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