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8/8/2019 Topical Trans Dermal Day 2

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Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

Transdermal Systems

Product Quality and Product Performance Tests

Margareth R. C. Marques, M.Sc., Ph.D.

Transdermal Systems

USP GC Pharmaceutical Dosage Forms Self-contained, discrete dosage forms Applied to the skin to deliver the drug(s) to the systemic

circulation Comprise

Outer covering (barrier) Drug reservoir with a rate-controlling membrane Contact adhesive

Protective liner


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Drug release

April 1, 2005

Harmonization of the GC Disintegration and Dissolution between USP, EP and JP

revised but NOT harmonized

Only for transdermal systems and non-disintegratingtablets (osmotic pumps)

Drug release

Apparatus 5 Paddle over disk


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Drug release

Drug release

Apparatus 6 Cylinder


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Drug release

Apparatus 7 (Reciprocating Holder)

Drug release



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Drug release


Transdermal systems

Quality tests only in the specific monograph, if applicable.

Special Drug release test conditions only in thespecific monograph, if applicable.


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TDS LEAK TESTrationale for the need for a leak test in transdermal patches

Gordon L. FlynnProfessor Emeritus, University of

Michigan College of Pharmacy

An apology!


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USP Mission Statement Promoting the Public Health

USPNF is published in continuing pursuit of the mission of the United States Pharmacopeial Convention (USP), which is:

to promote the public health and benefit practitioners and patients by disseminating authoritative standards and information developed by volunteers for medicines , other healthcare technologies, and related practices used to maintain and improve health and promote optimal health care delivery.

I hope to convince you that never in the past has the primary packaging of a drug delivery system been such an problematic issue with respect to patient

safety than with the delivery of a low therapeutic index drug out of a form fillseal transdermal delivery system; this is because leakage in the course of drug delivery from such systems expands the area of delivery, increasing the rate of

delivery, and, to date, leakage has not been under adequate control.

NEVER BEFORE BASED ON THE USPNF of 2005:

Injections Packaging : validation must include verification that package prevents microbial contamination (this a zero tolerance situation) Elastomeric Closures for Injections : evaluation should be made by appropriate additional specific tests to determine the suitability of an elastomericclosure for its intended use Aerosols, Nasal Sprays, etc. Leakage Test : weigh each container allow each container to stand in an upright position at a temperature of 25 for not less than 3 days again weighing each container Containers : many Pharmacopeial containers are of such nature as to require the greatest attention to the containers in which they are stored or even maintained for short periods of time Loss on Drying : the procedures set forth in this chapter determines the amount of volatile matter of any kind that is driven off under the conditions

specified Uniformity of Dosage Forms Content Uniformity: transdermal testing by content uniformity of individual units Packaging Practice : as it relates to transdermal units as opposed to single solid units Pharmaceutical Stability : as it relates to the integrity of transdermal units Pharmaceutical Dosage Forms Transdermal Systems : different types of systems not spelled out


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Let me start our by saying that there are two fundamentally different types of transdermal systems, form fillseal patches (liquid reservoir patches) and

matrix (monolithic)

patches.

Each

comes

in

a range

of

sizes

and each

has

a

range of phase configurations. The feature that most distinguishes these two types of systems is that liquid reservoir patches (pouched patches) contain the bulk of their drug in a walled off fluid, a relatively free flowing medium, while matrix patches contain their drug in either the adhesive layer, a thick, non flowing polymeric phase, or in a solid polymeric reservoir.

The two types of systems share some problems. They dont adhere to the skins of some individuals as firmly as they should; there is lifting of edges, particularly when patches are worn multiple days. And all too often they detach during showers, etc. To comparable extents, delivery from them suffers from percutaneous absorption variability inherent in the treated population.

However, in one important way they differ markedly. Form fillseal patches are known to leak; matrix patches dont share this problem.

