DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE (DSaRM)
CDER Advisory Committee Conference Room.
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.
Leslie Hendeles, Pharm.D.
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,
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
- 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
- Container Labeling Options using rommelag Blow-
Fill-Seal Technology - Mohammad Sadeghi, V.P.,
Research/Development, Holopack International
- 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
- American Association of Respiratory Therapy
Care - Karen Stewart, M.S., R.R.T. 93
Questions from Committee 94
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
Risk Management Program for Lotronex - Craig Metz,
Ph.D., V.P., U.S. Regulatory Affairs,
Lotronex Update - Robert Justice, M.D., M.S.,
Director, Division of Gastrointestinal and
Coagulation Drug Products 241
Questions from Committee 248
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
will continue to take advantage of your skills.
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
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
20 DR. FURBERG: Curt Furberg, professor of
21 public health sciences at the Wake Forest
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,
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
safety evaluator in the Division of Medication
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
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
screened for their financial interests as they may
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.
With respect to FDA's invited industry
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
Biotechnology and Sterile Life Sciences division.
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
11 Thank you.
x DR. SELIGMAN: Good morning. On behalf of
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
discussion today--the first related to the
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
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,
prevent ingress of chemical contaminants, and in
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
observations regarding issues raised by the use of
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
today's discussion regarding minimizing the
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
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
effects may be poorly tolerated by patients,
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
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
inhalation drug products that are packaged in LDPE
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,
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
feature known as airway hyperresponsiveness.
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
characterized by airway inflammation and airflow
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
20 Chemical contaminants in inhalation drug
21 products may be associated with a variety of
adverse effects, including irritant and immunologic
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
chemicals. Numerous volatile
chemicals exist in
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
look-alike packaging. The issue
of how best to
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.
Our error analysis included in your
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
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
error perspective is the issue of look-alike
1 packaging. Often there is very little on the
2 container itself to help people distinguish these
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
19 In this case, heparin is an injectable
20 medication. This photo was included with the
21 report of potential for confusion between heparin
Tobramycin due to look-alike containers.
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
be potential for contamination despite the
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
contribute to errors.
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
three strengths look alike when they are removed
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
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.
At this point we would like to stimulate
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
another approach with paper labels.
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
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
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
shape and possibly texture to help differentiate
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
products includes the use of a uniquely shaped
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
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
packaging contamination. However, there
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
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
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
it's going to get worse.
2 DR. SHAH: You were supposed to hear this
3 talk before Marci's talk, but, anyway, here it
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
21 With that, this slide gives you the
outline of my talk. I'm going to
start with a
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
quality concerns, what I have discussed so far.
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
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
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
blow-fill-seal or form-fill-seal process. The
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
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
reactant polymer. They include chain
1 agent, chain initiator, antioxidant, so on and so
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
21 However, it is permeable to volatile
chemicals and gases, and because of this
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
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
say, volatility, they may permeate through the LDPE
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
more than one chemical included into the ink
1 formulation. And, again, these are also propriety
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.
The thickness of aluminum foil, which is
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
may sensitize individuals; drug product
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
concerned that there may be other inhalation drug
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.
Twenty-nine out of 38 samples tested
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
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
20 It was also indicated that concentration
21 of these chemicals might be grater at the end of
expiry than what was detected at the time they were
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,
which is coming from resin components.
Some of the
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
many of these identified chemical contaminants.
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
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,
what I mean by leachable is leachable is any
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
physico-chemical properties of packaging
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
product is also recommended. This
in turn can
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
patients with respiratory illnesses, such as asthma
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
I'll start off with a couple questions.
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
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?
DR. COHEN: Dr. Lee mentioned
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
divisions, another agency, but we haven't received
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
DR. GROSS: Next question, Leslie?
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
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?
DR. HENDELES: I'd like to just
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.
DR. GROSS: Curt Furberg?
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?
DR. SULLIVAN: Well, I think
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.
DR. GROSS: Okay. Henri, and then we'll
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
infusion, leaching of the contaminants equally
1 impactful on all the active ingredients in these
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
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
population, we are more concerned.
And I don't
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.
T2A DR. GROSS: The first speaker will be
19 Mohammad Sadeghi, who will talk about container
20 labeling options using rommelag blow-fill-seal
DR. SADEGHI: Good morning. I'm Mohammad
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
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
formed into the container, the needle comes in, and
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,
which in this case instead of molding it during the
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
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;
ensure 100-percent labeling of containers; labels
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
Now, examples of these various things,
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
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
removed, and considered this is--it should be in
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
6 Thank you.
7 DR. GROSS: Okay. Now we'll hear from the
8 Cardinal Health team, Rick Schindewolf and Patrick
x MR. POISSON: Good morning. My name is
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
involves NDA, ANDA, 510(k), and USP Monograph
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
packaged in a secondary overwrap in multiple units
1 or single units, and that provides the additional
2 protection necessary to prevent chemical
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.
Now, we believe there are some
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
would be a one-time cost for the manufacturer to
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
those can also be provided in clear plastic. And
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
materials, and we believe it could be implemented
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
been touched upon. It provides
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
to increase label information font size on
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
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
health care professionals, are very concerned about
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
groups of respiratory therapists. The
1 is how the medication is labeled or not labeled
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
either be placed in a single patient medication
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
with the raised-letter labeling is an accident
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
shapes and sizes on a very few of the medications.
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
21 Now, low light--it's bad enough, you know,
with the age, but the low light.
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.
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.
21 DR. HENDELES: I have two questions for
Karen. First, is there any Joint
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
still carrying it physically on their person in a
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
from my interpretation were in the manufacturing
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
19 In regards to the recommendations, yes,
20 some of them are manufacturing--are good for the
21 manufacturing process. However, one that maybe
wasn't explained as well is the sterility of the
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
available to any manufacturer?
And can you foresee
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
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
print can be--
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
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
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
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.
MS. SHAPIRO: And the patient may
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
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
21 DR. SHAH: Let me just try to briefly
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
establish a profile. Once you
establish a profile,
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
21 So we go through a series of steps to
establish that, and once we are satisfied, then we
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?
DR. SELIGMAN: For all drug
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,
this doesn't--this won't do given these sorts of
T2B DR. SELIGMAN: I'm not aware of any. Some
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
patients are in the right column.
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
some intrinsic appeal because it seems to be
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
a way to identify a container. But the
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
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
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
look at how well these kinds of solutions work
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
21 DR. GROSS: Okay. Henri, you have a
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
afraid that they're going to double their dose
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
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
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
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
20 For example, the financial information may
21 include a company's or a group's payment of your
travel, lodging, or other expenses in connection
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
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
would like to give you some background about the
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
consumer organizations. In
addition to standards
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
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
when they work on our standards.
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
USP-ISMP Medication Error Reporting, or MER,
1 Program and MEDMARX--are reviewed and analyzed by
2 USP staff and USP's Safe Medication Use Expert
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
being used not only for respiratory therapy drugs
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
errors that have occurred and likely will continue
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?
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
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?
DR. SHEININ: I believe that the
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
either one of those issues to contemplate what's
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
refer to these rather than booting up the slides.
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
packaging design that would improve
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.
20 Thank you very much for the questions,
21 Paul, and we will initiate the discussion. The
agenda allows two hours for discussion, so why
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
nebulizer therapy that they won't let go of, for
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
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
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
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
bronchodilation as a nebulizer, it would be
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,
substances that don't belong in the solution into
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
need to talk about all of this.
You may not be
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.
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
number, and there are clearly many more out there