1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

                    DRUG SAFETY AND RISK MANAGEMENT

 

                       ADVISORY COMMITTEE (DSaRM)

 

                           COMMITTEE MEETING

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Wednesday, May 5, 2004

 

                               8:18 a.m.

 

 

 

 

 

 

 

 

 

                CDER Advisory Committee Conference Room.

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                        P A R T I C I P A N T S

 

      DSaRM Committee Members:

 

      Peter A. Gross, M.D., Chair

      Shalini Jain, PA-C, M.B.A., Executive Secretary

 

      Michael R. Cohen, R.Ph., M.S., D.Sc.

      Stephanie Y. Crawford, Ph.D., M.P.H.

      Curt D. Furberg, M.D., Ph.D.

      Jacqueline S. Gardner, Ph.D. M.P.H.

      Arthur A. Levin, M.P.H.

      Henri R. Manasse, Jr., Ph.D.

      Robyn S. Shapiro, J.D.

      Annette Stemhagen, Dr.PH

      Brian L. Strom, M.D., M.P.H.

 

      GI Advisory Committee Members:

 

      Alexander H. Krist, M.D.

      Maria H. Sjogren, M.D.

 

      Consultant:

 

      Leslie Hendeles, Pharm.D.

 

      FDA Participants:

 

      Carol Holquist, R.Ph.

      Marci Lee, Pharm.D.

      Paul Seligman, M.D., M.P.H. [a.m. and p.m.]

      Vibhakar Shah, Ph.D.

      Eugene Sullivan, M.D.

 

      Mark Avigan, M.D., C.M.

      Julie Beitz, M.D.

      Robert Justice, M.D., M.S.

      Ann Marie Trentacosti, M.D.

                                                                 3

 

                            C O N T E N T S

      AGENDA ITEM                                             PAGE

 

      Call to Order and Opening Remarks, Introduction of

      Committee - Peter Gross, M.D., Chair, DSaRM                5

 

      Conflict of Interest Statement - Shalini Jain,

      PA-C, M.B.A., Executive Secretary, DSaRM                   8

 

      Opening Remarks - Paul Seligman, M.D., M.P.H.,

      Director, Office of Pharmacoepidemiology &

      Statistical Science (OPSS) and Acting Director,

      Office of Drug Safety (ODS)                               11

 

      FDA Presentations

 

      - Permeability of LDPE Vials:  A Clinical

        Perspective - Eugene Sullivan, M.D., Deputy

        Director, Division of Pulmonary Drug Products.          13

      - Medication Errors and Low-Density Polyethylene

        (LDPE) Plastic Vials - Marci Lee, Pharm.D.,

        Safety Evaluator, Division of Medication Errors

        and Technical Support                                   23

      - LDPE Vials for Inhalation Drug Products:  A

        Chemistry, Manufacturing, and Controls (CMC)

        Perspective - Vibhakar Shah, Ph.D., Chemist,

        Division of New Drug Chemistry II                       36

 

      Questions from Committee                                  55

 

      Industry Presentations

 

      - Container Labeling Options using rommelag Blow-

        Fill-Seal Technology - Mohammad Sadeghi, V.P.,

        Research/Development, Holopack International

        Corp.                                                   65

      - Labeling of LDPE Containers:  Options for

        Improving Identification for Prevention of

        Medication Errors - Rick Schindewolf, V.P. & GM,

        Biotechnology & Sterile Life Sciences, and

        Patrick Poisson, Director of Technical Services,

        Biotechnology & Sterile Life  Sciences, Cardinal

        Health                                                  90

      - American Association of Respiratory Therapy

        Care - Karen Stewart, M.S., R.R.T.                      93

 

      Questions from Committee                                  94

                                                                 4

 

                      C O N T E N T S (Continued)

 

      Open Public Hearing                                      106

 

      Introduction of LDPE Issues

                Paul Seligman, M.D., M.P.H.                    118

 

      Committee Discussion                                     118

 

      Committee Discussion (Continued)                         182

 

      Opening Remarks and Reintroduction of Advisory

      Committee - Peter Gross, M.D., Chair                     182

 

      Conflict of Interest Statement - Shalini Jain,

      PA-C., M.B.A.                                            185

 

      Introduction of Lotronex Issue - Paul Seligman,

      M.D., M.P.H.                                             187

 

      Open Public Hearing                                      189

 

      Sponsor Presentation

 

      Risk Management Program for Lotronex - Craig Metz,

      Ph.D., V.P., U.S. Regulatory Affairs,

      GlaxoSmithKline                                          206

 

      FDA Presentation

 

      Lotronex Update - Robert Justice, M.D., M.S.,

      Director, Division of Gastrointestinal and

      Coagulation Drug Products                                241

 

      Questions from Committee                                 248

 

      Adjourn                                                  298

 

                                                                 5

 

  1                      P R O C E E D I N G S

 

  2             DR. GROSS:  Good morning.  I'm Peter

 

  3   Gross.  I'm Chair of the Drug Safety and Risk

 

  4   Management Committee, and starting with the person

 

  5   at my left with that famous laugh, Brian Strom,

 

  6   would you please introduce yourself?

 

  7             DR. STROM:  Thank you.  I'm Brian Strom

 

  8   from the University of Pennsylvania.

 

  9             MS. JAIN:  You know what?  Before we go

 

 10   on, Brian, Peter and the rest of the committee as

 

 11   well as the division wanted to say a warm thank-you

 

 12   for serving on our committee.  You've been a great

 

 13   asset for a year and a half, and we realize that

 

 14   you're going to continue as consultant, and we just

 

 15   wanted to say thanks.

 

 16             DR. STROM:  It's been a real pleasure, and

 

 17   it was a hard decision to let the rotation happen.

 

 18   I've enjoyed it, but given other commitments back

 

 19   home--but it's been fun.

 

 20             MS. JAIN:  Thank you.

 

 21             DR. GROSS:  You've been great, Brian.  We

 

 22   will continue to take advantage of your skills.

 

                                                                 6

 

  1             DR. MANASSE:  My name is Henri Manasse.

 

  2   I'm chief executive officer and executive vice

 

  3   president of the American Society of Health-System

 

  4   Pharmacists, a membership organization that

 

  5   represents about 32,000 pharmacists practicing in

 

  6   hospitals and organized health systems.

 

  7             MS. SHAPIRO:  Robyn Shapiro.  I'm a

 

  8   professor and director of the Center for the Study

 

  9   of Bioethics at the Medical College of Wisconsin.

 

 10             DR. STEMHAGEN:  I'm Annette Stemhagen.

 

 11   I'm Vice President of Strategic Development at

 

 12   Covance, a contract research organization, and I

 

 13   serve as an industry representative to this

 

 14   committee.

 

 15             DR. GARDNER:  Jacqueline Gardner,

 

 16   University of Washington, Department of Pharmacy.

 

 17             MR. LEVIN:  Art Levin, Center for Medical

 

 18   Consumers, and I serve as the consumer

 

 19   representative.

 

 20             DR. FURBERG:  Curt Furberg, professor of

 

 21   public health sciences at the Wake Forest

 

 22   University.

 

                                                                 7

 

  1             DR. HENDELES:  I'm Leslie Hendeles.  I'm a

 

  2   clinical pharmacist at the University of Florida,

 

  3   and I've done research on the bronchospastic

 

  4   effects of preservatives in nebulizer solutions.

 

  5             DR. CRAWFORD:  Good morning.  Stephanie

 

  6   Crawford, associate professor, College of Pharmacy,

 

  7   University of Illinois at Chicago.

 

  8             DR. COHEN:  Mike Cohen, Institute for Safe

 

  9   Medication Practices.

 

 10             DR. SELIGMAN:  Paul Seligman, Director,

 

 11   Office of Pharmacoepidemiology and Statistical

 

 12   Science, Center for Drug Evaluation and Research,

 

 13   FDA.

 

 14             DR. SULLVAN:  My name is Gene Sullivan.

 

 15   I'm the Deputy Director of the Division of

 

 16   Pulmonary and Allergy Drug Products here at FDA.

 

 17             MS. HOLQUIST:  I'm Carol Holquist.  I'm

 

 18   the Director of the Division of Medication Errors

 

 19   and Technical Support in the Office of Drug Safety,

 

 20   Center for Drug Evaluation and Research.

 

 21             DR. LEE:  Marci Lee, a pharmacist and

 

 22   safety evaluator in the Division of Medication

 

                                                                 8

 

  1   Errors and Technical Support.

 

  2             MS. JAIN:  Thank you, everyone.  My name

 

  3   is Shalini Jain.  I'm the Executive Secretary for

 

  4   the Drug Safety and Risk Management Advisory

 

  5   Committee.  I'll now read the conflict of interest

 

  6   statement for the meeting today.  The meeting issue

 

  7   is low-density polyethylene vials.

 

  8             The following announcement addresses the

 

  9   issue of conflict of interest with respect to this

 

 10   meeting and is made a part of the record to

 

 11   preclude even the appearance of such at this

 

 12   meeting.

 

 13             Based on the agenda, it has been

 

 14   determined that the topics of today's meeting are

 

 15   issues of broad applicability, and there are no

 

 16   products being approved at this meeting.  Unlike

 

 17   issues before a committee in which a particular

 

 18   product is discussed, issues of broader

 

 19   applicability involve many industrial sponsors and

 

 20   academic institutions.

 

 21             All special government employees have been

 

 22   screened for their financial interests as they may

 

                                                                 9

 

  1   apply to the general topics at hand.  To determine

 

  2   if any conflict of interest existed, the agency has

 

  3   reviewed the agenda and all relevant financial

 

  4   interests reported by the meeting participants.

 

  5   The Food and Drug Administration has granted

 

  6   general matters waivers to the special government

 

  7   employees participating in this meeting who require

 

  8   a waiver under Title 18, United States Code,

 

  9   Section 208.

 

 10             A copy of the waiver statements may be

 

 11   obtained by submitting a written request to the

 

 12   agency's Freedom of Information Office, Room 12A-30

 

 13   of the Parklawn Building.

 

 14             Because general topics impact so many

 

 15   entities, it is not prudent to recite all potential

 

 16   conflicts of interest as they apply to each member,

 

 17   consultants, and guest speaker.

 

 18             FDA acknowledges that there may be

 

 19   potential conflicts of interest, but because of the

 

 20   general nature of the discussion before the

 

 21   committee, these potential conflicts are mitigated.

 

 22             With respect to FDA's invited industry

 

                                                                10

 

  1   representative, we would like to disclose that Dr.

 

  2   Annette Stemhagen is participating in this meeting

 

  3   as an industry representative, acting on behalf of

 

  4   regulated industry.  Dr. Stemhagen is employed by

 

  5   Covance Periapproval Services, Incorporated.

 

  6             In addition, we would like to note that

 

  7   Karen Stewart, FDA's invited guest speaker, is

 

  8   participating as a representative of the

 

  9   respiratory therapists in the United States through

 

 10   the American Association for Respiratory Care.  She

 

 11   has no financial interest in or professional

 

 12   relationship with any of the products or firms that

 

 13   could be affected by the committee's discussions.