Form fillseal Patch

Matrix Patch

to illustrate the critical difference

releaseliner

drugreservoir

heat sealed

rimbioadhesive

backinglayer

internalpolymer

layer

bioadhesive

backinglayer

releaseliner


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To understand the issue that we are faced with today

during this sessionan issue that pertains to assuring that individuals who are being treated with transdermalpatches are being treated with products that are safe to usea scientist has to come to terms with the manners in which patches are manufactured and the inherent system frailties and

weaknesses that their manner of manufacture creates in them.

consider the form fill seal patch


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The finished form fillseal patches are cut by machine from the web, placed in sealed foil envelopes, and generally

packaged in boxes containing 5 foilsealed patches. Quality must be designed indifficult to do with form fillseal patches. What problems are form fillseal patches are particularly prone to?

Faulty heat seals during manufacturing inadequacy of production monitoring too high a production rate for adequate inspection lack of adequate post production leak testing (and method)

Evaporation of volatile content in storage (resolved by packaging) during distribution/storage in warehouse and pharmacy while in patients hands under less well controlled conditions

Rupture of faulty seals during patch patient use and wear lack of ruggedness due to climate (warmth, moisture, cold) pressure, particularly when sleeping

known form

fill

seal

patch defects


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the incomparable danger of such defects requires our fullest attention

Lets Be Honest! The major problem with form fillseal (liquid reservoir) patches has been with the leakage of a highly potent drug with a low therapeutic index out of the liquid reservoir as the result of a faulty seal. The drug is fentanyl.

Fentanyl is a drug with a low therapeutic index. As just one proof of this, it has been learned the hard way that patches containing fentanyl can be lethal in otherwise use conditioned patients if worn under a heating pad, heating

blanket, or

in

a hot

tub.

Reasonable

activation

energy

calculation indicates that such heating wouldnt represent so much as a doubling of the delivery rate. This danger is spelled out in the drugs prescribing warnings to physicians and package insert warnings to patients.


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Concerned about deaths associated with the proper use and also the abuse of the then existing fentanyl form fillseal transdermal patch, four years ago I submitted a citizens petition to the FDA.

The main emphasis of my stated concern related (relates) to the safety of patients using fentanyl form fillseal dosage forms that were legitimately prescribed , properly dispensed , and properly applied. In other words, I was most concerned about situations in which no error of judgment was made by the prescribing physician, in which the dispensing pharmacist correctly interpreted the physicians order and dispensed the right dose (dosing rate) patch, and in which the the patient applied the patch correctly.

My submission of the petition followed the first fentanyl patch recall due to leakage of its drug containing gel. Fentanyl transdermal systems have been the foremost source of gravely serious therapeutic mishaps. Yet lets not loose sight

of the

fact

that,

in

transdermal form,

fentanyl is

a drug

that

allows

patients

afflicted with severe chronic pain to live relatively normal lives. But when the drugs dose is increased by as little as a factor of two, it can produce a respiratory depression so deep that a patient simply ceases to breathe.

In the citizen petition I specifically recommended that the FDA:

a) not approve further liquid reservoir transdermal systems unless and until the potential manufacturers of such systems provide convincing evidence that the seals of the form fillseal patches they wish to introduce are failsafe with regard to leakage,

b) review the manufacturing procedures and controls now in place for the production of presently marketed liquid reservoir transdermalsystems to make sure that these are failsafe with regard to leakage,

c) review the overall safety of use of liquid reservoir patches now on the market from standpoint of risk of harm to patients using such patches appropriately and also from the standpoint of their relative ease of drug abuse.

I did this because in my view peoples lives were on the line. Im here before you today mainly as a result of filing this petition.


