1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE
(DSaRM)
COMMITTEE MEETING
CDER Advisory Committee Conference
Room.
2
P A R T I C I P A N T S
DSaRM Committee Members:
Peter A. Gross, M.D., Chair
Michael R. Cohen, R.Ph., M.S., D.Sc.
Stephanie Y. Crawford, Ph.D., M.P.H.
Curt D. Furberg, M.D., Ph.D.
Jacqueline S. Gardner, Ph.D. M.P.H.
Arthur A. Levin, M.P.H.
Henri R. Manasse, Jr.,
Ph.D.
Robyn S. Shapiro, J.D.
Annette Stemhagen, Dr.PH
Brian L. Strom, M.D., M.P.H.
GI Advisory Committee Members:
Alexander H. Krist, M.D.
Maria
H. Sjogren, M.D.
Consultant:
Leslie
Hendeles, Pharm.D.
FDA
Participants:
Carol
Holquist, R.Ph.
Marci
Lee, Pharm.D.
Paul Seligman, M.D., M.P.H.
[a.m. and p.m.]
Vibhakar Shah, Ph.D.
Eugene Sullivan, M.D.
Mark Avigan, M.D., C.M.
Julie Beitz, M.D.
Robert Justice, M.D., M.S.
Ann Marie Trentacosti,
M.D.
3
C O N T E N T S
AGENDA ITEM
PAGE
Call to Order and Opening Remarks,
Introduction of
Committee - Peter Gross, M.D., Chair,
DSaRM 5
Conflict of Interest Statement - Shalini
Jain,
PA-C, M.B.A., Executive Secretary,
DSaRM 8
Opening Remarks - Paul Seligman, M.D.,
M.P.H.,
Director, Office of Pharmacoepidemiology
&
Statistical Science (OPSS) and Acting
Director,
Office of Drug Safety (ODS) 11
FDA Presentations
- Permeability of LDPE Vials: A Clinical
Perspective - Eugene Sullivan, M.D.,
Deputy
Director, Division of Pulmonary Drug
Products. 13
- Medication Errors and Low-Density
Polyethylene
(LDPE) Plastic Vials -
Marci Lee, Pharm.D.,
Safety Evaluator, Division
of Medication Errors
and Technical Support 23
- LDPE Vials for Inhalation Drug
Products: A
Chemistry, Manufacturing, and Controls
(CMC)
Perspective - Vibhakar Shah, Ph.D.,
Chemist,
Division of New Drug Chemistry II 36
Questions from Committee 55
Industry Presentations
- Container Labeling Options using
rommelag Blow-
Fill-Seal Technology - Mohammad
Sadeghi, V.P.,
Research/Development, Holopack
International
Corp.
65
- Labeling of LDPE Containers: Options for
Improving Identification for Prevention
of
Medication Errors - Rick Schindewolf,
V.P. & GM,
Biotechnology & Sterile Life
Sciences, and
Patrick Poisson, Director of Technical
Services,
Biotechnology & Sterile Life Sciences, Cardinal
Health
90
- American Association of Respiratory
Therapy
Care - Karen Stewart, M.S., R.R.T. 93
Questions from Committee 94
4
C O N T E N T S
(Continued)
Open Public Hearing 106
Introduction of LDPE Issues
Paul Seligman, M.D.,
M.P.H. 118
Committee Discussion 118
Committee Discussion (Continued) 182
Opening Remarks and Reintroduction of
Advisory
Committee - Peter Gross, M.D., Chair 182
Conflict of Interest Statement - Shalini
Jain,
PA-C., M.B.A. 185
Introduction of Lotronex Issue - Paul
Seligman,
M.D., M.P.H.
187
Open Public Hearing 189
Sponsor Presentation
Risk Management Program for Lotronex -
Craig Metz,
Ph.D., V.P., U.S. Regulatory Affairs,
GlaxoSmithKline 206
FDA Presentation
Lotronex Update - Robert Justice, M.D.,
M.S.,
Director, Division of Gastrointestinal
and
Coagulation Drug Products 241
Questions from Committee 248
Adjourn
298
5
1 P R O C E E D I N G S
2
DR. GROSS: Good morning. I'm Peter
3
Gross. I'm Chair of the Drug
Safety and Risk
4
Management Committee, and starting with the person
5 at
my left with that famous laugh, Brian Strom,
6
would you please introduce yourself?
7
DR. STROM: Thank you. I'm Brian Strom
8
from the University of Pennsylvania.
9
MS. JAIN: You know what? Before we go
10 on,
Brian, Peter and the rest of the committee as
11
well as the division wanted to say a warm thank-you
12 for
serving on our committee. You've been a
great
13
asset for a year and a half, and we realize that
14
you're going to continue as consultant, and we just
15
wanted to say thanks.
16
DR. STROM: It's been a real
pleasure, and
17 it
was a hard decision to let the rotation happen.
18
I've enjoyed it, but given other commitments back
19
home--but it's been fun.
20
MS. JAIN: Thank you.
21
DR. GROSS: You've been great,
Brian. We
22
will continue to take advantage of your skills.
6
1
DR. MANASSE: My name is Henri
Manasse.
2 I'm
chief executive officer and executive vice
3
president of the American Society of Health-System
4
Pharmacists, a membership organization that
5
represents about 32,000 pharmacists practicing in
6
hospitals and organized health systems.
7
MS. SHAPIRO: Robyn Shapiro. I'm a
8
professor and director of the Center for the Study
9 of
Bioethics at the Medical College of Wisconsin.
10
DR. STEMHAGEN: I'm Annette
Stemhagen.
11 I'm
Vice President of Strategic Development at
12 Covance,
a contract research organization, and I
13
serve as an industry representative to this
14
committee.
15
DR. GARDNER: Jacqueline Gardner,
16
University of Washington, Department of Pharmacy.
17
MR. LEVIN: Art Levin, Center for
Medical
18
Consumers, and I serve as the consumer
19
representative.
20
DR. FURBERG: Curt Furberg,
professor of
21
public health sciences at the Wake Forest
22
University.
7
1
DR. HENDELES: I'm Leslie
Hendeles. I'm a
2
clinical pharmacist at the University of Florida,
3 and
I've done research on the bronchospastic
4
effects of preservatives in nebulizer solutions.
5
DR. CRAWFORD: Good morning. Stephanie
6
Crawford, associate professor, College of Pharmacy,
7
University of Illinois at Chicago.
8
DR. COHEN: Mike Cohen, Institute
for Safe
9
Medication Practices.
10 DR. SELIGMAN: Paul Seligman, Director,
11
Office of Pharmacoepidemiology and Statistical
12
Science, Center for Drug Evaluation and Research,
13
FDA.
14
DR. SULLVAN: My name is Gene
Sullivan.
15 I'm
the Deputy Director of the Division of
16
Pulmonary and Allergy Drug Products here at FDA.
17
MS. HOLQUIST: I'm Carol
Holquist. I'm
18 the
Director of the Division of Medication Errors
19 and
Technical Support in the Office of Drug Safety,
20
Center for Drug Evaluation and Research.
21
DR. LEE: Marci Lee, a pharmacist
and
22
safety evaluator in the Division of Medication
8
1
Errors and Technical Support.
2
MS. JAIN: Thank you,
everyone. My name
3 is
Shalini Jain. I'm the Executive
Secretary for
4 the
Drug Safety and Risk Management Advisory
5
Committee. I'll now read the
conflict of interest
6
statement for the meeting today.
The meeting issue
7 is
low-density polyethylene vials.
8
The following announcement addresses the
9
issue of conflict of interest with respect to this
10
meeting and is made a part of the record to
11
preclude even the appearance of such at this
12
meeting.
13
Based on the agenda, it has been
14
determined that the topics of today's meeting are
15
issues of broad applicability, and there are no
16
products being approved at this meeting.
Unlike
17
issues before a committee in which a particular
18
product is discussed, issues of broader
19
applicability involve many industrial sponsors and
20
academic institutions.
21
All special government employees have been
22
screened for their financial interests as they may
9
1
apply to the general topics at hand.
To determine
2 if
any conflict of interest existed, the agency has
3
reviewed the agenda and all relevant financial
4
interests reported by the meeting participants.
5 The
Food and Drug Administration has granted
6
general matters waivers to the special government
7
employees participating in this meeting who require
8 a
waiver under Title 18, United States Code,
9
Section 208.
10
A copy of the waiver statements may be
11
obtained by submitting a written request to the
12
agency's Freedom of Information Office, Room 12A-30
13 of
the Parklawn Building.
14
Because general topics impact so many
15
entities, it is not prudent to recite all potential
16
conflicts of interest as they apply to each member,
17
consultants, and guest speaker.
18
FDA acknowledges that there may be
19
potential conflicts of interest, but because of the
20
general nature of the discussion before the
21
committee, these potential conflicts are mitigated.
22
With respect to FDA's invited industry
10
1
representative, we would like to disclose that Dr.
2
Annette Stemhagen is participating in this meeting
3 as
an industry representative, acting on behalf of
4
regulated industry. Dr. Stemhagen
is employed by
5
Covance Periapproval Services, Incorporated.
6
In addition, we would like to note that
7
Karen Stewart, FDA's invited guest speaker, is
8
participating as a representative of the
9
respiratory therapists in the United States through
10 the
American Association for Respiratory Care.
She
11 has
no financial interest in or professional
12
relationship with any of the products or firms that
13 could
be affected by the committee's discussions.
14
With respect to the three invited industry
15
guest speakers, we would like to disclose that
16
Mohammad Sadeghi is employed by Holopack
17
International, Richard
Schindewolf is employed by
18
Cardinal Health and is vice president and general
19
manager of Biotechnology and Sterile Life Sciences.
20
Patrick Poisson is employed by Cardinal Health, and
21 he
serves as Director of Technical Services at the
22
Biotechnology and Sterile Life Sciences division.
11
1
In the event that the discussions involve
2 any
other products or firms not already on the
3
agenda for which FDA participants have a financial
4
interest, the participants' involvement and their
5
exclusion will be noted for the record.
6
With respect to all other participants, we
7 ask
in the interest of fairness that they address
8 any
current or previous financial involvement with
9 any
firm whose product they may wish to comment
10
upon.
11
Thank you.
x DR. SELIGMAN: Good morning.
On behalf of
12
13 the
Center for Drug Evaluation and Research, it is
14 my
pleasure to welcome members of the Drug Safety
15 and
Risk Management Advisory Committee and members
16 of
the public to today's meeting. As
always, we
17
greatly appreciate the time and efforts devoted by
18 the
committee members and all participants in
19
providing advice to the FDA on important public
20
health issues.
21
We have two topics on the agenda for
22
discussion today--the first related to the
12
1
prevention of medication errors and the second
2
providing an update on a risk management program
3
that was considered by this committee two years ago
4 and
was implemented in 2002.
5
The first topic will focus primarily on
6
minimizing the incidence of medication errors with
7
drug products packages in low-density polyethylene,
8 or
LDPE, containers. The package is
intended to
9
preserve drug product purity and quality. However,
10
current techniques used to label the product create
11
problems related to legibility of the product name
12 and
strength. Additionally, various products
are
13
packaged in containers that look similar. We've
14
found that these difficult-to-read labels and
15
look-alike containers have contributed to
16
medication errors involving the administration of
17
wrong dosage strength or wrong drug product to the
18
patient.
19 Today, we would like to discuss what
other
20
solutions or alternative packaging designs exist
21
that could improve the legibility of the label,
22
prevent ingress of chemical contaminants, and in
13
1 the
process reduce or eliminate medication errors.
2
Then later this afternoon, we will receive an
3
update on the Lotronex risk management program.
4
With that brief introduction, I look
5
forward to our discussions today and, again, I also
6
want to personally thank Dr. Strom for his service
7 on
this committee.
8
With that, I guess we may proceed with the
9
first speaker. Dr. Gross?
10
DR. GROSS: Dr. Sullivan will be
the first
11
speaker on the Permeability of LDPE Vials: A
12
Clinical Perspective.
13
DR. SULLIVAN: Good morning. As I
14
mentioned, my name is Gene Sullivan.
By training
15 I'm
a pulmonologist, and I'm the Deputy Director of
16 the
Division of Pulmonary and Allergy Drug Products
17 in
the Center for Drug Evaluation and Research here
18 at
FDA.
19
This morning, I'm going to spend about 15
20
minutes or so providing some background for the
21
discussions today. I'll be
conveying some clinical
22
observations regarding issues raised by the use of
14
1
LDPE vials in the packaging of inhalation drug
2
products, particularly as it relates to the
3
permeability of the vials.
4
This slide provides an overview of my
5
presentation. I'll begin with
some introductory
6
remarks which will put my presentation into the
7
context of today's discussions and will serve to
8
introduce the remainder of the talk.
Next I will
9
discuss the inhalation drug products that are
10
involved, providing some examples and a brief
11
description of the nature of these drugs.
12
Following this, I will discuss the patient
13
populations for which these drugs are used,
14
emphasizing aspects of these populations that put
15
them at risk for adverse effects of chemical
16
contaminants. Then I will discuss
the potential
17
sources of chemical contaminants, their potential
18
adverse effects, and the difficulties that exist in
19
terms of adequately monitoring for them.
Finally,
20 I
will summarize the issue and current state of
21
affairs in order to set the stage for the remainder
22 of
today's discussion regarding minimizing the
15
1
potential for medication errors.
2
The topic for discussion for today's
3
Advisory Committee meeting is how best to minimize
4 the
potential for medication errors associated with
5
LDPE containers, particularly given the clinical
6
concerns related to their permeability and the
7 resulting
move away from the paper labels that have
8
previously been used to identify the products. My
9
presentation is intended to review the nature of
10
these clinical concerns in order to provide
11
background for the remainder of the discussions
12
today.
13
This slide summarizes the clinical
14
concerns that I mentioned. Many
inhalation drug
15
products are packaged in LDPE containers. LDPE is
16 a
material that is permeable to volatile chemicals,
17 and
there are numerous volatile chemicals that
18
exist in the immediate packaging environment.
