference at each timepoint
f2 Calculation
Discussion
Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Lifecycle
EXERCISE: METHOD DEVELOPMENT DECISION TREE BASED ON ANALYTICAL

TARGET PROFILE
Validation of Dissolution Methods Using a Phased Approach
EXERCISE: Craft Guideline for Dissolution Method Validation
Method Troubleshooting
EXERCISE: Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

Review of Attendee Experiences Regarding Troubleshooting
How do you recognize you have a problem with your dissolution data?

Data Review for Dissolution
Daily checks
Typical notebook review
Review against specs (typically integers)
Review against historical data
Release data from other lots or stability data from other time points
Consider tabular data or control chart
Comparisons between potencies

Some Issues Related to Robustness
Coning
Sampling
Sample clarification
Post sampling dissolution
Sticking
Solution stability
Deaeration effects
Surfactant source
Automation
Sinkers
pH effects

Troubleshooting Differences in Dissolution Profiles
Differences could result when the method is not robust
Differences among potencies may be the result of amount of drug, drug loading or differences in images
Differences between stability time points for the sample formulation may indicate stability-related changes
Differences between lots may indicate changes in processing parameters

Fishbone Diagram
Machine
Environment
Measurement
Method
Materials
Man
Coning
Lagace, M. et al “Developing a Discriminating Dissolution Procedure for a Dual Active Pharmaceutical Product with Unique Solubility Characteristics, Dissolution Technologies, Feb. 2004

Sampling
Manual – cannula or pipette
Autosampler
In-situ probe
Fully automated dissolution device

Sample Clarification
Depth filter
Membrane filter
Centrifugation
Ultracentrifugation

How to choose? When to clarify relative to time sample is taken?

Drug Product #2: Variable Results Attributed to Tablet Sticking
Drug Product #3: Growth of a Degradant in Sample Solutions
Parent Drug
Degradant
Deaeration
Deaeration issues are probably the most frequent cause of dissolution instrument qualification failures.


Deaeration of Medium

Methods
USP method - heat, filtration, vacuum
Helium sparging
Automated methods – generally use gas-permeable membrane
Numerous variations
Media containing surfactants may not be amenable due to foaming
Bubbles from non-deaerated medium may increase or decrease dissolution rate
Effect should be evaluated for each product

Drug Product #5 :Effects of Surfactant Source on Dissolution Profile
Drug Product # 5

Drug Product #6: Biased Results using Automation
Results averaged 7% faster on automated equipment
Investigation of various parameters was undertaken. Some of the items investigated included:
V
essel type (Caliper vs. Varian)
Examination of multiple profiles of the same lot and application of statistics to evaluate bias
Filtration at the point of sampling (attaching filter at tip of Caliper cannula) or by standard Caliper method (filtration later in sampling pathway)
No root cause was determined.

Drug Product 7: Impact of Small Changes in pH on Dissolution of Different Drug Forms
The solubility curve for DP#7 is very sharp between pH 1 and 4
Using a medium with pH 1.8 or 2.6 appears to be more discriminating than SGF, pH 1.2
Further work is in progress to evaluate correlation between pH and in vivo data.

Some Issues Related to Differences Among Potencies
Sink
Size of the dosage form
Disintegration vs. erosion controlled
Surface area to volume ratio
Drug loading
Differences in composition
Hardness
Processing conditions

Drug Product #9: Effect of Drug Loading
Some Issues Related to Stability
Gelatin cross linking
Changes to tablet hardness, etc.
Polymorph changes

Drug Product #10: Gelatin Cross-Linking on Stability
Drug Product #11: Example of Gelatin Cross Linking
USP has convened an Expert Panel to address the issue of cross linking. Considerations include use of alternative enzymes, when it is reasonable to go directly to use of enzymes (e.g. on stability), and issues related to use of surfactants and enzyme deactivation.

Some Issues Related to Between-Lot Differences
Tablet hardness, etc.
Excipient differences
Processing differences
Coating differences
Polymorph differences

Drug Product #12: Impact of Tablet Hardness on Dissolution
Drug Product #13- Impact of Varying Levels of an Excipient
Drug Product #13: Varying Levels of Poloxamer
D. Pabla, et al “A comparative pH-dissolution profile study of selected commercial levothyroxine products using ICP-MS,”European Journal of Pharmaceutics and Biopharmaceutis 72(2009) 105-110.

