Usp 2008track2combined

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

Topics

Pharmexcil MOUDietary Supplement Verification Program (DSVP)Pharmaceutical Ingredient Verification Programs

APIsExcipients

Summary

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

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

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

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

USP’s Verification Programs

The Marks of Quality

Good quality medicines meet official standards for identity, strength, purity,

quality, packaging, and labeling.

USP Dietary Supplement Verification

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.

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.)

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.

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

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.

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.

USP Dietary Ingredient Verification

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)

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

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.

USP Pharmaceutical Ingredient Verification

Proposed new programs: Drug Substance and Excipient Verification and Qualification

“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.

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.

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.

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

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

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

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.


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.


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).


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.


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.


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.


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.


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.


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.

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.



Performance Verification Testing

William F. Koch, Ph.D.William F. Koch, Ph.D.Chief Reference Materials OfficerChief Reference Materials Officer

Drug Product Performance

Formulation performance is defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance and eventually leading to one or more pharmacologic effects, both desirable and undesirable.

Dale Conner, PharmD, FDA/OGD, 2004

Rate Process in Drug Bioavailability

Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from the drug product and becomes available at the site of action

Hence, the rate of Dissolution is related to Bioavailability.

Drug Product Attributes: Quality and Performance

Product quality, as measured by:Chemistry, manufacturing and controls (CMC)MicrobiologyIdentity, strength, quality, purity and potency of drug product

Product performance, as indicated by:Drug dissolution (for many dosage forms)

Goals of Dissolution Testing

Prediction of bioavailability, the 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

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

Classification of Pharmaceutical Dosage Forms

Three-Tier System

Delivery Route

Dosage Form

Release Category

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

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]

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

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

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

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

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

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

Dissolution Test Variability – Apparatus 2

Maria Glasgow et al.: The USP Performance Verification Test Part II: Collaborative Study of USP’s Lot P Prednisone Tablets, Pharm. Res. 2007

Dissolution Test - Causes Of Variability

The drug product under investigation

Dissolution equipment, apparatus and assembly

Environmental conditions

Dissolution procedure

Analytical method and procedure

Analyst

Experimental Variables Contributing to Dissolution Variance

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

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

Variability due to Dissolution Vessels

Mark Liddell et al.: Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources, American Pharm. Review, Vol. 10(6) Sept./Oct. 2007

USP Research on other Sources of Variability in Dissolution Testing

Dissolved gases (e.g. oxygen)published in Dissolution Technologies 13(3), 2006

Geometry of the dissolution vesselspublished in Dissolution Technologies 14(1), 2007

Stirring ratepublished in Dissolution Technologies 14(1), 2007

USP Research on Sources of Variability in Dissolution Testing - Conclusions

Based on USP research, data and statistical analysis, it is the USP position that:

the variability due to the Prednisone Tablets contributes no more than 5% to the total variability

the suitability of the Prednisone Tablets RS for the Performance Verification Test (PVT) for the Apparatus 2 (paddle) has been demonstrated

Draft FDA Guidance issued October 2007

The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 - Current Good Manufacturing Practice (CGMP)

The draft Guidance argues that only mechanical calibration without PVT is needed

http://www.fda.gov/cder/guidance/7232dft.htm

USP Response to Draft FDA Guidance

USP maintains that:Both PVT and mechanical calibration are critical to the dissolution procedure, and Mechanical calibration alone cannot ensure the validity of dissolution results.

USP emphasizes:That mechanical calibration is a necessary but not sufficient means of ensuring consistency and comparability of measurements obtained with a dissolution test system.The importance of a periodic performance verification test (PVT) together with careful mechanical calibration to ensure that the combined experimental study yields consistent results.

USP acknowledges that:Improvements to the mechanical specifications are required.New approaches to assess drug product performance in vitro are needed.

Current Activities at USP:Oral Dosage Forms

Investigations on the influence of vibration on the PVT results

Revision of the General Chapter <711> regarding the specifications of some instrument parameters

Manufacturing and evaluating a new batch of Prednisone Tablets RS

Future Research Directions at USP

Investigate the “ideal” Reference Standard for oral dosage form PVTs

Develop Performance Verification Tests (PVT) and Reference Standards for other dosage forms and apparati.

Topical/transdermalParenterals (by injection)Mucosal or other membranesInhalation

Investigate new approaches to assess drug product performance in vitro

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

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.].]


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.


