Transdermal Systems

Product Quality and Product Performance Tests

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

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

Transdermal Systems

• USP GC <1151> 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

1
 <724> Drug release

• April 1, 2005

• Harmonization of the GC <701> Disintegration and

<711> Dissolution between USP, EP and JP

• <724> revised but NOT harmonized

• Only for transdermal systems and non-disintegrating

tablets (osmotic pumps)

<724> Drug release

• Apparatus 5 – Paddle over disk

2
 <724> Drug release

<724> Drug release

• Apparatus 6 – Cylinder

3
 <724> Drug release

• Apparatus 7 (Reciprocating Holder)

<724> Drug release

•Apparatus 7 (Reciprocating Holder)

4
 <724> Drug release

•Apparatus 7 (Reciprocating Holder)

Transdermal systems

• Quality tests only in the specific monograph, if

applicable.

• Special Drug release test conditions only in the

specific monograph, if applicable.

5
 TDS LEAK TEST
rationale for the need for a leak test in transdermal patches

Gordon L. Flynn
Professor Emeritus, University of 
Michigan College of Pharmacy 

An apology!

6
 USP Mission Statement—Promoting the Public Health

“USP‐NF 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 health
care 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‐fill‐
seal 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 USP‐NF of 2005:

<1> Injections — Packaging: validation must  include verification that package 
prevents microbial contamination (this a zero tolerance situation)
<381> Elastomeric Closures for Injections:  … evaluation … should be made by 
appropriate additional specific tests to determine the suitability of an elastomeric
closure for its intended use
<601> 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
<661> 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
<731> 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
<905> Uniformity of Dosage Forms — Content Uniformity: … transdermal testing by 
content uniformity of individual units
<1146> Packaging Practice: as it relates to transdermal units as opposed to single 
solid units
<1150> Pharmaceutical Stability: … as it relates to the integrity of transdermal units
<1151> Pharmaceutical Dosage Forms — Transdermal Systems: … different types of 
systems not spelled out

7
 Let me start our by saying that there are two fundamentally different types 
of transdermal systems, form‐fill‐seal 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 don’t 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‐fill‐seal patches 
are known to leak; matrix patches don’t share this problem.

drug
backing
layer
reservoir to illustrate 
the critical 
heat‐
sealed
difference
bioadhesive rim

internal
release polymer
liner layer

Form‐fill‐seal Patch

backing
layer
bioadhesive
release
liner
Matrix Patch

8
To understand the issue that 
we are faced with today 
during this session—an issue 
that pertains to assuring that 
individuals who are being 
treated with transdermal
patches are being treated 
with products that are safe to 
use—a scientist has to come 
to terms with the manners in 
which patches are 
manufactured and the 
inherent system frailties and 
weaknesses that their  consider the 
manner of manufacture  form‐fill‐seal 
creates in them. patch

9
The finished form‐fill‐seal patches are cut by machine from 
the ‘web’, placed in sealed foil envelopes, and generally 
packaged in boxes containing ≥ 5 foil‐sealed patches.  
Quality must be designed in—difficult to do with form‐fill‐seal patches. 
What problems are form‐fill‐seal 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 patient’s 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

10
the incomparable danger of such defects requires our fullest attention

Let’s Be Honest!  The major problem with form‐fill‐seal 
(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 wouldn’t represent 
so much as a doubling of the delivery rate.  This danger is 
spelled out in the drug’s prescribing warnings to physicians 
and package insert warnings to patients.  

11
Concerned about deaths associated with the proper use and also the abuse of 
the then existing fentanyl form‐fill‐seal transdermal patch, four years ago I 
submitted a citizen’s petition to the FDA.

The main emphasis of my stated concern related (relates) to the safety of 
patients using fentanyl form‐fill‐seal 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 physician’s ‘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 let’s 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 
drug’s 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‐fill‐seal 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 transdermal
systems 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 people’s lives were on the line.  I’m here 
before you today mainly as a result of filing this petition.

