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IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008
Hyderabad International Convention CenterHyderabad, India
USP’s Verification Programs: Experience to Date
Richard AlemanUSP Verification Programs Lead Auditor
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Topics
Pharmexcil MOUDietary Supplement Verification Program (DSVP)Pharmaceutical Ingredient Verification Programs
APIsExcipients
Summary
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Pharmexcil MOU
Signed February 15, 2007Purpose:
Reinforce the links of understanding and cooperation between PHARMEXCIL and USPUnderstand the importance of access to good quality, safe and effective medicines, nutraceuticals, dietary supplements, and also other articles such as active and non-active ingredients used in the manufacture of health care products
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Pharmexcil MOU, continued
Recognize the importance of developing long-term strategies to ensure that medicines of assured quality, safety and efficacy are made available to individuals in the U.S., India, and other countries around the worldAdvance on the common goal of improving the quality of medicines, API’s, nutraceuticals, dietary supplements and their ingredients
Coordinate complementary activities to continue first, second and third party monitoring to facilitate the achievement of that goal
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Pharmexcil MOU—Implementation
Work Group consisting of an equal number of representatives from both Pharmexcil and USP
To evaluate and maintain activities undertaken by both parties related to the MoU objectivesTo develop annual work plans related to the objectives
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MOU Objectives
1. Promote cooperation between the two parties2. Improve transfer and exchange of information
between the parties3. Increase awareness of the importance of the
quality, safety, and efficacy of medicine4. Establish the basis for a long-term relationship by
encouraging members of Pharmexcil to participate in the USP public health programs• USP revision process• USP Verification Programs
5. To develop standards and include to the extent possible the commonly used pharmaceutical raw materials in India under USP resulting in promotion of trade of such products in international markets
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USP’s Verification Programs
The Marks of Quality
Good quality medicines meet official standards for identity, strength, purity,
quality, packaging, and labeling.
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USP Dietary Supplement Verification
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Look for the USP-Verified Mark on Your Dietary Supplements
Your assuranceWhat’s on the label is in the bottle.The supplement does not contain harmful levels of contaminants.The supplement will break down properly to allow ingredients to dissolve in your body.The supplement has been made under safe, sanitary,manufacturing processes.
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USP Dietary Supplement Product Verification
Products covered by this program
Vitamin supplements
Mineral supplements
Amino Acid supplements
Botanicals
Non-botanical dietary supplements covered by DSHEA and legally marketed in the U.S. (e.g. fish oil, chondroitinsulfate sodium, glucosamine, etc.)
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Rigorous Dietary Supplement Verification Process
1. Guidelines from USP
Expert Committees
2. Audit of manufacturing sites for GMP compliance
3. Review of documentation manufacturing,
QA, QC
4. Laboratory testing of product samples
5. Review of conformance
with mark usage
guidelines
6. Continuous off-the-shelf
tests of products using
the mark
Participating companies go through many months of rigorous tests and reviews to meet USP’s high standards and earn the USP-Verified mark.
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Off-the-shelf Testing
USP will continuously test and examine selected lots and marketplace samples of approved products to ensure that
The mark is being used in accordance with guidelinesThe product continues to meet the criteria to carry the markThe product has not been reformulatedThere have been no major changes in the manufacturing process, specifications, test methods, or any other critical quality parameters
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Dietary Supplement Findings:
1. Update specifications for raw materials and finished products to comply with USP-NF specification, where applicable.
2. Reformulate and/or to introduce overages to formulation for ingredients to provide 100% of label claim throughout the shelf life of the product.
3. Make numerous changes to the product labels. Some of these changes were made to ensure an accurate list of ingredient claims, corrections to the recommended daily intake, additional reference to chemical salt and sources, the addition of Latin binomial and plant part used for botanicals, etc…
4. Establish proper stability study protocols, and subject their products to the studies to justify and/or determine appropriate expiration dating.
5. Remove quantitative ingredient claims where no validated analytical method is available to support such claims. Additionally, have PC change quantitative ingredient claims to support the minimum requirement of meeting 100% of label claim.
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List of Corrective Actions Imposed on Participating Companies in DSVP – cont.
6. Establish a standardized method of reporting analytical test results for products in units and percentages of label claim and clearly indicate units in the reporting form.
7. Identify ingredients by more specific entity/marker compound(s) for proper identification and quantification of ingredients on label claim.
8. Reformulate product which fails to comply with performance characteristics.
9 . Remove ingredient claims that have not been approved by the USP-DSVP Executive Committee.
10. Have appropriate validation for all method(s) used for quantification of ingredient claim(s) and use reference standard that are suitable for intended use and incorporate purity in calculation to provide accurate test results.
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USP Dietary Ingredient Verification
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USP Dietary Ingredient Verification
Voluntary participation by ingredient manufacturersVerification of ingredients manufactured and marketed to the dietary supplement industry in the U.S. and worldwideProcedures: same as DSVP
Ingredients covered by this programVitaminsMineralsAmino acidsPowdered botanicals and botanical extractsOther non-botanical dietary ingredients legally marketed under DSHEA (e.g. fish oil, chondroitinsulfate sodium, glucosamine, etc)
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Findings
Lack of Personnel Training activitiesLack of Equipment Cleaning validation proceduresLack of Validation of suppliers of raw materialsLack of validation of analytical methodsLack of analytical instrument calibration procedures
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Natural Products Association: New Opportunities to Assure Ingredient Supplement
Natural Products Association (NPA) , Washington DC representing hundreds of dietary supplements manufacturers signed a Memorandum of Agreement with USP in July 2007.Raw materials from China shipped to US customers will be analyzed at the USP China Lab in Shanghai and certificates of analysis provided to the NPA.This arrangement will minimize rejection rate of raw materials imported into the US.
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USP Pharmaceutical Ingredient Verification
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Proposed new programs: Drug Substance and Excipient Verification and Qualification
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“Verification” and “Qualification” Defined
“Verification”
A procedure used to provide written assurance that a product, process, service or person’s qualifications conforms to specified requirements.
USP Verification services will be sold to suppliers of drug substances and excipients.
“Qualification”
A Good Manufacturing Practices (GMP) concept required of dosage form manufacturers to assure the quality of materials received from suppliers.
USP Qualification services will be sold to users of drug substances and excipients in the manufacture of drug products.
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Four New USP Services to be Offered Worldwide
For suppliers (ingredient manufacturers and distributors)1. Drug substance verification2. Excipient verification
For users (dosage form manufacturer or other purchasers)3. Drug substance qualification4. Excipient qualification
All four are applicable to drug substances and excipients currently used in pharmaceutical dosage forms. Participation in any program is voluntary.
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What USP Will do to Verify or Qualify Items?
AUDIT the manufacturing siteREVIEW chemistry, manufacturing, and controls (CMC) documentationTEST samples for compliance with USP-NF monograph or, if no monograph exists, the manufacturer’s own analytical proceduresREVIEW the manufacturer’s post-verification/qualification notification of changesRE-TEST items periodically after they first pass the initial verification/qualification lab testingRE-EVALUATE each article at least every third year
USP will examine records and perform tests on drug substances and excipients to assure they are properly manufactured and they meet USP’s high standards for quality.
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Pharmaceutical and Excipient Verification Programs
Drug substancesExcipientsCollaborate with Regulatory Authorities and other organizationsProgram should be helpful to:
SuppliersUsers (dosage form manufacturers)Regulatory AuthoritiesPublic
Program is voluntaryGlobal launch
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Audit Criteria
ICH Q7 Guideline Good Manufacturing Practices for Active Pharmaceutical IngredientsInternational Pharmaceutical Excipient Council/Pharmaceutical Quality Group GMPGuide for Pharmaceutical Excipients USP General Chapter <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients
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USP Mark and Certificate
For articles meeting the USP drug substance or excipient verification requirements, the manufacturer may
Display the USP Verified mark on containersShow customers a USP Verified certificate
For suppliers meeting the USP qualificationrequirements for an article, USP will provide
A report and a certificate indicating USP has qualified the supplier for that article
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Audit Findings for APIs and Excipients
QUALITY SYSTEM
The Quality Unit is inadequate in that it does not function as an independent department. For example, the quality unit responsible for the release of finished APIs currently reported to the manager in charge of production.Review of several Batch Production Records for the manufacture of API XYZ reveal the lot # failed to meet the water content of finished product specification. The manager in charge of production made the decision to release the lot for commercial distribution despite the objections from Quality Control. The firm does not have a sufficient number of personnel to conduct finished API testing in a timely manner. For example, several lots of finished APIs testing were not fully completed and released prior to commercial distribution. There are an insufficient number of QA inspectors, or QA engineers to cover the quantity of products manufactured. For example, the firm manufactures over 200 bulk APIs, but only has five QA inspectors.
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Audit Findings for APIs and Excipients
FACILITIES AND EQUIPMENT STSTEMFACILITIESThe firm does not a written SOP regarding the general cleaning and maintenance of the building facilities utilized in the manufacture of APIs. For example, the warehouse storage facilities for both raw materials and finished APIs was noted to be crowded with the accumulation of debris which could serve as rodent/insect harborage areas and prohibited audit in several area of the warehouse. The design of the building is inadequate in that it does not allow for the flow of materials and personnel without creating a potential cross contamination problem. For example, the manufacture of API XYZ is being conducted in a manufacturing suit located in the middle of the building with the raw material storage area located in the adjacent room. This situation requires that upon the receipt of raw materials, that they be transported prior to release, through the manufacturing suit creating a potential for cross contamination.
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Audit Findings for APIs and Excipients
The firm does not have a written SOP describing the use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents for the facility. Utilities such as steam, gas, compressed air, heating, ventilation, and the air conditioning (HAVAC) system used in the manufacture of APIs have not been qualified (IQ, OQ).
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Audit Findings for APIs and Excipients
PROCESS EQUIPMENT
Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ), has not been conducted on critical process equipment used in the manufacture of APIs.Equipment surfaces used in the manufacture of APIs have not been tested to ensure that they are not reactive, additive, or adsorptive.Piped raw materials used in the manufacture of APIs were not identified as to flow direction and content.
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Audit Findings for APIs and Excipients
MATERIALS SYSTEM
The firm does not have separate areas identified as quarantined, in process, and released for the storage of incoming raw materials. For example, different lots of raw materials are not identified as quarantined, in process, and released all stored next to each other commingled. The firm’s does not have a separate room for the sampling of incoming raw materials. Raw materials are sample in the opened warehouse, which could pose a cross contamination concern.