19
Volatile chemicals that find their way into
20
inhalation solutions may have a number of adverse
21
effects on the airways, and because these adverse
22
effects may be poorly tolerated by patients,
16
1
efforts should be made to minimize the potential
2 for
contamination of inhalation drug products.
3 Such
efforts have included minimizing the content
4 of
volatile chemicals in the immediate packaging
5
environment.
6
For instance, the practice of using paper
7
labels, which are applied directly to the LDPE
8
containers and which contain numerous volatile
9
chemicals, is not recommended.
However, as you
10
will see in subsequent presentations, the use of
11
alternative labeling approaches has raised the
12
issue of medication errors.
13
Now, I also want to point out that my
14
presentation is focused on the clinical concerns
15
related to chemical contamination of these
16
products. In the next
presentation, Dr. Shah will
17
also talk about product quality concerns. For
18 instance, ingress of volatile chemicals might
19
adversely affect the stability of the active drug
20
substance in a particular drug product.
21
This slide provides some examples of
22
inhalation drug products that are packaged in LDPE
17
1
containers. They include
bronchodilators, such as
2
Albuterol, Ipatropium, Metaproterenol, and
3
Levalbuterol; also a mass cell stabilizer, cromolyn
4
sodium; an inhaled steroid, Budesonide; and an
5
antibiotic, Tobramycin.
6
These products are inhalation solutions,
7 or
sometimes suspensions, that are intended for
8
oral inhalation using a nebulizer.
One thing to
9
keep in mind is that the manufacturing processes
10 and
materials for inhalation products are very
11
carefully controlled in order to maintain a very
12
high standard of product purity.
That is, a
13
significant amount of attention is paid to the
14
manufacturing processes and the materials used so
15
that the content of contaminants is minimized.
16
This would include contaminants that arise during
17 the
manufacturing processes, so-called process of
18
synthetic impurities; contaminants that arise due
19 to
degradation of components of the formulation; or
20 the
subject of today's concern, contaminants that
21
enter the formulation from the packaging materials,
22
so-called leachables.
18
1
These drugs may be used in a regular
2
dosing schedule or may be used as an as-needed
3
basis, and the bronchodilator products in
4
particular are common used in the inpatient and
5
acute-care settings, including emergency
6
departments and intensive care units.
7
These inhalation products are used by
8
patients with a variety of pulmonary disorders,
9
most commonly patients with asthma, COPD--which is
10
chronic obstructive pulmonary disease, a category
11 of
lung disease comprised of chronic bronchitis and
12
emphysema--and cystic fibrosis.
Although these
13
diseases are distinct, in general they are
14
characterized by fixed or variable obstruction to
15
airflow and a variety of patterns of histologic
16
abnormalities, including various patterns of airway
17
inflammation. In addition, asthma
in particular is
18
associated with an underlying propensity for
19
allergic responses. And most of
the diseases are
20
associated with a sensitivity to nonspecific
21
irritants which result in acute bronchospasm, a
22
feature known as airway hyperresponsiveness.
19
1
To focus specifically on asthmatics for a
2
moment, asthmatics may react adversely to both
3
nonspecific chemical irritants and to allergens to
4
which they have developed specific immunity.
5
Irritant reactions are characterized by symptoms of
6
wheezing and shortness of breath.
It is well known
7
that patients with severe asthma may react to very
8 low
levels of exposure to irritants.
Clinically,
9
this is often related to perfumes, cleaning agents,
10 or
smoke in the environment. In fact, we
commonly
11
make use of this feature of asthma to help
12
establish the diagnosis using methacholine
13
challenge testing. In the
methacholine challenge
14 test,
patients with suspect asthma are exposed to
15
successively higher concentrations of this irritant
16 in
order to elicit bronchospasm.
17
In addition to the nonspecific irritant
18
reactions, asthmatics may also develop bronchospasm
19
from inhaled allergens. This
allergic reaction is
20
associated with both an acute early-phase broncho-
21
constriction and a delayed late-phase response
22
characterized by airway inflammation and airflow
20
1
limitation.
2
So what are the potential sources of
3
contaminants in inhalation drug products packaged
4 in
LDPE? In general, these are from
volatile
5
chemicals found in the labels and secondary bulk
6
packaging. These chemicals may be
found in the
7
various glues, inks, and lacquers that are used.
8 One
thing to point out is that the specific
9
chemical nature of these inks, glues, et cetera,
10 may,
in fact, change after approval due to changes
11 in
the sources of these packaging materials.
12
The FDA conducted an analytical survey of
13
approved inhalation solutions marketed in LDPE
14
containers and found that 29 of the 37 samples
15
tested positive for various volatile chemicals that
16
were presumed to have originated in the packaging
17
materials. Dr. Shah will describe
this analysis in
18
much more detail in his presentation later this
19
morning.
20
Chemical contaminants in inhalation drug
21
products may be associated with a variety of
22
adverse effects, including irritant and immunologic
21
1
effects, leading to acute bronchospasm and airway
2
inflammation and hyperresponsiveness, other toxicologic
3
injury, or even potentially carcinogenicity.
4
In terms of monitoring for adverse effects
5
that might be attributed to chemical contaminants
6 in
these products, it is important to note that
7
appropriate attribution may be very difficult
8
because the expected adverse effects--bronchospasm
9 and
airway hyperresponsiveness--mimic the symptoms
10 for
which the drugs are being used. This is
a very
11
difficult circumstance and makes it quite likely
12
that adverse effects would not be recognized and
13
reported. For instance, modest
bronchospasm
14
related to chemical contaminants might lead to
15
reduced efficacy of the drug, but this would likely
16 not
be identified. Even if the adverse
effect were
17
more significant, the findings would likely be
18
attributed to refractory underlying disease.
19
So, to summarize, many inhalation drug
20
products are packaged in low-density polyethylene
21
containers. This material is
permeable to volatile
22
chemicals. Numerous volatile
chemicals exist in
22
1 the
immediate packaging environment.
2
Various volatile chemicals have, in fact,
3
been identified in these products.
These volatile
4
chemicals may have irritant as well as other
5
toxicologic effects. And because
these effects may
6 be
particularly poorly tolerated by patients,
7
efforts should be made to minimize the potential
8 for
contamination of inhalation drug products.
9
It was this line of reasoning that in part
10 led
to the development of the Draft Guidance
11
entitled "Inhalation Drug Products Packaged in
12
Semipermeable Container Closure Systems." Among
13
other things, the Draft Guidance recommends that
14
measures be taken to limit chemical contamination
15 of
these products. One such measure would
be the
16 use
of alternative approaches to paper labels, such
17 as
direct embossing or debossing of the containers.
18
However, as will be discussed in
19
subsequent presentations, the move away from paper
20
labels has introduced a new concern, that of
21
medication errors due to difficult-to-read and
22
look-alike packaging. The issue
of how best to
23
1
minimize the potential for medication errors will
2 be
the topic for today's discussion.
3
DR. GROSS: Thank you, Dr.
Sullivan.
4
The next speaker will be Shah.
5
MS. JAIN: He is not here.
6
DR. GROSS: Okay. Later for Dr. Shah.
7
Dr. Marci Lee will now talk about
8
medication errors and low-density polyethylene
9
plastic vials.
10
DR. LEE: Good morning. My name is Marci
11
Lee. I am a pharmacist and safety
evaluator in the
12
Division of Medication Errors and Technical Support
13 in
the Office of Drug Safety.
14
The purpose of this presentation is to
15
describe medication error reports and feedback from
16
patients and practitioners involving products
17
packaged in LDPE containers. I
will focus on some
18
factors we identified that may contribute to
19
confusion and errors with these products. Finally,
20 I
will describe packaging and labeling approaches
21 for
your consideration.
22
Our error analysis included in your
24
1
background package was from 87 relevant reports.
2 These
came from patients, caregivers, and
3
practitioners, such as respiratory therapists and
4
pharmacists, who reported to the programs listed.
5
These reports were received between January 1993
6 and
August 2002. Many reports involved difficulty
7
reading embossed product containers.
Some reports
8
were actual errors where the wrong medication or
9 the
wrong dosage strengths were dispensed.
10
Although some of these were detected before the
11
medication was administered to the patient, some
12
were not. The outcomes of these
reports ranged
13
from no harm to difficulty breathing, which can be
14
life-threatening. The remainder
of the reports
15
described the potential for confusion and errors
16
with these products.
Subsequently, as of April
17
2004, 51 additional relevant medication error
18
reports were identified for a total of 138 reports.
19
In addition to our analysis, FDA received
20
correspondence from ISMP, USP, and Senator Harkin
21
regarding the safe use of products packaged in LDPE
22
containers.
25
1
Several themes emerged from the narratives
2 of
the medication error reports as factors that can
3
contribute to errors. They
include
4
difficult-to-read containers, look-alike packaging,
5 and
routine handling of LDPE by patients and health
6
care practitioners.
7
Some of the slides for this portion of the
8
presentation will include direct quotes from the
9
error reporters. The first
contributing factor to
10
consider is the difficult-to-read labeling.
11
Concern was expressed in a medication error report
12 because it is difficult to see the name of
the drug
13 and
its ingredients. Another person noted
that if
14 the
lot and expiration date are on opposite sides
15 of
the same area of plastic, it is even more
16
difficult to read. In addition,
practitioners
17
described how the vials needed to be angled in the
18
light to read them. For some, the
text is
19
difficult or impossible to read.
20
In addition to difficult-to-read
21
containers, another concern from the medication
22
error perspective is the issue of look-alike
26
1
packaging. Often there is very
little on the
2
container itself to help people distinguish these
3 products.
4
This photo accompanied one medication
5
error report. It highlights the
potential for
6
confusion from look-alike vials from just a few of
7 the
products available in these containers.
Almost
8 all
of these vials contain a different drug
9
product. The paper labels and the
unique round
10
vial shape help to differentiate three of the vials
11
from the rest. However, these two
can be difficult
12 to
read.
13
In addition, this problem spans various
14
drug classes and routes of administration. This
15
complicates the picture for practitioners and
16
creates the opportunity for errors to occur among
17
inhalation, injection, ophthalmic, and oral
18
products.
19
In this case, heparin is an injectable
20
medication. This photo was
included with the
21
report of potential for confusion between heparin
22 and
Tobramycin due to look-alike containers.
27
1
Pharmacies may store a variety of these products,
2 and
the potential for confusion will likely
3
increase as we see more products other than
4
inhalation solutions packaged in the LDPE
5
containers. This increases the
likelihood for
6
administration of the wrong drug product by the
7
wrong route of administration.
8
Another example of an injectable drug
9
product with similar packaging is Naropin. These
10
ampules are specially design to fit both Luer lock
11 and
Luer slip syringes. Although this
feature may
12
minimize the likelihood for confusion with the
13
other LDPE containers, there is still potential for
14
confusion between the dosage strengths within the
15
Naropin product line. This vial
includes black
16
type on a clear background.
Again, for some this
17 may
be difficult to read.
18
Timoptic OCUDOSE is an example of an
19
ophthalmic solution packaged in an LDPE container.
20
This image shows that the tip of the container has
21
been extended to allow for a label.
However, there
22 may
be potential for contamination despite the
28
1
placement of this label.
2
Gastrocom is an example of a product for
3
oral administration that is packaged in an LDPE
4
container. This image illustrates
the instructions
5 for
use.
6
In summary, there are least four different
7
routes of administration for products packaged in
8
LDPE containers. Again, this
complicates the
9
picture for practitioners and creates the
10
opportunity for errors to occur among inhalation,
11
injection, ophthalmic, and oral drug products.
12
We have discussed several issues that
13
contribute to medication errors with LDPE
14
containers. We have seen examples
of containers
15
that are difficult to read and difficult to
16 distinguish from one another. We have noted that
17 the
look-alike contains look-alike containers are
18 not
from a single drug product category or
19
associated with a single route of administration.
20 Now
we will explore how routine handling of LDPE
21
containers by patients and practitioners can
22
contribute to errors.
29
1
The foil overwrap serves to protect the
2
containers from light and the environment. It is
3
recommended that the containers are stored in the
4
foil overwrap until time of use.
However, the
5
reality is that the foil overwraps are commonly
6
discarded. Once discarded, the
clearly labeled
7 portion
of the packaging is often eliminated.
8
One reason noted in our analysis for the
9
overwrap to be removed is an effort to fit the
10
products into a medication cart.
The foil overwrap
11 and
carton for many inhalation solutions use color
12 to
differentiate the dosage strength. Most
foil
13
overwraps contain multiple unit dose LDPE vials.
14 For
example, the foil overwrap for Xopenex contains
15 12
vials.
16
Carol, if you'll pass the sample?
17
This image includes the 12 vials which are
18
contents of a single foil pouch of Xopenex. All of
19 the
vials in this image are the same dosage
20
strength. However, Xopenex is
available in three
21
different dosage strengths. The
vials for all
22
three strengths look alike when they are removed
30
1
from the foil. Although the foil
helps to
2
differentiate them, it is possible that these vials
3 may
not remain in the foil pouch until their time
4 of
use. These individual LDPE containers
can be
5
stored in a variety of places once removed from the
6
foil overwrap.
7
It is a common practice for LDPE
8 containers
to be stored in the pockets or pouches
9 of
the practitioners who administer these
10
medications. In summary, while it
is possible for
11
various products to have clearly marked foil
12
overwraps, as long as the containers themselves are
13
poorly marked there is still potential for
14
confusion.
15
Once the container leaves the foil
16
overwraps, it no longer matters how well labeled
17 the
foil pouch is. This is a concern,
regardless
18 of
the number of vials contained in the foil
19
overwrap. However, a single
container in the foil
20
pouch may minimize the likelihood for the vial to
21
become separated from the overwrap.
22
At this point we would like to stimulate
31
1
ideas for discussion about how to address the
2
issues that have been raised so far.
The remainder
3 of
this presentation will include a series of
4
photos. These images will
highlight various
5
packaging and labeling approaches to consider.
6
Remember to keep in mind who will be using the
7
products and how they will be used.
Our goal is to
8
identify packaging that will resolve our concerns
9 but not introduce any new problems for those
who
10
manufacture or use the products.