 

 14             With respect to the three invited industry

 

 15   guest speakers, we would like to disclose that

 

 16   Mohammad Sadeghi is employed by Holopack

 

 17   International,  Richard Schindewolf is employed by

 

 18   Cardinal Health and is vice president and general

 

 19   manager of Biotechnology and Sterile Life Sciences.

 

 20   Patrick Poisson is employed by Cardinal Health, and

 

 21   he serves as Director of Technical Services at the

 

 22   Biotechnology and Sterile Life Sciences division.

 

                                                                11

 

  1             In the event that the discussions involve

 

  2   any other products or firms not already on the

 

  3   agenda for which FDA participants have a financial

 

  4   interest, the participants' involvement and their

 

  5   exclusion will be noted for the record.

 

  6             With respect to all other participants, we

 

  7   ask in the interest of fairness that they address

 

  8   any current or previous financial involvement with

 

  9   any firm whose product they may wish to comment

 

 10   upon.

 

 11             Thank you.

 

        x                   DR. SELIGMAN:  Good morning.  On behalf of         

   12

 

 13   the Center for Drug Evaluation and Research, it is

 

 14   my pleasure to welcome members of the Drug Safety

 

 15   and Risk Management Advisory Committee and members

 

 16   of the public to today's meeting.  As always, we

 

 17   greatly appreciate the time and efforts devoted by

 

 18   the committee members and all participants in

 

 19   providing advice to the FDA on important public

 

 20   health issues.

 

 21             We have two topics on the agenda for

 

 22   discussion today--the first related to the

 

                                                                12

 

  1   prevention of medication errors and the second

 

  2   providing an update on a risk management program

 

  3   that was considered by this committee two years ago

 

  4   and was implemented in 2002.

 

  5             The first topic will focus primarily on

 

  6   minimizing the incidence of medication errors with

 

  7   drug products packages in low-density polyethylene,

 

  8   or LDPE, containers.  The package is intended to

 

  9   preserve drug product purity and quality.  However,

 

 10   current techniques used to label the product create

 

 11   problems related to legibility of the product name

 

 12   and strength.  Additionally, various products are

 

 13   packaged in containers that look similar.  We've

 

 14   found that these difficult-to-read labels and

 

 15   look-alike containers have contributed to

 

 16   medication errors involving the administration of

 

 17   wrong dosage strength or wrong drug product to the

 

 18   patient.

 

 19             Today, we would like to discuss what other

 

 20   solutions or alternative packaging designs exist

 

 21   that could improve the legibility of the label,

 

 22   prevent ingress of chemical contaminants, and in

 

                                                                13

 

  1   the process reduce or eliminate medication errors.

 

  2   Then later this afternoon, we will receive an

 

  3   update on the Lotronex risk management program.

 

  4             With that brief introduction, I look

 

  5   forward to our discussions today and, again, I also

 

  6   want to personally thank Dr. Strom for his service

 

  7   on this committee.

 

  8             With that, I guess we may proceed with the

 

  9   first speaker.  Dr. Gross?

 

 10             DR. GROSS:  Dr. Sullivan will be the first

 

 11   speaker on the Permeability of LDPE Vials:  A

 

 12   Clinical Perspective.

 

 13             DR. SULLIVAN:  Good morning.  As I

 

 14   mentioned, my name is Gene Sullivan.  By training

 

 15   I'm a pulmonologist, and I'm the Deputy Director of

 

 16   the Division of Pulmonary and Allergy Drug Products

 

 17   in the Center for Drug Evaluation and Research here

 

 18   at FDA.

 

 19             This morning, I'm going to spend about 15

 

 20   minutes or so providing some background for the

 

 21   discussions today.  I'll be conveying some clinical

 

 22   observations regarding issues raised by the use of

 

                                                                14

 

  1   LDPE vials in the packaging of inhalation drug

 

  2   products, particularly as it relates to the

 

  3   permeability of the vials.

 

  4             This slide provides an overview of my

 

  5   presentation.  I'll begin with some introductory

 

  6   remarks which will put my presentation into the

 

  7   context of today's discussions and will serve to

 

  8   introduce the remainder of the talk.  Next I will

 

  9   discuss the inhalation drug products that are

 

 10   involved, providing some examples and a brief

 

 11   description of the nature of these drugs.

 

 12   Following this, I will discuss the patient

 

 13   populations for which these drugs are used,

 

 14   emphasizing aspects of these populations that put

 

 15   them at risk for adverse effects of chemical

 

 16   contaminants.  Then I will discuss the potential

 

 17   sources of chemical contaminants, their potential

 

 18   adverse effects, and the difficulties that exist in

 

 19   terms of adequately monitoring for them.  Finally,

 

 20   I will summarize the issue and current state of

 

 21   affairs in order to set the stage for the remainder

 

 22   of today's discussion regarding minimizing the

 

                                                                15

 

  1   potential for medication errors.

 

  2             The topic for discussion for today's

 

  3   Advisory Committee meeting is how best to minimize

 

  4   the potential for medication errors associated with

 

  5   LDPE containers, particularly given the clinical

 

  6   concerns related to their permeability and the

 

  7   resulting move away from the paper labels that have

 

  8   previously been used to identify the products.  My

 

  9   presentation is intended to review the nature of

 

 10   these clinical concerns in order to provide

 

 11   background for the remainder of the discussions

 

 12   today.

 

 13             This slide summarizes the clinical

 

 14   concerns that I mentioned.  Many inhalation drug

 

 15   products are packaged in LDPE containers.  LDPE is

 

 16   a material that is permeable to volatile chemicals,

 

 17   and there are numerous volatile chemicals that

 

 18   exist in the immediate packaging environment.

 

 19   Volatile chemicals that find their way into

 

 20   inhalation solutions may have a number of adverse

 

 21   effects on the airways, and because these adverse

 

 22   effects may be poorly tolerated by patients,

 

                                                                16

 

  1   efforts should be made to minimize the potential

 

  2   for contamination of inhalation drug products.

 

  3   Such efforts have included minimizing the content

 

  4   of volatile chemicals in the immediate packaging

 

  5   environment.

 

  6             For instance, the practice of using paper

 

  7   labels, which are applied directly to the LDPE

 

  8   containers and which contain numerous volatile

 

  9   chemicals, is not recommended.  However, as you

 

 10   will see in subsequent presentations, the use of

 

 11   alternative labeling approaches has raised the

 

 12   issue of medication errors.

 

 13             Now, I also want to point out that my

 

 14   presentation is focused on the clinical concerns

 

 15   related to chemical contamination of these

 

 16   products.  In the next presentation, Dr. Shah will

 

 17   also talk about product quality concerns.  For

 

 18   instance, ingress of volatile chemicals might

 

 19   adversely affect the stability of the active drug

 

 20   substance in a particular drug product.

 

 21             This slide provides some examples of

 

 22   inhalation drug products that are packaged in LDPE

 

                                                                17

 

  1   containers.  They include bronchodilators, such as

 

  2   Albuterol, Ipatropium, Metaproterenol, and

 

  3   Levalbuterol; also a mass cell stabilizer, cromolyn

 

  4   sodium; an inhaled steroid, Budesonide; and an

 

  5   antibiotic, Tobramycin.

 

  6             These products are inhalation solutions,

 

  7   or sometimes suspensions, that are intended for

 

  8   oral inhalation using a nebulizer.  One thing to

 

  9   keep in mind is that the manufacturing processes

 

 10   and materials for inhalation products are very

 

 11   carefully controlled in order to maintain a very

 

 12   high standard of product purity.  That is, a

 

 13   significant amount of attention is paid to the

 

 14   manufacturing processes and the materials used so

 

 15   that the content of contaminants is minimized.

 

 16   This would include contaminants that arise during

 

 17   the manufacturing processes, so-called process of

 

 18   synthetic impurities; contaminants that arise due

 

 19   to degradation of components of the formulation; or

 

 20   the subject of today's concern, contaminants that

 

 21   enter the formulation from the packaging materials,

 

 22   so-called leachables.

 

                                                                18

 

  1             These drugs may be used in a regular

 

  2   dosing schedule or may be used as an as-needed

 

  3   basis, and the bronchodilator products in

 

  4   particular are common used in the inpatient and

 

  5   acute-care settings, including emergency

 

  6   departments and intensive care units.

 

  7             These inhalation products are used by

 

  8   patients with a variety of pulmonary disorders,

 

  9   most commonly patients with asthma, COPD--which is

 

 10   chronic obstructive pulmonary disease, a category

 

 11   of lung disease comprised of chronic bronchitis and

 

 12   emphysema--and cystic fibrosis.  Although these

 

 13   diseases are distinct, in general they are

 

 14   characterized by fixed or variable obstruction to

 

 15   airflow and a variety of patterns of histologic

 

 16   abnormalities, including various patterns of airway

 

 17   inflammation.  In addition, asthma in particular is

 

 18   associated with an underlying propensity for

 

 19   allergic responses.  And most of the diseases are

 

 20   associated with a sensitivity to nonspecific

 

 21   irritants which result in acute bronchospasm, a

 

 22   feature known as airway hyperresponsiveness.

 

                                                                19

 

  1             To focus specifically on asthmatics for a

 

  2   moment, asthmatics may react adversely to both

 

  3   nonspecific chemical irritants and to allergens to

 

  4   which they have developed specific immunity.

 

  5   Irritant reactions are characterized by symptoms of

 

  6   wheezing and shortness of breath.  It is well known

 

  7   that patients with severe asthma may react to very

 

  8   low levels of exposure to irritants.  Clinically,

 

  9   this is often related to perfumes, cleaning agents,

 

 10   or smoke in the environment.  In fact, we commonly

 

 11   make use of this feature of asthma to help

 

 12   establish the diagnosis using methacholine

 

 13   challenge testing.  In the methacholine challenge

 

 14   test, patients with suspect asthma are exposed to

 

 15   successively higher concentrations of this irritant

 

 16   in order to elicit bronchospasm.

 

 17             In addition to the nonspecific irritant

 

 18   reactions, asthmatics may also develop bronchospasm

 

 19   from inhaled allergens.  This allergic reaction is

 

 20   associated with both an acute early-phase broncho-

 

 21   constriction and a delayed late-phase response

 

 22   characterized by airway inflammation and airflow

 

                                                                20

 

  1   limitation.

 

  2             So what are the potential sources of

 

  3   contaminants in inhalation drug products packaged

 

  4   in LDPE?  In general, these are from volatile

 

  5   chemicals found in the labels and secondary bulk

 

  6   packaging.  These chemicals may be found in the

 

  7   various glues, inks, and lacquers that are used.