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

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

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

ExcipientExcipient OriginsOrigins

From deep in the From deep in the EarthEarthSoilSoil

ExcipientExcipient OriginsOrigins

From crude oil to From crude oil to refined stagerefined stagePetroliumPetroliumPolyPoly--glycolsglycolsStarting materials Starting materials for synthetic for synthetic ChemistryChemistry

ExcipientExcipient originsoriginsAgriculture : Wheat, Corn, Agriculture : Wheat, Corn, Sugar Cane, Cotton etc.Sugar Cane, Cotton etc.

Tallow oils to glycerin and fattyTallow oils to glycerin and fattyacidsacids

Agriculture derived Agriculture derived excipientsexcipients

Maize, , Potato, Wheat, StarchesMaize, , Potato, Wheat, StarchesSugar (Beet, Sugarcane)Sugar (Beet, Sugarcane)DextrinsDextrinsCyclodextrinsCyclodextrinsSorbitolSorbitolGlycerinGlycerin

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)

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


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


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

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

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

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

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

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

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


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


Organic impuritiesOrganic impuritiesInorganic impuritiesInorganic impuritiesResidual solventsResidual solventsPesticides, antiPesticides, anti--fungalsfungalsMicrobial contaminationMicrobial contamination

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

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

Some examplesSome examples

Inorganic impuritiesInorganic impuritiesHeavy metals in Heavy metals in mineralsminerals

Hydrogenated fatsHydrogenated fatsGelatin, Acacia,Gelatin, Acacia,StearatesStearatesPolymersPolymersLiquids (containers)Liquids (containers)

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

Some examples Some examples

Inorganic impuritiesInorganic impurities

sulfites processing aid starches sulfites processing aid starches and refined sugars and refined sugars radioactive nuclidesradioactive nuclides


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


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


Organic impuritiesOrganic impuritiesmicrobial contamination microbial contamination mycotoxinsmycotoxinsresidues from antimicrobial treatment residues from antimicrobial treatment

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

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

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?

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

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 ?

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

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

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

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

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)

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)

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

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

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

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.

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

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?

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

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

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

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

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

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

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

Examples of functionality related characteristics (FRCs)

Particle shape, size and size distributionCrystallinityMoisture contentSpecific surface areaPowder flowCompaction propertiesViscosityMolecular weight, weight distributionRheological behavior

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>

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

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

Variable Raw Material + Fixed Process = Variable Product on

Raw Materials

Process

Process

Control

Variable raw material + (anti) variable process = constant process

Raw Materials

Process

Process

Control

Case Studies

Lactose anhydrousMagnesium stearate

Microcrystalline celluloseLactose hydrous

Gelatin in lyophilized dosage form

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

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

Physical characterization of 7 lots of anhydrous lactose from 2 different suppliers

Comparison of sieve fractions of selected lots of anhydrous lactose

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

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

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

Assessment of lubrication parameters

Specific surface area and mixing times

% Dissolved 10 minutes



4.9 m2/gm5 minutes

98 98 98

10.3 m2/gm5 minutes

95 95 95

10.3m2/gm10 minutes

93 93 94

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

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

Assessment of breaking strength

Breaking strength

% Dissolved15 minutes



10 Kps 97 99 100

25 Kps 94 97 98

30 Kps 91 96 98

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

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

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

Comparison of several lots of hydrous dense lactose from 2 different suppliers

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

Effect of normal variability of Fast-Flo lactose on drymix properties

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

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

Substitution of Fast-Flo with hydrous dense lactose

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

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

Effect of varying grade of microcrystalline cellulose on power mix and tablets

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

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

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

Questions and Answers

11

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

22

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

33

• 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

44

Chemical DegradationChemical Degradation

HydrolysisHydrolysisEstersEstersCarboxylic acid estersCarboxylic acid estersAmidesAmidesImidesImides

DehydrationDehydrationIsomerization and RacemizationIsomerization and RacemizationDecarboxylation and eliminationDecarboxylation and eliminationOxidationOxidationPhotodegradationPhotodegradation

55

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.

66

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-

77


Reactions of amines with reducing sugarsReactions of amines with reducing sugars

88

Transesterification ReactionsTransesterification Reactions

NH2 COOC2H5 N COOC2H5

O

O

Polyvinylacetate phthalate


99

Known IncompatibilitiesKnown Incompatibilities

1010

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


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.

1212

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

1313

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


1414

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.


1515

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.

1616

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.


1717

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.


1818

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.