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Before I speak to the situation of patch leakage, Id like to point out that there isnt a situation that I know of that cant be dealt with using a matrix patch. Consider that:

1. Nitroglycerin, introduced as a form fillseal patch, can obviously be bioequivalently delivered from a matrix system patch

2. Nicotine, introduced as a form fillseal patch, can be bioequivalentlydelivered from a matrix system

3. Estradiol, introduced as a form fillseal patch, can be bioequivalentlydelivered from a matrix system

4. Fentanyl, introduced as a form fillseal patch, can be bioequivalentlydelivered from a matrix system

and, despite questionable claims that the above form fillseal systems contain membranes that control delivery rates, the corresponding matrix patches are just about the same size (have essentially the same delivery area), have been proven bioequivalent, and yet dont contain rate controlling membranes.The trick is to build matrix systems that remain saturated or near saturated in terms of their drug over the greater fraction of time that they are worn.

Lets consider the nature of the problem that we do confront.

seeming defects

People live inand sleep inpatches as the one thats depicted to the right (here you see an internet

photo that is touted as representative of a faulty fentanyl patch)


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disclosure and trial documents published on the internet indicate

that the original 75 g/hr fentanylpatch has the following features

A particular problem with the original form fillseal fentanylpatch, again from documents found on the internet, seems to have been the formation of unseal channels due to stringer leakers formed in the course of filling the patch pouches. Apparently, a string of gel occasionally trailing the pouch filloperation deposits along the seam that is momentarily to be heat sealed. Consequently, the heat seal doesnt take at the locations where gel is deposited. Extrusion of gel from the weak or defective seals, particularly when placed under pressure, is surely a problem.

We can consider what stresses a worn patch has to bear and testing that might be performed, but keep in mind that quality has to be designed into a patchthe production of a patchand cant really be belatedly tested in.


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Given the propensity form fill seal patches have to leak, how much pressure must a patch withstand while in use? This is something that doesnt seem to have been adequately addressed. Consider that the

body surface area of a male who weighs 75 Kg (163 lb) and is 177.8 cm (510) tall is about 1.92 m 2 (19,200 cm 2)

Laying prone, the male would have something on the order of 40% of his body in contact with surface he is lying on. Using this figure, hed have 7,680 cm 2 of his body in continuous contact with the surface (note that with less contact the numbers below become even larger).

He would thus have his 75,000 gm weight distributed over 7,680 cm 2 or, on average , about 9.77 gm would be pressing down on each cm 2 of contact area. Since 1 pound = 453.6 gm, this amounts to 0.0215 lb/cm 2

A 10 cm 2 patch would experience, on average , something like 97.7 gm of weight pressing up against it. This amounts to about 0.2153 lb. The patchs seal would have to safely withstand such pressure. Using a safety factor of 10, the weight would be > 0.2 lb/cm 2 or > 2 lb/10 cm 2 patch, not an inconsequential weight relative to forcing leakage.

As shown in this drawing that

speaks to emergency accommodations in a school gym in the course of a hurricane or other natural disaster, people sleep in a variety of positions. Should any of them be wearing patches, theyd be rolling around on them for hours at a time. Of course, wearers tend to place patches over body sites where the patches are somewhat protectedand where there is less weight suffered by them, but in the course of twisting and turning during sleep, patches still face considerable weight stress.


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POINT # 1: There is a need for rigorous unstressed

testing of patches during production and, with statistically supportable sampling, further testing on post batch product:

1.continuous visible inspection2.inspection aided by microscopic examination of samples3.Identification of leakage by placing sheets of patches between adsorbent sheets of paper4.swab patch samples to identify leakage (there should be no drug outside the primary envelope.

POINT # 2: There is a need for a post manufacture test of proof of seal strength under pressure on every batch of form fillseal product that is made. Considering that, with a drug like fentanyl, their has to be zero tolerance for weak and faulty seals, the test has to be statistically rigorous with respect to:

1.the means of sampling for such testing2.the number of samples subject to post

production pressure testing (always with limited sampling of a batch)3.Pressure stressed patches should also be swabbed


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But to build quality in theres a need to improve manufacturing methods and in process controls so that the integrity of every patch is assessed as it is

coming off the production line. What kind of production surveillance is needed?