 

  8   One thing to point out is that the specific

 

  9   chemical nature of these inks, glues, et cetera,

 

 10   may, in fact, change after approval due to changes

 

 11   in the sources of these packaging materials.

 

 12             The FDA conducted an analytical survey of

 

 13   approved inhalation solutions marketed in LDPE

 

 14   containers and found that 29 of the 37 samples

 

 15   tested positive for various volatile chemicals that

 

 16   were presumed to have originated in the packaging

 

 17   materials.  Dr. Shah will describe this analysis in

 

 18   much more detail in his presentation later this

 

 19   morning.

 

 20             Chemical contaminants in inhalation drug

 

 21   products may be associated with a variety of

 

 22   adverse effects, including irritant and immunologic

 

                                                                21

 

  1   effects, leading to acute bronchospasm and airway

 

  2   inflammation and hyperresponsiveness, other toxicologic

 

  3   injury, or even potentially carcinogenicity.

 

  4             In terms of monitoring for adverse effects

 

  5   that might be attributed to chemical contaminants

 

  6   in these products, it is important to note that

 

  7   appropriate attribution may be very difficult

 

  8   because the expected adverse effects--bronchospasm

 

  9   and airway hyperresponsiveness--mimic the symptoms

 

 10   for which the drugs are being used.  This is a very

 

 11   difficult circumstance and makes it quite likely

 

 12   that adverse effects would not be recognized and

 

 13   reported.  For instance, modest bronchospasm

 

 14   related to chemical contaminants might lead to

 

 15   reduced efficacy of the drug, but this would likely

 

 16   not be identified.  Even if the adverse effect were

 

 17   more significant, the findings would likely be

 

 18   attributed to refractory underlying disease.

 

 19             So, to summarize, many inhalation drug

 

 20   products are packaged in low-density polyethylene

 

 21   containers.  This material is permeable to volatile

 

 22   chemicals.  Numerous volatile chemicals exist in

 

                                                                22

 

  1   the immediate packaging environment.

 

  2             Various volatile chemicals have, in fact,

 

  3   been identified in these products.  These volatile

 

  4   chemicals may have irritant as well as other

 

  5   toxicologic effects.  And because these effects may

 

  6   be particularly poorly tolerated by patients,

 

  7   efforts should be made to minimize the potential

 

  8   for contamination of inhalation drug products.

 

  9             It was this line of reasoning that in part

 

 10   led to the development of the Draft Guidance

 

 11   entitled "Inhalation Drug Products Packaged in

 

 12   Semipermeable Container Closure Systems."  Among

 

 13   other things, the Draft Guidance recommends that

 

 14   measures be taken to limit chemical contamination

 

 15   of these products.  One such measure would be the

 

 16   use of alternative approaches to paper labels, such

 

 17   as direct embossing or debossing of the containers.

 

 18             However, as will be discussed in

 

 19   subsequent presentations, the move away from paper

 

 20   labels has introduced a new concern, that of

 

 21   medication errors due to difficult-to-read and

 

 22   look-alike packaging.  The issue of how best to

 

                                                                23

 

  1   minimize the potential for medication errors will

 

  2   be the topic for today's discussion.

 

  3             DR. GROSS:  Thank you, Dr. Sullivan.

 

  4             The next speaker will be Shah.

 

  5             MS. JAIN:  He is not here.

 

  6             DR. GROSS:  Okay.  Later for Dr. Shah.

 

  7             Dr. Marci Lee will now talk about

 

  8   medication errors and low-density polyethylene

 

  9   plastic vials.

 

 10             DR. LEE:  Good morning.  My name is Marci

 

 11   Lee.  I am a pharmacist and safety evaluator in the

 

 12   Division of Medication Errors and Technical Support

 

 13   in the Office of Drug Safety.

 

 14             The purpose of this presentation is to

 

 15   describe medication error reports and feedback from

 

 16   patients and practitioners involving products

 

 17   packaged in LDPE containers.  I will focus on some

 

 18   factors we identified that may contribute to

 

 19   confusion and errors with these products.  Finally,

 

 20   I will describe packaging and labeling approaches

 

 21   for your consideration.

 

 22             Our error analysis included in your

 

                                                                24

 

  1   background package was from 87 relevant reports.

 

  2   These came from patients, caregivers, and

 

  3   practitioners, such as respiratory therapists and

 

  4   pharmacists, who reported to the programs listed.

 

  5   These reports were received between January 1993

 

  6   and August 2002.  Many reports involved difficulty

 

  7   reading embossed product containers.  Some reports

 

  8   were actual errors where the wrong medication or

 

  9   the wrong dosage strengths were dispensed.

 

 10   Although some of these were detected before the

 

 11   medication was administered to the patient, some

 

 12   were not.  The outcomes of these reports ranged

 

 13   from no harm to difficulty breathing, which can be

 

 14   life-threatening.  The remainder of the reports

 

 15   described the potential for confusion and errors

 

 16   with these products.  Subsequently, as of April

 

 17   2004, 51 additional relevant medication error

 

 18   reports were identified for a total of 138 reports.

 

 19             In addition to our analysis, FDA received

 

 20   correspondence from ISMP, USP, and Senator Harkin

 

 21   regarding the safe use of products packaged in LDPE

 

 22   containers.

 

                                                                25

 

  1             Several themes emerged from the narratives

 

  2   of the medication error reports as factors that can

 

  3   contribute to errors.  They include

 

  4   difficult-to-read containers, look-alike packaging,

 

  5   and routine handling of LDPE by patients and health

 

  6   care practitioners.

 

  7             Some of the slides for this portion of the

 

  8   presentation will include direct quotes from the

 

  9   error reporters.  The first contributing factor to

 

 10   consider is the difficult-to-read labeling.

 

 11   Concern was expressed in a medication error report

 

 12   because it is difficult to see the name of the drug

 

 13   and its ingredients.  Another person noted that if

 

 14   the lot and expiration date are on opposite sides

 

 15   of the same area of plastic, it is even more

 

 16   difficult to read.  In addition, practitioners

 

 17   described how the vials needed to be angled in the

 

 18   light to read them.  For some, the text is

 

 19   difficult or impossible to read.

 

 20             In addition to difficult-to-read

 

 21   containers, another concern from the medication

 

 22   error perspective is the issue of look-alike

 

                                                                26

 

  1   packaging.  Often there is very little on the

 

  2   container itself to help people distinguish these

 

  3   products.

 

  4             This photo accompanied one medication

 

  5   error report.  It highlights the potential for

 

  6   confusion from look-alike vials from just a few of

 

  7   the products available in these containers.  Almost

 

  8   all of these vials contain a different drug

 

  9   product.  The paper labels and the unique round

 

 10   vial shape help to differentiate three of the vials

 

 11   from the rest.  However, these two can be difficult

 

 12   to read.

 

 13             In addition, this problem spans various

 

 14   drug classes and routes of administration.  This

 

 15   complicates the picture for practitioners and

 

 16   creates the opportunity for errors to occur among

 

 17   inhalation, injection, ophthalmic, and oral

 

 18   products.

 

 19             In this case, heparin is an injectable

 

 20   medication.  This photo was included with the

 

 21   report of potential for confusion between heparin

 

 22   and Tobramycin due to look-alike containers. 

 

                                                                27

 

  1   Pharmacies may store a variety of these products,

 

  2   and the potential for confusion will likely

 

  3   increase as we see more products other than

 

  4   inhalation solutions packaged in the LDPE

 

  5   containers.  This increases the likelihood for

 

  6   administration of the wrong drug product by the

 

  7   wrong route of administration.

 

  8             Another example of an injectable drug

 

  9   product with similar packaging is Naropin.  These

 

 10   ampules are specially design to fit both Luer lock

 

 11   and Luer slip syringes.  Although this feature may

 

 12   minimize the likelihood for confusion with the

 

 13   other LDPE containers, there is still potential for

 

 14   confusion between the dosage strengths within the

 

 15   Naropin product line.  This vial includes black

 

 16   type on a clear background.  Again, for some this

 

 17   may be difficult to read.

 

 18             Timoptic OCUDOSE is an example of an

 

 19   ophthalmic solution packaged in an LDPE container.

 

 20   This image shows that the tip of the container has

 

 21   been extended to allow for a label.  However, there

 

 22   may be potential for contamination despite the

 

                                                                28

 

  1   placement of this label.

 

  2             Gastrocom is an example of a product for

 

  3   oral administration that is packaged in an LDPE

 

  4   container.  This image illustrates the instructions

 

  5   for use.

 

  6             In summary, there are least four different

 

  7   routes of administration for products packaged in

 

  8   LDPE containers.  Again, this complicates the

 

  9   picture for practitioners and creates the

 

 10   opportunity for errors to occur among inhalation,

 

 11   injection, ophthalmic, and oral drug products.

 

 12             We have discussed several issues that

 

 13   contribute to medication errors with LDPE

 

 14   containers.  We have seen examples of containers

 

 15   that are difficult to read and difficult to

 

 16   distinguish from one another.  We have noted that

 

 17   the look-alike contains look-alike containers are

 

 18   not from a single drug product category or

 

 19   associated with a single route of administration.

 

 20   Now we will explore how routine handling of LDPE

 

 21   containers by patients and practitioners can

 

 22   contribute to errors.

 

                                                                29

 

  1             The foil overwrap serves to protect the

 

  2   containers from light and the environment.  It is

 

  3   recommended that the containers are stored in the

 

  4   foil overwrap until time of use.  However, the

 

  5   reality is that the foil overwraps are commonly

 

  6   discarded.  Once discarded, the clearly labeled

 

  7   portion of the packaging is often eliminated.

 

  8             One reason noted in our analysis for the

 

  9   overwrap to be removed is an effort to fit the

 

 10   products into a medication cart.  The foil overwrap

 

 11   and carton for many inhalation solutions use color

 

 12   to differentiate the dosage strength.  Most foil

 

 13   overwraps contain multiple unit dose LDPE vials.

 

 14   For example, the foil overwrap for Xopenex contains

 

 15   12 vials.

 

 16             Carol, if you'll pass the sample?

 

 17             This image includes the 12 vials which are

 

 18   contents of a single foil pouch of Xopenex.  All of

 

 19   the vials in this image are the same dosage

 

 20   strength.  However, Xopenex is available in three

 

 21   different dosage strengths.  The vials for all

 

 22   three strengths look alike when they are removed

 

                                                                30

 

  1   from the foil.  Although the foil helps to

 

  2   differentiate them, it is possible that these vials

 

  3   may not remain in the foil pouch until their time

 

  4   of use.  These individual LDPE containers can be

 

  5   stored in a variety of places once removed from the

 

  6   foil overwrap.