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Audit Findings for APIs and Excipients
The firm’s Inventory Materials Management Computerized System has not been validated nor qualified. A challenge of the materials computerized system revealed that it is not always accurate. For example, a review of the computer system for Lot XYZ of an API, stored in warehouse slot # 135 revealed that there were 150 containers, 25 lbs. per container. A physical count of the contents in slot # 135 revealed that there were 300 containers. This discrepancy was investigated and determined to have been caused by human error.
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Audit Findings for APIs and Excipients
PRODUCTION SYSTEM
Review of Master Manufacturing instructions for the five of seven APIs manufactured by the firm revealed that they were not approved by the Quality Unit. For example, the firm’s production manager stated that the company manufactures too many products and that review of master instructions by the quality unit was taking too much time to approve. The president of the firm and the production manager simply decided to remove the quality unit from the approval process.Review of completed batch production and control records revealed that for the past nine months, production has been approving the batch records for final commercial distribution and not the quality unit.
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Audit Findings for APIs and Excipients
PACKAGING AND LABELING SYSTEM
Bulk product packaging room was not identified as to status e.g., in use, to be cleaned, etc.During the audit of the product label cage, the auditor observed in some cases, approved rolls of product labels without the approved green sticker per SOP #000, Label and Product Box Receipt.Weigh scale used during the filling operations of bulk API was observed not to have a calibration sticker, and no written documentation was provided to confirm that it had been previously calibrated.The API Certificate of Analysis, for each finished lot of API, does not list the date of manufacture nor the expiration date.
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Audit Findings for APIs and Excipients
LABORATORY CONTROL SYSTEMNo sample logbook is maintained by, the QC laboratory which shows the sample number, date of receipt, status of testing, initial of person who obtains the sample and tests the sample, completion date, and number of samples received by the laboratory. Review of the laboratory’s sub sampling practice regarding finished products was noted to, be accomplished, without the benefit of formal documentation. Discussion with the laboratory technician performing this sub sampling revealed that she was merely taking approximation of samples without specific measurements, and without a formal Standard Operating Procedure.Audit of the Laboratory’s refrigerator used to store standards and reagents, revealed the storage of standards and reagents passed their expiration dates or without expiry dates and use before date.
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Summary
Pharmexcil MOU and USP’s ‘third party certification programs’ create opportunity to promote Indian exports of:
Dietary Supplements (AYUSH Medicines)Dietary IngredientsAPIsExcipients
USP’s certification efforts are valuable to sponsors directly—support improvements in advance of stringent regulatory inspectionsThe joint manufacturer-USP activities also support USP’s public monographs and reference materials, which in turn also support manufacturersThe certification will benefit from regulatory recognition—USP is working on this but for now has no regulatory recognition for its third party programs.
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IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008
Hyderabad International Convention CenterHyderabad, India
Performance Verification Testing
William F. Koch, Ph.D.William F. Koch, Ph.D.Chief Reference Materials OfficerChief Reference Materials Officer
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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
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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.
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Drug Product Attributes: Quality and Performance
Product quality, as measured by:Chemistry, manufacturing and controls (CMC)MicrobiologyIdentity, strength, quality, purity and potency of drug product
Product performance, as indicated by:Drug dissolution (for many dosage forms)
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Goals of Dissolution Testing
Prediction of bioavailability, the surrogate-parameter 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 stabilityManufacturingStorage
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Pharmaceutical Dosage Forms <1151>
Terminology1. Aerosols2. Boluses3. Capsules4. Concentrate for DIP5. Creams6. Elixirs7. Emulsions8. Extracts & Fluid Extracts9. Gels10. Implants11. Infusions, Intramammary12. Inhalations13. Injections14. Irrigations
15. Lotions16. Lozenges17. Ointments18. Ophthalmic Prep. 19. Pastes20. Pellets21. Powders22. Premixes23. Solutions24. Suppositories25. Suspensions26. Syrups27. Systems28. Tablets
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Classification of Pharmaceutical Dosage Forms
Three-Tier System
Delivery Route
Dosage Form
Release Category
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Pharmaceutical Dosage Form Taxonomy
First Tier: classification by route of deliveryoral dosage forms topical/transdermalparenterals (by injection)mucosal or other membranesInhalation
Second Tier: classification by physical statesolid liquid gaseousMixed
Third Tier: classification by release patternconventional modified
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First Tier of Pharmaceutical Dosage FormsFIRST TIER CATEGORY: DELIVERY ROUTE - based on region of the body to which active delivered
SECOND TIER CATEGORY: DOSAGE FORM [i.e. based on the general type of dosage form]
dermal
Skin surface
topical
trans-dermal
nasal otic
ophth-
vaginal
Mucosal Membranes
rectalalmic urethral
oro-pharyngeal
oral
Gastro-intestinal Tract Lungs
IVIM etc
SC
Body Tissues or Fluids
[by injection]
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solids
tablets
chewable tablets solutions
suppositories solutions
THIRD TIER CATEGORY TYPE OF RELEASE [i.e. based on the RELEASE PATTERN OF THE ACTIVE]
suspensions
powders
oro- rectal
SECOND TIER CATEGORY DOSAGE FORM [i.e. based on the general type of dosage form]
liquids solids liquids
Mucosal Membranes
pharyngeal
semi-solids
gels
pastes
gumssemi-solids
Tiers 2 & 3 of Mucosal Dosage Forms
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Oral Dosage Forms
Immediate Release Modified Release
Extended Release Delayed Release
Solid oral dosage forms Liquid oral dosage forms
Tiers 2 & 3 of Oral Dosage Forms
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Compendial Use of the Dissolution Test
The Dissolution Test provides the compendialcorrelation to Drug Product Performance for the following dosage forms:
Solid oral dosage forms
Topical, dermals
Mucosal
Injectables – parenterals
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USP apparatiApparatus 1 (basket)Apparatus 2 (paddle)
Apparatus 3 (reciprocating cylinder)Apparatus 4 (flow-through cell)
Apparatus 5 (paddle over disk)Apparatus 6 (cylinder)Apparatus 7 (reciprocating holder)
USP Chapters <711>, <724>
solid oral dosage forms
various dosage forms
topical dosage forms
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RelevantPredictiveDiscriminating
ReproducibleTransferableRugged
Hence, there is a need for verification of the performance of the entire system
Critical Elements of Dissolution Testing
influenced also by the performance of the dissolution equipment and execution of the procedure
influenced by the design of the method, procedure, and dissolution equipment
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USP Performance Verification Tests
USP General Chapter <711> DissolutionApparatus 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
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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
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Dissolution Test - Causes Of Variability
The drug product under investigation
Dissolution equipment, apparatus and assembly
Environmental conditions
Dissolution procedure
Analytical method and procedure
Analyst
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Experimental Variables Contributing to Dissolution Variance
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
CV% Residual as Assembly Geometric
Mean
95% Confidence
Limits Between Analyst
Between Position
Between Experiment
Residual Total % of Total 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%
Statistical Analysis Summary for Apparatus 2
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Variability of Different Assemblies
Apparatus 2 - Assembly Alpha
25303540455055606570758085
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 #
Pred
niso
ne D
isso
lved
Per
cent
(%)
MinMaxMean
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
Apparatus 2 - Assembly Gamma
25303540455055606570758085
0 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031
Experiment #Pr
edni
sone
Dis
solv
ed P
erce
nt (%
)
MinMaxMean
Individual results obtained with Apparatus 2 on two different assemblies
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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
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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 vesselspublished in Dissolution Technologies 14(1), 2007
Stirring ratepublished in Dissolution Technologies 14(1), 2007
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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
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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
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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.
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Current Activities at USP:Oral Dosage Forms
Investigations on the influence of vibration on the PVT results
Revision of the General Chapter <711> regarding the specifications of some instrument parameters
Manufacturing and evaluating a new batch of Prednisone Tablets RS
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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/transdermalParenterals (by injection)Mucosal or other membranesInhalation
Investigate new approaches to assess drug product performance in vitro
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ExcipientsExcipients –– FunctionalityFunctionalitySpecifications and Specifications and MonographsMonographs
S D JoagS D JoagHon Gen Secretary, IPAHon Gen Secretary, IPADirector, Dr. M K Director, Dr. M K RangnekarRangnekar Lab, Lab, MumbaiMumbai77thth February 2008February 2008AtAtUSP 7USP 7thth Annual Meeting, HyderabadAnnual Meeting, Hyderabad
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ExcipientsExcipients
Pharmaceutical Pharmaceutical excipientsexcipients are are substances other than API/APIs, or substances other than API/APIs, or prodrugprodrug that are included in a finished that are included in a finished pharmaceutical dosage form [IPEC]pharmaceutical dosage form [IPEC]
OriginOriginex·cip·i·entex·cip·i·ent ((kk--spsp--ntnt) : Noun) : NounAn inert substance used as a An inert substance used as a diluentdiluent or vehicle for a drug.or vehicle for a drug.[Latin [Latin excipinsexcipins, , excipientexcipient--, present participle of , present participle of excipereexcipere, , to take out, excludeto take out, exclude; see ; see exceptexcept.].]
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ExcipientsExcipients
ExcipientsExcipients are used in virtually all drug are used in virtually all drug dosage forms.dosage forms.They are essential to product They are essential to product performance.performance.