When pH affects dissolution profiles
Exercise
Develop a Troubleshooting Guide
Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Lifecycle
EXERCISE: Method Development Decision Tree Based On Analytical Target Profile
Validation of Dissolution Methods Using a Phased Approach
EXERCISE: Craft Guideline for Dissolution Method Validation
Method Troubleshooting
EXERCISE: Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

FDA Documents
Mechanical Qualification of Dissolution Apparatus 1 and 2 Division of Pharmaceutical Analysis DPA-LOP.002
GFI Dissolution Testing of Immediate Release Solid Oral Dosage Forms Aug 1997
GFI Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations Sept 1997
GFI Immediate Release Solid Oral Dosage Forms Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence
Documentation Nov 1995
GFI Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Aug 2000
GFI Orally Disintegrating Tablets Dec 2008

EMEA Documents
Concept Paper On BCS-Based Biowaiver Aug 2007
Guideline On The Investigation Of Bioequivalence Jan 2009

USP Documents
<711> Dissolution
<724> Drug Release
<1092> The Dissolution Procedure: Development And Validation
<701> Disintegration
<1088> In Vitro And In Vivo Evaluation Of Dosage Forms
<1090> Assessment Of Drug Product Performance-Bioavailability, Bioequivalence, And Dissolution - Dissolution And In Vitro Product Performance
<1058> Analytical Instrument Qualification
<1225> Validation Of Compendial Procedures
<1226> Verification Of Compendial Procedures
<1224> Transfer of Analytical Procedures
<2040> Disintegration And Dissolution Of Dietary Supplements

Other Interesting Articles
Brown, C.K., et al, “Acceptable Analytical Practices for Dissolution Testing of Poorly Soluble Compounds”, Pharm. Tech Dec 2006
Dokoumetzidis, A. et al, “A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System”, International Journal of Pharmaceutics 321 (1 and 2), Sep 2006
Shah, V.P., et al, “In Vitro Dissolution Profile Comparison – Statistics and Analysis of the Similarity Factor, f2”, Pharm. Res. Vol. 15 No. 6, 1998

Additional Resources

AAPS In Vitro Release and Dissolution Testing Focus Group
aaps.org/In_Vitro_Release_and_Dissolution_Testing

Dissolution Technologies
dissolutiontech.com

USP <1058> Instrument Qualification
Systematic, documented process
Design Qualification
Define functional and operational specifications
Installation Qualification
Delivered as designed
Properly installed in a suitable environment
Operational qualification
Instrument functions according to operational specifications or user needs
Performance qualification
Demonstrate that the instrument consistently performs according to specifications
May include performance checks, analysis of known standards and/or tests performed during OQ

Daily Checks
Analogous to System Suitability for HPLC
Typically include
Paddle/basket height
Temperature check
Rotational speed
Centering
Autosampler parameters

Dissolution Instrument Qualification
Design Qualification
Meets the intent described in USP <711> for Apparatus 1 and 2, i.e. mechanical requirements and dissolution test results
Installation Qualification
Instrument

delivered in good shape with all parts; proper power and temperature control available; free from vibration
Operational Qualification
Meets the specifications established by the supplier; typically mechanical measurements
Performance Qualification
Meets the user’s needs; suitable for intended use. May be demonstrated by Performance Verification Test or Enhanced Mechanical Calibration.

Dissolution Instrument Qualification
Design Qualification
Typically left to the vendor
There may be special design requirements established by the user; these would require more user involvement in DQ
Supported by reputation and history of vendor
Detailed information may be available for review
More likely, a statement from the vendor may be available
Installation Qualification
User needs to address factors which could influence temperature or vibration
Air vent location; temperature change in evening
Nearby centrifuge, shaker; construction

Dissolution Instrument Qualification
Operational Qualification
Does the instrument conform to the vendor specs?
Typically measurable parameters; not directly product or dissolution related
Should be as tight as or tighter than routine requirements

Dissolution Instrument Qualification
Operational Qualification: Measurable Parameters
Vessel height and diameter
Stirring units
Dimensions for paddles and baskets
Wire mesh dimensions
Assembled unit
Wobble or runout
Shaft centering and verticality
Vessel verticality
Height of stirrer from bottom of vessel
Rotational Speed
Temperature of medium

Dissolution Instrument Qualification
Performance Qualification
Does the instrument conform to the user specs? Is the instrument suitable for its intended use?
Historically, the USP Performance Verification Test (“Dissolution Calibrator Tablets”) described in USP <711> has been used to demonstrate suitability.
USP Prednisone Tablets RS Technical Data Sheet
Dissolution Toolkit
Challenge: Does a failure correlate with an unsuitable instrument?
An FDA Guidance for Industry provides an alternative, based solely on mechanical measurements.