 

  7             It is a common practice for LDPE

 

  8   containers to be stored in the pockets or pouches

 

  9   of the practitioners who administer these

 

 10   medications.  In summary, while it is possible for

 

 11   various products to have clearly marked foil

 

 12   overwraps, as long as the containers themselves are

 

 13   poorly marked there is still potential for

 

 14   confusion.

 

 15             Once the container leaves the foil

 

 16   overwraps, it no longer matters how well labeled

 

 17   the foil pouch is.  This is a concern, regardless

 

 18   of the number of vials contained in the foil

 

 19   overwrap.  However, a single container in the foil

 

 20   pouch may minimize the likelihood for the vial to

 

 21   become separated from the overwrap.

 

 22             At this point we would like to stimulate

 

                                                                31

 

  1   ideas for discussion about how to address the

 

  2   issues that have been raised so far.  The remainder

 

  3   of this presentation will include a series of

 

  4   photos.  These images will highlight various

 

  5   packaging and labeling approaches to consider.

 

  6   Remember to keep in mind who will be using the

 

  7   products and how they will be used.  Our goal is to

 

  8   identify packaging that will resolve our concerns

 

  9   but not introduce any new problems for those who

 

 10   manufacture or use the products.

 

 11             The paper label approach allows for use of

 

 12   color to distinguish look-alike vials.  For some,

 

 13   these may difficult to read due to the small font

 

 14   size of the text.  The reports in our analysis

 

 15   demonstrated that some people may identify these

 

 16   medications by the color of their label alone.

 

 17   Based on the earlier presentation, we learned of

 

 18   the potential safety and product quality concerns

 

 19   with this approach for inhalation solutions.

 

 20             Although this packaging no longer appears

 

 21   to be used for Timoptic, this image illustrates

 

 22   another approach with paper labels.  The paper

 

                                                                32

 

  1   label is applied to the tip of the container.  The

 

  2   packaging allows for use of color to differentiate

 

  3   the containers and dosage strengths.  However, it

 

  4   may not address the potential for ingress.

 

  5             Again, consider the size of the label and

 

  6   the potential font size issues which may make the

 

  7   text difficult to read.

 

  8             We have a sample of this also going

 

  9   around.

 

 10             Here is an approach that extends the tip

 

 11   of the container to allow for the text to be

 

 12   embossed in the flange instead of the body of the

 

 13   vial.  This approach allows for more space for

 

 14   printed text; however, if both sides are embossed,

 

 15   they tend to interfere with the readability of the

 

 16   text.

 

 17             In contrast, this approach includes an

 

 18   embossed container without an extended flange.  In

 

 19   addition, the container is topped with the letter

 

 20   V-shaped tip.  In this case, V is for Ventolin.

 

 21   This approach allows for use of the unique vial

 

 22   shape and possibly texture to help differentiate

 

                                                                33

 

  1   the product.

 

  2             Another approach used to differentiate the

 

  3   various products in LDPE vials is the use of the

 

  4   embossed letters A, I, and R at the tip of the

 

  5   container.  In addition to a visual cue, the vial

 

  6   makes use of texture to distinguish the products.

 

  7   A is for Albuterol, I is for Ipatropium, and so on.

 

  8   Again, for some this is difficult to read.

 

  9             One approach that has contributed to

 

 10   medication errors with acetylcysteine is the use of

 

 11   a glass vial.  The packaging has led to medication

 

 12   errors where practitioners inject the product

 

 13   instead of administering the drug via inhalation

 

 14   because the vials look similar to those that

 

 15   contain an injectable product.  According to the

 

 16   May 30, 2001, ISMP newsletter article, these error

 

 17   occur despite warnings on the label that state "Not

 

 18   for injection" or "For inhalation."  In addition,

 

 19   they have a target area on the rubber stopper

 

 20   similar to the injectable products.

 

 21             Another approach used to distinguish these

 

 22   products includes the use of a uniquely shaped

 

                                                                34

 

  1   container.  Although these round vials distinguish

 

  2   Pulmicort from other drug products, it is difficult

 

  3   to differentiate between the two dosage strengths

 

  4   of Pulmicort once they are removed from the foil.

 

  5   The image on the right illustrates what the

 

  6   containers look like once the foil overwrap is

 

  7   removed.

 

  8             Some products, such as sodium chloride

 

  9   inhalation solution, utilize a tinted vial as a

 

 10   means of differentiation.  This approach allows for

 

 11   the use of color to help differentiate the

 

 12   containers from other products.  However, this

 

 13   particular packaging has not been evaluated by CDER

 

 14   at FDA.  These vials also include embossed text.

 

 15             Another approach is the shrink wrap

 

 16   approach which allows for the combination of

 

 17   embossed information on the end of the vial and the

 

 18   use of black print on a clear background.  Again,

 

 19   for some this may be difficult to read.  The

 

 20   printed portion of this label clings to the vials

 

 21   without adhesives, eliminating one potential source

 

 22   of packaging contamination.  However, there are

 

                                                                35

 

  1   still sources of volatile chemicals with the shrink

 

  2   wrap approach.

 

  3             There's also a sample of this going

 

  4   around.  The individual foil overwrap approach was

 

  5   described in the Draft Guidance that Dr. Sullivan

 

  6   referred to in his presentation.  This method will

 

  7   protect the drug product from contamination from

 

  8   the environment and minimize the opportunity for

 

  9   contamination from the packaging itself.

 

 10             Each foil overwrap contains a single vial.

 

 11   This is thought to increase the likelihood of the

 

 12   pouch staying with the container and minimize the

 

 13   risk for errors.  The overwrap allows for the use

 

 14   of color and other means of differentiation to help

 

 15   distinguish these products.

 

 16             At this time we are seeking other ideas

 

 17   and approaches to consider.  What other materials

 

 18   could we use?  What has been done for other

 

 19   products?  What will meet the needs of those using

 

 20   the products in both the inpatient and outpatient

 

 21   setting?  How should FDA evaluate any proposed

 

 22   changes?

 

                                                                36

 

  1             Also ask yourself, Will it prevent

 

  2   contamination from secondary packaging in the

 

  3   environment?  Will it be difficult to read?  Will

 

  4   it look like other containers?  Will it create new

 

  5   problems?  Will it be difficult to use?  And,

 

  6   finally, should inhalation products be handled

 

  7   separately from products with other routes of

 

  8   administration?  We look forward to hearing your

 

  9   ideas and suggestions.

 

 10             DR. GROSS:  Okay.  To round out the

 

 11   presentations, Dr. Shah will talk about the

 

 12   perspective for chemistry, manufacturing, and

 

 13   controls.

 

 14             DR. SHAH:  Good morning.  My name is

 

 15   Vibhakar Shah, and I'm a chemist in the Office of

 

 16   New Drug Chemistry for Pulmonary and Allergy Drug

 

 17   Products.  Before I start, I would like to

 

 18   apologize for my delay.  I was stuck in traffic for

 

 19   almost one and a half hours.  Let me tell you, it's

 

 20   not a pleasant experience.  But, in any case,

 

 21   that's life.  And I'm sure when we move to White

 

 22   Oak it's going to get worse.

 

                                                                37

 

  1             [Laughter.]

 

  2             DR. SHAH:  You were supposed to hear this

 

  3   talk before Marci's talk, but, anyway, here it

 

  4   goes.

 

  5             You already heard from Dr. Sullivan the

 

  6   clinical concerns arising due to the permeability

 

  7   of LDPE vials, especially when used with paper

 

  8   labels for inhalation drug products, and also you

 

  9   heard some of the medication errors which are

 

 10   caused because of legibility issues with the paper

 

 11   labels.  And I'm going to talk about in the next 20

 

 12   minutes regarding the problems and issues with

 

 13   product quality concerns arising due to the use of

 

 14   LDPE containers, with or without paper labels and

 

 15   with or without overwrap, for these drug products.

 

 16             In the context of today's discussion, my

 

 17   presentation will also focus on how best to

 

 18   minimize the potential medication errors given the

 

 19   quality concerns associated with these container

 

 20   closures.

 

 21             With that, this slide gives you the

 

 22   outline of my talk.  I'm going to start with a

 

                                                                38

 

  1   brief introduction to the type of inhalation drug

 

  2   products that are packaged in LDPE containers, and

 

  3   after that I'll be overviewing the current

 

  4   container-closure systems that are used.  Following

 

  5   that, I would like to discuss the results of an

 

  6   analytical survey conducted by the agency for

 

  7   several inhalation drug products under the Drug

 

  8   Product Quality Surveillance Program.  This survey

 

  9   particularly identified the clinical concerns as

 

 10   well as the quality concerns arising from the drug

 

 11   product contamination by packaging components

 

 12   because of the permeability of LDPE.

 

 13             Following that, I would like to discuss

 

 14   some of the quality concerns arising with the use

 

 15   of LDPE vials, with or without paper label and foil

 

 16   overwrap.  I will discuss the agency's current

 

 17   approaches to control and minimize the product

 

 18   contamination from packaging components and discuss

 

 19   current recommendations for packaging of inhalation

 

 20   drug products as provided in the Draft Guidance.

 

 21   And I will end my presentation with summarizing the

 

 22   quality concerns, what I have discussed so far.

 

                                                                39

 

  1             This slide lists the inhalation dosage

 

  2   forms administered by oral inhalation, and these

 

  3   drug products include inhalation solutions,

 

  4   suspensions, spray, inhalation aerosol, and

 

  5   inhalation powder.  However, for today's

 

  6   discussion, the remainder of the talk will focus on

 

  7   inhalation solutions and suspensions as they are

 

  8   the only two dosage forms that are packaged in LDPE

 

  9   containers.

 

 10             This slide you have already seen in Dr.

 

 11   Sullivan's presentation.  It just shows the type of

 

 12   drug products which are packaged into LDPE

 

 13   containers.

 

 14             Currently, inhalation solutions and

 

 15   suspensions are packaged in LDPE vials, and there

 

 16   are three components, basically:  LDPE vials, vial

 

 17   labels, and foil overwrap pouch.  Not all the

 

 18   inhalation solutions and suspensions may have foil

 

 19   overwrap pouch or adhesive paper label.  But in any

 

 20   case, the unit-dose vial--that is, the LDPE

 

 21   vial--is made up of low-density polyethylene by

 

 22   blow-fill-seal or form-fill-seal process.  The

 

                                                                40

 

  1   labeling information on a vial is conveyed either

 

  2   by a self-adhesive printed paper label or by

 

  3   embossing or debossing the labeling information on

 

  4   the LDPE vial itself during the fabrication of the

 

  5   vial.

 

  6             Foil overwrap acts as a protective

 

  7   secondary package and may contain anywhere from one

 

  8   to 12 vials per pouch.  The labeling information

 

  9   may be conveyed by a self-adhesive paper label on

 

 10   the foil overwrap, or the foil overwrap may be

 

 11   printed.  Furthermore, different colors for foil

 

 12   pouches may be used to differentiate the multiple

 

 13   strengths of the drug product.