11
The paper label approach allows for use of
12
color to distinguish look-alike vials.
For some,
13
these may difficult to read due to the small font
14
size of the text. The reports in
our analysis
15
demonstrated that some people may identify these
16
medications by the color of their label alone.
17
Based on the earlier presentation, we learned of
18 the
potential safety and product quality concerns
19
with this approach for inhalation solutions.
20
Although this packaging no longer appears
21 to
be used for Timoptic, this image illustrates
22
another approach with paper labels.
The paper
32
1
label is applied to the tip of the container. The
2
packaging allows for use of color to differentiate
3 the
containers and dosage strengths.
However, it
4 may
not address the potential for ingress.
5
Again, consider the size of the label and
6 the
potential font size issues which may make the
7
text difficult to read.
8
We have a sample of this also going
9
around.
10 Here is an approach that extends the
tip
11 of
the container to allow for the text to be
12
embossed in the flange instead of the body of the
13
vial. This approach allows for
more space for
14
printed text; however, if both sides are embossed,
15
they tend to interfere with the readability of the
16
text.
17
In contrast, this approach includes an
18
embossed container without an extended flange. In
19
addition, the container is topped with the letter
20
V-shaped tip. In this case, V is
for Ventolin.
21
This approach allows for use of the unique vial
22
shape and possibly texture to help differentiate
33
1 the
product.
2
Another approach used to differentiate the
3
various products in LDPE vials is the use of the
4
embossed letters A, I, and R at the tip of the
5
container. In addition to a
visual cue, the vial
6
makes use of texture to distinguish the products.
7 A
is for Albuterol, I is for Ipatropium, and so on.
8
Again, for some this is difficult to read.
9
One approach that has contributed to
10
medication errors with acetylcysteine is the use of
11 a
glass vial. The packaging has led to
medication
12
errors where practitioners inject the product
13
instead of administering the drug via inhalation
14
because the vials look similar to those that
15
contain an injectable product. According
to the
16 May
30, 2001, ISMP newsletter article, these error
17
occur despite warnings on the label that state "Not
18 for
injection" or "For inhalation."
In addition,
19
they have a target area on the rubber stopper
20
similar to the injectable products.
21
Another approach used to distinguish these
22
products includes the use of a uniquely shaped
34
1
container. Although these round
vials distinguish
2
Pulmicort from other drug products, it is difficult
3 to
differentiate between the two dosage strengths
4 of
Pulmicort once they are removed from the foil.
5 The
image on the right illustrates what the
6
containers look like once the foil overwrap is
7
removed.
8
Some products, such as sodium chloride
9
inhalation solution, utilize a tinted vial as a
10
means of differentiation. This
approach allows for
11 the
use of color to help differentiate the
12
containers from other products.
However, this
13
particular packaging has not been evaluated by CDER
14 at
FDA. These vials also include embossed
text.
15
Another approach is the shrink wrap
16
approach which allows for the combination of
17
embossed information on the end of the vial and the
18 use
of black print on a clear background.
Again,
19 for
some this may be difficult to read. The
20
printed portion of this label clings to the vials
21
without adhesives, eliminating one potential source
22 of
packaging contamination. However, there
are
35
1
still sources of volatile chemicals with the shrink
2 wrap
approach.
3
There's also a sample of this going
4
around. The individual foil
overwrap approach was
5
described in the Draft Guidance that Dr. Sullivan
6
referred to in his presentation.
This method will
7
protect the drug product from contamination from
8 the
environment and minimize the opportunity for
9
contamination from the packaging itself.
10
Each foil overwrap contains a single vial.
11
This is thought to increase the likelihood of the
12
pouch staying with the container and minimize the
13
risk for errors. The overwrap
allows for the use
14 of
color and other means of differentiation to help
15
distinguish these products.
16
At this time we are seeking other ideas
17 and
approaches to consider. What other
materials
18
could we use? What has been done
for other
19
products? What will meet the
needs of those using
20 the
products in both the inpatient and outpatient
21
setting? How should FDA evaluate
any proposed
22
changes?
36
1
Also ask yourself, Will it prevent
2
contamination from secondary packaging in the
3
environment? Will it be difficult
to read? Will
4 it
look like other containers? Will it
create new
5
problems? Will it be difficult to
use? And,
6
finally, should inhalation products be handled
7
separately from products with other routes of
8
administration? We look forward
to hearing your
9
ideas and suggestions.
10
DR. GROSS: Okay. To round out the
11
presentations, Dr. Shah will talk about the
12
perspective for chemistry, manufacturing, and
13
controls.
14 DR. SHAH: Good morning.
My name is
15
Vibhakar Shah, and I'm a chemist in the Office of
16 New
Drug Chemistry for Pulmonary and Allergy Drug
17
Products. Before I start, I would
like to
18
apologize for my delay. I was
stuck in traffic for
19
almost one and a half hours. Let
me tell you, it's
20 not
a pleasant experience. But, in any case,
21
that's life. And I'm sure when we
move to White
22 Oak
it's going to get worse.
37
1
[Laughter.]
2
DR. SHAH: You were supposed to
hear this
3
talk before Marci's talk, but, anyway, here it
4
goes.
5
You already heard from Dr. Sullivan the
6
clinical concerns arising due to the permeability
7 of
LDPE vials, especially when used with paper
8
labels for inhalation drug products, and also you
9
heard some of the medication errors which are
10
caused because of legibility issues with the paper
11
labels. And I'm going to talk
about in the next 20
12
minutes regarding the problems and issues with
13
product quality concerns arising due to the use of
14
LDPE containers, with or without paper labels and
15
with or without overwrap, for these drug products.
16
In the context of today's discussion, my
17
presentation will also focus on how best to
18
minimize the potential medication errors given the
19
quality concerns associated with these container
20
closures.
21
With that, this slide gives you the
22
outline of my talk. I'm going to
start with a
38
1
brief introduction to the type of inhalation drug
2
products that are packaged in LDPE containers, and
3
after that I'll be overviewing the current
4
container-closure systems that are used.
Following
5
that, I would like to discuss the results of an
6
analytical survey conducted by the agency for
7
several inhalation drug products under the Drug
8
Product Quality Surveillance Program.
This survey
9
particularly identified the clinical concerns as
10
well as the quality concerns arising from the drug
11 product
contamination by packaging components
12
because of the permeability of LDPE.
13
Following that, I would like to discuss
14
some of the quality concerns arising with the use
15 of
LDPE vials, with or without paper label and foil
16
overwrap. I will discuss the
agency's current
17
approaches to control and minimize the product
18
contamination from packaging components and discuss
19
current recommendations for packaging of inhalation
20
drug products as provided in the Draft Guidance.
21 And
I will end my presentation with summarizing the
22
quality concerns, what I have discussed so far.
39
1
This slide lists the inhalation dosage
2
forms administered by oral inhalation, and these
3
drug products include inhalation solutions,
4
suspensions, spray, inhalation aerosol, and
5
inhalation powder. However, for
today's
6
discussion, the remainder of the talk will focus on
7
inhalation solutions and suspensions as they are
8 the
only two dosage forms that are packaged in LDPE
9
containers.
10
This slide you have already seen in Dr.
11
Sullivan's presentation. It just
shows the type of
12
drug products which are packaged into LDPE
13
containers.
14
Currently, inhalation solutions and
15
suspensions are packaged in LDPE vials, and there
16 are
three components, basically: LDPE vials,
vial
17
labels, and foil overwrap pouch.
Not all the
18
inhalation solutions and suspensions may have foil
19
overwrap pouch or adhesive paper label.
But in any
20
case, the unit-dose vial--that is, the LDPE
21
vial--is made up of low-density polyethylene by
22
blow-fill-seal or form-fill-seal process. The
40
1
labeling information on a vial is conveyed either
2 by
a self-adhesive printed paper label or by
3
embossing or debossing the labeling information on
4 the
LDPE vial itself during the fabrication of the
5
vial.
6
Foil overwrap acts as a protective
7
secondary package and may contain anywhere from one
8 to
12 vials per pouch. The labeling
information
9 may
be conveyed by a self-adhesive paper label on
10 the
foil overwrap, or the foil overwrap may be
11
printed. Furthermore, different
colors for foil
12
pouches may be used to differentiate the multiple
13
strengths of the drug product.
14
Now, let me go over the container-closure
15
components of the LDPE vial, paper label, and
16
foil-laminate. I'll start the
LDPE vial.
17
The unit-dose vial, which is made up of
18
low-density polyethylene, is chemically a
19
polyethylene homo-polymer resin.
The polyethylene
20
resin is made by polymerization process and may
21
contain several chemical additives in addition to
22 the
reactant polymer. They include chain
transfer
41
1
agent, chain initiator, antioxidant, so on and so
2
forth.
3
Furthermore, it is available in different
4
grades for different applications.
That indicates
5
that the composition of the LDPE may change
6
depending upon how it is being used.
There are
7
many manufacturers and suppliers of this LDPE.
T1B This slide lists some of
the 8
9
characteristics and properties offered by LDPE or
10
LDPE vials which probably makes it a material of
11
choice for packaging of inhalation solution and
12
suspensions from a manufacturer's point of view.
13
These include: they are flexible
and malleable;
14
stress crack, impact, and tear resistant; they are
15
considered chemically inert at room temperature; or
16 it
may be used at elevated temperature for extended
17
periods of time; or it can be sterilized. They are
18
used on high-speed production lines and,
19
aesthetically, they can be clear to translucent in
20
appearance.
21
However, it is permeable to volatile
22
chemicals and gases, and because of this
42
1
permeability, there are several quality concerns
2
which I'll be discussing later in my talk.
3
The next I would like to talk about is the
4
paper label, the components of a self-adhesive
5
paper label and how it may contribute to the
6
quality concerns of inhalation solutions and
7
suspensions.
8
Typically, a paper label consists of a
9
base paper, adhesive, inks, pigments and dyes,
10 varnishes,
over-lacquer, et cetera, and depending
11
upon the application, the base paper may contain or
12 may
be treated with all or many of the chemicals
13
that I have listed here.
14
Adhesive is the layer which comes in
15 immediate contact with the LDPE vial when it
is use
16
with self-adhesive paper labels.
This slide lists
17
typical chemical composition of an adhesive. This
18 is
not an all-inclusive list. There are
many more
19
proprietary chemicals used in the formulation of
20
these adhesives. Depending upon
the physical
21
chemical properties of these chemicals, that is to
22
say, volatility, they may permeate through the LDPE
43
1
vial into the drug product.
2
I have listed here some of the
3
over-lacquer components.
Over-lacquer is an
4
evaporative(?) coating which is typically comprised
5 of
chemicals such as plasticizers, resins, (?)
6
solvents, diluents, surfactants, and many more.
7
Some of these chemicals are proprietary in nature.
8
Over-lacquer, or varnish, may be used for a
9
transparent glassy appearance of the label, also a
10
stabilizer for the print work and art work, or it
11 can
be used as a protective barrier to the moisture
12 and
overall to extend the longevity of the label.
13
Again, in this case also, depending upon the
14
physical chemical properties of some of these
15 chemicals
and their constituents, also the
16
concentration and storage conditions, these
17
chemicals may have a potential to permeate through
18 the
LDPE vials into the drug product.
19
These are typical ink components.
One may
20
think that ink might be just a single-component
21
formulation. However, if you look
at it, there is
22
more than one chemical included into the ink
44
1
formulation. And, again, these
are also propriety
2
formulations.
3
These ink formulations may be
(?)-based
4 or
organic solvent-based, and depending upon the
5
brand of solvents which are used in the
6
formulation, they may have a potential to permeate
7
through the LDPE vials into the drug product.
8
The last I would like to talk about is the
9
foil-laminate. Primarily,
foil-laminate is used as
10 a
protective secondary packaging for the drug
11 formulations
that may be sensitive to light and
12
react to gases such as oxygen.
13
Typically, foil-laminate is a flexible
14
packaging composed of multiple layers of various
15
types of plastic films which are fused together
16 either by heat or pressure-sensitive adhesives
17
applied to one or both sides of an aluminum foil.
18 In
this cartoon, aluminum foil is represented by
19
layer D, and as you can see, the whole foil
20
overwrap surrounds the drug product vial on an
21
automated packaging line.
22
The thickness of aluminum foil, which is
45
1 D,
and the number of pinholes per unit area are
2
crucial for ensuring the consistent barrier to
3
permeability. Furthermore, each
of the composite
4
layers may contain volatility chemicals, organic
5
solvents, as they are used in adhesives, which may
6
permeate through a LDPE vial into the drug product,
7 especially the adhesive layer that is closer
to the
8
drug product. In this case, that
is shown by G.
9 So
the composition of these are very critical.
One
10 has
to really have a knowledge of its composition
11
before they can be selected for the foil overwrap.
12
Alternate approaches to adhesive can be considered,
13
such as fusion of the multiple layers of
14
foil-laminate by heat-set process.
15
In addition to the clinical concerns
16
discussed by Dr. Sullivan, the permeability of LDPE
17
raises several quality concerns, and these are
18
listed on this slide, mainly the drug product
19
contamination through ingress of volatile chemicals
20
which may be originating from the environment that
21 may
be irritant or toxic to the respiratory tract
22 and
may sensitize individuals; drug product
46
1
degradation because of the reactive gases and light
2
that permeate through the LDPE vial and cause
3
degradation of the drug product; and change in
4
product concentration because of the water
5
evaporation through the LDPE vials.
This in turn
6 can
accelerate the drug product degradation because
7 of
the concentration of the drug product.
8
Now, let me share with you the results of
9 an
analytical survey of approved NDA and ANDA
10
inhalation solutions marketed in LDPE vials without
11
protective overwrap. The basis
for this survey was
12 a
large-scale voluntary recall of inhalation
13
solution by a firm due to contamination of the drug
14
product with 1-phenoxypropanol.
This is a known
15
component present in the packaging components.
16 This
recall was conducted with FDA's knowledge and
17
followed by a health hazard evaluation.
It was
18
later found out that the source of this chemical
19 was
the varnish or over-lacquer that was used for a
20
shelf carton.