12
Before I speak to the situation of patch leakage, I’d like to point out that 
there isn’t a situation that I know of that can’t be dealt with using a matrix 
patch.  Consider that:

1. Nitroglycerin, introduced as a form‐fill‐seal patch, can obviously be 
bioequivalently delivered from a matrix system patch
2. Nicotine, introduced as a form‐fill‐seal patch,  can be bioequivalently
delivered from a matrix system
3. Estradiol, introduced as a form‐fill‐seal patch,  can be bioequivalently
delivered from a matrix system
4. Fentanyl, introduced as a form‐fill‐seal patch,  can be bioequivalently
delivered from a matrix system

and, despite questionable claims that the above form‐fill‐seal 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 don’t 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.

Let’s consider the nature of the problem that we 
do confront.
seeming defects

People ‘live in’
and ‘sleep in’
patches as the 
one that’s 
depicted to the 
right (here you 
see an internet 
photo that is 
touted as 
representative 
of  a faulty 
fentanyl patch)

13
 disclosure and trial documents 
published on the internet indicate 
that the original 75 µg/hr fentanyl
patch has the following features

A particular problem with the original form‐fill‐seal fentanyl
patch, 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 fill
operation deposits along the seam that is momentarily to be 
heat sealed.  Consequently, the heat seal doesn’t ‘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 patch—the production of a patch—
and can’t really be belatedly tested in.

14
Given the propensity form‐fill‐seal patches have to leak, how much 
pressure must a patch withstand while in use? This is something that 
doesn’t 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 (5’
10”) tall is about 1.92 m2 (19,200 cm2)

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, he’d have 
7,680 cm2 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 cm2 or, 
on average, about 9.77 gm would be pressing down on each cm2 of 
contact area.  Since 1 pound = 453.6 gm, this amounts to 0.0215 lb/cm2

A 10 cm2 patch would experience, on average, something like 97.7 gm of 
weight pressing up against it. This amounts to about 0.2153 lb. The 
patch’s seal would have to safely withstand such pressure.  Using a safety 
factor of 10, the weight would be > 0.2 lb/cm2 or > 2 lb/10 cm2 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, they’d 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 ‘protected’
and where there is less 
weight suffered by them, but 
in the course of twisting and 
turning during sleep, patches 
still face considerable weight 
stress.

15
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 inspection
2.inspection aided by microscopic examination 
of samples
3.Identification of leakage by placing sheets of 
patches between adsorbent sheets of paper
4.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‐fill‐seal 
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 testing
2.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

16
But to build quality in there’s 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?

It’s 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‐fill‐seal 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 
weren’t 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 aren’t an 
area of USP ‘involvement’, but perhaps should be.

I’m 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.  

17
 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‐fill‐seal 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 developed—non‐destructive image 
analysis
2.There is no question that visual human inspection isn’t 
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 second
3.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)

18
This is the end of my thoughts.  I can see the 
problem, and it’s a big problem, but, admittedly, I’m 
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.  I’m 
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 END
And thanks to Mike 
Houghton for his thoughts 
on these matters!

Adhesion and Other Product Quality 
Tests (Rationale for Inclusion)

Kris Derdzinski, Ph.D.
Principal Scientist
Ortho‐McNeil‐Janssen Pharmaceutical
September 14‐15, 2009

USP Workshop on Topical & Transdermal Drugs

Sep 14-15, 2009
Adhesion Testing

19
Transdermal Delivery Systems
y Physical units that deliver active ingredient at a desired 
rate over a prolonged period of time
y Mechanism of delivery may be a passive diffusion or a 
different mechanism depending on the systems design
y common designs currently marketed are transdermal
patches:  
y a form‐fill‐seal type (reservoir systems) 
y multilayer laminates with drug substance contained within a 
solid phase (matrix), including drug in adhesive patches
y peripheral adhesive patches 
y systems that use other mechanism for delivery
USP Workshop on Topical & Transdermal Drugs
(i.e. iontophoresis, microneedles, heat‐assisted delivery)
Sep 14-15, 2009
Adhesion
USP Workshop on Topical & Transdermal Testing
Drugs Sep 14-15, 2009 Adhesion Testing