USP Performance Verification Tests
Chapter <711> requires conformance to Dimensions and Tolerances (Mechanical Calibration) and to Performance Verification Test
Mechanical Calibration described in Dissolution Toolkit Version 2.0
PVT described in USP Certificate for USP Prednisone Tablets RS

USP Performance Verification Test
Mechanical Calibration described in Dissolution Toolkit Version 2.0
Basket and Paddle dimensions and wobble
Vessel dimensions, and support plate level
Shaft and vessel verticality
Centering
Rotational speed
Temperature control

USP Performance Verification Tests
PVT described in USP Certificate for USP Prednisone Tablets RS
Apparatus 1
and/or
2
50 rpm, 500 mL, 30 minutes, UV 242 nm
Two Stage (6 + 6) or One Stage (12) options
Limits for Geometric Mean and %CV

FDA Mechanical Qualification of Apparatus 1 and 2
Mechanical Qualification described in FDA Division of Pharmaceutical Analysis DPA-LOP.002
Vessel dimensions
Basket and Paddle dimensions
Shaft wobble and verticality
Basket and Paddle wobble
Shaft and vessel centering
Vessel verticality
Basket and Paddle height
Rotational speed


Areas Needing Attention
Training
Analysts must be well trained before generating official data; will probably take longer than some other instruments
Will instrument calibration be performed by analysts or metrologists?
Deaeration
Variety of techniques have been identified
Pouring or stirring medium can reintroduce air
Vessel geometry
Very difficult to measure in the laboratory
Obtain vessels from reliable sources
Procedural details
Dropping of tablets: paddles up or down? Rotation on or off?
Filter qualification

Vibration
No definitive tests at this time
Major research project underway at FDA
Confirm no obvious vibration (hand)
Confirm no near-by contributors
Centrifuge, shaker, slamming door
Construction

Water Bath

Temperature control/uniformity of temperature in all vessels
Water motion can cause vibration or turbulence if not designed well
Clarity of water needed so good observations can be made
Water level at least to top of medium in a filled vessel
Bathless vessels are permitted and have been widely accepted

Dissolution Vessel
The hemisphere may be distorted due to the method of manufacture :
Dissolution Vessels
Even with perfect manufacture, “within specification” differences are significant
FAQs
What if there is a dissolution calibration failure?
Remember to retain ‘as found’ and ‘as left’ data
If mechanical parameter failure, must be corrected (if not a measurement error)
If PVT failure
Qualification, training of analyst
Verification of PVT test
DO NOT use the newest chemist in the lab
Deaeration
History of the prednisone tablets (bottle opened?)
Filtration: qualified? New filter for each pot?
Cleanliness of vessels (history?)
Technique for dropping tablets
Timing and location of sampling

FAQs
How can deaeration be controlled?
Techniques
U
SP (heating, vacuum filtration)
Helium sparging
Commercial devices (frequently gas permeable membrane)
Handling medium
Pouring, stirring can reintroduce air
Measurements
Meters to measure dissolved oxygen or total gases available
Use meters to develop an understanding of deaeration control in your laboratory

Agenda
Assessment of Attendees Needs
What is the Purpose of the Dissolution Method?
History of Dissolution and the Compendial Apparatus
A Practical Approach to Method Development Using a QbD Approach to Method Lifecycle
EXERCISE: METHOD DEVELOPMENT DECISION TREE BASED ON ANALYTICAL TARGET PROFILE
Validation of Dissolution Methods Using a Phased Approach
EXERCISE: Craft Guideline for Dissolution Method Validation
Method Troubleshooting
EXERCISE: Craft Guideline for Dissolution Troubleshooting
Regulatory and Compendial Documents
Dissolution Instrument Qualification
Learner Challenges and Questions

Acknowledgments
Vivian Gray
Merck colleagues, especially Joe Konieczny
USP staff and volunteers
AAPS In Vitro Release and Dissolution Testing Focus Group members
Course participants

What Does the Future Hold for Dissolution Testing?
Continuing pursuit of relationship between
iv vitro
and
iv vivo
data
Improvements in current compendial apparatuses
Vibration, vessel geometry, performance verification
New apparatuses which provide meaningful data
Use of QbD to eliminate the need for dissolution testing

Discussion
Distek ezfill 4500
Dissolution Heating, Media Degassing and Dispensing
USP Hot Topics
Use of enzymes

Gelatin capsules

<1092> Major Revision
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