Its been pointed out that stringer leaker defects, fold over defects, and cuts have been noted in the course of patch production. In addition, notably, according to records, form fillseal patches produced in the past were visually inspected by production staff teams, with two members of the production team always operating as inspectors for 30 min periods at a time. The inspectors had to judge the integrity of patches moving through their fields of vision at a rate of about 4 patches per second. In process instrumental measurements also appear to have been made in the course of production, but if this was so, these werent anywhere close to adequate relative to preventing the formation of leakers and thus protecting the public.

Instrumental methods of inspection have to be developed that adequately identify and sort out defective patches from well formed ones. The commercial instrument below was designed to inspect nicotine patches; it is presented just as an idea of what is needed. As far as I can tell, in process controls arent an area of USP involvement, but perhaps should be.

Im informed that automatic machine inspection might be possible. This would seemingly be the only way to really counteract the problem associated with identifying leakers. The problem here is serious enough that a task force, a consortium of surveillance machine manufacturers, pharmaceutical company scientists, and perhaps academic scientists, might be formed to address the problem.


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Here again is the problem. You tell me whether or not you think you could find all production

flaws in patches moving through your view at four per second.

POINT # 3: Given that a leaky form fillseal patch systems can result in death, there has to be much better control of quality than now exists, if not for all patches, then at least for patches containing potent, low therapeutic index drugs:

1.there is no question that superior inspection machinery has to be developednon destructive image analysis2.There is no question that visual human inspection isnt adequate for the kinds of defects that are known to exist, especially when patches are moving past them on a belt at 4 patches per second3.Together the above two methods have to be failsafe (have to lead to zero tolerance) to the same degree as sterile products have to be failsafe (with respect to microbes)


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This is the end of my thoughts. I can see the problem, and its a big problem, but, admittedly, Im not an engineer who might be able to solve it. I have no background in fractal geometry, let along any idea of how this mathematical tool might be statistically applied to successfully monitor production. Im informed machines and software can be developed that might make fractal geometry perform the task, but can do nothing more than suggest the possibility.

THE ENDAnd thanks to Mike

Houghton for his thoughts on these matters!

USP Workshop on Topical & Transdermal DrugsSep 14-15, 2009Adhesion Testing

Adhesion and Other Product Quality Tests (Rationale for Inclusion)

Kris Derdzinski, Ph.D.Principal Scientist

Ortho McNeil Janssen PharmaceuticalSeptember 1415, 2009


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Transdermal Delivery SystemsPhysical units that deliver active ingredient at a desired rate over a prolonged period of timeMechanism of delivery may be a passive diffusion or a different mechanism depending on the systems design

common designs currently marketed are transdermalpatches:

a form fillseal type (reservoir systems)

multilayer laminates with drug substance contained within a

solid phase (matrix), including drug in adhesive patchesperipheral adhesive patches

systems that use other mechanism for delivery (i.e. iontophoresis, microneedles, heat assisted delivery)

USP Workshop on Topical & Transdermal Drugs Sep 14-15, 2009 Adhesion Testing


Adhesion is Critical to QualityAdhesives are used to assure an intimate contact with the patient skin and delivery of the desired dose per label

Adhesives in TDS products must allow for an easy removal of release liner before useadhere properly to human skin upon application and maintain the adhesion during the prescribed time of useallow for easy removal at the end of use without leaving a residue or causing damage to the skin (adverse affects) be able to maintain the acceptable performance through the end of product shelf life



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Adhesion Quality ProblemsA review of adhesion related quality problems was published by

FDA scientists [Eur J. Pharm Biopharm, 64 (2006) 18]

Based on review of complaints received for various TDS (TDDS) products the problems included:

failure of adhesive (lack of adhesion) during routine use when worn over several daysneed to use tape to hold TDDS in place (prevent loss of patch)increased cost , need to use more patches due to poor adhesion loss of efficacy due to unreliable adhesive propertiesreport of adverse events skin damage during patch removalpatch damage during removal of release liner loss of patch during use (stray patches in linens, hair , food)