Adhesion is Critical to Quality
y Adhesives are used to assure an intimate contact with the 
patient skin and delivery of the desired dose per label         
y Adhesives in TDS products must 
Î allow for an easy removal of release liner before use
Î adhere properly to human skin upon application and 
maintain the adhesion during the prescribed time of use
Î allow for easy removal at the end of use without leaving a 
residue or causing damage to the skin (adverse affects) 
Î be able to maintain the acceptable performance through 
the end of product shelf‐life

USP Workshop on Topical & Transdermal Drugs

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

20
Adhesion Quality Problems
y A review of adhesion related quality problems was published by 
FDA scientists  [Eur J. Pharm Biopharm, 64 (2006) 1‐8]   

y Based on review of complaints received for  various TDS (TDDS) 
products the problems included: 
Î failure of adhesive (lack of adhesion) during routine use when
worn over several days
Î need to use tape to hold TDDS in place (prevent loss of patch)
Î increased cost , need to use more patches due to poor adhesion  
Î loss of efficacy due to unreliable adhesive properties
Î report of adverse events – skin damage during patch removal
Î patch damage during removal of release liner 
Î loss of patch during use (stray patches in linens, hair , food…)
USP Workshop on Topical & Transdermal Drugs
Sep 14-15, 2009
Adhesion
USP Workshop on Topical & Transdermal Testing
Drugs Sep 14-15, 2009 Adhesion Testing

Adhesion Tests  
y Adhesion tests are typically used in product development 
by manufacturers and as in‐house quality control tests
y Three types of adhesion tests provide information relevant 
to functional performance of adhesive 
Î Peel force (from standard substrate  / release line
Î Probe tack test
Î Shear strength (creep compliance)
y Generally in vitro tests that predict adhesion to human 
skin are not available 
USP Workshop on Topical & Transdermal Drugs
Sep 14-15, 2009
Adhesion
USP Workshop on Topical & Transdermal Testing
Drugs Sep 14-15, 2009 Adhesion Testing

21
Rationale revisited 
y Adhesion tests are critical for efficacy, safety and quality
y Choice of specific tests method and acceptance criteria 
will depend on the product design and specific 
formulation 
y 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
y Manufacturers’ knowledge on adhesion testing methods is 
available and validated tests are available  
USP Workshop on Topical & Transdermal Drugs
Sep 14-15, 2009
Adhesion
USP Workshop on Topical & Transdermal Testing
Drugs Sep 14-15, 2009 Adhesion Testing

References
Transdermal 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) 1‐8]

Skin adhesives and skin adhesion 1. Transdermal drug delivery systems,
Venkatraman, S., Gale, R., Biomaterials 19 (1998) 1119‐1136

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

USP Workshop on Topical & Transdermal Drugs

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

22
 Thank you 

USP Workshop on Topical & Transdermal Drugs

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

USP Workshop on Topical and Transdermal Drug Products

September 14-15, 2009
USP Headquarters

USP Perspectives

Roger L. Williams, M.D.

Chair, Council of Experts

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

23
 1974 Drug Bioequivalence Panel

• Berliner • Standards: no BE
• Cluff • BA causes therapeutic failures
• Doluisio • Procedures available
• Melmon • BA critical for some drugs/not all
• Nadas • GMPs and compendial standards inadequate
• Oates • New standards needed
• Riegelman • Research needed, including in vitro/animal
• Shideman models
• Zelen • Strengthen current standards/submit studies
• Robbins • Eliminate exemptions
• New organization

Gaps and Opportunities

24
 What’s 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 21st Century, Q8, 9, 10, QbD
• 2005-10 USP—calibrators 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 In
Vitro/In Vivo Correlations (final)

25
 WHO Interchangeability Document: Table of
Contents

• 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

WHO’s 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

26
 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 to
ascertain the proper correction factors
– To adjust precisely for a particular function