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ExcipientsExcipients
Product performance and functionality of Product performance and functionality of excipientexcipient are two sides of the same coin and are two sides of the same coin and are interare inter--dependable dependable Right choice of the Right choice of the excipient/sexcipient/s makes the makes the product stable, safe and effective and product stable, safe and effective and makes it superior than other productsmakes it superior than other productsThus the formulation of Thus the formulation of excipientsexcipients in many in many cases is considered a trade secretcases is considered a trade secret
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Some of the known Functional Some of the known Functional CatagoriesCatagories of of ExcipientsExcipients
DiluentDiluent / Filler/ FillerLubricantLubricantSurfactant (Emulsifying, Wetting and Surfactant (Emulsifying, Wetting and SolubilisingSolubilisingAgent )Agent )BinderBinderColorantsColorantsSuspending / Viscosity increasingSuspending / Viscosity increasing AgentsAgentsSweetening AgentsSweetening AgentsGlidantGlidant and or and or AnticakingAnticaking AgentsAgentsCoating AgentsCoating Agents
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Some of the known Functional Some of the known Functional purposes of purposes of ExcipientsExcipients
Vehicle Vehicle –– Pharmaceutical WaterPharmaceutical WaterTonicity AgentTonicity AgentPlasticizers Plasticizers Suppository BaseSuppository BaseOintment BaseOintment BaseBufferBufferDisintegrationDisintegrationFlavors Flavors PreservativesPreservativesAntiAnti--oxidantsoxidants
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ExcipientExcipient OriginsOrigins
From deep in the From deep in the EarthEarthSoilSoil
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ExcipientExcipient OriginsOrigins
From crude oil to From crude oil to refined stagerefined stagePetroliumPetroliumPolyPoly--glycolsglycolsStarting materials Starting materials for synthetic for synthetic ChemistryChemistry
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ExcipientExcipient originsoriginsAgriculture : Wheat, Corn, Agriculture : Wheat, Corn, Sugar Cane, Cotton etc.Sugar Cane, Cotton etc.
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Tallow oils to glycerin and fattyTallow oils to glycerin and fattyacidsacids
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Agriculture derived Agriculture derived excipientsexcipients
Maize, , Potato, Wheat, StarchesMaize, , Potato, Wheat, StarchesSugar (Beet, Sugarcane)Sugar (Beet, Sugarcane)DextrinsDextrinsCyclodextrinsCyclodextrinsSorbitolSorbitolGlycerinGlycerin
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Minerals & Minerals & Natural originNatural origin
TalcTalcKaolinKaolinSodium chloride ( Sea Water)Sodium chloride ( Sea Water)Silicon Dioxide ( Silica Silicon Dioxide ( Silica -- AerosilAerosil))Calcium Carbonate (Oyster Shell)Calcium Carbonate (Oyster Shell)
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ProcessesProcesses
From very simple to complex e.g.From very simple to complex e.g.
Talc: mining Talc: mining ---- drying drying ---- milling milling Sugarcane Sugarcane ---- Refined sugarRefined sugarSorbitolSorbitol ---- Maize Maize ---- 20 steps 20 steps ---- SorbitolSorbitolBones Bones ---- Gelatin (Animal Based)Gelatin (Animal Based)Tallow oils Tallow oils ---- glycerin and fatty acidsglycerin and fatty acids
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ExcipientsExcipients
A very diverse collection of materialsA very diverse collection of materialsAbout 1200 ingredients are in use currently About 1200 ingredients are in use currently in marketed pharmaceutical products as in marketed pharmaceutical products as excipientsexcipients excluding colors and flavorsexcluding colors and flavorsAbout 250 documented in the European About 250 documented in the European PharmacopoeiaPharmacopoeiaNow 60 monographs in the international Now 60 monographs in the international harmonization process, USP, JP and Ph harmonization process, USP, JP and Ph EurEur
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ExcipientsExcipients
Successful manufacture of robust product Successful manufacture of robust product requires wellrequires well--defined defined excipientsexcipients and and processes.processes.PharmacopoeialPharmacopoeial Monographs: Monographs: 14 out of 40 functional categories identified 14 out of 40 functional categories identified in USP 30 in USP 30 -- NF 25NF 25EP (EDQM) plans to list specific functionality EP (EDQM) plans to list specific functionality related characteristics in some of its related characteristics in some of its excipientexcipient monographsmonographs
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USP General Chapters useful USP General Chapters useful for formulators for consistent for formulators for consistent excipientexcipient performanceperformance
<616><616>Bulk and Tapped densityBulk and Tapped density<695> <695> CrystallanityCrystallanity<699> <699> Density of solids Density of solids <731> <731> Loss on DryingLoss on Drying<786> <786> Particle size Particle size distributiondistribution-- sievingsieving<846> <846> Specific surface areaSpecific surface area<911> <911> ViscosityViscosity
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PharmaPharma use of use of ExcipientsExcipients
Contrary to APIs, Contrary to APIs, excipientsexcipients are are not specifically made for use in not specifically made for use in medicinal products e, g.medicinal products e, g.
Cellulose Cellulose Propellants Propellants SugarSugarGlycerinGlycerinStarchStarchColorsColorsFlavorsFlavors
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Types of Types of ExcipientsExcipients
ExcipientsExcipients also in use as API: usually also in use as API: usually one one pharmapharma grade is made e.g.grade is made e.g.DiDi--calcium Phosphate, Calcium calcium Phosphate, Calcium CarbonateCarbonateExcipientsExcipients developed and developed and manufactured specifically for manufactured specifically for pharmapharmause: special grade or grades use: special grade or grades
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ExcipientExcipient grade grade considerations considerations
Material should be fit for its intended Material should be fit for its intended useuseFood grade material usually acceptable Food grade material usually acceptable for (oral) for (oral) pharmapharma use, however use, however consider : functionality, interactions, consider : functionality, interactions, stability issues due to inconsistency in stability issues due to inconsistency in qualityqualitySpecial grades needed for Special grades needed for parenteralsparenterals, , inhalation and speciality productsinhalation and speciality products
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Impurities in Impurities in ExcipientsExcipientsIssues with Issues with Excipient/sExcipient/s
SourceSourceQuantity in formulationQuantity in formulationPurity / GradePurity / GradeInteractions with other Interactions with other excipient/sexcipient/sDegradation during shelfDegradation during shelf--life of the productlife of the product
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Impurities in Impurities in ExcipientsExcipients
GeneralGeneral
impurities related to starting materials impurities related to starting materials manufacturing processing aids manufacturing processing aids Contaminants Contaminants –– storage, packing, storage, packing,
To be controlled by GMPTo be controlled by GMP
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Impurities in Impurities in ExcipientsExcipients
Definition of the material: single or multiple Definition of the material: single or multiple component substancecomponent substance
Related substances from the starting Related substances from the starting materials, the process or instability materials, the process or instability
Additives, components added intentionallyAdditives, components added intentionally
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Impurities in Impurities in ExcipientsExcipients
Organic impuritiesOrganic impuritiesInorganic impuritiesInorganic impuritiesResidual solventsResidual solventsPesticides, antiPesticides, anti--fungalsfungalsMicrobial contaminationMicrobial contamination
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PharmacopoeialPharmacopoeialExcipientsExcipients
Monograph in general sufficient to Monograph in general sufficient to distinguish technical grades from distinguish technical grades from pharmapharmaMonograph represents acceptance criteria Monograph represents acceptance criteria for general usefor general useDebate on functionality related Debate on functionality related characteristics on going characteristics on going 14 high14 high--priority functional categories have priority functional categories have been identified in USP 30 been identified in USP 30 –– NF 25 NF 25
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PharmacopoeialPharmacopoeialExcipientsExcipients, issues, issues
GenotoxicGenotoxic impurities impurities Heavy metals (residues of catalysts)Heavy metals (residues of catalysts)Heavy metals test not satisfactoryHeavy metals test not satisfactory
MycotoxinsMycotoxins
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Some examplesSome examples
Inorganic impuritiesInorganic impuritiesHeavy metals in Heavy metals in mineralsminerals
Hydrogenated fatsHydrogenated fatsGelatin, Acacia,Gelatin, Acacia,StearatesStearatesPolymersPolymersLiquids (containers)Liquids (containers)
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Non Non pharmacopoeialpharmacopoeialexcipientsexcipients
Well known substances:Well known substances:reference to literaturereference to literature
Novel Novel excipientsexcipients::Stringent Regulatory requirements for Stringent Regulatory requirements for approvalapproval
follow ICH guidance as for API follow ICH guidance as for API but look for quality, safety and functionalitybut look for quality, safety and functionality
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Some examples Some examples
Inorganic impuritiesInorganic impurities
sulfites processing aid starches sulfites processing aid starches and refined sugars and refined sugars radioactive nuclidesradioactive nuclides
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Some examples Some examples
Organic impuritiesOrganic impuritiesproteins e.g. gluten, proteins e.g. gluten, prionprion, protein , protein additives e.g. Silicon dioxide additives e.g. Silicon dioxide BHT/BHA BHT/BHA TocopherolTocopherolHydrogen peroxideHydrogen peroxide
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Some examples Some examples
Organic impurities:Organic impurities:monomers and processing aids inmonomers and processing aids inpolymers, special instructions onpolymers, special instructions onethylene oxide residuesethylene oxide residuesresidual solventsresidual solventspesticidespesticides
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Some examples Some examples
Organic impuritiesOrganic impuritiesmicrobial contamination microbial contamination mycotoxinsmycotoxinsresidues from antimicrobial treatment residues from antimicrobial treatment
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ExcipientsExcipientsCritical ConsiderationsCritical ConsiderationsChallenges for FormulatorsChallenges for Formulators
DisintegrationDisintegrationDissolution/BADissolution/BA--BEBEContent uniformityContent uniformitySustained / Delayed Release consistencySustained / Delayed Release consistencyStability Stability –– Climatic conditionsClimatic conditionsPatient compliancePatient compliance
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Conclusions Conclusions
Definition of substance Definition of substance composition, very importantcomposition, very importantKnowledge of origin and main use Knowledge of origin and main use of the of the ExcipientExcipientApply general ICH guidance Apply general ICH guidance philosophy for novel materialsphilosophy for novel materialsStrictly adhere to monograph Strictly adhere to monograph specificationsspecificationsDevise additional functionality tests Devise additional functionality tests and specifications as inand specifications as in--househouse
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Questions to be askedQuestions to be asked
What is What is excipientexcipient? ? A Commodity, a very special product, main A Commodity, a very special product, main use in the world, grades available?use in the world, grades available?Who is the provider? Who is the provider? A manufacturer, a distributor, a trader, a A manufacturer, a distributor, a trader, a broker...?broker...?Is the provider a specialist in the Is the provider a specialist in the pharmapharmaworld?world?
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Security Security
What are the credentials of the provider?What are the credentials of the provider?
What kind of quality system is in place?What kind of quality system is in place?