Adhesion Tests

Adhesion tests are typically used in product development by manufacturers and as inhouse quality control testsThree types of adhesion tests provide information relevant to functional performance of adhesive

Peel force (from standard substrate / release line

Probe tack

test

Shear strength (creep compliance)Generally in vitro tests that predict adhesion to human skin are not available



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Rationale revisited Adhesion tests are critical for efficacy, safety and quality Choice of specific tests method and acceptance criteria will depend on the product design and specific formulation

Large variance of adhesion results does not preclude setting meaningful criteria to assure consistent products quality from batch to batch and similarity to the adhesion performance for the registration batches

Manufacturers knowledge on adhesion testing methods is available and validated tests are available



ReferencesTransdermal drug delivery system (TDDS) adhesion as a critical safety,efficacy and quality attribute, Wokovich, A.M., Prodduturi, S., Doub, W.H., Hussain,A.S., Buhse, L.F., Eur J. Pharm Biopharm, 64 (2006) 18]

Skin adhesives and skin adhesion 1. Transdermal drug delivery systems, Venkatraman, S., Gale, R., Biomaterials 19 (1998) 11191136

Pressure sensitive adhesives for transdermal drug delivery systems, Tan, H.S., Pfister, W.R., PSTT, Vol 2, No 2, Feb 1999



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Thank you



USP Workshop on Topical and Transdermal Drug ProductsSeptember 14-15, 2009

USP Headquarters

USP Perspectives

Roger L. Williams, M.D.Chair, Council of Experts


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1974 Drug Bioequivalence Panel

Berliner Cluff Doluisio Melmon Nadas Oates Riegelman Shideman Zelen Robbins

Standards: no BE BA causes therapeutic failures Procedures available BA critical for some drugs/not all GMPs and compendial standards inadequate New standards needed Research needed, including in vitro/animal

models Strengthen current standards/submit studies Eliminate exemptions New organization

Gaps and Opportunities


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Whats the Further History

1977 BA/BE regulations 1984 Hatch-Waxman 1980s IND/NDA rewrite/314.70 1990s BA/BE guidances/SUPACs/FDAMA PAC 2000s GMPs for 21 st Century, Q8, 9, 10, QbD 2005-10 USPcalibrators to PVT with RMs

FDA BA/BE Guidances

General Guidance Criteria Guidance Bioanalytical Guidance Biopharmaceutics Classification System

Guidance Food-Effects Guidance Nasal Drug Products Oral Inhalation Drug Products (delayed)

Topically Applied Drug Products (withdrawn) Dissolution Testing of Immediate Release Solid

Oral Dosage Forms (final) Extended Release Oral Dosage Forms:

Development, Evaluation, and Application of InVitro/In Vivo Correlations (final)


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WHO Interchangeability Document : Table ofContents

1. Introduction 2. Definitions 3. Documentation of equivalence for marketing

authorization 4. When equivalence studies are not necessary 5. When in vivo equivalence studies are necessary

and types of studies required 6. Bioequivalence studies in humans 7. Pharmacodynamic studies 8. Clinical trials 9. In vitro testing 10. References

WHOs Essential Medicines List: Annex 8

Three Tables: A, B, C A Table Indicates:

Highest recommended dosage form strength Solubility Permeability BCS Class Dissolution Test Requirements Risks Indications and Comments

~ 130 Molecules

~ 60- 70% Suitable for BCS Biowaivers Implications BE Part of Drug Development Company Does It No CRO


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And Calibration?