FDA, ICH, PDG—Dissolution (NSOADF)

• Q6A: specifies characterization and setting specifications

during 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 the
drug product
• A key procedure in the drug product specification is dissolution,
which relies on USP General Chapter <711>
• The dissolution procedure requires special care to assure
adequate performance
• In this decade, FDA and USP separated over the use of
‘calibrator tablets’
• Q4B: <711> for regulatory filings—mechanical calibration
only/FDA guidance: mechanical calibration only

27
 Current Lots and Applications

• Salicylic Acid Non-disintegrating Calibrator Tablets, Lot

P0C404
– Apparatus 1 and 2
– 100 rpm
• Prednisone Disintegrating Calibrator Tablets, Lot P0E203
– Apparatus 1 and 2
– 50 rpm
• Chlorpheniramine Maleate Extended-Release Tablets, Lot
G0B259
– Apparatus 3
– Two test conditions
– Ranges applied at two time-points for each condition

Salicylic Acid Tablets, Lot Q

Blister Pack

28
 Lot P Collaborative Ranges

Apparatus Collaborative BPC Approved RDL’s

Mean Collaborative Estimate of
Range Truth

1 65 47 - 82 60 +/- 5

2 53 37 – 70 40 +/- 3

USP Publications

• Deng G., 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
• Liddell M., et al.: Evaluation of Dissolution Glass Vessel Dimensions
and Irregularities, Dissolution Technologies, Vol. 14 Issue 1, Febr.
2007
• Liddell M., et al.: Dissolution Testing Variability: Effect of Using Vessels
from 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 using
Apparatus 2, Dissolution Technologies, Vol. 13 Issue 3, Aug. 2006
• Eaton J., et. al.: Perturbations Study of Dissolution Apparatus
Variables – A Design of Experiment Approach, Dissolution
Technologies, Vol. 14 Issue 1, Feb. 2007

29
 USP Publications

• Hauck WW, Manning RG, Cecil TL, Brown WE, Williams RL. Proposed
change to acceptance criteria for dissolution performance verification
testing. Pharm Forum. 2007;33(3):574–579. Reprinted in: Dissolution
Technol. 2007;14(3): 8–12
• Hauck WW, DeStefano AJ, Brown WE, et al. Description of the
upcoming change in acceptance criteria for USP dissolution
performance verification tests. Pharm Forum. 2008;34(6):1630–1629.
Reprinted in: Dissolution Technol. 2009;16(1): 7–12
• Hauck WW, DeStefano AJ, Brown WE, et al. Change in criteria for
USP dissolution performance verification tests. AAPS PharSciTech.
2009;10(1): 21–26

Variability of Lot P Prednisone as

Determined in USP’s R&D Lab

• Weight 1% CV
• Hardness 6% CV
• Assay <1% CV
• Content Uniformity 2% CV
• Disintegrant Content 3% CV
• Disintegration Times ~10% CV*
• Dissolution Percentage <4% CV**

*Only measured to +/- 1 second for events taking 3 -30 seconds

**Dissolution Percentage at 30 minutes, 50 rpm

30
 Intra-Lab Variances Smaller than Inter-Lab
80

%Dissolved at
30 minutes
75

Lot P
Apparatus 1

Sets of 6
70

Standard
errors
65

Approved
range
47 -- 82
60

55

One Lab
below range
50
in this chart
0 50 100 150 200 250 300

B l i nde d R un C ode

Lot P Apparatus 2 Same Trend Shows

80

70

Approved Range 37 – 70%

%Dissolved Geometric Mean

Sets of 6 tablets, standard errors

60

50

40

30
0 50 100 150 200 250 300

B l i nde d R un C ode

31
 ISO Framework

• ISO Guide 43-1, Proficiency testing by inter-laboratory

comparisons − Development and operation of proficiency testing
schemes
– Describes proficiency testing as the use of inter-laboratory
comparisons to “determine the performance of individual
laboratories for specific tests or measurements and to monitor
laboratories’ continuing performance.”
– “Participation in proficiency testing schemes provides
laboratories with an objective means of assessing and
demonstrating the reliability of the data they are producing,”
– “One of the main uses of proficiency testing schemes is to
assess laboratories’ ability to perform tests competently. .. It
thus supplements laboratories’ own internal quality control
procedures by providing an additional external measure of their
testing capability.”