 

 14             Now, let me go over the container-closure

 

 15   components of the LDPE vial, paper label, and

 

 16   foil-laminate.  I'll start the LDPE vial.

 

 17             The unit-dose vial, which is made up of

 

 18   low-density polyethylene, is chemically a

 

 19   polyethylene homo-polymer resin.  The polyethylene

 

 20   resin is made by polymerization process and may

 

 21   contain several chemical additives in addition to

 

 22   the reactant polymer.  They include chain transfer

 

                                                                41

 

  1   agent, chain initiator, antioxidant, so on and so

 

  2   forth.

 

  3             Furthermore, it is available in different

 

  4   grades for different applications.  That indicates

 

  5   that the composition of the LDPE may change

 

  6   depending upon how it is being used.  There are

 

  7   many manufacturers and suppliers of this LDPE.

 

        T1B                 This slide lists some of the               8

 

  9   characteristics and properties offered by LDPE or

 

 10   LDPE vials which probably makes it a material of

 

 11   choice for packaging of inhalation solution and

 

 12   suspensions from a manufacturer's point of view.

 

 13   These include:  they are flexible and malleable;

 

 14   stress crack, impact, and tear resistant; they are

 

 15   considered chemically inert at room temperature; or

 

 16   it may be used at elevated temperature for extended

 

 17   periods of time; or it can be sterilized.  They are

 

 18   used on high-speed production lines and,

 

 19   aesthetically, they can be clear to translucent in

 

 20   appearance.

 

 21             However, it is permeable to volatile

 

 22   chemicals and gases, and because of this

 

                                                                42

 

  1   permeability, there are several quality concerns

 

  2   which I'll be discussing later in my talk.

 

  3             The next I would like to talk about is the

 

  4   paper label, the components of a self-adhesive

 

  5   paper label and how it may contribute to the

 

  6   quality concerns of inhalation solutions and

 

  7   suspensions.

 

  8             Typically, a paper label consists of a

 

  9   base paper, adhesive, inks, pigments and dyes,

 

 10   varnishes, over-lacquer, et cetera, and depending

 

 11   upon the application, the base paper may contain or

 

 12   may be treated with all or many of the chemicals

 

 13   that I have listed here.

 

 14             Adhesive is the layer which comes in

 

 15   immediate contact with the LDPE vial when it is use

 

 16   with self-adhesive paper labels.  This slide lists

 

 17   typical chemical composition of an adhesive.  This

 

 18   is not an all-inclusive list.  There are many more

 

 19   proprietary chemicals used in the formulation of

 

 20   these adhesives.  Depending upon the physical

 

 21   chemical properties of these chemicals, that is to

 

 22   say, volatility, they may permeate through the LDPE

 

                                                                43

 

  1   vial into the drug product.

 

  2             I have listed here some of the

 

  3   over-lacquer components.  Over-lacquer is an

 

  4   evaporative(?) coating which is typically comprised

 

  5   of chemicals such as plasticizers, resins,  (?)

 

  6   solvents, diluents, surfactants, and many more.

 

  7   Some of these chemicals are proprietary in nature.

 

  8   Over-lacquer, or varnish, may be used for a

 

  9   transparent glassy appearance of the label, also a

 

 10   stabilizer for the print work and art work, or it

 

 11   can be used as a protective barrier to the moisture

 

 12   and overall to extend the longevity of the label.

 

 13   Again, in this case also, depending upon the

 

 14   physical chemical properties of some of these

 

 15   chemicals and their constituents, also the

 

 16   concentration and storage conditions, these

 

 17   chemicals may have a potential to permeate through

 

 18   the LDPE vials into the drug product.

 

 19             These are typical ink components.  One may

 

 20   think that ink might be just a single-component

 

 21   formulation.  However, if you look at it, there is

 

 22   more than one chemical included into the ink

 

                                                                44

 

  1   formulation.  And, again, these are also propriety

 

  2   formulations.

 

  3             These ink formulations may be  (?)-based

 

  4   or organic solvent-based, and depending upon the

 

  5   brand of solvents which are used in the

 

  6   formulation, they may have a potential to permeate

 

  7   through the LDPE vials into the drug product.

 

  8             The last I would like to talk about is the

 

  9   foil-laminate.  Primarily, foil-laminate is used as

 

 10   a protective secondary packaging for the drug

 

 11   formulations that may be sensitive to light and

 

 12   react to gases such as oxygen.

 

 13             Typically, foil-laminate is a flexible

 

 14   packaging composed of multiple layers of various

 

 15   types of plastic films which are fused together

 

 16   either by heat or pressure-sensitive adhesives

 

 17   applied to one or both sides of an aluminum foil.

 

 18   In this cartoon, aluminum foil is represented by

 

 19   layer D, and as you can see, the whole foil

 

 20   overwrap surrounds the drug product vial on an

 

 21   automated packaging line.

 

 22             The thickness of aluminum foil, which is

 

                                                                45

 

  1   D, and the number of pinholes per unit area are

 

  2   crucial for ensuring the consistent barrier to

 

  3   permeability.  Furthermore, each of the composite

 

  4   layers may contain volatility chemicals, organic

 

  5   solvents, as they are used in adhesives, which may

 

  6   permeate through a LDPE vial into the drug product,

 

  7   especially the adhesive layer that is closer to the

 

  8   drug product.  In this case, that is shown by G.

 

  9   So the composition of these are very critical.  One

 

 10   has to really have a knowledge of its composition

 

 11   before they can be selected for the foil overwrap.

 

 12   Alternate approaches to adhesive can be considered,

 

 13   such as fusion of the multiple layers of

 

 14   foil-laminate by heat-set process.

 

 15             In addition to the clinical concerns

 

 16   discussed by Dr. Sullivan, the permeability of LDPE

 

 17   raises several quality concerns, and these are

 

 18   listed on this slide, mainly the drug product

 

 19   contamination through ingress of volatile chemicals

 

 20   which may be originating from the environment that

 

 21   may be irritant or toxic to the respiratory tract

 

 22   and may sensitize individuals; drug product

 

                                                                46

 

  1   degradation because of the reactive gases and light

 

  2   that permeate through the LDPE vial and cause

 

  3   degradation of the drug product; and change in

 

  4   product concentration because of the water

 

  5   evaporation through the LDPE vials.  This in turn

 

  6   can accelerate the drug product degradation because

 

  7   of the concentration of the drug product.

 

  8             Now, let me share with you the results of

 

  9   an analytical survey of approved NDA and ANDA

 

 10   inhalation solutions marketed in LDPE vials without

 

 11   protective overwrap.  The basis for this survey was

 

 12   a large-scale voluntary recall of inhalation

 

 13   solution by a firm due to contamination of the drug

 

 14   product with 1-phenoxypropanol.  This is a known

 

 15   component present in the packaging components.

 

 16   This recall was conducted with FDA's knowledge and

 

 17   followed by a health hazard evaluation.  It was

 

 18   later found out that the source of this chemical

 

 19   was the varnish or over-lacquer that was used for a

 

 20   shelf carton.

 

 21             Alarmed by this incident, the agency was

 

 22   concerned that there may be other inhalation drug

 

                                                                47

 

  1   products with such contamination from packaging

 

  2   components.  As a result, it was decided to conduct

 

  3   a product quality survey of some of the marketed

 

  4   inhalation solutions.

 

  5             This was initiated by the Office of

 

  6   Generic Drugs in consultation with the Division of

 

  7   Pulmonary and Allergy Drug Products and in

 

  8   coordination with the Office of Compliance, Office

 

  9   of Regulatory Affairs, field offices, and Pacific

 

 10   Regional Laboratory.  Seven ANDAs and one NDA for

 

 11   inhalation solutions covering five different drug

 

 12   substances were selected.

 

 13             There were 38 samples representing 37 lots

 

 14   of various drug products in LDPE vials without a

 

 15   protective overwrap foil pouch.  The samples were

 

 16   screened for potential volatile chemicals which are

 

 17   known to be present in the packaging components,

 

 18   such as vanillin, 2-phenoxyethanol, and

 

 19   1-phenoxy-2-propanol by sensitive analytical

 

 20   techniques such as GCMS and HPLC methods.  Let me

 

 21   share the results of this survey.

 

 22             Twenty-nine out of 38 samples tested

 

                                                                48

 

  1   positive for chemical contamination originating

 

  2   from packaging components.  Five known chemical

 

  3   contaminants, as listed below, were detected

 

  4   originating from packaging, such as benzophenone,

 

  5   polyethylene glycol, 2-(2-butoxyethoxy)ethanol,

 

  6   2-(2-ethoxyethoxy) ethanol acetate, and

 

  7   2-hydroxy-2-methylpropriophenone.

 

  8             A health hazard evaluation was conducted

 

  9   at the levels these components were detected in

 

 10   these drug products.  However, it was indicated

 

 11   that the levels of these components did not raise

 

 12   sufficient safety concern in the intended

 

 13   population to warrant a recall of these drug

 

 14   products.  Nonetheless, the following issues were

 

 15   of concern:

 

 16             It was indicated that potential for these

 

 17   chemicals to cause bronchospasm at levels detected

 

 18   is unknown, especially in patients with respiratory

 

 19   diseases.

 

 20             It was also indicated that concentration

 

 21   of these chemicals might be grater at the end of

 

 22   expiry than what was detected at the time they were

 

                                                                49

 

  1   tested.

 

  2             It also showed that permeation through

 

  3   LDPE vial is a real phenomenon.

 

  4             It was also concluded that additional

 

  5   chemicals may be present, but may not get detected

 

  6   because the analytical techniques which were used

 

  7   may not be suitable, not knowing what components

 

  8   might be present into those solutions.

 

  9             And, also, future changes in the materials

 

 10   used in labeling and packaging may result in

 

 11   contamination with different chemicals.

 

 12             So, in a nutshell, product contamination

 

 13   can occur because of the formulation component

 

 14   degradation or by leaching of chemical constituents

 

 15   from packaging components, such as resin components

 

 16   I have listed, paper label components, foil

 

 17   overwrap components, cartons, and environment.

 

 18             These are the typical extractable or

 

 19   leachable components which have been found in the

 

 20   drug product from packaging components.  Some of

 

 21   them are irganox 129, 2, 2, 6-trimethyloctane,

 

 22   which is coming from resin components.  Some of the

 

                                                                50

 

  1   paper label components that we have seen is benzoic

 

  2   acid, ethyl phthalate, benzophenone, danocur 1173,

 

  3   cyclic phthalates.  From the foil overwrap, we have

 

  4   seen methacrylic acid, 2-phenoxyethanol, and some

 

  5   of the organic solvents such as acetone,

 

  6   2-butanone, ethylacetate, propylacetate, heptane,

 

  7   and toluene.  And from cartons, methacrylic acid

 

  8   and 1-phenoxy-2-propanol.