Merriam-Webster: calibrate To ascertain the caliber of (as a thermometer tube) To determine, rectify, or mark the graduations of (as a

thermometer tube) To standardize (as a measuring instrument) by

determining the deviation from a standard so as toascertain the proper correction factors

To adjust precisely for a particular function

FDA, ICH, PDGDissolution (NSOADF)

Q6A: specifies characterization and setting specificationsduring development

For drug products, BA and BE are characterization studies The drug product specification is a set of tests, procedures,

and acceptance criteria that legally defines the identity of thedrug product

A key procedure in the drug product specification is dissolution,which relies on USP General Chapter

The dissolution procedure requires special care to assure

adequate performance In this decade, FDA and USP separated over the use of

calibrator tablets Q4B: for regulatory filingsmechanical calibration

only/FDA guidance: mechanical calibration only


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Current Lots and Applications

Salicylic Acid Non-disintegrating Calibrator Tablets, LotP0C404 Apparatus 1 and 2 100 rpm

Prednisone Disintegrating Calibrator Tablets, Lot P0E203 Apparatus 1 and 2 50 rpm

Chlorpheniramine Maleate Extended-Release Tablets, LotG0B259 Apparatus 3 Two test conditions Ranges applied at two time-points for each condition

Salicylic Acid Tablets, Lot Q

Blister Pack


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Lot P Collaborative Ranges

40 +/- 337 70532

60 +/- 547 - 82651

RDLsEstimate of

Truth

BPC ApprovedCollaborative

Range

CollaborativeMean

Apparatus

USP Publications

Deng G., et. al.: The USP Performance Verification Test Part I: USPLot P Prednisone Tablets Quality Attributes and ExperimentalVariables Contributing to Dissolution Variance, Pharm. Res. 2007

Liddell M., et al.: Evaluation of Dissolution Glass Vessel Dimensionsand Irregularities, Dissolution Technologies, Vol. 14 Issue 1, Febr.2007

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

Nithyanandan P., et al.: Evaluation of the Sensitivity of USP

Prednisone Tablets to Dissolved Gas in Dissolution Medium usingApparatus 2, Dissolution Technologies, Vol. 13 Issue 3, Aug. 2006 Eaton J., et. al.: Perturbations Study of Dissolution Apparatus

Variables A Design of Experiment Approach, DissolutionTechnologies, Vol. 14 Issue 1, Feb. 2007


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Intra-Lab Variances Smaller than Inter-Lab

50

55

60

65

70

75

80

0 50 100 150 200 250 300

Bl inded Run Code

%Dissolved at30 minutes

Lot PApparatus 1

Sets of 6Standarderrors

Approvedrange47 -- 82

One Labbelow rangein this chart

Lot P Apparatus 2 Same Trend Shows

% D i s s o l v e

d G e o m e t r i c

M e a n

30

40

50

60

70

80

0 50 100 150 200 250 300

B l i n d e d R u n C od e

Approved Range 37 70%Sets of 6 tablets, standard errors


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ISO Framework

ISO Guide 43-1, Proficiency testing by inter-laboratorycomparisons Development and operation of proficiency testingschemes Describes proficiency testing as the use of inter-laboratory

comparisons to determine the performance of individuallaboratories for specific tests or measurements and to monitor laboratories continuing performance.

Participation in proficiency testing schemes provideslaboratories with an objective means of assessing anddemonstrating the reliability of the data they are producing,

One of the main uses of proficiency testing schemes is toassess laboratories ability to perform tests competently. .. Itthus supplements laboratories own internal quality controlprocedures by providing an additional external measure of their testing capability.

MetrologyTraceability

A Std

Std

TS

TSB

YA = g A (X0)

YB = g B (X0)

CRM

X0

YA and Y B are now traceable to the same reference, X 0

Where Std is a standard and TS is test sample

Lab A and B make measurements


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National Traceability Chain

NIST

USP

Calibration Labs

Routine Measurement Labs

SISI Base Units

meter

kilogram

second

ampere

kelvin

candela

mole

Selected SI CoherentDerived Units

frequency

force

pressure, stress

electromotive force

electric conductance

Celsius temperature

catalytic activity

Katal

katal is now adopted under the Convention of the Metre of 1875 by the highestmetrologic authority, the intergovernmental diplomatic CGPM, to express quantityvalues of catalytic activity of enzymes and other catalysts in any field of science andtechnology. Further derived kinds-of-quantity and derived units may be defined in theconventional manners.