21
Alarmed by this incident, the
agency was
22
concerned that there may be other inhalation drug
47
1
products with such contamination from packaging
2
components. As a result, it was
decided to conduct
3 a
product quality survey of some of the marketed
4
inhalation solutions.
5
This was initiated by the Office of
6
Generic Drugs in consultation with the Division of
7
Pulmonary and Allergy Drug Products and in
8
coordination with the Office of Compliance, Office
9 of
Regulatory Affairs, field offices, and Pacific
10
Regional Laboratory. Seven ANDAs
and one NDA for
11
inhalation solutions covering five different drug
12 substances
were selected.
13
There were 38 samples representing 37 lots
14 of
various drug products in LDPE vials without a
15
protective overwrap foil pouch.
The samples were
16
screened for potential volatile chemicals which are
17
known to be present in the packaging components,
18
such as vanillin, 2-phenoxyethanol, and
19
1-phenoxy-2-propanol by sensitive analytical
20
techniques such as GCMS and HPLC methods. Let me
21
share the results of this survey.
22
Twenty-nine out of 38 samples tested
48
1
positive for chemical contamination originating
2
from packaging components. Five
known chemical
3
contaminants, as listed below, were detected
4
originating from packaging, such as benzophenone,
5
polyethylene glycol, 2-(2-butoxyethoxy)ethanol,
6
2-(2-ethoxyethoxy) ethanol acetate, and
7
2-hydroxy-2-methylpropriophenone.
8
A health hazard evaluation was conducted
9 at
the levels these components were detected in
10
these drug products. However, it
was indicated
11
that the levels of these components did not raise
12
sufficient safety concern in the intended
13
population to warrant a recall of these drug
14
products. Nonetheless, the
following issues were
15 of
concern:
16
It was indicated that potential for these
17
chemicals to cause bronchospasm at levels detected
18 is
unknown, especially in patients with respiratory
19
diseases.
20
It was also indicated that concentration
21 of
these chemicals might be grater at the end of
22
expiry than what was detected at the time they were
49
1
tested.
2
It also showed that permeation through
3
LDPE vial is a real phenomenon.
4
It was also concluded that additional
5
chemicals may be present, but may not get detected
6
because the analytical techniques which were used
7 may
not be suitable, not knowing what components
8
might be present into those solutions.
9
And, also, future changes in the materials
10
used in labeling and packaging may result in
11
contamination with different chemicals.
12
So, in a nutshell, product contamination
13 can
occur because of the formulation component
14
degradation or by leaching of chemical constituents
15
from packaging components, such as resin components
16 I
have listed, paper label components, foil
17
overwrap components, cartons, and environment.
18
These are the typical extractable or
19
leachable components which have been found in the
20
drug product from packaging components.
Some of
21
them are irganox 129, 2, 2, 6-trimethyloctane,
22
which is coming from resin components.
Some of the
50
1
paper label components that we have seen is benzoic
2
acid, ethyl phthalate, benzophenone, danocur 1173,
3
cyclic phthalates. From the foil
overwrap, we have
4
seen methacrylic acid, 2-phenoxyethanol, and some
5 of
the organic solvents such as acetone,
6
2-butanone, ethylacetate, propylacetate, heptane,
7 and
toluene. And from cartons, methacrylic
acid
8 and
1-phenoxy-2-propanol.
9
So this raises a significant quality
10
concern, and there are several other factors.
11
These are the factors. Because of
the proprietary
12
nature of components and composition of this
13
packaging material, we may not know what is present
14 in
the solution. The composition of these
15
components which are present in the packaging may
16
change without the knowledge of applicant and the
17
agency. And you cannot detect if
you don't know
18
what you are looking for. As a
result, there is no
19 one
analytical procedure to detect unknown chemical
20
contaminants. And there is
incomplete
21
toxicological data or information available for
22
many of these identified chemical contaminants.
51
1 And
as the environmental conditions change, that
2 may
introduce new contaminants.
3
So what are the potential approaches the
4
agency has taken to minimize and control the
5
contamination from packaging components to the
6
extent possible? Our approach has
been and we have
7
recommended that characterize or identify all
8
possible extractables and establish a profile for
9
each packaging component, for resin, vial, paper
10
label, foil-laminate overwrap.
11
What I mean by extractable is
extractable
12 is
a chemical compound, which can be volatile or
13
non-volatile, that gets extracted from a packaging
14
component in a suitable solvent by utilizing
15
optimum extraction conditions, such as time and
16
temperature.
17
Extractable profile for a given packaging
18
component typically can be a chromatogram
19
representing all possible extractables.
20
After that, establish a correlation
21
between extractable and its leachable potential,
22 and
what I mean by leachable is leachable is any
52
1
chemical compound that leaches into the drug
2
product formulation either from a packaging
3
component or a local environment on storage through
4
expiry of the drug product. An
extractable can be
5 a
leachable.
6
And to ensure batch-to-batch consistency
7 of
the drug product, appropriate specification for
8 a
leachable is established based on its
9
qualification and observed levels in the drug
10
product on storage.
11
As a result, the next approach is we asked
12
them to set meaningful acceptance criteria for a
13 given
extractable in corresponding incoming
14
packaging components based on its qualification
15
level and actual observed data.
Once that is
16
accomplished, meaningful acceptance criteria for a
17
given leachable based on actual observed data in
18 the
drug product also be established.
19
These are the recommendations we have
20
provided in the Draft Guidance.
We have
21
recommended that adequate knowledge of composition
22 and
physico-chemical properties of packaging
53
1
components is essential for appropriate selection
2 of
these components. We discourage paper
label
3
directly on the LDPE vial and encourage alternative
4
approaches, including embossing or debossing, in
5
lieu of the paper label on the LDPE vial because of
6 the
reasons I discussed, because of the product
7
contamination. This can be
accomplished by
8
extended bottom flanges to unit-dose vial that can
9
carry essential vial labeling information and can
10
retain the product identity.
11
We have also recommended use of protective
12
overwrap foil pouch for the LDPE unit-dose vial.
13
This in turn can minimize the ingress and leaching
14 of
chemical contaminants from the local environment
15
provided that the components that have been
16
selected for the fabrication of the overwrap foil
17
pouch are appropriately selected.
18
The self-adhesive paper label on a foil
19
pouch or pre-printed foil pouch is also
20
recommended, and different color schemes to
21
differentiate multiple strengths of the drug
22
product is also recommended. This
in turn can
54
1
prevent ingress or leaching of chemical
2
contaminants from paper labels and may improve the
3
legibility issues.
4
The last recommendation we have in our
5
Draft Guidance is to limit the number of unit-dose
6
vials per pouch, ideally to one LDPE vial per foil
7
pouch. This can minimize the risk
of medication
8
error by patients and health care professionals,
9 and
it can prevent unnecessary exposure to local
10
environment when compared to packaging of
11
multi-unit-dose vials in a foil pouch.
12
So, in summary, so far I have presented to
13 you
that volatile chemicals present in the
14
packaging components and local environment have a
15
great potential to permeate through LDPE vials into
16
drug product formulation on storage.
The agency's
17
analytical survey and other supportive data have
18
confirmed ingress and leaching of such volatile
19 chemicals into the drug product formulations.
20
Ingress or leaching of such chemicals into
21
drug product formulation poses a safety concern for
22
patients with respiratory illnesses, such as asthma
55
1 and
COPD. Embossing or debossing of LDPE
vial in
2
lieu of paper label is recognized to have
3
legibility issue. However, paper
labels, although
4
perceived to address legibility issue, overall may
5 not
be the optimum solution because of the safety
6
concerns associated with potential leaching and
7
ingress of paper label components in the drug
8
product through LDPE vial.
9
The agency's current recommendations as
10
stated in the Draft Guidance may serve as a first
11
step in the right direction to address the issues
12
that are being discussed today.
And the agency is
13
seeking other viable approaches to address these
14
issues to promote safe product use without
15
compromising the integrity of the drug product.
16
With that, I will conclude my talk, and
17
thank you for your attention.
18
DR. GROSS: Thank you very much,
Dr. Shah,
19 and
I want to thank the first three speakers who
20
presented a very clear review of the problem.
21
We are now open for discussion.
Perhaps
22
I'll start off with a couple questions.
56
1
We talk about low-density polyethylene.
2
Does high-density polyethylene reduce transmission,
3
number one? Number two, would
increasing the
4
thickness of the container reduce transmission?
5
And, number three, have other plastics been
6
considered? I'm not a chemist so
I don't know, but
7
polypropylene, polystyrene? And
are any of those
8
possibilities?
9
DR. SHAH: So far, traditionally,
LDPE is
10 the
choice of material by the manufacturer because
11 of
some of the properties it can offer. And
I
12
guess one can increase the thickness of the LDPE
13
vial or may use a different polymer.
However, one
14 has
to keep in mind that by nature, when you do the
15
fabrication of the vials, it may have some kind of
16 a
permeability. But that depends on the
degree of
17
permeability. LDPE offers one
side of the
18
spectrum, or other polymers may offer a different
19
type of permeability. But one has
to conduct some
20 of
the studies to show that it does not permeate.
21
DR. GROSS: Michael?
22
DR. COHEN: Dr. Lee mentioned
shrink wrap
57
1 at
one point, and then added that there might still
2 be
some concern about, you know, the volatility, I
3
guess, of the inks in the shrink wrap itself. It
4
does not come in contact with the actual LDPE
5
plastic, though, so I'm trying to figure out why
6
that would be a concern. Do you
think it's still
7
possible for that to leach in?
8
DR. SHAH: Yes, let me answer
that.
9
Shrink wrap, again, it's a plastic and it suffers
10
through the same thing. It comes
in direct contact
11
with the LDPE vial. So depending
upon the chemical
12
components of the ink and how it is being used, in
13 a
shelf carton or anything, it still will have the
14
same unit problems that I discussed.
15
DR. COHEN: Can I ask a follow-up?
16
DR. GROSS: Yes, go ahead,
Michael.
17
DR. COHEN: Have you done
testing--
18
DR. SHAH: No, we--I mean, we have
not
19
even received--or we have not approved a drug
20
product with the shrink wrap.
There is no example
21 of
that, at least to CDER. Maybe in other
22
divisions, another agency, but we haven't received
58
1
any.
2 DR. GROSS: Jackie, next question?
3
DR. GARDNER: I understand the
problem of
4
potentially masking the effect of contamination by
5 the
condition, but I was surprised to see only 87
6
reports of medication errors that you're working
7
from. And given the excellent
presentation and the
8
potential for confusion, I'm surprised that there
9
were so few because it looks like it would happen a
10
lot. I wondered if we could have
some perspective
11 on
why there would be so few, and maybe Mike can
12
help with that.
13
And then the second thing is I wondered
14
whether any of the potential suggested
15
recommendations or the different packaging types
16
have been tested in any way that we could
17
reasonably expect that they might reduce the
18
potential for error if they were implemented,
19
whether the foil wrap or any of these things have
20
been tested among the people who would be using
21
them.
22
DR. GROSS: Next question, Leslie?
59
1
Does anybody have an answer?
Marci?
2
DR. LEE: Thank you. As to the number of
3
reports being few, since the review was done, there
4
have been additional reports submitted to the
5
agency for a total, I think I said, of 138 reports,
6
which may still sound like a small number, but
7
considering the problem is probably very underreported. We
8
also had some reports that were
9
describing errors that had to do with restocking.
10 For
example, a transport team's pouch was supposed
11 to
contain three Albuterol and three Ipatropium
12
vials, and at this one given time it contained one
13
vial of one drug and five of the other.
So, you
14
know, in the report the narrative says, "We suspect
15
that at least one patient has been affected by this
16
problem."
17
The same thing can happen in an inpatient
18
setting where the drugs are getting intermixed in a
19
bin. So it's really an unknown,
the actual impact
20 of
the problem.
21
DR. GROSS: Leslie?
22
DR. HENDELES: I'd like to just
respond to
60
1
Jackie's comment. Mixing these
medicines up is
2
very unlikely to be associated with a visible toxic
3
reaction, so that might be--if anything, the
4
adverse consequences is a lack of therapeutic
5
effect when you're treating a disease that's
6
involving acute bronchospasm. So
the clinician
7
can't distinguish between lack of drug effect from
8
worsening of the disease.
9
But the question I had was: Is
there any
10
evidence that these contaminants in any way
11
interact with the active drugs to either decrease
12
their stability or to in some way inactivate them?
13
DR. SHAH: They may not
inactivate, but
14
they will increase the degradation of the products.
15
They may react with the active, and then you will
16
form an adduct. But you are not
going to, you
17
know, inactivate the drug product.
18
DR. SULLIVAN: The other thing t
keep in
19
mind is that the list of potential contaminants is
20
innumerable. So what may be true
of one chemical
21 may
not be true of the others.
22
DR. GROSS: Curt Furberg?
61
1
DR. FURBERG: I'd like to expand
on that
2
question. What are the health
effects of these
3
contaminants? Are they all
toxants? And if we
4
don't know that these contaminants have adverse
5 health
effects, is this a big issue?
6
DR. SULLIVAN: Well, I think the
unknown
7 is
part of the problem, and being a clinician at
8 the
agency, we've been tasked with addressing the
9
specific risk of specific chemicals that have been
10
found in assays done, particularly--it was
11
discussed in the analytical survey and so forth.
12 So
we get asked this question: What's the
13
toxicologic potential of this chemical?
And we
14
don't know most of the time.
There haven't been
15
toxicologic studies done. We
don't know the
16
carcinogenic potential. We don't
know the extent
17 to
which it acts as an irritant or has other toxic
18
effects. And then we have to
judge, okay, what's
19 the
risk out there, and it's very difficult.
20
DR. FURBERG: Yes, but shouldn't
you add
21
that to your recommendation that we find out?
22
DR. SULLIVAN: Well, I think
that's part
62
1 of
why we're saying it's best to just try to limit
2
potential exposure, because you can't list all of
3
these chemicals. For instance,
the one that was
4
mentioned was found in a drug product, and it was
5
traced back to the fact that the actual carton that
6
these vials were contained in, the manufacturer of
7
that carton, who isn't the drug manufacturer,
8
changed the glue or lacquer in that carton. And so
9 a
chemical that we wouldn't have previously been
10
aware of made its way into the drug.