What is the capacity to provide stable What is the capacity to provide stable quality in the amounts necessary quality in the amounts necessary
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OpenessOpeness
Is the provider open to discuss Is the provider open to discuss -- under under confidentiality agreementconfidentiality agreementparticulars of the ingredient, particulars of the ingredient, the manufacturing processthe manufacturing processIs the provider open to audit?Is the provider open to audit?Is the provider interested in Is the provider interested in coco--development of improved qualitydevelopment of improved qualitybetter performing ingredients ?better performing ingredients ?
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IPC-USP 7th Annual Scientific Meeting - India
Functionality Testing and Characterization of Excipients Helps Build Quality into the Drug Product
Dr. Ashok Katdare, Ph.D. Vice-Chair, Excipients Monograph I Expert Committee
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Outline
What is Quality?Cornerstones of FDA’s Pharmaceutical GMP
initiative for the 21st centuryICH Q8, Q9 and Q10Quality by Design (QbD)QbD considerations for excipientsExcipient selection and controlExcipient functionalityCase studiesQuestions and Answers
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What is Quality?
Compliance with specificationsActive IngredientExcipientsDrug ProductPackaging components
Predictable and consistentRobust process-ability and yieldReproducible functionality and utilitySum total larger than addition of individual parts
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The desired state: A mutual goal of industry and the regulators
A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversightManufacturers understand their products well in terms of critical product and process parameters and quality attributesManufacturers strive for continuous improvementNo manufacturing supplements are needed Patients are assured access to high quality, high performing drug products
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How to achieve the desired state?
Three key concepts
Quality by Design (QbD) and the design space concept (ICH Q8)
Quality risk management (ICH Q9)
Robust quality systems (ICH Q10)
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ICH Q8 – first element of the road-map
Why adopt ICH Q8Quality can not be tested into a product, it has to be designed and built into it from the initial concept through to all elements of production
• Without QbD industry could be validating processes without understanding
• Without QbD there is no way to know if the process is changing
• Industry could be wasting precious resources (time and money)
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Advantages of adopting ICH Q8
Product quality and performance achieved predictably and assured by design of effective and efficient manufacturing processesProduct and component specifications based on mechanistic understanding of formulation and how manufacturing unit operations are impactedAn ability to practice continual improvement and ‘real time’ assurance of quality
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Quality by design (QbD)
QbD is a key component of the FDA’s Pharmaceutical GMP initiative for the 21st
centuryQuality should be built by design and not simply tested in final productRather than fixed process parameters and stability data, developers can demonstrate broader understanding of the formula and process to support design space, specifications and controls demonstrating robustness
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Quality by Design QbD (cont)
Manufacturing within the design space relieves the manufacturer of filing post-approval changesTools include design of experiments (DOE), miniaturization, use of process analytic technologies (PAT), robust quality systems to establish design space and control systems
QbD is not necessarily a new concept, what is new is its utility in the regulatory arena i.e. granting regulatory flexibility and relief allowing enhanced efficiency, cost benefits and ability to respond to short term market needs
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What’s an excipient?
Pharmaceutical excipients are any substance other than the active drug product which has been appropriately evaluated for safety and is included in a drug delivery system to eitheraid processing of the system during manufacture orprotect, support or enhance stability, bioavailability, or patient acceptability orassist in product identification orenhance any other attribute of the overall safety and effectiveness of the drug product during storage and use.
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What’s the origin of excipients?
Mining of mineralsVegetation, plants and cropsChemical synthesisFormulated productsBiotechnologyAnimal by-products
Only a small percentage finds use in pharmaceuticalsQuality and level of control can differ from lot-to-lot supplier-to-supplier
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QbD considerations for excipients
What is critical to functioning of the drug product?What are the critical process parameters?What variances can be tolerated by the process, still ensuring predictable, high quality, reproducible product?Will the excipient specs ensure product performance with desired quality attributes?What specification ranges can the process tolerate and still produce product with desired critical performance attributes?
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Application of QbD to excipients
Increased understanding of formula and process desire for greater understanding of excipientsScience and risk-based approach
Focus on meaningful tests• Tests that provide knowledge and improved
understanding of impact on formula, process and product
• Meaningful specifications
Design space and QbD does not mean tightening of specification
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Excipients - basic understanding
Excipients come from variety of sources is acknowledgedNormal variability from batch-to-batch is recognized and acceptedUnderstanding of the ‘normal’ variability and its potential impact on processes through meaningful tests is achievedFormulators and engineers need to work with this variability, rather than against itExcipient manufacturers should engage in science and risk-based concepts
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Excipient selection - considerations
Excipient compatibility testing allows to determine the level of interaction between a given active pharmaceutical ingredient (API) and a selection of excipientsIntent is to proactively eliminate or minimize risk(s) in selection of a formula for the drug product as early as possible in the process of new drug delivery system development
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Excipient selection and control
Selection is based upon following considerations:What functionality is requiredDesired Drug delivery systemPhysical, chemical and biopharmaceutical attributes of APIPhysical, chemical attributes of excipients
Design and ControlManage normal variabilityUnderstand interactions and their impact on key processing unit operations, critical process parameters and critical product attributes
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What is excipient functionality?
A desirable property of a material (excipient) that improves manufacturability, quality and performance of the drug product.
Most excipients impart different types of functionality depending on their use in a particular product and dosage formFunctionality related characteristics (FRCs) cannot be defined by ‘type’ or ‘use’ of an excipient
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USP 29/NF 24 functional categories
Table 1: USP 29 / NF 24 Functional Categories Tablet/capsule diluents Tablet/capsule binders Colors
Lubricants Coatings Surfactants (Emulsifying, Wetting and Solubilizing agents)
Plasticizers Anticaking agents and glidants Desiccants
Antimicrobial preservatives Humectants Bulking agents for freeze-drying
Acidifying, alkalizing and buffering agents Antioxidants Antifoaming agents
Alcohol denaturants Chelating, Complexing, Sequestering agents Sweetening agents
Ointment bases Tonicity agents Emollients
Water repelling agents Suppository bases Aerosol propellants
Filtering aids Sorbents Pharmaceutical Waters
Solvents Viscosity increasing/suspending agents Vehicles
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Examples of functional mechanisms
Diluents impart desirable manufacturing properties (like powder flow, compaction strength, mitigation of overlubrication tendency etc) or performance attributes (like disintegration, dissolution) Lubricants (boundary type) adhere to solid surfaces, reduce particle-particle or particle-metal friction where as fluid- film lubricants melt under pressure creating a thin film around particles reducing frictionSurfactants reduce interfacial tension through a variety of mechanisms allowing emulsification, and wettingpH modifying agents adjust and maintain pH during processing or shelf-life
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Examples of functionality related characteristics (FRCs)
Particle shape, size and size distributionCrystallinityMoisture contentSpecific surface areaPowder flowCompaction propertiesViscosityMolecular weight, weight distributionRheological behavior
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USP general chapters relevant to FRCs
Crystallinity <695>Crystallinity determination by solution calorimetry <696>Particle size distribution by analytical sieving <786>; light diffraction measurement <429>Specific surface area <846>Powder low <1174>pH <791>Saponification and acid value <401>Gel strength for gelatin <1081>
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Context of excipient functionality
Excipient functionality can only be assessed in the context of a particular formulation and manufacturing processIt depends on the following
Active ingredient propertiesManufacturing processFunction it serves (relative to other excipients) and trade-offsIntended use (dosage form) and patient populationMany other factors
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Relevance of compendial compliance
Compendial monographs primarily focus on purity and safetyMainly chemical with a few physical testsFunctionality related characteristics (FRCs) in USP and Pharm Eur
Physical testing can be useful but provides insufficient guarantee of functionalitiesAnd then there are excipients with multiple functionalities
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Variable Raw Material + Fixed Process = Variable Product on
Raw Materials
Process
Process
Control
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Variable raw material + (anti) variable process = constant process
Raw Materials
Process
Process
Control
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Case Studies
Lactose anhydrousMagnesium stearate
Microcrystalline celluloseLactose hydrous
Gelatin in lyophilized dosage form
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Case study 1
Formula26% active ingredient (highly soluble)40% microcrystalline cellulose32.5% Lactose anhydrous1% superdisintegrant0.5% Magnesium stearate
Manufacturing processDirect compressible powder mixture followed by tabletting
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Design space
Anhydrous lactose was identified as a critical excipient with respect to flow of drymix
Note that it is added to the formulation to improve flow of the drymix (containing API)
Scope also included comparison of lots from two main suppliersFlowability of drymix was determined to be the critical process parameter for evaluation
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Physical characterization of 7 lots of anhydrous lactose from 2 different suppliers
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Comparison of sieve fractions of selected lots of anhydrous lactose
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Assessment of anhydrous lactose variability on dry mix
Rate of flow of lactose anhydrous
Lot 1 Lot 2 Lot 3
In seconds (bulk API alone was 150 sec)
13 34 76
Rate of flow of dry mix (with API)
Dry mix 1 Dry mix 2 Dry mix 3
In seconds 24 27 26
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Summary conclusions
The API, by itself. Exhibited poor flowAs expected, significant variability was noted among lots and between suppliersExcipient levels were selected to circumvent poor flow of drugDespite lot-to-lot variability (of almost 6 fold), very little effect was noted on flow of drymixFormula was determined to be robust with respect to
CompositionNormal variability of a key excipient
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Design space
Magnesium stearate is identified as a key component of the formula because of its potential adverse impact on dissolution
Level in formula was already optimizedSpecific surface area (2X range)Lubrication time (2X range)
Effect on dissolution rate was assessed
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Assessment of lubrication parameters
Specific surface area and mixing times
% Dissolved 10 minutes
% Dissolved 20 minutes
% Dissolved 30 minutes
4.9 m2/gm5 minutes
98 98 98
10.3 m2/gm5 minutes
95 95 95
10.3m2/gm10 minutes
93 93 94
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Summary conclusion
Formula was shown to be robust with respect to
2X range in specific surface area2X range in lubrication time
Dissolution profile remained acceptable despite stressing ‘the system’ to limits
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Design space
Impact of increase in breaking strength of tablet was assessed.