Thus, we now have, for example:

Catalytic activity ( z ): katal , 4 (kat)

Catalytic activity concentration ( b ): katal per litre (kat/L; kat/l)

Catalytic activity content ( z/m s): katal per kilogram (kat/kg)

Catalytic activity fraction ( z f): one = katal /katal (1 = kat/kat)

If the measurement procedure has an indicator reaction that can be described byconversion of amount of substances of reactants, the results involving the katal aremetrologically traceable to the SI and thereby comparable across time and space.For such results, the conversion from the IUB unit, U, to katal is available.

Journals subscribing to the preferred use of SI units can now with the blessing of theCGPM promote international standardization of units by including the katal in their Information for Authors, thus facilitating the globalization of medicine.


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USP Position

Mechanical calibration alone is not sufficient to ensureconsistency and comparability of measurementsobtained with a dissolution test system

A periodic Performance Verification Test (PVT) together with careful mechanical calibration isimportant to ensure consistent results

Prednisone RS Tablets are suitable for the PVT of USP Apparatus 1 and 2

SA calibrators discontinued Statistics of PVT revised

Brief Description

This is a single test of 12-16 tablets with the optionalpossibility of stopping after the first six to eight. Step 1: For each position in the assembly, test one USP

Prednisone Tablet RS and record the percent dissolved at30 minutes. Determine the geometric mean (GM) andpercent coefficient of variation (%CV). Compare the GMand %CV to the acceptance criteria. If both meetacceptance criteria, test finished. If not, go to Step 2.

Step 2: Test another USP Prednisone Tablet RS in eachposition and record the percent dissolved at 30 minutes.Compute a pooled GM and pooled intra-run %CV.Compare to the acceptance criteria. If both meetacceptance criteria, test finished. If not, further work isneeded

Pass if meet acceptance criteria at either step


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And Whats Next?

(in revision) General Chapters for all five routes of administration, e.g., Performance Test General Chapters for all five routes of

administration with reference to PVT PVT/reference materials for periodic PVT, e.g., web toolkit Science dialogues (e.g., in house calibrator) ? Something beyond dissolution Regulatory implications

Chapter VDrugs and Devices Subchapter ADrugs and Devices/Adulterated Drugs and

Devices Section 501(a)(1) if substance; or (2)(A) if unsanitary

conditions; or (B) if drug; or (3) if container; or (4) if coloradditive (A) or (B); or (5) new animal drug; or (6) animal feedbearing or containing a new animal drug

Section 501 (b) official compendium (three) Sections (c) through (i) or more

Implications for US/other markets



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PRODUCT QUALITY ANDPERFORMANCE:

CLINICAL PERSPECTIVE

HOWARD I. MAIBACH, M.D.PROFESSOR

DEPARTMENT OF DERMATOLOGYUNIVERSITY OF CALIFORNIA, SAN FRANCISCO

94143-0989

I. WHY Quality/PerformanceTests?

1. Rational approach2. Great theory3. Underpinning for in vivo data


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II. CLINICAL OBSERVATIONS - ? FAIL!

Corticoid Why:

high placebo role No phase 4 efficacy system just switch drug Likely potency not failure

III. BASED ON CLINICALOBSERVATIONS WHAT TESTS?

Those best fitting clinical efficacy! To be determined!


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IV.WHY Drug Release Data?

Highly cost efficient drugdevelopment

Standard for Orals/Transdermal Await validation in vivo

ExemplarClinical Testing Fluocinonide

Innovator >Generic

Replication awaited


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Scientific Weakness

Parallel Design Clinical Trial Relatively weak

SOLUTIONS?

Paired comparison Armitage Stats Bioengineering techniques


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Why are We waiting? A mandate!

(the next Kefauver)

The Concept:Comparative effectiveness Research(An Intern Med 151:203)

HOWARD I. MAIBACH, M.D.

0700 - 0800 SFO TIME

PHONE: (415) 673-9693

[email protected]

topical trans dermal day 2

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