Hence, the rate of Dissolution is related to Bioavailability. ... >Drug dissolution (for many dosage forms) .... published in Dissolution Technologies 13(3), 2006.
IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008 Hyderabad International Convention Center Hyderabad, India
Performance Verification Testing
William F. Koch, Ph.D. Chief Reference Materials Officer
Drug Product Performance
Formulation performance is defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance and eventually leading to one or more pharmacologic effects, both desirable and undesirable.
Dale Conner, PharmD, FDA/OGD, 2004
Rate Process in Drug Bioavailability Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from the drug product and becomes available at the site of action
Hence, the rate of Dissolution is related to Bioavailability.
Drug Product Attributes: Quality and Performance
Product quality, as measured by: Chemistry, manufacturing and controls (CMC) Microbiology Identity, strength, quality, purity and potency of drug product
Product performance, as indicated by: Drug dissolution (for many dosage forms)
Goals of Dissolution Testing
Prediction of bioavailability, the surrogateparameter of therapeutic efficacy
Evaluation of the drug product’s robustness, as a parameter of the drug product-related safety
Evaluation of critical manufacturing variables
Evaluation of uniformity and stability Manufacturing Storage
Pharmaceutical Dosage Forms Terminology 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Aerosols Boluses Capsules Concentrate for DIP Creams Elixirs Emulsions Extracts & Fluid Extracts Gels Implants Infusions, Intramammary Inhalations Injections Irrigations
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Lotions Lozenges Ointments Ophthalmic Prep. Pastes Pellets Powders Premixes Solutions Suppositories Suspensions Syrups Systems Tablets
Classification of Pharmaceutical Dosage Forms
Three-Tier System Delivery Route
Dosage Form
Release Category
Pharmaceutical Dosage Form Taxonomy
First Tier: classification by route of delivery oral dosage forms topical/transdermal parenterals (by injection) mucosal or other membranes Inhalation
Second Tier: classification by physical state solid liquid gaseous Mixed
Third Tier: classification by release pattern conventional modified
First Tier of Pharmaceutical Dosage Forms FIRST TIER CATEGORY: DELIVERY ROUTE - based on region of the body to which active delivered Mucosal Membranes
Gastro-intestinal Tract Body Tissues or Fluids [by injection]
IV IM
Lungs Skin surface
etc
SC
otic
nasal
vaginal transdermal dermal
oral
rectal orophary ngeal
ophthalmic
urethral
topical
SECOND TIER CATEGORY: DOSAGE FORM [i.e. based on the general type of dosage form]
Tiers 2 & 3 of Mucosal Dosage Forms Mucosal Membranes oropharyngeal
SECOND TIER CATEGORY
solids
semi-solids
rectal
DOSAGE FORM [i.e. based on the general type of dosage form]
liquids
liquids
solids powders
gels
suppositories
suspensions
pastes gums semi-solids tablets chewable tablets
THIRD TIER CATEGORY
solutions
solutions
TYPE OF RELEASE [i.e. based on the RELEASE PATTERN OF THE ACTIVE]
Tiers 2 & 3 of Oral Dosage Forms Oral Dosage Forms
Solid oral dosage forms
Immediate Release
Extended Release
Liquid oral dosage forms
Modified Release
Delayed Release
Compendial Use of the Dissolution Test
The Dissolution Test provides the compendial correlation to Drug Product Performance for the following dosage forms: Solid oral dosage forms Topical, dermals Mucosal Injectables – parenterals
USP Chapters , USP apparati Apparatus 1 (basket) Apparatus 2 (paddle)
solid oral dosage forms
Apparatus 3 (reciprocating cylinder) Apparatus 4 (flow-through cell)
various dosage forms
Apparatus 5 (paddle over disk) Apparatus 6 (cylinder) Apparatus 7 (reciprocating holder)
topical dosage forms
Critical Elements of Dissolution Testing
Relevant Predictive Discriminating
influenced by the design of the method, procedure, and dissolution equipment
Reproducible Transferable Rugged
influenced also by the performance of the dissolution equipment and execution of the procedure
Hence, there is a need for verification of the performance of the entire system
USP Performance Verification Tests
USP General Chapter Dissolution Apparatus 1 and 2 • Disintegrating Tablets for USP Dissolution Performance Verification Test: Prednisone RS Tablets, lot P0E203 • USP Dissolution Calibrator, Non-disintegrating Type: Salicylic Acid Tablets RS, lot Q0D200