Hardness of the tablet was varied 3X (10-30 Kps)
Dissolution profiles were evaluated
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Assessment of breaking strength
Breaking strength
% Dissolved15 minutes
% Dissolved30 minutes
% Dissolved45 minutes
10 Kps 97 99 100
25 Kps 94 97 98
30 Kps 91 96 98
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Overall summary conclusions for Case 1
Formula is robustDesign space includes a rather broad range
Variability in excipients (broad specs justified)Alternate suppliersLubrication timeHardness
Critical process parameters are insensitive to normal variability in key excipients (within the design space studied)Manufacturing process is rugged
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Case study 2
Formula33.3% active ingredient (moderately soluble) 35% Microcrystalline cellulose17% Lactose hydrous dense14% Pregelatinized starch0.7% Magnesium stearate
Manufacturing processDirectly compressible powder mix followed by tabletting
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Design space
Identification of key componentsLactose from the perspective of flow and stickingMicrocrystalline cellulose from the perspective of flow
Impact of using different grades was evaluatedFormula composition was arrived at from a formal statistical design of experiments
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Comparison of several lots of hydrous dense lactose from 2 different suppliers
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Design space
As expected, wide variations in lot-to-lot flow properties were noted
Lots covering a range of 8X were evaluatedDifferences in control of physical characteristics were noted
Impact on flow of drymix was evaluated since a good flow is essential to tablet production for direct compression processes
Karr indices were evaluated as a potential surrogate
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Effect of normal variability of Fast-Flo lactose on drymix properties
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Summary conclusion
Despite selecting lots of lactose covering a range of 8X with respect to flow properties, the drymixes behaved indistinguishablyIt can be concluded that
The optimized formula is robust and can easily accommodate normal lot-to-lot variability in Fast-Flo lactose
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Design space
Once the formula was proven to be robust with respect to normal variability of lactose, impact of different grades (suppliers) was assessedIn addition to drymix characterization, tablet properties were also evaluated
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Substitution of Fast-Flo with hydrous dense lactose
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Summary conclusion
Despite some differences in performance, different grades of lactose (from two different suppliers) were established to be acceptable
Fast-Flo lactose, as expected, exhibited better compressibility and friabilityA less expensive grade (hydrous dense) allowed achieving cost-optimization goals
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Design space
Microcrystalline cellulose is commercially available in several grades
Avicel PH200 was customized to have better flow (essential for direct compression mixes)Two different grades (Avicel PH200 and PH102) were evaluated for interchangeability
Flow properties of drymix as well as tablet properties were evaluated
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Effect of varying grade of microcrystalline cellulose on power mix and tablets
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Summary conclusion
The formula is robust to allow use of different grades of microcrystalline lactose
Processing characteristics (drymix evaluation) as well as tabletting properties easily met critical desirable attributesInterchangeability of grades is possiblePaved the way for switching to a less expensive and more widely available grade
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Summary
Idea of Quality by Design (QbD) is not entirely newFDA’s new initiative provides a basis and framework to create a ‘win-win’ situation for both industry and regulatory authorities
Regulatory flexibility and reliefBetter science and understandingRobust formula, rugged processes and high quality drug productsBenefits to patients
• Predictability of high quality supply
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Summary (cont)
Functionality of excipients exists only in the context of a specific formulationLot-to-lot variability in excipients is to be fully expected; therefore formulas and processes need to be designed accordinglyProduct developers must make a good-faith effort in building quality into the productExcipient manufacturers are encouraged to adopt QbD, continuous improvement and quality risk management systems
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Questions and Answers
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Drug Drug -- Excipient interactionsExcipient interactions
USP ASM 2008USP ASM 2008
Dr.A.Lakshmi PrasadDr.A.Lakshmi PrasadSenior Manager (Analytical Research)Senior Manager (Analytical Research)Sun Pharma Advanced Research Co.LtdSun Pharma Advanced Research Co.LtdTandalja ,VadodaraTandalja ,Vadodara..
International Convention CenterInternational Convention CenterFebruary 7, 2008February 7, 2008
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StabilityStabilityExtensive chemical degradation: a substantial loss of potency
Degradation products may result in adverse events or be unsafe
Instability may cause
Undesired change in performance, i.e. dissolution/bioavailability
Substantial changes in physical appearance of the dosage form
causing product failures
Requirement for approval by regulatory agencies
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• Drug & Excipient
Chemical structure Impurity profile
Physical form
Moisture content
Particle size
Surface area
Morphology
Factors Affecting Formulation Stability
• Formulation
Drug : excipient ratio Processing method
Mixing/milling
Powder packing
• Environment
Temperature
Relative humidity
Packaging
Light
Oxygen
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Chemical DegradationChemical Degradation
HydrolysisHydrolysisEstersEstersCarboxylic acid estersCarboxylic acid estersAmidesAmidesImidesImides
DehydrationDehydrationIsomerization and RacemizationIsomerization and RacemizationDecarboxylation and eliminationDecarboxylation and eliminationOxidationOxidationPhotodegradationPhotodegradation
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DrugDrug--Excipient InteractionExcipient InteractionExcipients are usually biologically inactive, the same cannot be said froma chemical perspective. Excipients, and any impurities present, can stabilise and/or destabilise drug products.
Considerations for the formulation scientist:Chemical structure of the API Type of delivery system requiredProposed manufacturing process
Initial selection of excipients should be based on:Expert systems; predictive toolsDesired delivery characteristics of dosage formknowledge of potential mechanisms of degradation, e.g. Maillardreaction
The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quickly as possible, real and possible interactions between potential formulation excipients and the API. This is an important risk reduction exercise early in formulation development.
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Excipient InteractionsExcipient Interactions
Reactions of BisulfateReactions of Bisulfate
CH2NHCH3
OH
HOH
OH
CHCH2NHCH3OH
OH
SO3-
HSO3- / SO32-
HF
OHCH3CH3
OH
H
CH3
O
CH2OPO
OOH
ONa
HF
OHCH3CH3
OH
H
CH3
O
CH2OPO
SO3-
OOH
ONa
HSO3-
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Excipient InteractionsExcipient Interactions
Reactions of amines with reducing sugarsReactions of amines with reducing sugars
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Transesterification ReactionsTransesterification Reactions
NH2 COOC2H5 N COOC2H5
O
O
Polyvinylacetate phthalate
Excipient InteractionsExcipient Interactions
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Known IncompatibilitiesKnown Incompatibilities
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Excipient MoistureExcipient Moisture
Amount of water: High moisture content of poly vinyl Amount of water: High moisture content of poly vinyl pyrrolidonepyrrolidone and urea enhances Aspirin hydrolysis.and urea enhances Aspirin hydrolysis.
Decreased drug stability for ascorbic acid, dry syrups of Decreased drug stability for ascorbic acid, dry syrups of cephalexincephalexin, powders of , powders of cysteinecysteine derivatives and ureaderivatives and urea--linoliclinolicacid inclusion complex.acid inclusion complex.
Ascorbic acid and silica gel Ascorbic acid and silica gel
Thiamine hydrochloride tablets : Magnesium Thiamine hydrochloride tablets : Magnesium stearatestearate and MCC and MCC
PropanthelinePropantheline bromide : Sodium bromide : Sodium alluminumalluminum gelgel
Excipient InteractionsExcipient Interactions
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1111
Excipient MoistureExcipient MoisturePhysical state of water:Physical state of water:
Weakly absorbed water: Loose water or surface water Weakly absorbed water: Loose water or surface water
Strongly absorbed water: Excipient having higher adsorptionStrongly absorbed water: Excipient having higher adsorption energy energy decrease water reactivity, decrease in relative hydrolysis ratesdecrease water reactivity, decrease in relative hydrolysis rates..
Moisture adsorption Equilibrium: Excipient that adsorbs morMoisture adsorption Equilibrium: Excipient that adsorbs more e moisture adsorbs more strongly, resulting less free water for stmoisture adsorbs more strongly, resulting less free water for strongly rongly adsorbing excipient before it is reaching equilibrium. Relative adsorbing excipient before it is reaching equilibrium. Relative reactivity is decreased.reactivity is decreased.
Hydrated Drugs and excipient: Excipients can form hydrates may Hydrated Drugs and excipient: Excipients can form hydrates may enhance drug degradation by giving up their water of crystallizaenhance drug degradation by giving up their water of crystallization tion during grinding. during grinding.
Lactose hydrate enhances degradation of 4Lactose hydrate enhances degradation of 4--Methoxyphenylamino Methoxyphenylamino acetate hydrochloride upon grinding.acetate hydrochloride upon grinding.
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Mobility of water molecules :Mobility of water molecules :
Effect of water mobilityEffect of water mobility on drug stability, spin on drug stability, spin –– lattice lattice
relaxation time and spinrelaxation time and spin--spin relaxation time by NMR and spin relaxation time by NMR and
dielectric relaxation time by dielectric relaxation spectroscopydielectric relaxation time by dielectric relaxation spectroscopy..
Water mobility in polymer solutions/gels will effect the druWater mobility in polymer solutions/gels will effect the drug g
degradation. Mainly used for polymeric excipients like Poly degradation. Mainly used for polymeric excipients like Poly
vinyl pyrrolidone, Gelatin , PEG.vinyl pyrrolidone, Gelatin , PEG.
Excipient MoistureExcipient Moisture
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pH : Surface acidity of excipients contribute to pH : Surface acidity of excipients contribute to drug degradationdrug degradation
EgEg: Isomerization of vitamin D2: Isomerization of vitamin D2
OxazolamOxazolam degrades in the presence of MCC may be attributed to degrades in the presence of MCC may be attributed to carboxylic acid groups on the cellulose surface in addition to ecarboxylic acid groups on the cellulose surface in addition to effect of ffect of water.water.
Melting :Melting : Effect of Effect of steratesterate in Aspirinin Aspirin is due to change in melting is due to change in melting behavior.behavior.
Oxidation:Oxidation: Dye excipients enhance oxidation and Dye excipients enhance oxidation and photodegradationphotodegradation
Catalysis :Catalysis : Metal ions used as Pharmaceutical excipients or Metal ions used as Pharmaceutical excipients or present as impurities catalyze drug degradation. Triggers oxidatpresent as impurities catalyze drug degradation. Triggers oxidation and ion and photodegradationphotodegradation
Excipient InteractionsExcipient Interactions
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Physical stabilityPhysical stability
Crystallization of amorphous drugs:Crystallization of amorphous drugs:
NifedipineNifedipine co precipitated with PVP undergoes partial co precipitated with PVP undergoes partial crystallization during storage.crystallization during storage.