11
DR. SHAH: Again, the agency does
not
12
control the cartons. We will
control to a point
13 and
look into the things. The carton is
something
14
very--and as a result, I think our approach has
15
been--or we recommend the use of overwrap pouch.
16
That can also limit to a certain extent.
I mean,
17
there is no 100-percent guarantee that it may not
18
permeate or the glues which are used in the
19
foil-laminate itself may get into the drug product.
20
But one needs to study these things
21
before, you know, providing to the agency.
22
DR. GROSS: Okay. Henri, and then we'll
63
1
hold questions after that until later.
2
DR. MANASSE: I have a couple of
3
questions. One is: Do we see the impact of the
4
degradation on all of the active ingredients, that
5 is,
for the Albuterol and the Tobramycin and the
6
cromolyn? Is that pretty much
standard across all
7 of
the ingredients that these volatile substances
8 do
have a degrading impact?
9
The other question I had is: What
10 experiences
can we gain from either the food and/or
11 the
cosmetic industry? Are there experiences
there
12
since so much of this packaging is also with
13
low-density polyethylene containers?
14
And my last question relates to the
15
potential application of the bar code to packages
16
vis-a-vis the incoming rule. To
what extent will
17
symbology printing either exacerbate or lessen this
18
particular issue?
19
DR. SHAH: I kind of lost
you. What was
20 the
first question?
21
DR. MANASSE: The first question,
Is the
22
infusion, leaching of the contaminants equally
64
1
impactful on all the active ingredients in these
2
products?
3
DR. SHAH: I think some of these
will stay
4 as
a degradation product. They may not
impact the
5
active ingredient, but it will be just a product
6
contamination.
7
Now, itself, how it will affect the
8
particular patient population, that is--as Dr.
9
Sullivan said, we don't know the potential of that.
10 So
it may not probably reduce the concentration of
11 the
active into the drug product. However,
that
12 uncertainty
regarding the safety is a concern.
13
The second question was?
14
DR. MANASSE: The second question
relating
15 to
experiences in the food and cosmetic industry
16 and
what may be learned there.
17
DR. SHAH: Okay.
I think by far the
18
most--these packaging components are used also in
19
tablets and other solid oral dosage forms. There
20 the
risk is less because you are taking it orally.
21
Here the problem is because of the patient
22
population, we are more concerned.
And I don't
65
1
know what else can be learned from food and other
2
industries because there is--I don't know that much
3 scrutiny
is there. The only thing that is there
is
4
whether they are adequate in terms of oral dosage
5
use. That's it.
6
Does that answer--
7
DR. MANASSE: And my last question
related
8 to
the upcoming application of the bar coding rule
9 and
the imprinting of symbologies to implement that
10
particular rule.
11
DR. LEE: Actually, LDPE vials was
one of
12 the
products that was exempt from that rule.
It
13
won't be required down to the vial, but any outer
14
packaging it will be on.
15
DR. GROSS: Okay. We'll take a break now
16 and
reconvene at 9:45.
17
[Recess.]
T2A DR. GROSS: The first speaker will be
18
19
Mohammad Sadeghi, who will talk about container
20
labeling options using rommelag blow-fill-seal
21
technology.
22
DR. SADEGHI: Good morning. I'm Mohammad
66
1
Sadeghi with Holopack International.
I'm here to
2
talk about container labeling options using
3
blow-fill-seal technology, and most of all these
4
products you've been hearing today about and
5
packaging and LDPE, low-density polyethylene,
6
they're all manufactured using blow-fill-seal
7
technology.
8
So what I'm going to do is go over what
9 the
blow-fill-seal process is, what container
10
labeling options you have, what are the pros and
11
cons on each, and some examples.
12
Blow-fill-seal technology is an integrated
13
aseptic technology for manufacturing aseptic
14
products. That's an example of a
machine. The way
15 it
works is you feed in raw pellet resins from one
16 end
and the (?) solution from another, and the
17
machine will actually melt the pellet, created the
18
container, fill it aseptically, and seal it.
19
The process consists of four major steps.
20 As
you see, the plastic is molten first and
21
extruded in a cylindrical shape, and the molds are
22
formed into the container, the needle comes in, and
67
1
there is the Class 100 in this
(?) area, fills
2 the
container, and it withdraws, and then the
3
container is sealed and ejected from the machine.
4
Now, labeling options that you can have
5
with this technology consist of embossing, paper
6
label on tab if you do not want to put it directly
7 on
the container, or printing on the tabs.
8
Embossing consists of a mirror--engraving
9
mold with a mirror image of the information. You
10
have small vacuum ports on the mold surface that
11
actually will do this, such into the softened
12
plastic into the engraving embossing, hence
13
embossing the container.
14
This is an example of what a mold cavity
15
looks like, and you see the surface inside the main
16
cavity where the engraving takes place.
17
This is a close-up of what it's like to
18
have as the imprint. What you see
in the bottom
19
would be replaceable magazines that you can change
20 for
lot number and expiration date.
21
Another option of embossing is hot stamp,
22
which in this case instead of molding it during the
68
1
production, as the container is ejected from the
2 BFS
machine, it's actually put into a machine where
3 it
actually is a hot stamp that would actually
4
emboss the container, again, and this is done on
5 the
tabs and not directly on the body of the
6
container.
7
Paper labels on tabs, one of the
reasons
8
this container was developed was to avoid direct
9
contact labels with--paper labels with the actual
10
container body, and the secondary was the
11
small-volume containers that required information
12 and
there was not enough surface area to put the
13
engraving on the container. They
developed a tab.
14
Either it can be on the cap or as a tail, have the
15
embossed information.
16
You can use the same tab, actually,
17
instead of--it's a solid surface, so you can use it
18
either to print or add paper to the label.
19
The pros and cons of each labeling option:
20
Embossing has been discussed here.
The pros are
21
there is no maintenance of label inventories;
22
ensure 100-percent labeling of containers; labels
69
1
cannot be removed; and ensure each unit is
2
traceable and no leachables. The
cons are, which
3 has
been discussed also, it is difficult to read on
4
clear containers.
5
Paper label on tabs is--paper label
6
obviously makes it clearer to read, and you can use
7
colors. It greatly reduces
potential leaching into
8 the
solution because it's not directly applied to
9 the
container body. However, there is still
10
potential leaching of adhesive.
11
Direct printing on the tab, it's clearer
12
than embossing on the tab to be read; it eliminates
13
potential leaching from paper, adhesive, varnish
14 and
stuff that goes with the paper label; and it
15
greatly reduces potential leaching into the
16
solution, again, because it's on the tab, on a
17
separate space on the container, not directly on
18 the
container body; and, lastly, allows for bar
19
code printing on line as well.
However, you still
20
have the ink, which potentially can leach into the
21
solution.
22
Now, examples of these various things,
70
1
there's a container with embossed labeling. The
2
containers can be also embossed and color-coded
3
because the same container can be used for
4 different
concentrations of products, or you can
5
have color-coded and embossed to represent the same
6
product in different concentrations or doses.
7
You can apply the paper on the tab, both
8
removing the paper from direct exposure to the
9
solution, but also it is readable.
Or having
10
direct printing on the tab for bar code
11
information.
12
Also, you have traditional paper on the
13
container, which is...
14
Now, the other thing is the issue of--one
15 of
the things that comes to mind is the size of the
16
containers, is eliminating paper containers--paper
17
labels from all outside containers or is it
18
dependent--it is a size-dependent solution.
19
Obviously, if you have a liter container such as
20
viewed here and you have a paper label, is that
21
also going to be--it's something that has to be
22
removed, and considered this is--it should be in
71
1
relation to the size of the container.
If it is a
2
three- (?) container, you have the same treatment
3 as
one-liter container.
4
Another example of various container
5
sizes.
6
Thank you.
7
DR. GROSS: Okay. Now we'll hear from the
8
Cardinal Health team, Rick Schindewolf and Patrick
9
Poisson.
x MR. POISSON: Good morning.
My name is
10
11
Patrick Poisson. I'm the Director
of Technical
12
Services at Cardinal Health Woodstock.
With me
13
today is Mr. Rick Schindewolf, who's the general
14
manager of the Woodstock, Illinois, facility.
15
Just a little bit about our role in the
16 industry.
Cardinal is a diversified health care
17
company with operations in distribution, manufacturing,
18
research, and management solutions.
The
19
Cardinal Health Woodstock facility is a
20
blow-fill-seal facility that produces approximately
21 1
billion units annually. Our product
portfolio
22
involves NDA, ANDA, 510(k), and USP Monograph
72
1
products.
2
Some of the advantages of why people
3
select low-density polyethylene in blow-fill-seal
4 is
blow-fill-seal is recognized as an advanced
5
aseptic process. There's also an
immense
6
flexibility in container design that allows various
7
applications of the container and its use. It's
8
also a very cost-effective approach to producing
9
pharmaceutical products.
10
Now, some of the limitations: As
11
previously mentioned, LDPE is a semipermeable
12
material. The technology also uses
heat to form
13 the
container, and there may be issues with
14
heat-sensitive products. And
based on the focus of
15
this meeting today, there are obviously some
16
labeling issues as well.
17
Now, the general industry approach has
18
been to emboss and deboss the containers to display
19 the
necessary information, which includes product
20
name, concentration, manufacturer, lot number, et
21
cetera. Typically, respiratory
products are
22
packaged in a secondary overwrap in multiple units
73
1 or
single units, and that provides the additional
2
protection necessary to prevent chemical
3
contamination.
4
This has already been touched upon, but
5
these are the main highlights of the Draft
6
Guidance, and I won't spend any time on this since
7
this has been discussed already.
8
Now, what are some of the advantages to
9 the
embossing/debossing approach? It
provides an
10
immediate tamper-evident identification of the
11
product. It eliminates the
potential for
12
contamination from labels. And it
provides ease of
13
label copy control.
14
Some of the limitations associated with
15
that: It can be difficult to read
on clear
16
containers. It does not provide a
very readily bar
17
code-readable print. And the vial
size affects
18
legibility of the print that's embossed and
19 debossed. We cannot emboss or deboss down to a
20
very small font size that's readable that could
21
compete with a paper label.
22
Now, we believe there are some
74
1
possibilities for enhancing product identification
2 in
the low-density polyethylene container, and
3
these are listed here: reduce the
content
4
requirement to allow an increased text size;
5
addition of physical/tactile identifiers for
6
generic product groups; alternative label
7
approaches such as a sleeve label; color coding
8
unit-dose vials for generic product groups; and
9
individual secondary overwrap.
10
Increased text size. There's a limited
11
surface area on the container that is available for
12
embossing/debossing. Due to the
technology, we
13
cannot emboss or deboss on the sides of the vial.
14 We
can only emboss and deboss on the front.
The
15
text size can be significantly increased; however,
16 we
would have to remove some of the information
17
that's normally provided. This
approach would not
18
change any of the materials involved in the
19
process, so there would be no impact on the current
20
product chemistry. This could
also be implemented
21
fairly quickly, eight to ten weeks.
And there
22
would be a one-time cost for the manufacturer to
75
1 buy
the appropriate equipment.
2
This is a drawing of what that concept
3
would look like.
4
In addition to that, physical/tactile
5
identifiers could be added to the container. This
6
would provide an easily recognizable/legible symbol
7 on
the container that would represent a product
8
type, for instance, A for Albuterol sulfate, I for
9
Ipatropium bromide, et cetera.
This is already
10
currently being implemented on products
11
manufactured at Cardinal Health.
This also does
12 not
change any of the container materials or
13
process, so, again, no impact on the current
14
product chemistry. This also
could be implemented
15 in
eight to ten weeks, depending on the regulatory
16
approval of this label change, possibly as a CBE
17
30. Again, there would be a
one-time minimal cost
18 to
buy the necessary equipment to do such a change.
19
This is a drawing of what that concept
20
could look like. And we have some
samples which
21
we'll pass around for the committee to see. And
22
those can also be provided in clear plastic. And
76
1
here are some photos of the same vials.
2
This is a picture contrasted with one of
3 the
current formats that is out on the market, so
4 you
can see that there's a definite increase in the
5
identification of the products resulting from this
6
type of change.
7
The sleeve label concept would involve a
8
redesign of the extended tab to make that area
9
amenable for application of a non-paper label.
10
Cardinal has designed such a vial that has a patent
11
pending that would be capable of receiving a shrink
12
wrap sleeve.
13
This label provides a contrasted
14
background for enhanced legibility and also provide
15 a
bar code-readable print. This would
involve no
16
changes to the product contacting surfaces of the
17
container. The shrink of pressure
sensitive label
18
would be applied to an appendage of the container,
19 not
in direct contact with the product.
20
This would also involve an increased
21
manufacturing cost for equipment, labor, and
22
materials, and we believe it could be implemented
77
1 in
12 to 14 months following regulatory approval
2
with associated stability testing data.
3
This is a picture of what that concept
4
looks like, and we have some samples that we'll
5
pass around. This particular
product was mentioned
6 in
an earlier presentation as the catheter flush
7
saline and heparin.
8
Color coding. Products could be
9
color-coded to aid in identification.
That would
10 be
a similar approach to the AAO recommendations
11 for
cap color for ophthalmic products. It
provides
12 a
contrasting background to aid the legibility.
A
13
colored vial is easier to read.
However, it could
14
impact the product chemistry with leachables and
15
extractables. There would be a
slight increase in
16
manufacturing costs for raw materials.
Again,
17 implementation
time would be based on stability
18
data and regulatory approval of such a change.
19
This is a picture of what that concept
20
would look like.
21
Individual secondary overwrap, that has
22
been touched upon. It provides
enhanced labeling
78
1
opportunities, bar code-readable print for a
2
single-dose vial. However, the
overwrap can and
3
will be separated from that unit at some point in
4
time during its use, and we don't control that, so
5 we
cannot predict when that will happen. So
there
6
could be legibility/identification issues still at
7 the
time of use. There's a significant
8
manufacturing cost increase with the raw materials,
9
equipment necessary, and labor.