Metrology—Traceability

Lab A and B make measurements

YA and YB are now traceable to the same reference, X0

A Std
TS YA = gA (X0)

CRM

X0 B Std TS YB = gB (X0)

Where Std is a standard and TS is test sample

32
 National Traceability Chain

Selected SI Coherent SI Base Units

Derived Units SI meter
frequency
kilogram
force
NIST second
pressure, stress
ampere
electromotive force
USP kelvin
electric conductance
candela
Celsius temperature
mole
catalytic activity

Calibration Labs

Routine Measurement Labs

Katal

• katal is now adopted under the Convention of the Metre of 1875 by the highest
metrologic authority, the intergovernmental diplomatic CGPM, to express quantity
values of catalytic activity of enzymes and other catalysts in any field of science and
technology. Further derived kinds-of-quantity and derived units may be defined in the
conventional 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/ms): katal per kilogram (kat/kg)

– Catalytic activity fraction (zf): one = katal/katal (1 = kat/kat)

• If the measurement procedure has an indicator reaction that can be described by

conversion of amount of substances of reactants, the results involving the katal are
metrologically 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 the
CGPM promote international standardization of units by including the katal in their
Information for Authors, thus facilitating the globalization of medicine.

33
 USP Position

• Mechanical calibration alone is not sufficient to ensure

consistency and comparability of measurements
obtained with a dissolution test system
• A periodic Performance Verification Test (PVT)
together with careful mechanical calibration is
important 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 optional

possibility 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 at
30 minutes. Determine the geometric mean (GM) and
percent coefficient of variation (%CV). Compare the GM
and %CV to the acceptance criteria. If both meet
acceptance criteria, test finished. If not, go to Step 2.
– Step 2: Test another USP Prednisone Tablet RS in each
position and record the percent dissolved at 30 minutes.
Compute a pooled GM and pooled intra-run %CV.
Compare to the acceptance criteria. If both meet
acceptance criteria, test finished. If not, further work is
needed
• Pass if meet acceptance criteria at either step

34
 And What’s Next?
• <1151> (in revision)
• General Chapters for all five routes of administration, e.g., <1>
• 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 V—Drugs and Devices
• Subchapter A—Drugs 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 color
additive (A) or (B); or (5) new animal drug; or (6) animal feed
bearing or containing a new animal drug
• Section 501 (b) official compendium (three)
• Sections (c) through (i) or more
• Implications for US/other markets

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

35
PRODUCT QUALITY AND
PERFORMANCE:
CLINICAL PERSPECTIVE
HOWARD I. MAIBACH, M.D.
PROFESSOR
DEPARTMENT OF DERMATOLOGY
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
94143-0989

I. WHY Quality/Performance
Tests?

1. Rational approach
2. Great theory
3. Underpinning – for in vivo data

36
II. CLINICAL OBSERVATIONS - ? FAIL
!

• Corticoid
• Why:
– high placebo role
– No phase 4 efficacy system
– “just” switch drug
– Likely potency – not failure

III. BASED ON CLINICAL

OBSERVATIONS – WHAT TESTS?

• Those best fitting clinical efficacy!

• To be determined!

37
 IV. WHY Drug Release Data?

• Highly cost efficient drug

development
• Standard for Orals/Transdermal
• Await “validation” in vivo

Exemplar
Clinical Testing
• Fluocinonide
Innovator >Generic
• Replication awaited

38
 Scientific Weakness

• Parallel Design Clinical Trial –

Relatively weak

SOLUTIONS?

• Paired comparison
• Armitage Stats
• Bioengineering techniques

39
 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

MaibachH@derm.ucsf.edu

40