OxyphenbutazoneOxyphenbutazone converts to anhydrous form with lower converts to anhydrous form with lower solubility during storage under conditions of high humiditsolubility during storage under conditions of high humidityy
HaloperidoneHaloperidone converts to crystalline in presence of HPC,MC, converts to crystalline in presence of HPC,MC, HPMC and PVA.HPMC and PVA.
Crystallization of amorphous excipients also occur during Crystallization of amorphous excipients also occur during storage effects the drug release. storage effects the drug release.
Excipient InteractionsExcipient Interactions
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Drug-Excipient Compatibility Testing
In the typical drug/excipient compatibility testing program, binary (1:1 or customised) powder mixes are prepared by triturating API with the individual excipients.
These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions (8080°°/75%RH, 60/75%RH, 60°C/ambient RH, °C/ambient RH, 4040°°/75%RH)/75%RH) and analysed by stability-indicating methodology, e.g. HPLC.
Alternatively, binary samples can be screened using thermal methods, such as DSC/ITC. No need for stability set-downs; hence cycle times and sample consumption are reduced. However, the data obtained are difficult to interpret and may be misleading; false positives and negatives are routinely encountered.
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Prototype formulations: The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend.
However, the binary mix approach takes time and resources and….it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi-component prototype formulation.
This is a more complex system to interpret.
Drug-Excipient Compatibility Testing
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Drug-excipient interactions can be studied using both approaches in acomplementary fashion. The first tier approach is to conduct short-term (1-3m) stability studies using generic prototype formulations understressed conditions, with binary systems as diagnostic back-up:
Chemical stability measured by chromatographic methods Physical stability measured by microscopic, particle analysis, in vitrodissolution methods, etc.The idea is to diagnose any observed incompatibility from the prototype formulation work then hopefully identify the “culprit”excipients from the binary mix data.Hopefully, a prototype formulation can then be taken forward as a foundation for product development.
Can apply statistical models (e.g. 2n factorial design) to determine the chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture.
Drug-Excipient Compatibility Testing
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Drug-Excipient Compatibility Testing – More predictive Model
Storage of 200 mg drug excipient blends in Storage of 200 mg drug excipient blends in a closed vials at 50°C with 20 % added a closed vials at 50°C with 20 % added water.water.Study reveals: role of chemical nature of Study reveals: role of chemical nature of excipient, ratio of drugexcipient, ratio of drug--excipient blend, pH, excipient blend, pH, role of moisture , temperature, humidity, role of moisture , temperature, humidity, light.light.This approach avoids late stage This approach avoids late stage development surprises. development surprises.
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Detection & CharacterizationDetection & Characterization
Thermal AnalysisThermal AnalysisDSC, DTA, DTG & Isothermal DSC, DTA, DTG & Isothermal calorimetrycalorimetry
ChromatographyChromatographyHPLC, GCHPLC, GC
Diffuse reflectance spectroscopyDiffuse reflectance spectroscopy
IR, XRDIR, XRD
LCLC--MS/MS,NMRMS/MS,NMR
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IbuprofenIbuprofen--Mg Oxide interaction Mg Oxide interaction by DSC by DSC
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Excipient Interaction StudyExcipient Interaction Study((OxethazaineOxethazaine))
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Excipient Interaction Study Excipient Interaction Study ((GlimiperideGlimiperide))
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Isothermal Isothermal CalorimetryCalorimetry
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LevocetirizineLevocetirizine-- Lactose anhydrous Lactose anhydrous interaction study by HPLCinteraction study by HPLC
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RosuvastatinRosuvastatin with Acwith Ac--DiDi--sol sol (Cross (Cross carmasolcarmasol))
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RosuvastatinRosuvastatin with Acwith Ac--DiDi--sol sol (Cross (Cross carmasolcarmasol))
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Ropinirole interaction with Ropinirole interaction with with colloidal silicondioxidewith colloidal silicondioxide
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AtorvastatinAtorvastatin with with MeglumineMeglumine
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Drug CombinationsDrug CombinationsObjective is to minimise incompatibilities: Degradation pathways of the two APIs could be different, so a stabilisation strategy for API #1 could destabilise API #2.
In this situation, first intent strategy could be to prepare, separate compression blends of each individual API and compress as a bi-layer tablet– Disadvantages: adds complexity and bi-layer rotary presses are
expensive
Alternatively, could compress one of the APIs and over-encapsulate this into a capsule product, along with the powder blend from the second API– Disadvantage are that capsule size could be large, it requires
specialised encapsulation equipment to fill tablets and blend… process is more complex and expensive
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SymyxSymyx work stationwork station
Prepare: Increase the Scope of Your Study• Test a variety of excipients and excipient compositionsfor compatibility with a range of drug/API concentrations/loadings.• Create, schedule, and replicate sample stressing conditions including temperature, time/duration, humidity/moisture level, pH, and light exposure.
www.symyx.com
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Concluding RemarksConcluding Remarks
DrugDrug--excipient studies are an important foundation tool early in the excipient studies are an important foundation tool early in the development of drug products. They influence stability by ….development of drug products. They influence stability by ….
Drug dissolutionDrug dissolutionMelting time of suppositoriesMelting time of suppositoriesDrug release rate Drug release rate Drug leakageDrug leakageAggregation, precipitation & conformationAggregation, precipitation & conformationMoisture adsorptionMoisture adsorptionDiscolorationDiscolorationmechanical strengthmechanical strength
Know more about your drug and excipients to minimize Late Know more about your drug and excipients to minimize Late stage stage development surprisesdevelopment surprises
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Thanks…….Thanks…….
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BioequivalenceBioequivalenceBridge to Quality, Bridge to Quality,
Safety and EfficacySafety and Efficacyfor Generic Productsfor Generic Products
Dr.Prashant [email protected]
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Basic principles of QABasic principles of QAQuality safety and effectiveness must be built into the productQuality can not be measured or tested or inspected into all finished productEach step of the development and manufacturing process must be controlled, analyzed & performed to maximize the probability that the finished product meets all the quality, safety and efficacy parameters
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Questions during Drug DevelopmentQuestions during Drug Development
How do we build quality into products that are tested in the clinic to establish safety and efficacy?How do we utilize product development and also manufacturing experience to establish appropriate specifications for the to be marketed product?
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Evolution of BAEvolution of BA
Response is related to drug dose.Response is better related to drug concentration at site of action.Plasma drug concentration reflects drug concentration at site of action (systemic exposure)Bioavailability (BA) determines plasma concentration profile
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Bioavailability, Safety & EffectBioavailability, Safety & Effect
Systemic exposure profile during early trialsFairly defined relationshipIntrinsic property
Formulation
Plasma Levels
Drug Safety & Effect
Needs to be establishedBA and BE studies by innovatorBioequivalence studies for Generics
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BA: What does it mean? BA: What does it mean? Bioavailability
Provides data on the fraction of drug absorbed, its subsequent distribution and elimination as documented by its systemic exposure profile.
A drug is bioavailable if it is present at the site of action
In right quantity and right concentrationIn an intrinsically active conformation For required duration
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Bioavailability CFR DefinitionBioavailability CFR Definition320.1 Definitions Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent
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Bioavailability: Regulatory DefinitionBioavailability: Regulatory Definition
Rate and extent of absorptionRate
CmaxTmax
ExtentArea under the Curve (AUC)
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Prescribable New DrugPrescribable New Drug
New drug development program leads to a new productClinical Trial FormulationStability StudiesMarketed FormulationPrescribable
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Generic Drug: Physicians DilemmaGeneric Drug: Physicians Dilemma
Can I replace innovators brand with generic?Are two products switchable?Yes! If
they are bioequivalentAnd consistently bioequivalent
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BE PrincipleBE Principle
BioequivalenceCompares the systemic exposure profile of a test product (Generic) to that of a reference product (Innovator Brand)For the test product to be bioequivalent it should exhibit the same rate and extent of absorption as the reference product
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BE: CFR DefinitionBE: CFR Definition
Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
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Bioequivalence: MeaningBioequivalence: Meaning
Essentially similar or NOT DIFFERENT bioavailabilityRegulatory definition: ComparableRate and extent of absorptionRate• Cmax• Tmax
ExtentArea under the Curve (AUC)
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BE documentationBE documentation
during the IND or NDA period to establish links between
early and late clinical trial formulationsformulations used in clinical trial and stability studies, if differentclinical trial formulations and to-be-marketed drug product; and other comparisons, as appropriate.
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To Establish therapeutic equivalence or similarityTo establish lack of food effect or proper label claim w.r.t. foodTo establish the claim of modified releaseTo establish safety of MRTo establish lack of dose dumping
BE documentationBE documentation
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Assumptions in BEAssumptions in BEPharmaceutical EquivalentPharmaceutical Alternative
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Pharmaceutical EquivalentPharmaceutical Equivalent
Contain identical amounts of the identical API , i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms Different inactive ingredientsMeet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
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Pharmaceutical AlternativePharmaceutical Alternativecontain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates.