If that was done
10
with the current process, that change, the
11
implementation time would be 12 to 14 months
12
following regulatory approval of the packaging
13
change with associated stability data.
14
In summary, we believe there are
15
opportunities for improvement of the labeling of
16
low-density polyethylene containers.
Each
17
alternative is a viable alternative, we believe,
18 and
it should be assessed based on impact to the
19
product, speed of implementation, ease of
20
regulatory approval, and cost to the patient.
21
Thank you--oh, sorry. Our
recommendations
22 are
to increase label information font size on
79
1
individual vials. Add a tactile
symbol for generic
2
identification based on the following advantages:
3
quick approach, no impact on product chemistry or
4
stability, and no impact on patient cost. For
5
hospital-dispensed unit-dose vials, add a sleeve
6
label to accommodate bar coding.
7
Thank you.
8
DR. GROSS: Thank you very much.
9
Our next speaker is Karen Stewart of the
10
American Association of Respiratory Care.
x MS. STEWART: Good morning.
Thank you for
11
12
giving me the opportunity to present today. I
13
think in your packets you have my written
14
statement, and I have a couple of slides here that
15 I
want to share with you.
16
I've been a registered respiratory
17
therapist since 1971, and I am here as the
18
spokesperson for the American Association for
19
Respiratory Care representing respiratory
20
therapists both nationwide and internationally.
21
Respiratory therapists, like all other
22
health care professionals, are very concerned about
80
1
medication errors. In recent
years, since the
2
elimination of most paper labels on unit-dose vials
3 of
medication, it has become increasingly difficult
4 to
determine the content of the unit-dose vial.
5 I'm
going to share with you some pictures of what
6 the
therapist typically has on their person as
7
they're making rounds.
8
Not only is the print on the vial
9
difficult to read, the size and the shape of the
10
vial contributes to this difficulty.
11
In 2001, the American Association for
12
Respiratory Care completed a human resource survey,
13 and
at that time the average age of a respiratory
14
therapist was 44. This is another
contributing
15
factor to the difficulty of reading the content of
16 the
medication vial. While I may have just
17
emphasized that the current relative age of the
18
respiratory therapist and the difficulty the older
19
therapist experiences in reading the labels, I want
20 to
clarify to you that deciphering respiratory care
21
medication labels is a problem that cuts across all
22 age
groups of respiratory therapists. The
problem
81
1 is
how the medication is labeled or not labeled
2
appropriately.
3
The work flow of the respiratory therapist
4 I
think is probably most important for you to
5
understand. The therapist
typically includes
6
delivering medications and treatments to a number
7 of
patients for a local geographic region in a
8
hospital. The patients that are
assigned have a
9
very wide variety of medications that are being
10
delivered to them. Once the
medication is checked
11 by
the pharmacist for drug interactions, the
12
therapist typically carries medication with them as
13
they begin rounds. It would not
be unusual for a
14
therapist to carry between 14 and 15 different
15
vials of medication. The
medications must be under
16
control so that therapists either carry the
17
medication in a fanny pack or they carry the
18
medication in a locked draw on a cart they carry
19
with them.
20 In some institutions, medications are
in a
21
Pyxsis system. In this situation,
the medication
22 can
either be placed in a single patient medication
82
1
labeled drawer or they come from stock supply. So,
2
again, multiple vials in a stock drawer.
3
I just wanted to give you a view of what's
4 in
somebody's pocket typically.
5
Another concern that faces the respiratory
6 therapist
is the lack of bar coding on the vial.
7
Many hospitals are moving toward the scanning of
8
medication bar codes. The driving
force for this
9 use
of technology is to identify the correct
10
patient, identify the correct medication, confirm
11 the
correct dose of medication, confirm the correct
12
route of medication, and record the time of the
13
medication delivery.
14
I want to share with you a few comments
15
that I picked up from some respiratory therapists
16 in
just the most recent weeks.
17
Staff have complained about the inability
18 to
see clearly the medication information.
For
19
this reason, we switched to a different product
20
that is individually wrapped in clearly labeled,
21
color-coded foil packaging. The
current situation
22
with the raised-letter labeling is an accident
83
1
waiting to happen. I know you
talked earlier about
2
underreporting. It's because
we've given the dose
3 and
never know we gave the wrong one in some cases.
4
This is a second therapist: I
complained
5
bitterly when the look-alike vials came out. We
6 did
not leave them for any nurses to confuse.
We
7 do
not know of any medication errors beck of the
8
look-alikes. Doesn't mean it
didn't happen. We
9
just don't know.
10
So, again, a little bit more emphasis on
11 the
fact that we are seeing probably underreporting.
12
This is a third one: We have had
problems
13
with the unit-doze Xopenex and Atrovent looking
14
alike and labeled in the same clear package. We
15 use
Pyxsis and it's still a problem.
16 So even moving the medication into
a more
17
controlled environment continues to be a problem
18 for
the therapist who's on the floor.
19
This is a fourth therapist: One
20
encouraging thing that I have seen is differing
21
shapes and sizes on a very few of the medications.
84
1
Since the death of the multi-dose vial of
2
Albuterol, we have a supplier who sends us
3
unit-dose vials of Albuterol that have a very
4
distinctive teardrop shape and a
much smaller size
5 for
medication. I give that a Bravo. A similar
6
thing has happened with the octagonal unit-dose
7
vials of Pulmicort.
8
And I think if you look at the very end of
9
this, that small round is the Pulmicort.
But this
10 is
what's in the pocket of the therapist, and all
11
they have to read on most of those are just that
12
clear lettering.
13
I was at a program, I did a program in
14
Cincinnati last week, and I mentioned this in a
15
patient safety presentation that I did to
16
therapists. About 600 were there,
and what was
17
interesting about it is several of them came up to
18 me
afterward and said, Can you imagine what the
19
night shift therapist goes through trying to read
20
these?
21
Now, low light--it's bad enough, you know,
22
with the age, but the low light.
85
1
There's a couple more comments from
2
therapists in there. I think that
you've probably
3 got
those. You get the gist of what we're
trying
4 to
say. So on behalf of the American
Association
5 of
Respiratory Care, I really appreciate the
6
opportunity to share the association comments.
7
I have one more slide that I want to share
8
with you, and it's this one. What
you're seeing
9
here are just the different medications.
One of
10
those happens to be Tobramycin.
One of them--two
11 of
them are bronchodilators. Two of them
are
12
exactly the same medication in different doses.
13
Just to really emphasize what the packaging is
14
doing to the therapist at the bedside.
15
Thank you.
x DR. GROSS: Okay.
Thank you very much.
16
17 We
will not have the committee ask some questions
18 of
the speakers, and you can ask questions of any
19 of
the speakers that have presented this morning.
20
Leslie?
21
DR. HENDELES: I have two
questions for
22
Karen. First, is there any Joint
Commission
86
1
requirements in terms of how respiratory therapists
2 are
supposed to handle medication?
3
MS. STEWART: There's been--
4
DR. HENDELES: And I have a second
5
question, which is: Would
respiratory therapists
6
mind carrying these single-unit dose vials wrapped
7 in
foil in their pockets?
8
MS. STEWART: There are
recommendations
9
around the delivery of medications from JCAHO, and
10
most of that is surrounding the control. It is
11
first the pharmacist's review of that medication to
12 see
if there are any other interactions, and the
13
second being that that medication is always under
14
control. And you'll see as you go
across the
15
country a number of different ways that hospitals
16 are
handling the medication control issue.
Some of
17
them--the folks that I talked to last week, some of
18
them have a cart where they carry all their
19
plastics and other things that they need with a
20
locked drawer, and their medications are in that
21
drawer. Other ones are using
Pyxsis, and some are
22
still carrying it physically on their person in a
87
1
side pocket or a fanny pack.
2
Your second question is, if they were
3
individually wrapped, I think that therapists would
4 use
those either in any of those devices under
5
control. The problem is that they
open, for
6
example, a packet of Xopenex with 12 vials in it.
7
That's just too much for them to carry when they've
8 got
so many different types to carry.
9
DR. HENDELES: If it's just one,
they
10
would be able to?
11
MS. STEWART: I think they would
be able
12 to
carry it, yes.
13
DR. GROSS: Yes, Stephanie?
14
DR. CRAWFORD: Thank you. This question
15 is
for Patrick Poisson, but, Ms. Stewart, don't go
16 too
far just in case you want to add to it.
I
17
thank each of the speakers for their presentations.
18
Mr. Poisson, with respect to your
19
presentation, the sixth slide was talking about the
20
advantages and disadvantages--I'm sorry, the
21
advantages and limitations. Each
of the advantages
22
from my interpretation were in the manufacturing
88
1
process. As you presented, each
of the limitations
2 was
from the clinical use. So my question
is:
3
From the recommendation--potential alternatives
4
that you suggested, have you conducted, your
5
company, or performed any studies using clinical
6
groups such as the respiratory therapists to see
7
acceptability of each of these options?
8
MR. POISSON: One thing I probably
failed
9 to
mention is that Cardinal Health is a contract
10
manufacturer, and the products that we manufacture
11 are
distributed by our customers. And it's
12
difficult for us to step in front of them and ask
13 for
this type of work to be done.
14
Now, we have done some work with the
15
shrink wrap sleeve label, and the feedback from
16
that was very positive. However,
that was a very
17
unique opportunity for us to get involved with
18
that.
19
In regards to the recommendations, yes,
20
some of them are manufacturing--are good for the
21
manufacturing process. However,
one that maybe
22
wasn't explained as well is the sterility of the
89
1
product. Using a blow-fill-seal
technology to
2
manufacture products is recognized as providing a
3
better microbiological quality of product out to
4 the
market versus a conventional process.
5
DR. GROSS: Michael? I'm sorry.
6
Stephanie, another question?
7
DR. CRAWFORD: Thank you. Just one quick
8
follow-up. One of your recommendations
was
9
increase text size. You mentioned
that, of course,
10
something would have to come off if that were
11
happening--would come off if--
12
MR. POISSON: I think we'd have to
13
undertake those discussions with the agency as to
14
what could come off.
15
DR. GROSS: Michael?
16
DR. COHEN: I've been looking at
these
17
LDPE plastics for several years, actually, and
18
trying to come up with solutions.
And actually the
19 best
thing I've ever seen is that shrink wrap, that
20
overwrap, or sleeve, or whatever you want to call
21
it. Is that a proprietary system,
or is that
22
available to any manufacturer?
And can you foresee
90
1 the
actual use across the entire spectrum of LDPE
2
containers, even the parenterals?
3
MR. POISSON: Well, we're very
pleased
4
with the progress we've made on the sleeve label.
5 It did
involve some development that we regard as
6
intellectual property. So
regarding availability
7 to
the whole industry, I really can't speak on
8
that.
9
There will be potentially some leachable
10
extractables even from that system.
There is ink
11 on
that label. So that has to be evaluated
for
12
each product that it's used for.
It still may not
13
work for every product.
14
MR. SCHINDEWOLF: If I could just
make a
15
comment on the proprietary nature, what's
16
proprietary about that vial is the rounded end. A
17 lot
of the vials that you'll see and I think some
18
that were presented earlier can be on a flat end as
19
well. And we found that the
rounded end helped the
20
legibility. As the sleeve
shrinks, there tends to
21 be
some--what's the word I'm looking for?
The
22
print can be--
91
1
MR. POISSON: It can be distorted.
2
MR. SCHINDEWOLF: Yes,
"distortion,"
3
that's the word. So this was to
help the
4
readability of the bar code label itself, so that's
5
what's proprietary in that particular design.
6
DR. GROSS: Yes, Henri?
7
DR. MANASSE: In terms of patient
safety,
8 one
of the biggest issues that I think most
9
practitioners confront is the kind of work-arounds
10
that people utilize to make things convenient for
11
them, and this notion of carrying drugs around in
12
your pocket is a very good example.
But it seems
13
that the sleeve is a pretty critical issue with
14
respect to the capacity of adding more information
15
coupled with bar codes, symbologies, et cetera.
16
Have you all thought about how you can
17
eliminate the dissociation of the sleeve from the
18
package itself? Because the
work-around, people
19 are
tearing off the sleeves and then carrying the
20
package by themselves. And is
there a way that you
21 can
avoid that other than at the direct point of
22
care?
92
1
MR. POISSON: I'll try and address
that.
2 One
of the ways that these are used is that the cap
3 is
actually twisted off of the vial. And
one of
4 the
problems I see with individually foil
5
overwrapping is the removal of that foil could
6
potentially damage the vial in that process. So
7
it's a difficult thing to overcome.
We could
8
tighten the foil potentially around the vial, but
9 it
just opens it up for damage in the transfer
10
process from the location within the hospital to
11 its
use point.
12
You know, there are a lot of advancements
13
going on in packaging. Certainly
five years ago I
14
don't think we would have all the options that we
15
have now. Maybe at some point in
time we can get
16 to
a better alternative with the foil.
17 DR. GROSS: Robyn?
18
MS. SHAPIRO: I have two
questions. One
19 is
actually Henri's. And this is to the
agency.
20
What factors, if any, are considered currently in
21 the
approval process with respect to these
22 problems?
93
1
And the second question is: It
seems to
2 me
that this morning we have much more information
3
about the potential error, problem, than the
4 leachability
and contamination problem, and much
5
more potential risk. Has there
been--maybe this is
6 for
Karen. Has there been litigation over
this?
7
And, if so, what has happened?
8
MS. STEWART: I can't speak to any
9
litigation, and I think one of the concerns that we
10
have as therapists is that this probably goes underreported.
11 The
therapist delivers that care
12 and
leaves the bedside to treat the next patient.
13 So
they may not see an adverse effect or, as stated
14
earlier by Dr. Sullivan, I believe, the patient
15
does not get the potential relief of the
16
medication.
17
In other words, if you have Tobramycin and
18 a
bronchodilator in your pocket, they both look
19
alike, you give the Tobramycin to the patient who
20
needs the bronchodilator, you may not see the
21
effect. So it becomes
underreported.
22
MS. SHAPIRO: And the patient may
not
94
1
either. I mean, they may not
realize--the patient
2 or
the family or whomever, the error may not be
3
disclosed to anyone.