 

  9             So this raises a significant quality

 

 10   concern, and there are several other factors.

 

 11   These are the factors.  Because of the proprietary

 

 12   nature of components and composition of this

 

 13   packaging material, we may not know what is present

 

 14   in the solution.  The composition of these

 

 15   components which are present in the packaging may

 

 16   change without the knowledge of applicant and the

 

 17   agency.  And you cannot detect if you don't know

 

 18   what you are looking for.  As a result, there is no

 

 19   one analytical procedure to detect unknown chemical

 

 20   contaminants.  And there is incomplete

 

 21   toxicological data or information available for

 

 22   many of these identified chemical contaminants. 

 

                                                                51

 

  1   And as the environmental conditions change, that

 

  2   may introduce new contaminants.

 

  3             So what are the potential approaches the

 

  4   agency has taken to minimize and control the

 

  5   contamination from packaging components to the

 

  6   extent possible?  Our approach has been and we have

 

  7   recommended that characterize or identify all

 

  8   possible extractables and establish a profile for

 

  9   each packaging component, for resin, vial, paper

 

 10   label, foil-laminate overwrap.

 

 11             What I mean by extractable is extractable

 

 12   is a chemical compound, which can be volatile or

 

 13   non-volatile, that gets extracted from a packaging

 

 14   component in a suitable solvent by utilizing

 

 15   optimum extraction conditions, such as time and

 

 16   temperature.

 

 17             Extractable profile for a given packaging

 

 18   component typically can be a chromatogram

 

 19   representing all possible extractables.

 

 20             After that, establish a correlation

 

 21   between extractable and its leachable potential,

 

 22   and what I mean by leachable is leachable is any

 

                                                                52

 

  1   chemical compound that leaches into the drug

 

  2   product formulation either from a packaging

 

  3   component or a local environment on storage through

 

  4   expiry of the drug product.  An extractable can be

 

  5   a leachable.

 

  6             And to ensure batch-to-batch consistency

 

  7   of the drug product, appropriate specification for

 

  8   a leachable is established based on its

 

  9   qualification and observed levels in the drug

 

 10   product on storage.

 

 11             As a result, the next approach is we asked

 

 12   them to set meaningful acceptance criteria for a

 

 13   given extractable in corresponding incoming

 

 14   packaging components based on its qualification

 

 15   level and actual observed data.  Once that is

 

 16   accomplished, meaningful acceptance criteria for a

 

 17   given leachable based on actual observed data in

 

 18   the drug product also be established.

 

 19             These are the recommendations we have

 

 20   provided in the Draft Guidance.  We have

 

 21   recommended that adequate knowledge of composition

 

 22   and physico-chemical properties of packaging

 

                                                                53

 

  1   components is essential for appropriate selection

 

  2   of these components.  We discourage paper label

 

  3   directly on the LDPE vial and encourage alternative

 

  4   approaches, including embossing or debossing, in

 

  5   lieu of the paper label on the LDPE vial because of

 

  6   the reasons I discussed, because of the product

 

  7   contamination.  This can be accomplished by

 

  8   extended bottom flanges to unit-dose vial that can

 

  9   carry essential vial labeling information and can

 

 10   retain the product identity.

 

 11             We have also recommended use of protective

 

 12   overwrap foil pouch for the LDPE unit-dose vial.

 

 13   This in turn can minimize the ingress and leaching

 

 14   of chemical contaminants from the local environment

 

 15   provided that the components that have been

 

 16   selected for the fabrication of the overwrap foil

 

 17   pouch are appropriately selected.

 

 18             The self-adhesive paper label on a foil

 

 19   pouch or pre-printed foil pouch is also

 

 20   recommended, and different color schemes to

 

 21   differentiate multiple strengths of the drug

 

 22   product is also recommended.  This in turn can

 

                                                                54

 

  1   prevent ingress or leaching of chemical

 

  2   contaminants from paper labels and may improve the

 

  3   legibility issues.

 

  4             The last recommendation we have in our

 

  5   Draft Guidance is to limit the number of unit-dose

 

  6   vials per pouch, ideally to one LDPE vial per foil

 

  7   pouch.  This can minimize the risk of medication

 

  8   error by patients and health care professionals,

 

  9   and it can prevent unnecessary exposure to local

 

 10   environment when compared to packaging of

 

 11   multi-unit-dose vials in a foil pouch.

 

 12             So, in summary, so far I have presented to

 

 13   you that volatile chemicals present in the

 

 14   packaging components and local environment have a

 

 15   great potential to permeate through LDPE vials into

 

 16   drug product formulation on storage.  The agency's

 

 17   analytical survey and other supportive data have

 

 18   confirmed ingress and leaching of such volatile

 

 19   chemicals into the drug product formulations.

 

 20             Ingress or leaching of such chemicals into

 

 21   drug product formulation poses a safety concern for

 

 22   patients with respiratory illnesses, such as asthma

 

                                                                55

 

  1   and COPD.  Embossing or debossing of LDPE vial in

 

  2   lieu of paper label is recognized to have

 

  3   legibility issue.  However, paper labels, although

 

  4   perceived to address legibility issue, overall may

 

  5   not be the optimum solution because of the safety

 

  6   concerns associated with potential leaching and

 

  7   ingress of paper label components in the drug

 

  8   product through LDPE vial.

 

  9             The agency's current recommendations as

 

 10   stated in the Draft Guidance may serve as a first

 

 11   step in the right direction to address the issues

 

 12   that are being discussed today.  And the agency is

 

 13   seeking other viable approaches to address these

 

 14   issues to promote safe product use without

 

 15   compromising the integrity of the drug product.

 

 16             With that, I will conclude my talk, and

 

 17   thank you for your attention.

 

 18             DR. GROSS:  Thank you very much, Dr. Shah,

 

 19   and I want to thank the first three speakers who

 

 20   presented a very clear review of the problem.

 

 21             We are now open for discussion.  Perhaps

 

 22   I'll start off with a couple questions.

 

                                                                56

 

  1             We talk about low-density polyethylene.

 

  2   Does high-density polyethylene reduce transmission,

 

  3   number one?  Number two, would increasing the

 

  4   thickness of the container reduce transmission?

 

  5   And, number three, have other plastics been

 

  6   considered?  I'm not a chemist so I don't know, but

 

  7   polypropylene, polystyrene?  And are any of those

 

  8   possibilities?

 

  9             DR. SHAH:  So far, traditionally, LDPE is

 

 10   the choice of material by the manufacturer because

 

 11   of some of the properties it can offer.  And I

 

 12   guess one can increase the thickness of the LDPE

 

 13   vial or may use a different polymer.  However, one

 

 14   has to keep in mind that by nature, when you do the

 

 15   fabrication of the vials, it may have some kind of

 

 16   a permeability.  But that depends on the degree of

 

 17   permeability.  LDPE offers one side of the

 

 18   spectrum, or other polymers may offer a different

 

 19   type of permeability.  But one has to conduct some

 

 20   of the studies to show that it does not permeate.

 

 21             DR. GROSS:  Michael?

 

 22             DR. COHEN:  Dr. Lee mentioned shrink wrap

 

                                                                57

 

  1   at one point, and then added that there might still

 

  2   be some concern about, you know, the volatility, I

 

  3   guess, of the inks in the shrink wrap itself.  It

 

  4   does not come in contact with the actual LDPE

 

  5   plastic, though, so I'm trying to figure out why

 

  6   that would be a concern.  Do you think it's still

 

  7   possible for that to leach in?

 

  8             DR. SHAH:  Yes, let me answer that.

 

  9   Shrink wrap, again, it's a plastic and it suffers

 

 10   through the same thing.  It comes in direct contact

 

 11   with the LDPE vial.  So depending upon the chemical

 

 12   components of the ink and how it is being used, in

 

 13   a shelf carton or anything, it still will have the

 

 14   same unit problems that I discussed.

 

 15             DR. COHEN:  Can I ask a follow-up?

 

 16             DR. GROSS:  Yes, go ahead, Michael.

 

 17             DR. COHEN:  Have you done testing--

 

 18             DR. SHAH:  No, we--I mean, we have not

 

 19   even received--or we have not approved a drug

 

 20   product with the shrink wrap.  There is no example

 

 21   of that, at least to CDER.  Maybe in other

 

 22   divisions, another agency, but we haven't received

 

                                                                58

 

  1   any.

 

  2             DR. GROSS:  Jackie, next question?

 

  3             DR. GARDNER:  I understand the problem of

 

  4   potentially masking the effect of contamination by

 

  5   the condition, but I was surprised to see only 87

 

  6   reports of medication errors that you're working

 

  7   from.  And given the excellent presentation and the

 

  8   potential for confusion, I'm surprised that there

 

  9   were so few because it looks like it would happen a

 

 10   lot.  I wondered if we could have some perspective

 

 11   on why there would be so few, and maybe Mike can

 

 12   help with that.

 

 13             And then the second thing is I wondered

 

 14   whether any of the potential suggested

 

 15   recommendations or the different packaging types

 

 16   have been tested in any way that we could

 

 17   reasonably expect that they might reduce the

 

 18   potential for error if they were implemented,

 

 19   whether the foil wrap or any of these things have

 

 20   been tested among the people who would be using

 

 21   them.

 

 22             DR. GROSS:  Next question, Leslie?

 

                                                                59

 

  1             Does anybody have an answer?  Marci?

 

  2             DR. LEE:  Thank you.  As to the number of

 

  3   reports being few, since the review was done, there

 

  4   have been additional reports submitted to the

 

  5   agency for a total, I think I said, of 138 reports,

 

  6   which may still sound like a small number, but

 

  7   considering the problem is probably very underreported.  We

 

  8   also had some reports that were

 

  9   describing errors that had to do with restocking.

 

 10   For example, a transport team's pouch was supposed

 

 11   to contain three Albuterol and three Ipatropium

 

 12   vials, and at this one given time it contained one

 

 13   vial of one drug and five of the other.  So, you

 

 14   know, in the report the narrative says, "We suspect

 

 15   that at least one patient has been affected by this

 

 16   problem."

 

 17             The same thing can happen in an inpatient

 

 18   setting where the drugs are getting intermixed in a

 

 19   bin.  So it's really an unknown, the actual impact

 

 20   of the problem.

 

 21             DR. GROSS:  Leslie?

 

 22             DR. HENDELES:  I'd like to just respond to

 

                                                                60

 

  1   Jackie's comment.  Mixing these medicines up is

 

  2   very unlikely to be associated with a visible toxic

 

  3   reaction, so that might be--if anything, the

 

  4   adverse consequences is a lack of therapeutic

 

  5   effect when you're treating a disease that's

 

  6   involving acute bronchospasm.  So the clinician

 

  7   can't distinguish between lack of drug effect from

 

  8   worsening of the disease.