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In vivo BABE studiesIn vivo BABE studiesThese are also Clinical trials, ICH E6 GCP definition1.12 Clinical trial/study: Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous
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Clinical relevance of BA & BEClinical relevance of BA & BE
For Innovator ProductTo be prescribable, a new product (T) (to be marketed DF) must have the similar BA as the reference product (R) (Formulation used during clinical trials) with which efficacy and safety were proved
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Process for Generics (ANDA) developmentProcess for Generics (ANDA) developmentPr
oduc
t Id
entif
icat
ion
Product Development
4-6 M
Pilot BE
4-6 M
Executionof
Exhibit Batches
2-3 M
3 MStability
Data
ANDA Filing
18 – 24 MONTHS
Note: Generalised Timelines are for Products to US market
4-6 M
PivotalBE
4-6 M
10 to 15 months 6 to 9 months
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Clinical relevance of BA & BEClinical relevance of BA & BE
For Generic ProductTo be approved for ANDA, a new product [T] must have BA that is equivalent to that of the reference product [R]To be switchable, a new product [T] must have BA that is consistent and equivalentto that of the reference product [R], in this case a marketed product
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Therapeutic acceptance of ProductsTherapeutic acceptance of Products
Innovator to generic product switchOr
New patient on a generic product
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Variable Response in patientVariable Response in patientReduction in BP is variable when switched to generic brand from innovator in otherwise stable patient
Patient factor? NoFormulation effect? Possible But products are bioequivalent
Could be higher within subject variation attributable to formulation, manufacturing, process variable
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Therapeutic Rejection of ProductsTherapeutic Rejection of Products
Lack of consistent response or safety will lead to
NoncomplianceSwitch back to innovatorSwitch to another generic product
Lower market share
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Relevant QuestionsRelevant Questions
How does T compare with R on an average (average BE or BEA )? √
How variable is T compared with R ×(population BE or BEP )Do the results vary more with T in somesubjects and more with R in others ×(individual BE or BEI )
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Compliance to regulationsCompliance to regulations
Acceptable bioequivalence data and comparable in vitro dissolution and CMC data are required for approval of abbreviated new drug applications But it does not assure a successful market life for the product
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Validation & Verification of in vitro and in vivo Specifications
Pilot studies on different formulations with different dissolution profileEach formulation has been subjected to discriminating dissolution testing Process and formulation parameters have been analyzedUsing complex statistical analysis and matrices various correlations can be established
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Failed bioequivalenceFailed bioequivalenceInappropriate study designinadequate numbers of subjects in the otherwise adequately designed and execution of BE study May be due to higher or lower measures of rate and extent of absorption for test product compared to the reference product orbecause the performance of the test or reference is more variable cf to each other orBoth reference and test are different or varying in different ways
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Failed BioequivalenceFailed Bioequivalence1. Passing, ratio = 1, 0.8 < CI < 1.252. Passing, ratio < 1, 0.8 < CI < 1.253. Failed, ratio = 1, 0.8 > CI > 1.25
Highly variable drugs, can pass with >N4. Failed, ratio > 1, 0.8 < CI > 1.25
Formulation effect, can pass with >N5. Failed, ratio < 1, 0.8 > CI < 1.25
Formulation effect, can pass with >N6. Failed, ratio > 1.25, 0.8 < CI > 1.25
Completely different products7. Failed, ratio > 1, CI > 1.25
Completely different products
0.8 1.25
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Reasons for failureReasons for failure
High variability of PK parametersUnder-powered, N < than requiredCost??Lower enrollmentWithdrawalMissing data, Outliers
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Statistical Techniques help inStatistical Techniques help inidentifying the sources of variabilityisolating these sources of variabilitymeasuring the variability due to different sourcestesting statistically if each variability is big or small - i.e. statistically significant or not
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Statistical significance
Clinical Significance
e.g. Statistically Sequence effect in a single dose study of non-endogenous drug
1. Study was conducted as per appropriate design and all applicable guidelines and regulations
2. BE is established otherwise satisfactorily3. Wash-out period is adequate4. In second period all pre-dose values are zero5. All the variables and restrictions were same in
both periods
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The Concept of Pharmaceutical QualityThe Concept of Pharmaceutical Quality
Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004:"For the purposes of clinical use, the established drug quality attributes are generally adequate because they achieve much tighter control of the level of variability than could be detected in patients without extensive study.”
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The Concept of Pharmaceutical QualityThe Concept of Pharmaceutical Quality
Dr. Janet Woodcock, Pharmaceutical Review, 7, 10, 2004:“In contrast, for regulatory and manufacturing processes, the lack of detailed understanding of the real-world importance of quality attributes is a serious problem, leading to many disputes that might be resolved easily were relevant information available on the relationships between various quality parameters and clinical performance."
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In vitro, In vivo evaluationIn vitro, In vivo evaluation
Disintegration test (1950)Dissolution test (1968, apparatus 1)Apparatus 1 to 7Defining specification of dissolutionIVIVCModel based approach
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Dissolution SpecificationsDissolution Specifications
In vitro dissolution specifications have to be established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability
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Data available for Innovator ProductsData available for Innovator Products
Dissolution results under a variety of agitation and media conditionsA method that provides (rapid) dissolution profileMean & range of dissolution values of bio lot(s) Mean & range of dissolution values of several production lotsBA results of one or more lots (relative BA trials, BE trials)Formulation, process variables on lots used and not used in efficacy trials & / or BABE trialsStability data
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Data available for Generic ProductsData available for Generic ProductsDissolution results under a variety of agitation and media conditionsA method that provides (rapid) dissolution profileMean & range of dissolution values of bio lot(s) Mean and range of dissolution values of Few production lots ?? N=smallerBA results of one or more lots (Pilot trial 0 to few)Lots used in efficacy trials (Rarely Available)Stability dataComparative In vitro dataFormulation, process variables on lots used and not used in BABE trials
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Expectations from Dissolution testingExpectations from Dissolution testingto assess batch-to-batch quality, where the dissolution tests, with defined procedures and acceptance criteria, are used to allow batch releasedissolution testing is also used to
(1) provide process control and quality assurance, and (2) assess whether further BE studies relative to minor postapproval changes be conducted, wheredissolution can function as a signal of bioinequivalence.
In vitro dissolution characterization is needed for all product formulations investigated. Such efforts may enable the establishment of an in vitro-in vivo correlation.When an in vitro-in vivo correlation or association is available (21 CFR 320.24(b)(1)(ii)), the in vitro test can serve not only as a quality control specification for the manufacturing process, but also as an indicator of how the product will perform in vivo.
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When Equivalence Studies are When Equivalence Studies are Not NecessaryNot Necessary
Parenteral preparations – aqueous solutionsSolutions for oral usePowders for reconstitution as a solutionGasesOtic or ophthalmic products prepared as aqueous solutionsTopical products prepared as solutionsAqueous solutions for nebulizerinhalation or nasal sprays
VPShah-Ukraine-07
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Documentation of equivalence is necessary Documentation of equivalence is necessary
Oral immediate release pharmaceutical products with systemic action, &Indicated for serious conditions requiring assured therapeutic response; Narrow therapeutic window/safety margin, steep dose-response curve;Pharmacokinetics complicated by variable or incomplete absorption or absorption window, nonlinear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%Unfavorable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability, etc.,Where a high ratio of excipients to active ingredients exists.
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Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, etc.)Sustained or otherwise modified releasepharmaceutical products designed to act by systemic absorption.Fixed combination products
Documentation of equivalence is necessary Documentation of equivalence is necessary
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Non-solution pharmaceutical products which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and are intended to act without systemic absorption. In these cases, the bioequivalence concept is not suitable and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.
Documentation of equivalence is necessary Documentation of equivalence is necessary
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USP General ChapterUSP General Chapter1088 IN VITRO AND IN VIVO EVALUATION
OF DOSAGE FORMS Characterization PK properties of Dosage forms
Case A - applies to the original modified-release oral dosage form of an active drug entity already marketed in immediate-release form and for which extensive pharmacodynamic and pharmacokinetic data exist
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Case A : IR & New MRCase A : IR & New MR
A single-dose crossover study should include the following treatments:
the modified-release dosage form administered under fasting conditionsa dosage form that is rapidly available administered under fasting conditionsmodified-release dosage form administered
at the same time as a high-fat meal (or another type of meal that has potential for causing maximum perturbation).
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Evaluating Food Effect Evaluating Food Effect
whether a food effect is a result of problems with the dosage form?
a single-dose crossover study comparing the solution (or immediate-release dosage form) under fed and fasting conditions
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Effect of Timing on FoodEffect of Timing on Food--Drug EffectDrug Effect
four-way crossover study with the modified-release dosage form administered under the following treatment conditions:
fasting, taken with a high-fat meal, 1 hour before a high-fat meal, and 2 hours after a high-fat meal
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Alternative appropriate studies could be conducted if the applicant were to label the drug for administration with a meal that is not fat-loaded. In this case, an alternative meal composition should be considered For delayed-release (enteric-coated) dosage forms, bioavailability studies to characterize adequately the food effects and to support the dosing claims stated in the labeling should be performed
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MultipleMultiple--dose, Steadydose, Steady--state Studies state Studies
STUDY I : IR with linear pharmacokineticsa steady-state study with the MR dosage form at one dose rate (preferably at the high end) using an IR dosage form as a control
STUDY II: Nonlinear kinetics or no cf dataa steady-state study with MR dosage form at Two dose rate (preferably at low & high end) using an IR dosage form as a control
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Case BCase BCase B applies to a non-oral, modified-release dosage form of an already marketed active drug entity for which extensive pharmacodynamic /pharmacokinetic data exist.Case A studies (omitting the food effect studies)
if the pattern of biotransformation to active metabolites is identical for the two routes. If the biotransformation patterns are different, then clinical efficacy studies should be performed with MR productIn addition, special studies may be necessary to assess specific risk factors related to the dosage form (e.g., irritation and/or sensitization at the site of application)
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Case CCase C
Case C applies to a generic equivalent of an approved modified-release dosage form.crossover single-dose and steady-state studies. For an oral modified-release dosage form, the food studies described under Case A should also be performed
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CFR 320.27 CFR 320.27 A multipleA multiple--dose study may be requireddose study may be requiredto determine the bioavailability of a drug product in the following circumstances:
(i) There is a difference in the rate of absorption but not in the extent of absorption.
(ii) There is excessive variability in bioavailability from subject to subject.
(iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method.