4
MS. STEWART: Except the patient's
5
therapeutic treatment regime is going to be longer
6
with a longer length of stay because they didn't
7 get
the proper--
8
MS. SHAPIRO: Sure, but they may
not know
9
why.
10
MS. STEWART: Right.
11
DR. GROSS: Are there any other
questions?
12
MS. SHAPIRO: Can I have the first
13
question answered by Paul or somebody about what
14
currently is considered?
15
DR. SHAH: You are talking about
in terms
16 of
the quality controls?
17 MS. SHAPIRO: In the approval process for
18 any
new drugs, what, if any, is considered with
19
respect to safety relating to this possibility for
20
error?
21
DR. SHAH: Let me just try to
briefly
22
summarize.
95
1
When we get an application and we have
2
these kind of packaging components, then usually
3 the
applicant may provide this information for all
4 the
components of each and every packaging
5
component into the NDA, or they may choose to
6
provide that information, if it proprietary,
7
through a Drug Master File. Then
we review the
8
chemical composition of each and very packaging
9
component in a Drug Master File, but we cannot
10
relay that information to the applicant.
11
Once we know from the composition that
12
there is a potential for volatile chemicals to be
13
present in the component and they may permeate
14
through the LDPE vials, then we ask the applicant
15
indirectly, without revealing the other
16
information, Have you studied any legibility or
17
extractable--have you found any extractable, what
18
kind of solvent conditions you have used to extract
19
this leachable? And we encourage
them to contact
20 the
DMF supplier, work with them, and develop some
21
procedures to find out what can be present and
22
establish a profile. Once you
establish a profile,
96
1
then you may identify, okay, these are the typical
2
components present into a component, packaging
3
component, and we are going to use that as a basis
4 for
screening the incoming packaging material.
And
5
then you may have some kind of acceptance criteria.
6
That may be a GC profile. Or if
you have
7
identified a particular component by its chemical
8
structure, then you may say, okay, it is extracted
9 at,
say, one milligram per ml or something like
10
that, okay? So then you will
conduct some kind of
11 a
study for the shelf life, over the shelf life,
12
whether that particular extractable gets into the
13
drug product or not. If it does
not, then at least
14 you
have established that if I control the amount
15 of
incoming acceptance criteria, I have established
16
incoming packaging material, then I do not see the
17
leachable into the drug product.
So then you don't
18
have to have a test for leachable into the drug
19
product, but you have to establish that
20
relationship.
21
So we go through a series of steps to
22
establish that, and once we are satisfied, then we
97
1 may
decide, okay, you are going to control or
2
minimize this particular component at acceptance
3
level in incoming packaging material.
Or you will
4
have to carry out the leachable testing.
5
MS. SHAPIRO: What about the
analysis with
6
respect to the possible safety problems on account
7 of
the error issues?
8
DR. SHAH: Okay. Once we get that, we see
9
that, okay, it is present into the drug product at
10 a
certain level. And if we know the
identity of
11
that chemical, then we ask our pharmacology and
12
toxicology person to review that data and decide
13
whether that will have any safety issue.
And if
14 they
decide that it may have a safety issue, then
15
they may ask the applicant to qualify that
16
particular material or chemical at that level.
17
MS. SHAPIRO: Okay. And all that has to
18 do
with the leachability question. But what
about
19 the
question having to do with the confusion
20
problems on account of the labeling and its impact
21 on
safety?
22
DR. SELIGMAN: For all drug
products that
98
1 are
approved by the agency, we look at the accuracy
2 of
the label, whether it's misleading or not,
3
whether it's nonpromotional in nature.
We look at
4 the
name for potential confusion. We look at
the
5
packaging regarding dose and frequency.
And if at
6 the
time we find, either at the time of approval or
7
even subsequent to approval, that there is such a
8
potential for either name confusion, for misleading
9
dose, or any kind of misleading information that
10
might lead to medication error, we make a
11
recommendation to the manufacturers to try to--to
12
alter that.
13
I think the reason we're bringing this
14
particular issue to this committee is that this is
15 a
particularly vexing issue. But for the
vast
16
majority of products that we review, when we find
17
such potential for confusion or potential error, we
18
recommend to the manufacturer that that be
19
addressed prior to approval of the product.
20
MS. SHAPIRO: Have you ever, with
21
containers like this, sent it back and said, no,
22
this doesn't--this won't do given these sorts of
99
1 problems?
T2B DR. SELIGMAN: I'm not aware of any. Some
2
3 of
them go through generics.
4
Carol, did you want to respond to that?
5
MS. HOLQUIST: Yes. Actually, our office
6 in Office of Drug Safety, we only get
whatever--we
7
only see the packaging material that comes in with
8 new
products. A lot of these products have
been on
9 the
market for years and years. So if indeed
one
10 of
these products came in today with this packaging
11
labeling, yes, of course, that would be one of our
12
recommendations in our review that, based on
13
post-marketing reports and evidence, we wouldn't
14
recommend this. But then the
agency's hands are
15 kind of tied because of the ingress
issue. So
16
until we find an alternative packaging, it's a
17
conundrum we're in.
18
DR. GROSS: Gene, did you want to
comment?
19
DR. SULLIVAN: Yes, I just wanted
to
20
follow up on a couple things that have been said so
21
far: one, to just make sure the
categories of harm
22 to
patients are in the right column.
There's the
100
1
harm that the legibility issue brings in, so the
2
harm that a patient suffers if he or she doesn't
3
receive Tobramycin but instead receives Albuterol.
4 And
then what I was trying to touch on and the
5
thing that's hard to get your hands around is the
6
harm from the actual presence of these chemicals,
7 and
that it's well known that a patient may come to
8 the
emergency department and receive a few
9
treatments of Albuterol and recover and be
10
discharged. Another patient may
come in and not
11
seem to respond and end up mechanically ventilated.
12 And
to what extent that could be related to
13
contaminants in the drug product would be anyone's
14
guess and impossible to day. So I
just wanted to
15
make sure we consider those two sort of as they're
16 the
competing harms.
17
The other issue I just wanted to talk
18
about a little bit was the issue of the use of the
19
flange or labeling that's not directly applied to
20 the
actual body of the nebule, be it with a shrink
21
wrap or an applied label and so forth; that there
22 is
some intrinsic appeal because it seems to be
101
1
less in contact with the LDPE, but keep in mind
2
that if these are then put into an overwrap, a foil
3
overwrap, perhaps for other
4
reasons--light-sensitive products and so
5
forth--that then you have sort of a micro
6
environment, you know, like a little humidor with
7
these chemical vapors that could then make their
8
way--even though they're here on the flange, they
9
could easily make their way into the product, and
10
that's sort of evidenced by that case where we had
11 the
cardboard carton and that chemical made its way
12
in. So it's not, you know, a
complete solution.
13 We
have to keep that in mind.
14
DR. GROSS: Arthur, you had a
question?
15
MR. LEVIN: One is just a point of
16 information.
Mike, is that the packaging with that
17
label, that's what you are referencing when you say
18 so
far that's the best--
19
DR. COHEN: Not necessarily.
20
MR. LEVIN: Okay.
21
DR. COHEN: This is certainly
acceptable
22 as
a way to identify a container. But the
ones
102
1
I've seen have actually had a similar type of film,
2 but
it's been around the body of the ampule device.
3 And
there was a tear-off so that you would
4
literally pull the tab and tear off the top part of
5 the
plastic. It was a total overwrap.
6
MR. LEVIN: But it's something
more than
7
that.
8
DR. COHEN: Leaving the identify, even
9
though this was exposed.
10
MR. LEVIN: Okay. So the whole thing is
11
shrink wrapped to something.
12
DR. COHEN: That's correct.
13
MR. LEVIN: Right, okay. I didn't think
14 we
had seen one of those.
15
DR. COHEN: We didn't.
16
MR. LEVIN: Yes, okay. So that clarifies
17
that.
18
The second thing is we seem to be sort of
19
entirely focusing in inpatient and, you know, the
20
issue of outpatient is certainly significant. And
21 I'm
just wondering from, you know, what you've done
22 to
look at how well these kinds of solutions work
103
1 in
the outpatient pharmacy setting as opposed to
2
inpatient settings where it's really--making sure
3
that the respiratory therapist who administers the
4
drug is clear on the right drug and the dosage et
5
cetera. What about an outpatient
pharmacy?
6
MR. POISSON: Well, one of the
reasons
7
why--and someone may question why there's 12 vials
8 in
a pouch or even 28 or up to 60. A lot of
the
9
reason behind that is because of the use period in
10 the
outpatient--outside of the hospital. And
based
11 on
feedback we've received, they view that as an
12
advantage to have that type of packaging in that
13
particular environment. And the
possibility exists
14
that maybe some of these options we've presented
15
today, such as the symbol on the vial would help
16
them in that area from using the wrong product.
17
So I think, you know, there's
18
opportunities for a number of these options to be
19 implemented
based on the setting that they're used
20 in.
21
DR. GROSS: Okay. Henri, you have a
22
question?
104
1
DR. MANASSE: I just want to
follow up on
2
Art's point in terms of outpatient use.
I can't
3
imagine given the size of these containers, given
4 the
unreadability of these containers, and the
5
obvious confusion that is brought to bear to those
6
problems, that outpatients, particularly elderly
7
outpatients, can manage this on their own. I think
8
somehow we've got to contemplate where we go with
9
that because the increasing number of people who
10 are
using these on an outpatient basis and the
11
increasing aging of the population presents us with
12 an
incredible challenge.
13
DR. GROSS: Okay. Marci would like to
14
make a comment.
15
DR. LEE: Thank you. I just wanted to add
16 to
that. Based on the medication error
reports
17
that we have received most recently, there are many
18
comments about the elderly population using these
19
drugs. There are several reports
from a pharmacist
20
saying that his patients are expressing that
21
they're afraid to use the product because they're
22
afraid that they're going to double their dose
105
1
accidentally because they're not sure what is in
2
each ampule.
3
Then, also, the letter in the background
4
package that was sent to Senator Harkin, that also
5
involved a woman who was writing in about her
6
elderly mother that was having the same problem
7
also from a mail-order pharmacy.
So in addition to
8 a
regular outpatient pharmacy where there's direct
9
interaction with the pharmacist, you have people
10 who
are unable to get out of their home and receive
11
their medications by mail having the same
12 experiences.
13
Carol wants to add something.
14
MS. HOLQUIST: Also, just in
relation to
15 the
letters at the top of the vials themselves, we
16
actually have gotten some reports as well where
17
there's a question as to what the actual letter
18
stands for, like A, is it for Albuterol or for
19
Atrovent. So some simple fixes,
sometimes you also
20
have to think beyond, that there's more than one
21
product that begins with that letter.
x
DR. GROSS: Okay.
We are a little bit
22
106
1
ahead of schedule, and we will proceed at this time
2
with the open public hearing. Dr.
Eric Sheinin
3
will present. First I need to--
4
MS. JAIN: We need to read a
statement
5
first.
6
DR. GROSS: Both the Food and Drug
7
Administration and the public believe in a
8
transparent process for information gathering and
9
decisionmaking. To ensure such
transparency at the
10
open public hearing session of this Advisory
11
Committee meeting, the FDA believes that it is
12
important to understand the context of an
13
individual's presentation. For
this reason, FDA
14
encourages you, the open public hearing speaker, at
15 the
beginning of your written or oral statement to
16
advise the committee of any financial relationship
17
that you may have with any company or any group
18
that is likely to be impacted by the topic of this
19
meeting.
20
For example, the financial information may
21
include a company's or a group's payment of your
22
travel, lodging, or other expenses in connection
107
1
with your attendance at the meeting.
Likewise, FDA
2
encourages you at the beginning of your statement
3 to
advise the committee if you do not have any such
4
financial relationships. If you
choose not to
5
address this issue of financial relationships at
6 the
beginning of your statement, it will not
7
preclude you from speaking.
x DR. SHEININ: Thank you, Dr. Gross. I
8
9
have no financial ties or interests in any
10
pharmaceutical company or any other company or
11
organization that would be interested in the
12
proceedings before the committee today, so I think
13 I'm
okay with that.
14 DR. GROSS: Thank you.
15
DR. SHEININ: My name is Eric
Sheinin, and
16 I'm
here today to represent the United States
17
Pharmacopeia. At the UPS, I am
the Vice President
18 for
Information and Standards Development.
We do
19
have an expert committee that deals with safety
20
issues, and much of what I'm going to say today is
21 a
direct result of work that they have done.
But I
22
would like to give you some background about the
108
1 USP
for those of you who may not be familiar with
2 us
and also to have it in the record.
3
The USP is a nongovernmental organization
4
that promotes the public health by establishing
5
state-of-the-art standards to ensure the quality of
6
medicines and other health care technologies.
7
These standards are developed by a unique process
8 of
public involvement and they're accepted
9
worldwide. Many other countries
around the world
10
recognize the USPNF standards as their own
11
standards in terms of regulatory procedures within
12
those countries.
13
USP is a not-for-profit organization that
14
achieves this goal through the scientific
15
contribution of volunteers, and the volunteers
16
represent pharmacy, medicine, and many other health
17
care professions. These
individuals work in
18
academia, they work in government, both U.S. and
19
international. In fact, there are
many FDA
20
scientists who serve as volunteer to USP. They
21
also come from the pharmaceutical industry and
22
consumer organizations. In
addition to standards
109
1
development, USP's has several other public health
2
programs that focus on promoting optimal public
3
health care delivery.
4
In our mission statement, it says the
5
mission is to promote the public health, and I
6
always liken that to the mission of CDER, which is
7
also basically to promote the public health. So I
8
believe we're all interested in the same types of
9
standards.
10
At the USP, the volunteers, many of them
11 serve
on our Council of Experts and its expert
12
committees. The members of these
committees are
13 USP
scientific decisionmakers, and they form our
14
standard-setting body. Council
members are elected
15 by
USP's membership at our five-year convention.
16
They're elected on the basis of their knowledge and
17
expertise, and they serve five-year terms. So even
18
individuals who come from industry, from their
19
companies, when they volunteer to work with USP,
20
they represent themselves. They
do not represent
21
their employer, their organization, or anybody else
22
when they work on our standards.