1919

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

2020

IbuprofenIbuprofen--Mg Oxide interaction Mg Oxide interaction by DSC by DSC

2121

Excipient Interaction StudyExcipient Interaction Study((OxethazaineOxethazaine))

2222

Excipient Interaction Study Excipient Interaction Study ((GlimiperideGlimiperide))

2323

Isothermal Isothermal CalorimetryCalorimetry

2424

LevocetirizineLevocetirizine-- Lactose anhydrous Lactose anhydrous interaction study by HPLCinteraction study by HPLC

2525

RosuvastatinRosuvastatin with Acwith Ac--DiDi--sol sol (Cross (Cross carmasolcarmasol))

2626

RosuvastatinRosuvastatin with Acwith Ac--DiDi--sol sol (Cross (Cross carmasolcarmasol))

2727

Ropinirole interaction with Ropinirole interaction with with colloidal silicondioxidewith colloidal silicondioxide

2828

AtorvastatinAtorvastatin with with MeglumineMeglumine

2929

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

3030

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

3131

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

3232

Thanks…….Thanks…….

BioequivalenceBioequivalenceBridge to Quality, Bridge to Quality,

Safety and EfficacySafety and Efficacyfor Generic Productsfor Generic Products

Dr.Prashant [email protected]

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

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?

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

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

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

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

Bioavailability: Regulatory DefinitionBioavailability: Regulatory Definition

Rate and extent of absorptionRate

CmaxTmax

ExtentArea under the Curve (AUC)

Prescribable New DrugPrescribable New Drug

New drug development program leads to a new productClinical Trial FormulationStability StudiesMarketed FormulationPrescribable

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

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

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.

Bioequivalence: MeaningBioequivalence: Meaning

Essentially similar or NOT DIFFERENT bioavailabilityRegulatory definition: ComparableRate and extent of absorptionRate• Cmax• Tmax

ExtentArea under the Curve (AUC)

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.

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

Assumptions in BEAssumptions in BEPharmaceutical EquivalentPharmaceutical Alternative

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.

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.

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

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

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

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

Therapeutic acceptance of ProductsTherapeutic acceptance of Products

Innovator to generic product switchOr

New patient on a generic product

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

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

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 )

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

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

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

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

Reasons for failureReasons for failure

High variability of PK parametersUnder-powered, N < than requiredCost??Lower enrollmentWithdrawalMissing data, Outliers

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

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

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.”

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."

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

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

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

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

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.

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

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.

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


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.


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

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).

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

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

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

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

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)

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

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

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

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

SUPAC-IR (1995) and

SUPAC-MR Guidances (1997) Summary

(Equipment Addendum (1999); FDAMA (1997) and “Changes Approved to an NDA or ANDA” Guidance

(2000)

General Aspects: (Change) General Aspects: (Change) Variables CoveredVariables Covered

Components and CompositionNon Release ControllingRelease Controlling

SiteBatch Size (Scale-Up/Scale-Down)Manufacturing

EquipmentProcess

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

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

Resourcefulness and Commitment



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

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)

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

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

Principles Document: Advantages of FDCs

Improved adherenceConvenience of useReduced pill burden/simpler treatment regimensFacilitation of logistics of procurement, distribution, dispensing

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

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


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


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


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

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

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

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

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

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

Draft FDA Guidance: Submissions to FDA

Chemistry, manufacturing, controlsDrug substanceDrug productStabilityIssues unique to FDCs

• Lack of interaction between active ingredients

Microbiology/virologyAdverse event reporting

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

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



Pharmacological Appraisal of Fixed-Dose Combination Therapy

Darrell R. Abernethy, M.D., Ph.D.Chief Science Officer

Fixed-Dose Combinations

Ideal Characteristics

All Components Have Wide Therapeutic Index

All Components Are Highly bioavailable

All Components Have Similar Clearance/ half-life

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



Lopinavir + Ritonavir

Artemether + Lumefantrine

Sulfadoxine + Pyrimethamine



Ferrous Salt + Folic Acid

Levodopa + Carbidopa

Benzoic Acid + Salicyclic Acid - topical

Neomycin + Bacitracin - topical

Ethinylestradiol + Levonorgestrel

Ethinylestradiol + Norethisterone


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


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


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


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


Clinical Advantages

Improved Adherence

Convenience

Reduced Pill Burden / Simpler Treatment Regime

Improved Availability of Drugs to Patients Due to Simplified Procurement, Distribution, and Dispensing


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?


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.


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


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].


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].

The Standard of QualityTM

Health & Medicine

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