(iv) The drug product is an extended release dosage form.But CDER guidance generally recommends single-dose pharmacokinetic studies for both IR, MR drug products to demonstrate BE
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CDER Guidance : MR ANDACDER Guidance : MR ANDAsingle-dose, nonreplicate, fasting study comparing the highest strength of the test and reference listed drug product and food-effect, nonreplicate study comparing the highest strength of the test and reference product Because single-dose studies are considered more sensitive in addressing the primary question of BE (i.e., release of the drug substance from the drug product into the systemic circulation), multiple-dose studies are generally not recommended, even in instances where nonlinear kinetics are present
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Food effect studies not required Food effect studies not required for IRfor IR
When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I) the product should be taken only on an empty stomachNo food effect
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SUPAC-IR (1995) and
SUPAC-MR Guidances (1997) Summary
(Equipment Addendum (1999); FDAMA (1997) and “Changes Approved to an NDA or ANDA” Guidance
(2000)
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General Aspects: (Change) General Aspects: (Change) Variables CoveredVariables Covered
Components and CompositionNon Release ControllingRelease Controlling
SiteBatch Size (Scale-Up/Scale-Down)Manufacturing
EquipmentProcess
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General Aspects: Supporting DataGeneral Aspects: Supporting Data
• Level I (Minor) change• Level II (Moderate) change• Level III (Major) change
• Chemistry (A/C test, Stability)• In Vitro dissolution/release• In Vivo bioequivalence test / IVIVC
• Annual report• Change being effected supplement• Prior approval supplement
Level ofChange
Tests
Filing
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SUPACSUPAC-- IR and MR SUMMARYIR and MR SUMMARY
The following changes need a bio study & / or IVIVC): level 3 RC and NRC, level 2 RC for NTR drugslevel 3 site changelevel 3 process change
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Resourcefulness and Commitment
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IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008
Hyderabad International Convention CenterHyderabad, India
Developing Fixed-Dose Combination Drug Products to Treat HIV Disease: The
HHS/UNAIDS/WHO/SADC Principles Documentand the FDA Guidance for Industry
Darrell R. Abernethy, M.D., Ph.D.Chief Science Officer
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Topics Discussed
Scientific and Technical Principles for Fixed Dose Combination Drug Products for the Treatment of HIV/AIDS, Malaria and Tuberculosis (Principles Document)FDA Draft Guidance for Industry: Fixed-Dose Combination and Co-Packaged Drug Products for Treatment of HIV (Draft FDA Guidance)
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Principles Document: Intro
HIV/AIDS, tuberculosis, malaria are the foremost infectious disease threats facing the world todayCombination therapy is considered essential in treating these diseasesAn important approach is developing fixed-dose combinations (FDC) of drugsA principles document was developed to address development of FDCs
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Principles Document: Development
Dec ’04: Final version posted at
www.globalhealth.gov
Feb ‘04: Small group met in South Africa,
drafted document
March ‘04: Document
presented at conference in
Botswana
Apr ‘04: Document posted
on web, comments accepted
May – Aug ‘04: Planning group incorporated
comments into document
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Principles Document: Advantages of FDCs
Improved adherenceConvenience of useReduced pill burden/simpler treatment regimensFacilitation of logistics of procurement, distribution, dispensing
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Principles Document: Purpose
Contains guidelines to facilitate and promote development of FDCsNot intended to be a regulatory guidelineApplies to both innovator and generic pharmaceutical companiesEmphasizes efficacy, safety, qualityDescribes four possible scenarios
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Principles Document: Scenario 1
In vivo bioequivalence (BE), compare generic to FDCClinical
Not neededNonclinical pharm/tox
Not neededMicrobiology
A generic bioequivalent (BE) to existing FDCScenario
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Principles Document: Scenario 2
In vivo BE, compare new FDC to drug components given togetherClinical
Not neededNonclinical pharm/tox
Not neededMicrobiology
Proposed new FDC, established safety & efficacy of active drug components in combination
Scenario
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Principles Document: Scenario 3
PK or PD drug-drug interaction studiesClinical trials to demonstrate safety/efficacy of
new combination or regimenMay be acceptable to substitute historical clinical
data, PK bridging data
Clinical
Case-by-case basis
Nonclinical pharm/tox
May be needed to determine the advantage of FDC over individual active components
Microbiology
New FDC, safety & efficacy established for individual active components but not combinationScenario
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Principles Document: Scenario 4
A comprehensive clinical program is neededClinical
A complete evaluationInclude genotox, reprotox, toxicokinetic studies
Nonclinical pharm/tox
May be needed to determine the advantage of FDC over individual active components
Microbiology
New FDC comprised of one or more new molecular entitiesScenario
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Principles Document: Postlicensing Surveillance
Shared responsibilityPhysicians, patients, other healthcare providers, manufacturers, regulators
Concerns specific to FDCs for HIV/AIDS, malaria, tuberculosis
Adverse events due to one of the componentsAdditive, synergistic toxicitiesChanges in pathogen resistance profilesDiminishing efficacy
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Principles Document: Quality
Specific for geographic regionStability
Process developmentCompatibility of individual activecomponents in dosage formCompliance with regulatory or compendial specificationsIn-process controls
Drug Product
Characterize impurities, particle size, polymorphism
Drug Substance
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FDA Draft Guidance: Development
Encourage sponsors to submit to FDA applications for marketing approval of new and generic FDCs and co-packaged drug products to treat HIV
Intended to
Several Offices within FDA/CDERDrafted by
May 2004 (as draft)Issued in
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Draft FDA Guidance: Appropriate Combinations
Individual components or FDCs must be already approved by FDACombinations should be supported by adequate evidence of safety, efficacyFDC components should have same dosing frequency and similar food instructionsGuidance lists example combinations
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Draft FDA Guidance: Submissions to FDA
Regulatory proceduresPriority review, fast track
Clinical considerationsNew clinical trials not neededShould reference material previously submitted to FDA and peer-reviewed literature
Clinical pharmacology/biopharmaceuticsPivotal clinical studies are BA or BE studies
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Draft FDA Guidance: Submissions to FDA
Chemistry, manufacturing, controlsDrug substanceDrug productStabilityIssues unique to FDCs
• Lack of interaction between active ingredients
Microbiology/virologyAdverse event reporting
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Draft FDA Guidance: Approval Mechanisms
Patent on drug substance still validProduct cannot be marketed in USTentative
Two or more innovators develop a new FDC or co-packaged product
Innovator grants license to use drugPatent on drug has expiredFirm challenges unexpired patent, and
Innovator doesn’t sue; orInnovator sues but court finds patent
invalid or not infringed
Full
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Summary
HHS/UNAIDS/WHO/SADC developed a scientific/technical principles document addressing development of FDCs to treat HIV/AIDS, tuberculosis and malariaThe FDA provides guidance to industry together with expedited review for FDC and co-packaged drug products to treat HIV/AIDS The goal of these efforts is to impact public health throughout the world
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IPC-USP 7th Annual Scientific Meeting February 6 - 7, 2008
Hyderabad International Convention CenterHyderabad, India
Pharmacological Appraisal of Fixed-Dose Combination Therapy
Darrell R. Abernethy, M.D., Ph.D.Chief Science Officer
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Fixed-Dose Combinations
Ideal Characteristics
All Components Have Wide Therapeutic Index
All Components Are Highly bioavailable
All Components Have Similar Clearance/ half-life
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Fixed-Dose Combinations, cont.
WHO List of Essential Medicines (rev. March, 2005)
Amoxicillin + Clavulanic Acid
Sulfamethexazole + Trimethoprim – oral, iv
Isoniazid + Ethambutol
Rifampicin + Isoniazid
Rifampicin + Isoniazid + Pyrazinamide
Rifampicin + Isoniazid + Pyrazinamide + Ethambutol
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Fixed-Dose Combinations, cont.
WHO List of Essential Medicines (rev. March, 2005)
Lopinavir + Ritonavir
Artemether + Lumefantrine
Sulfadoxine + Pyrimethamine
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Fixed-Dose Combinations, cont.
WHO List of Essential Medicines (rev. March, 2005)
Ferrous Salt + Folic Acid
Levodopa + Carbidopa
Benzoic Acid + Salicyclic Acid - topical
Neomycin + Bacitracin - topical
Ethinylestradiol + Levonorgestrel
Ethinylestradiol + Norethisterone
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Fixed-Dose Combinations, cont.
Strategies
I. One Agent Prolongs the Effect of the Other
a) Levodopa + Carbidopab) Lopinavir + Ritonavir
II. Prevent Drug Resistance
a) Anti-infectivesb) Anti-tuberculosisc) Anti-HIV
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Fixed-Dose Combinations, cont.
Challenges
I. Dose Titration of the Individual Component
II. Interplay of Adverse Effects
III. Allergies to One or More Components
IV. Complex Pharmacokinetic and/or Pharmacodynamic Profiles
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Fixed-Dose Combinations, cont.
Important Considerations
Safety and Efficacy of Individual Components
Safety and Efficacy of Simultaneous Use of Individual Active Components
Potential Interaction (Physical or Chemical) Among Active Components When Formulated Into a Fixed-Dose Combination
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Fixed-Dose Combinations, cont.
Clinical and Pharmacological Rationale to Support Development
Increased Efficacy (Additive or Synergistic)
Reduced Toxicity
Limiting Development of Pathogen Resitance
Pharmacokinetic Interaction to Increase Drug Exposure
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Fixed-Dose Combinations, cont.
Clinical Advantages
Improved Adherence
Convenience
Reduced Pill Burden / Simpler Treatment Regime
Improved Availability of Drugs to Patients Due to Simplified Procurement, Distribution, and Dispensing
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Fixed-Dose Combinations, cont.
Issues for Consideration
Combining Active Components with Different PK. Antimicrobials with Short and Long t ½ May Promote Development of Drug Resistance
Absorption of Some Drugs Facilitated by Food, Others are Impaired by Food
Are Components Physically and Chemically Compatible?
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Fixed-Dose Combinations, cont.
Comparability Among Products
Development of Reference Formulatione.g. – Establishment of a reference formulationfor bioequivalence assessment of rifampicin-containing FDC’s: an essential step towards improving tuberculosis treatment.
Ashokraj, Singh, Kau, Kohdi,Bhade, Varma, Kaul, and Panchagnula.Int. J. Tuberc Lung Dis 2005; 9:791-796.
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Fixed-Dose Combinations, cont.
Table 1. Fixed-Dose Combination Antiretrovirals Used toTreat HIV Infection
Antiretroviral Agents Usual Adult Dosage
NRTI CombinationsZDV/3TC (Combivir, GlaxoSmithKline) 1 tablet twice daily
ZDV/3TC/ABC (Trizivir, GlaxoSmithKline) 1 tablet twice daily
TDV/FTC (Truvada, Gilead Sciences) 1 tablet daily
ABC/3TC (Epzicom, GlaxoSmithKline) 1 tablet daily
PI Combinations LPV/RTV (Kaletra, Abbott Laboratories) 3 capsules twice daily
Adapted from The Aids Reader, October 2004
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Fixed-Dose Combinations, cont.
Sites of action of the principal anti-TB drugs.Adapted in part from Rattan et al.; Parsons et al.; Somoskovi et al. [16,17,18].
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Fixed-Dose Combinations, cont.
Proposed mechanisms for interaction between RIF and INH:(a) Schiff's Reaction of RIF and INH, (b) Carbonyl Condensation of RIF and INH, (c) Fischer's Esterification Reaction between RIF and INH.
Adapted in part from Rattan et al.; Parsons et al.; Somoskovi et al. [16,17,18].
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The Standard of QualityTM