110
1
The 2000-2005 Council of Experts comprises
2 62
nationally recognized scientists, academicians,
3 and
clinicians. Each one of these
individuals
4
chairs an expert committee, and the expert
5
committees are made up then in turn of
6
distinguished experts.
7
One of the committees is named the USP
8
Safe Medication Use Expert Committee.
This
9
committee is comprised of 18 members representing
10
pharmacy, nursing, and medicine.
It includes an
11 FDA
liaison, Carol Holquist. It includes
Captain
12
Jerry Phillips, who was formerly the Associate
13
Director for Medication Error Prevention in FDA's
14
Office of Drug Safety.
15
For more than 30 years, USP has promoted
16 the
importance of collecting and sharing
17
experiential data from health care professionals.
18 In
the last decade, particular emphasis has focused
19 on
medication error reporting and prevention as a
20 way
for USP to positively affect the public health.
21 The
data collected from two of our programs--the
22
USP-ISMP Medication Error Reporting, or MER,
111
1
Program and MEDMARX--are reviewed and analyzed by
2 USP
staff and USP's Safe Medication Use Expert
3
Committee.
4
In October of 2002, USP sent a letter to
5 the
chief of CDER's Compendial Operations staff,
6
Yanna Mille, to inform her, on behalf of the Safe
7
Medication Use Expert Committee, of the continuing
8
concerns of the committee and of health care
9
professionals and practitioners regarding both the
10
difficulty in identifying drug products packaged in
11
low-density polyethylene ampules and vials and the
12
resultant medication errors from their misuse.
13
Plastic ampule packaging is frequently
14
used for respiratory therapy drugs.
The ampules
15
often do not bear labels but are labeled by
16
debossing or embossing the actual plastic
17 container.
This debossing or embossing is
18
described by health care practitioners who have
19
reported to the USP reporting programs as being
20
unreadable, causing difficulty in identifying the
21
product within. Because this
packaging is now
22
being used not only for respiratory therapy drugs
112
1 but
also for injectables and oral solution, it is
2
even more important that the subject products be
3 easily
identified and readily distinguishable from
4
each other.
5
USP has provided the Compendial Operations
6
staff, the Dockets Branch, and the Office of Drug
7
Safety with more than 42 specific case studies
8
where mediation errors occurred because of the use
9 of
these products. We also have submitted
copies
10 of
the actual product containers involved in the
11
medication errors that were reported through the
12 two
USP reporting programs.
13 In addition to providing comment on the
14
concerns expressed to USP by health care
15
practitioners, the USP Safe Medication Use Expert
16
Committee unanimously voted to encourage FDA to
17
establish an alternate method of labeling for the
18
various drug products packaged in the plastic vials
19
being discussed today. This would
be in order for
20
these products to be clearly identifiable,
21
hopefully thereby reducing the numerous medication
22
errors that have occurred and likely will continue
113
1 to
occur.
2
The expert committee also suggested that
3 the
FDA cease approval of products in these
4
containers because their use continues to be the
5
subject of numerous medication error reports.
6
From April 20, 2002, through January 31,
7
2004, an additional 26 reports of actual and
8
potential medication errors have been received
9 through
USP's medication errors reporting programs
10
regarding the similarity in the labeling of
11
products in low-density polyethylene vials. The
12
problems with these containers continue, and the
13 USP
and the USP Safe Medication Use Expert
14
Committee recommends that FDA take any necessary
15
action to improve the labeling of low-density
16
polyethylene ampules and vials.
17
I thank you for your attention and your
18
consideration of USP's concerns.
If you have any
19
questions, I'll certainly try to answer them.
20
DR. GROSS: Thank you very much.
21
Are there any questions from the panel?
22
Jackie?
114
1
DR. GARDNER: I would just like to
ask,
2 Dr.
Sheinin, does USP have a recommendation of one
3 of
these methods over another?
4
DR. SHEININ: A recommendation?
5
DR. GARDNER: For solving this problem?
6
DR. SHEININ: Not at this point,
not that
7 I'm
aware of. The obvious solution to
me--and I
8
actually worked at FDA for 30 years before I went
9 to
USP--would be to have a label on the containers.
10 But
there are concerns with migration through the
11
low-density polyethylene. I'm
sorry I missed the
12 end
of the previous presentation where they were
13
describing perhaps some way to help identify these
14
products.
15
DR. GROSS: Robyn Shapiro?
16
MS. SHAPIRO: I just have a
question about
17
these report forms. Was patient
counseling
18
provided? And then, if yes,
before or after error
19 was
discovered? Does that mean about what
the drug
20 is,
how to take it, how to read it? What
does the
21
counseling refer to?
22
DR. SHEININ: I believe that the
115
1
counseling is provided by the professional who's
2 reporting
the problem to us. I don't believe USP
3
does the counseling.
4
MS. SHAPIRO: So we don't really
know what
5
that refers to.
6
DR. SHEININ: Unfortunately, the
Safe
7
Medication Use Expert Committee is not under my
8
area of responsibility. But as
far as I know, that
9
counseling would not be provided by USP, and we
10
probably do not know what the nature of that
11
counseling was. The form is
asking if there has
12
been any counseling.
13
DR. GROSS: Henri?
14
DR. MANASSE: Good morning, Eric.
15
DR. SHEININ: Hi, Henri.
16
DR. MANASSE: Two questions. We've talked
17
today about two major issues: one
is the leaching
18 of
chemical agents from various labeling techniques
19 and
embossments; the other having to do with the
20
readability issues and the packages themselves.
21
Has USP convened any technical experts on
22
either one of those issues to contemplate what's
116
1 the
existing science, what do we know, what do we
2 not
know, as well as what our reasonable solutions,
3
given what's known, in other industries or other
4
options for dealing with this problem?
5
DR. SHEININ: Not that I'm aware
of. It
6
certainly is a good suggestion, and I will take
7
that back to the committee and to Diane Cousins,
8
whom I think many of you probably know, and see if
9
there is a way that we could proceed in that
10
manner. I think it's a very good
suggestion and
11
something that should be done.
12
DR. GROSS: Okay. Thank you very much.
13
DR. SHEININ: Thank you.
x DR. GROSS: If there are no further 14
15
questions, since we remain ahead of schedule, Dr.
16
Paul Seligman will now introduce the issues and
17
questions that he has for the Advisory Committee.
18
DR. SELIGMAN: You should all,
members of
19 the
committee, have a one-page LDPE Discussion
20
Points. These, I believe, are in
the packages as
21
well for public distribution. Why
don't we simply
22
refer to these rather than booting up the slides.
117
1
You've heard this morning about the issue
2
related to the ingress of volatile compounds as a
3
problem with these particular containers and
4
various approaches to deal with this issue as well
5 as
not only--to deal with both the preservation of
6 the
purity of the drug, as well as ways in which to
7
improve the legibility of the label.
8
What we've asked in the first
question is:
9
Given the various approaches that you've heard
10
today, including embossing and debossing of
11
containers, the use of unit package overwraps, the
12
elongation of the bottom tab and using that as an
13
place to print critical information, the use of
14
paper labels, the use of ink directly on the vial,
15
various potential approaches including tactile
16
recognition, shrink wrap labels, and then we
17
actually even saw the use of glass ampules or
18
vials, what we're interested in the committee
19
addressing first off is to discuss the potential
20
advantages or disadvantages of these approaches and
21 to
identify in 1b any creative solutions or
22 alternate
packaging design that would improve
118
1
legibility and address the problem of ingress of
2
chemical contaminants and at the same time not
3
create additional problems.
4
We'd also like to have you put on your
5
thinking caps and consider if there are stakeholder
6
groups, such as manufacturers, practitioners,
7
consumers, and others, who might best advise FDA
8
about possible new packaging configurations that
9
might resolve some of these issues.
10
And then given what you've heard today and
11
based on our discussion, describe and advise us on
12 an
appropriate course of action to address not only
13 the
problem of ingress of contaminants but also
14
medication errors due to legibility and similar
15
packaging issues.
16
So those are the issues before us.
Peter?
17
DR. GROSS: We share in your
perplexity.
18
DR. SELIGMAN: Thank you.
x DR. GROSS: This is a difficult issue.
19
20
Thank you very much for the questions,
21
Paul, and we will initiate the discussion. The
22
agenda allows two hours for discussion, so why
119
1
don't we do roughly an hour, and then maybe we can
2
have lunch and then finish up, if that's okay.
3
MS. JAIN: Lunch is on its way.
4
DR. GROSS: Okay. Well, whenever lunch is
5
here, we will re-evaluate our timing.
But let's
6
begin the discussion now.
7
Anyone have any comments? Why
don't we do
8
this in an orderly fashion and take the issues as
9
Paul presented them, with 1a being the first.
10
They're all sort of interrelated, but why don't we
11 get
specific and talk about 1a first.
Leslie?
12
DR. HENDELES: I'd like to preface
my
13
comments by saying that nebulization of
14
bronchodilators is an obsolete way of treating
15
acute bronchospasm, and part of whatever we do
16
needs to focus on an educational program designed
17 at
using the meter-dose inhaler through a valve
18
holding chamber, which is far more efficient,
19
causes fewer side effects, less expensive way, and
20
it's the way the rest of the world treats acute
21
asthma. The United States has a
fixation on
22
nebulizer therapy that they won't let go of, for
120
1
some reason, especially pediatricians, but there's
2
clearly 10 to 15 double-blind, placebo-controlled
3
trials, a Cochran review, et cetera, that indicate
4
that there are much more efficient ways and it
5
would, of course, circumvent this problem for
6
asthma.
7
Now, having said that, I really like the
8
idea of having that foil pack, like the Nephron,
9
with a single unit, and I think that would solve
10 the
problem. It would allow for the bar
coding.
11 And
according to Karen, respiratory therapists
12
would be willing to carry that in their pocket. As
13 I
understand it, the reason why they carry single
14 units in their pocket is because when they
open the
15
foil pack, there's 12 of them there.
If there's
16
only one, they would probably carry it.
And, of
17
course, that could also be addressed through
18
professional education as well.
19
DR. GROSS: Leslie, for myself and
anyone
20
else who is not 100 percent clear on what you said,
21
would you contrast the two methods of medication
22
delivery again?
121
1
DR. HENDELES: Bronchodilators as
well as
2
inhaled steroids can be delivered by a pressurized,
3
meter-dose inhaler that's attached to a valve
4
holding chamber with an age-appropriate connection,
5
either a mouthpiece for older folks or a mask for
6
preschool kids that seals around their nose and
7
mouth, and you fire off a few puffs, such as four
8
puffs, into this chamber and it's equivalent in
9
efficacy to nebulizing a bronchodilator in the
10
emergency room. It causes fewer
side effects. It
11
takes a minute or two to give the treatment instead
12 of
15 to 20 minutes, and it's far more convenient
13 for
patients and cheaper. They don't have to
buy a
14
compressor for $150.
15
DR. GROSS: Could someone from the
FDA
16
comment on whether or not they want to tackle that
17
issue?
18
DR. SULLIVAN: That may not be an
issue
19 for
the FDA really to address. I don't think
there
20
would be any--the evidence being what it is, that
21
MDIs may effect just as great a degree of
22
bronchodilation as a nebulizer, it would be
122
1
something that physicians should interpret and use
2 in
their clinical judgment. I don't think
there
3
would be any rationale for the agency to pull
4
nebulizer solutions off the market.
I think that
5
would be very drastic. So from
our perspective, we
6
have to deal with them.
7
Now, if the medical community starts to
8
learn that maybe they are overusing nebulizers
9
through Dr. Hendeles' shaking the cage a little
10
bit, that's just great. But the
issue will still
11
remain for us.
12
DR. HENDELES: And, indeed, there
are
13
patients who might be unconscious, for example, or
14
would need the nebulizer, and there are drugs such
15 as
Tobramycin that can't be delivered by MDI.
16
DR. GROSS: Arthur?
17
MR. LEVIN: I realize it isn't
within the
18
scope of authority of the FDA to dictate clinical
19
practice, but part of the problem here is we're
20
dealing with a tension between an issue of
21
potential harm, which is the leaching of, you know,
22
substances that don't belong in the solution into
123
1 the
solution and the documented potential harm of
2
error. And we're looking at a
variety of
3
solutions, none of which is perfect and each of
4
which brings with it some question:
You know, does
5 it
solve the error problem entirely? Or by
solving
6 the
error problem entirely, does it still leave us
7
open to the problem of possible impurity?
8
In that context, I think the FDA does have
9
something to say, and then when we move to the
10
ambulatory setting particularly, where these issues
11 I
think get even more complicated--and we really
12
haven't talked about it--that if there are better
13
ways to deliver the product that relief us of the
14
burden of trying to figure out the perfect solution
15 on
these two different potential harms, that's
16 worthy
of comment. I mean, nobody expects you
to
17 be
able to pull the product from the market, but in
18
dealing with improving safety of products, I don't
19
think it's entirely out of character for the FDA to
20
make a comment that one of the solutions here is to
21 use
a different form of delivery that obviates the
22
need to talk about all of this.
You may not be
124
1
able to say, "You can't use the other," but you can
2
certainly say, "Moving in this direction seems to
3 be
a way to solve the problem," and I would say
4
particularly in the ambulatory populations.
5
DR. GROSS: Maybe we'll have one
or two
6
more comments on this particular issue.
Then we'll
7
have to get back to the questions raised by Dr.
8
Seligman in 1a.
9
Brian?
10
DR. STROM: yes, I'd like to in my
initial
11
start be more provocative. We're
hearing, as
12
Arthur is saying, between two safety problems,
13
without good data on either side to quantify each
14 of
them. We're using in one case
physiological
15
chemical tests and the theory that leaching might
16 be
a problem, and it's clearly understandable why
17 it
can't be quantified more than that. And
we're
18
hearing on the other side about medication errors
19
based on the spontaneous reporting system, which is
20
grossly incomplete. We don't know
how many there
21 are
out there other than the fact that we're seeing
22 a
number, and there are clearly many more out there
125