 

  9             But the question I had was:  Is there any

 

 10   evidence that these contaminants in any way

 

 11   interact with the active drugs to either decrease

 

 12   their stability or to in some way inactivate them?

 

 13             DR. SHAH:  They may not inactivate, but

 

 14   they will increase the degradation of the products.

 

 15   They may react with the active, and then you will

 

 16   form an adduct.  But you are not going to, you

 

 17   know, inactivate the drug product.

 

 18             DR. SULLIVAN:  The other thing t keep in

 

 19   mind is that the list of potential contaminants is

 

 20   innumerable.  So what may be true of one chemical

 

 21   may not be true of the others.

 

 22             DR. GROSS:  Curt Furberg?

 

                                                                61

 

  1             DR. FURBERG:  I'd like to expand on that

 

  2   question.  What are the health effects of these

 

  3   contaminants?  Are they all toxants?  And if we

 

  4   don't know that these contaminants have adverse

 

  5   health effects, is this a big issue?

 

  6             DR. SULLIVAN:  Well, I think the unknown

 

  7   is part of the problem, and being a clinician at

 

  8   the agency, we've been tasked with addressing the

 

  9   specific risk of specific chemicals that have been

 

 10   found in assays done, particularly--it was

 

 11   discussed in the analytical survey and so forth.

 

 12   So we get asked this question:  What's the

 

 13   toxicologic potential of this chemical?  And we

 

 14   don't know most of the time.  There haven't been

 

 15   toxicologic studies done.  We don't know the

 

 16   carcinogenic potential.  We don't know the extent

 

 17   to which it acts as an irritant or has other toxic

 

 18   effects.  And then we have to judge, okay, what's

 

 19   the risk out there, and it's very difficult.

 

 20             DR. FURBERG:  Yes, but shouldn't you add

 

 21   that to your recommendation that we find out?

 

 22             DR. SULLIVAN:  Well, I think that's part

 

                                                                62

 

  1   of why we're saying it's best to just try to limit

 

  2   potential exposure, because you can't list all of

 

  3   these chemicals.  For instance, the one that was

 

  4   mentioned was found in a drug product, and it was

 

  5   traced back to the fact that the actual carton that

 

  6   these vials were contained in, the manufacturer of

 

  7   that carton, who isn't the drug manufacturer,

 

  8   changed the glue or lacquer in that carton.  And so

 

  9   a chemical that we wouldn't have previously been

 

 10   aware of made its way into the drug.

 

 11             DR. SHAH:  Again, the agency does not

 

 12   control the cartons.  We will control to a point

 

 13   and look into the things.  The carton is something

 

 14   very--and as a result, I think our approach has

 

 15   been--or we recommend the use of overwrap pouch.

 

 16   That can also limit to a certain extent.  I mean,

 

 17   there is no 100-percent guarantee that it may not

 

 18   permeate or the glues which are used in the

 

 19   foil-laminate itself may get into the drug product.

 

 20             But one needs to study these things

 

 21   before, you know, providing to the agency.

 

 22             DR. GROSS:  Okay.  Henri, and then we'll

 

                                                                63

 

  1   hold questions after that until later.

 

  2             DR. MANASSE:  I have a couple of

 

  3   questions.  One is:  Do we see the impact of the

 

  4   degradation on all of the active ingredients, that

 

  5   is, for the Albuterol and the Tobramycin and the

 

  6   cromolyn?  Is that pretty much standard across all

 

  7   of the ingredients that these volatile substances

 

  8   do have a degrading impact?

 

  9             The other question I had is:  What

 

 10   experiences can we gain from either the food and/or

 

 11   the cosmetic industry?  Are there experiences there

 

 12   since so much of this packaging is also with

 

 13   low-density polyethylene containers?

 

 14             And my last question relates to the

 

 15   potential application of the bar code to packages

 

 16   vis-a-vis the incoming rule.  To what extent will

 

 17   symbology printing either exacerbate or lessen this

 

 18   particular issue?

 

 19             DR. SHAH:  I kind of lost you.  What was

 

 20   the first question?

 

 21             DR. MANASSE:  The first question, Is the

 

 22   infusion, leaching of the contaminants equally

 

                                                                64

 

  1   impactful on all the active ingredients in these

 

  2   products?

 

  3             DR. SHAH:  I think some of these will stay

 

  4   as a degradation product.  They may not impact the

 

  5   active ingredient, but it will be just a product

 

  6   contamination.

 

  7             Now, itself, how it will affect the

 

  8   particular patient population, that is--as Dr.

 

  9   Sullivan said, we don't know the potential of that.

 

 10   So it may not probably reduce the concentration of

 

 11   the active into the drug product.  However, that

 

 12   uncertainty regarding the safety is a concern.

 

 13             The second question was?

 

 14             DR. MANASSE:  The second question relating

 

 15   to experiences in the food and cosmetic industry

 

 16   and what may be learned there.

 

 17             DR. SHAH:  Okay.  I think by far the

 

 18   most--these packaging components are used also in

 

 19   tablets and other solid oral dosage forms.  There

 

 20   the risk is less because you are taking it orally.

 

 21   Here the problem is because of the patient

 

 22   population, we are more concerned.  And I don't

 

                                                                65

 

  1   know what else can be learned from food and other

 

  2   industries because there is--I don't know that much

 

  3   scrutiny is there.  The only thing that is there is

 

  4   whether they are adequate in terms of oral dosage

 

  5   use.  That's it.

 

  6             Does that answer--

 

  7             DR. MANASSE:  And my last question related

 

  8   to the upcoming application of the bar coding rule

 

  9   and the imprinting of symbologies to implement that

 

 10   particular rule.

 

 11             DR. LEE:  Actually, LDPE vials was one of

 

 12   the products that was exempt from that rule.  It

 

 13   won't be required down to the vial, but any outer

 

 14   packaging it will be on.

 

 15             DR. GROSS:  Okay.  We'll take a break now

 

 16   and reconvene at 9:45.

 

 17             [Recess.]

 

        T2A                 DR. GROSS:  The first speaker will be            

18

 

 19   Mohammad Sadeghi, who will talk about container

 

 20   labeling options using rommelag blow-fill-seal

 

 21   technology.

 

 22             DR. SADEGHI:  Good morning.  I'm Mohammad

 

                                                                66

 

  1   Sadeghi with Holopack International.  I'm here to

 

  2   talk about container labeling options using

 

  3   blow-fill-seal technology, and most of all these

 

  4   products you've been hearing today about and

 

  5   packaging and LDPE, low-density polyethylene,

 

  6   they're all manufactured using blow-fill-seal

 

  7   technology.

 

  8             So what I'm going to do is go over what

 

  9   the blow-fill-seal process is, what container

 

 10   labeling options you have, what are the pros and

 

 11   cons on each, and some examples.

 

 12             Blow-fill-seal technology is an integrated

 

 13   aseptic technology for manufacturing aseptic

 

 14   products.  That's an example of a machine.  The way

 

 15   it works is you feed in raw pellet resins from one

 

 16   end and the  (?)  solution from another, and the

 

 17   machine will actually melt the pellet, created the

 

 18   container, fill it aseptically, and seal it.

 

 19             The process consists of four major steps.

 

 20   As you see, the plastic is molten first and

 

 21   extruded in a cylindrical shape, and the molds are

 

 22   formed into the container, the needle comes in, and

 

                                                                67

 

  1   there is the Class 100 in this  (?)  area, fills

 

  2   the container, and it withdraws, and then the

 

  3   container is sealed and ejected from the machine.

 

  4             Now, labeling options that you can have

 

  5   with this technology consist of embossing, paper

 

  6   label on tab if you do not want to put it directly

 

  7   on the container, or printing on the tabs.

 

  8             Embossing consists of a mirror--engraving

 

  9   mold with a mirror image of the information.  You

 

 10   have small vacuum ports on the mold surface that

 

 11   actually will do this, such into the softened

 

 12   plastic into the engraving embossing, hence

 

 13   embossing the container.

 

 14             This is an example of what a mold cavity

 

 15   looks like, and you see the surface inside the main

 

 16   cavity where the engraving takes place.

 

 17             This is a close-up of what it's like to

 

 18   have as the imprint.  What you see in the bottom

 

 19   would be replaceable magazines that you can change

 

 20   for lot number and expiration date.

 

 21             Another option of embossing is hot stamp,

 

 22   which in this case instead of molding it during the

 

                                                                68

 

  1   production, as the container is ejected from the

 

  2   BFS machine, it's actually put into a machine where

 

  3   it actually is a hot stamp that would actually

 

  4   emboss the container, again, and this is done on

 

  5   the tabs and not directly on the body of the

 

  6   container.

 

  7             Paper labels on tabs, one of the reasons

 

  8   this container was developed was to avoid direct

 

  9   contact labels with--paper labels with the actual

 

 10   container body, and the secondary was the

 

 11   small-volume containers that required information

 

 12   and there was not enough surface area to put the

 

 13   engraving on the container.  They developed a tab.

 

 14   Either it can be on the cap or as a tail, have the

 

 15   embossed information.

 

 16             You can use the same tab, actually,

 

 17   instead of--it's a solid surface, so you can use it

 

 18   either to print or add paper to the label.

 

 19             The pros and cons of each labeling option:

 

 20   Embossing has been discussed here.  The pros are

 

 21   there is no maintenance of label inventories;

 

 22   ensure 100-percent labeling of containers; labels

 

                                                                69

 

  1   cannot be removed; and ensure each unit is

 

  2   traceable and no leachables.  The cons are, which

 

  3   has been discussed also, it is difficult to read on

 

  4   clear containers.

 

  5             Paper label on tabs is--paper label

 

  6   obviously makes it clearer to read, and you can use

 

  7   colors.  It greatly reduces potential leaching into

 

  8   the solution because it's not directly applied to

 

  9   the container body.  However, there is still

 

 10   potential leaching of adhesive.

 

 11             Direct printing on the tab, it's clearer

 

 12   than embossing on the tab to be read; it eliminates

 

 13   potential leaching from paper, adhesive, varnish

 

 14   and stuff that goes with the paper label; and it

 

 15   greatly reduces potential leaching into the

 

 16   solution, again, because it's on the tab, on a

 

 17   separate space on the container, not directly on

 

 18   the container body; and, lastly, allows for bar

 

 19   code printing on line as well.  However, you still

 

 20   have the ink, which potentially can leach into the

 

 21   solution.

 

 22             Now, examples of these various things,

 

                                                                70

 

  1   there's a container with embossed labeling.  The

 

  2   containers can be also embossed and color-coded

 

  3   because the same container can be used for

 

  4   different concentrations of products, or you can

 

  5   have color-coded and embossed to represent the same

 

  6   product in different concentrations or doses.