Apparatus 3 • USP Drug Release Calibrator for Apparatus 3: USP Chlorpheniramine Maleate Extended Release Tablets RS lot G0B259
Apparatus 4 • to come
Apparatus 5, 6 and 7 • to be specified
Dissolution Test Variability – Apparatus 2
Maria Glasgow et al.: The USP Performance Verification Test Part II: Collaborative Study of USP’s Lot P Prednisone Tablets, Pharm. Res. 2007
Dissolution Test - Causes Of Variability
The drug product under investigation
Dissolution equipment, apparatus and assembly
Environmental conditions
Dissolution procedure
Analytical method and procedure
Analyst
Experimental Variables Contributing to Dissolution Variance Statistical Analysis Summary for Apparatus 2 CV% Residual as 95% Geometric Assembly Confidence Between Between Between Residual Total % of Total Mean Limits Analyst Position Experiment Variance Alpha
58.7
(51.1–67.4)
6.6%
11.1%
1.6%
11.8% 17.7%
45.0%
Beta
48.4
(46.5–50.3)
0.0%
3.7%
1.0%
11.6% 12.3%
90.3%
Gamma
44.9
(41.4–48.6)
6.3%
1.0%
0.7%
4.3%
7.8%
30.8%
Delta
48.0
(43.2–53.3)
6.2%
2.3%
2.3%
8.1% 10.7%
57.4%
Epsilon
46.9
(43.0–51.0)
5.4%
3.9%
0.3%
8.7% 11.0%
63.2%
Gang D, et. al.: The USP Performance Verification Test Part I: USP Lot P Prednisone Tablets – Quality Attributes and Experimental Variables Contributing to Dissolution Variance, Pharm. Res. 2007
Variability of Different Assemblies Individual results obtained with Apparatus 2 on two different assemblies Apparatus 2 - Assembly Gamma 85
85 80 75 70 65 60 55 50 45 40 35 30 25
Min Max Mean
Prednisone Dissolved Percent (%)
Prednisone Dissolved Percent (%)
Apparatus 2 - Assembly Alpha
80 75 70 65 60 55 50 45 40 35
Min Max Mean
30 25
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Experiment #
0 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031 Experiment #
Gang D, et. al.: The USP Performance Verification Test Part I: USP Lot P Prednisone Tablets – Quality Attributes and Experimental Variables Contributing to Dissolution Variance, Pharm. Res. 2007
Variability due to Dissolution Vessels
Mark Liddell et al.: Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources, American Pharm. Review, Vol. 10(6) Sept./Oct. 2007
USP Research on other Sources of Variability in Dissolution Testing
Dissolved gases (e.g. oxygen)
published in Dissolution Technologies 13(3), 2006
Geometry of the dissolution vessels
published in Dissolution Technologies 14(1), 2007
Stirring rate
published in Dissolution Technologies 14(1), 2007
USP Research on Sources of Variability in Dissolution Testing - Conclusions
Based on USP research, data and statistical analysis, it is the USP position that: the variability due to the Prednisone Tablets contributes no more than 5% to the total variability the suitability of the Prednisone Tablets RS for the Performance Verification Test (PVT) for the Apparatus 2 (paddle) has been demonstrated
Draft FDA Guidance issued October 2007
The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 - Current Good Manufacturing Practice (CGMP) The draft Guidance argues that only mechanical calibration without PVT is needed http://www.fda.gov/cder/guidance/7232dft.htm
USP Response to Draft FDA Guidance USP maintains that: Both PVT and mechanical calibration are critical to the dissolution procedure, and Mechanical calibration alone cannot ensure the validity of dissolution results. USP emphasizes: That mechanical calibration is a necessary but not sufficient means of ensuring consistency and comparability of measurements obtained with a dissolution test system. The importance of a periodic performance verification test (PVT) together with careful mechanical calibration to ensure that the combined experimental study yields consistent results. USP acknowledges that: Improvements to the mechanical specifications are required. New approaches to assess drug product performance in vitro are needed.
Current Activities at USP: Oral Dosage Forms
Investigations on the influence of vibration on the PVT results
Revision of the General Chapter regarding the specifications of some instrument parameters
Manufacturing and evaluating a new batch of Prednisone Tablets RS
Future Research Directions at USP
Investigate the “ideal” Reference Standard for oral dosage form PVTs
Develop Performance Verification Tests (PVT) and Reference Standards for other dosage forms and apparati.
Topical/transdermal Parenterals (by injection) Mucosal or other membranes Inhalation
Investigate new approaches to assess drug product performance in vitro