 

  7             You can apply the paper on the tab, both

 

  8   removing the paper from direct exposure to the

 

  9   solution, but also it is readable.  Or having

 

 10   direct printing on the tab for bar code

 

 11   information.

 

 12             Also, you have traditional paper on the

 

 13   container, which is...

 

 14             Now, the other thing is the issue of--one

 

 15   of the things that comes to mind is the size of the

 

 16   containers, is eliminating paper containers--paper

 

 17   labels from all outside containers or is it

 

 18   dependent--it is a size-dependent solution.

 

 19   Obviously, if you have a liter container such as

 

 20   viewed here and you have a paper label, is that

 

 21   also going to be--it's something that has to be

 

 22   removed, and considered this is--it should be in

 

                                                                71

 

  1   relation to the size of the container.  If it is a

 

  2   three-  (?)  container, you have the same treatment

 

  3   as one-liter container.

 

  4             Another example of various container

 

  5   sizes.

 

  6             Thank you.

 

  7             DR. GROSS:  Okay.  Now we'll hear from the

 

  8   Cardinal Health team, Rick Schindewolf and Patrick

 

  9   Poisson.

 

        x                   MR. POISSON:  Good morning.  My name is            

10

 

 11   Patrick Poisson.  I'm the Director of Technical

 

 12   Services at Cardinal Health Woodstock.  With me

 

 13   today is Mr. Rick Schindewolf, who's the general

 

 14   manager of the Woodstock, Illinois, facility.

 

 15             Just a little bit about our role in the

 

 16   industry.  Cardinal is a diversified health care

 

 17   company with operations in distribution, manufacturing,

 

 18   research, and management solutions.  The

 

 19   Cardinal Health Woodstock facility is a

 

 20   blow-fill-seal facility that produces approximately

 

 21   1 billion units annually.  Our product portfolio

 

 22   involves NDA, ANDA, 510(k), and USP Monograph

 

                                                                72

 

  1   products.

 

  2             Some of the advantages of why people

 

  3   select low-density polyethylene in blow-fill-seal

 

  4   is blow-fill-seal is recognized as an advanced

 

  5   aseptic process.  There's also an immense

 

  6   flexibility in container design that allows various

 

  7   applications of the container and its use.  It's

 

  8   also a very cost-effective approach to producing

 

  9   pharmaceutical products.

 

 10             Now, some of the limitations:  As

 

 11   previously mentioned, LDPE is a semipermeable

 

 12   material.  The technology also uses heat to form

 

 13   the container, and there may be issues with

 

 14   heat-sensitive products.  And based on the focus of

 

 15   this meeting today, there are obviously some

 

 16   labeling issues as well.

 

 17             Now, the general industry approach has

 

 18   been to emboss and deboss the containers to display

 

 19   the necessary information, which includes product

 

 20   name, concentration, manufacturer, lot number, et

 

 21   cetera.  Typically, respiratory products are

 

 22   packaged in a secondary overwrap in multiple units

 

                                                                73

 

  1   or single units, and that provides the additional

 

  2   protection necessary to prevent chemical

 

  3   contamination.

 

  4             This has already been touched upon, but

 

  5   these are the main highlights of the Draft

 

  6   Guidance, and I won't spend any time on this since

 

  7   this has been discussed already.

 

  8             Now, what are some of the advantages to

 

  9   the embossing/debossing approach?  It provides an

 

 10   immediate tamper-evident identification of the

 

 11   product.  It eliminates the potential for

 

 12   contamination from labels.  And it provides ease of

 

 13   label copy control.

 

 14             Some of the limitations associated with

 

 15   that:  It can be difficult to read on clear

 

 16   containers.  It does not provide a very readily bar

 

 17   code-readable print.  And the vial size affects

 

 18   legibility of the print that's embossed and

 

 19   debossed.  We cannot emboss or deboss down to a

 

 20   very small font size that's readable that could

 

 21   compete with a paper label.

 

 22             Now, we believe there are some

 

                                                                74

 

  1   possibilities for enhancing product identification

 

  2   in the low-density polyethylene container, and

 

  3   these are listed here:  reduce the content

 

  4   requirement to allow an increased text size;

 

  5   addition of physical/tactile identifiers for

 

  6   generic product groups; alternative label

 

  7   approaches such as a sleeve label; color coding

 

  8   unit-dose vials for generic product groups; and

 

  9   individual secondary overwrap.

 

 10             Increased text size.  There's a limited

 

 11   surface area on the container that is available for

 

 12   embossing/debossing.  Due to the technology, we

 

 13   cannot emboss or deboss on the sides of the vial.

 

 14   We can only emboss and deboss on the front.  The

 

 15   text size can be significantly increased; however,

 

 16   we would have to remove some of the information

 

 17   that's normally provided.  This approach would not

 

 18   change any of the materials involved in the

 

 19   process, so there would be no impact on the current

 

 20   product chemistry.  This could also be implemented

 

 21   fairly quickly, eight to ten weeks.  And there

 

 22   would be a one-time cost for the manufacturer to

 

                                                                75

 

  1   buy the appropriate equipment.

 

  2             This is a drawing of what that concept

 

  3   would look like.

 

  4             In addition to that, physical/tactile

 

  5   identifiers could be added to the container.  This

 

  6   would provide an easily recognizable/legible symbol

 

  7   on the container that would represent a product

 

  8   type, for instance, A for Albuterol sulfate, I for

 

  9   Ipatropium bromide, et cetera.  This is already

 

 10   currently being implemented on products

 

 11   manufactured at Cardinal Health.  This also does

 

 12   not change any of the container materials or

 

 13   process, so, again, no impact on the current

 

 14   product chemistry.  This also could be implemented

 

 15   in eight to ten weeks, depending on the regulatory

 

 16   approval of this label change, possibly as a CBE

 

 17   30.  Again, there would be a one-time minimal cost

 

 18   to buy the necessary equipment to do such a change.

 

 19             This is a drawing of what that concept

 

 20   could look like.  And we have some samples which

 

 21   we'll pass around for the committee to see.  And

 

 22   those can also be provided in clear plastic.  And

 

                                                                76

 

  1   here are some photos of the same vials.

 

  2             This is a picture contrasted with one of

 

  3   the current formats that is out on the market, so

 

  4   you can see that there's a definite increase in the

 

  5   identification of the products resulting from this

 

  6   type of change.

 

  7             The sleeve label concept would involve a

 

  8   redesign of the extended tab to make that area

 

  9   amenable for application of a non-paper label.

 

 10   Cardinal has designed such a vial that has a patent

 

 11   pending that would be capable of receiving a shrink

 

 12   wrap sleeve.

 

 13             This label provides a contrasted

 

 14   background for enhanced legibility and also provide

 

 15   a bar code-readable print.  This would involve no

 

 16   changes to the product contacting surfaces of the

 

 17   container.  The shrink of pressure sensitive label

 

 18   would be applied to an appendage of the container,

 

 19   not in direct contact with the product.

 

 20             This would also involve an increased

 

 21   manufacturing cost for equipment, labor, and

 

 22   materials, and we believe it could be implemented

 

                                                                77

 

  1   in 12 to 14 months following regulatory approval

 

  2   with associated stability testing data.

 

  3             This is a picture of what that concept

 

  4   looks like, and we have some samples that we'll

 

  5   pass around.  This particular product was mentioned

 

  6   in an earlier presentation as the catheter flush

 

  7   saline and heparin.

 

  8             Color coding.  Products could be

 

  9   color-coded to aid in identification.  That would

 

 10   be a similar approach to the AAO recommendations

 

 11   for cap color for ophthalmic products.  It provides

 

 12   a contrasting background to aid the legibility.  A

 

 13   colored vial is easier to read.  However, it could

 

 14   impact the product chemistry with leachables and

 

 15   extractables.  There would be a slight increase in

 

 16   manufacturing costs for raw materials.  Again,

 

 17   implementation time would be based on stability

 

 18   data and regulatory approval of such a change.

 

 19             This is a picture of what that concept

 

 20   would look like.

 

 21             Individual secondary overwrap, that has

 

 22   been touched upon.  It provides enhanced labeling

 

                                                                78

 

  1   opportunities, bar code-readable print for a

 

  2   single-dose vial.  However, the overwrap can and

 

  3   will be separated from that unit at some point in

 

  4   time during its use, and we don't control that, so

 

  5   we cannot predict when that will happen.  So there

 

  6   could be legibility/identification issues still at

 

  7   the time of use.  There's a significant

 

  8   manufacturing cost increase with the raw materials,

 

  9   equipment necessary, and labor.  If that was done

 

 10   with the current process, that change, the

 

 11   implementation time would be 12 to 14 months

 

 12   following regulatory approval of the packaging

 

 13   change with associated stability data.

 

 14             In summary, we believe there are

 

 15   opportunities for improvement of the labeling of

 

 16   low-density polyethylene containers.  Each

 

 17   alternative is a viable alternative, we believe,

 

 18   and it should be assessed based on impact to the

 

 19   product, speed of implementation, ease of

 

 20   regulatory approval, and cost to the patient.

 

 21             Thank you--oh, sorry.  Our recommendations

 

 22   are to increase label information font size on

 

                                                                79

 

  1   individual vials.  Add a tactile symbol for generic

 

  2   identification based on the following advantages:

 

  3   quick approach, no impact on product chemistry or

 

  4   stability, and no impact on patient cost.  For

 

  5   hospital-dispensed unit-dose vials, add a sleeve

 

  6   label to accommodate bar coding.

 

  7             Thank you.

 

  8             DR. GROSS:  Thank you very much.

 

  9             Our next speaker is Karen Stewart of the

 

 10   American Association of Respiratory Care.

 

        x                   MS. STEWART:  Good morning.  Thank you for         

   11

 

 12   giving me the opportunity to present today.  I

 

 13   think in your packets you have my written

 

 14   statement, and I have a couple of slides here that

 

 15   I want to share with you.

 

 16             I've been a registered respiratory

 

 17   therapist since 1971, and I am here as the

 

 18   spokesperson for the American Association for

 

 19   Respiratory Care representing respiratory

 

 20   therapists both nationwide and internationally.

 

 21             Respiratory therapists, like all other

 

 22   health care professionals, are very concerned about

 

                                                                80

 

  1   medication errors.  In recent years, since the

 

  2   elimination of most paper labels on unit-dose vials

 

  3   of medication, it has become increasingly difficult

 

  4   to determine the content of the unit-dose vial.

 

  5   I'm going to share with you some pictures of what

 

  6   the therapist typically has on their person as

 

  7   they're making rounds.

 

  8             Not only is the print on the vial

 

  9   difficult to read, the size and the shape of the

 

 10   vial contributes to this difficulty.

 

 11             In 2001, the American Association for

 

 12   Respiratory Care completed a human resource survey,

 

 13   and at that time the average age of a respiratory

 

 14   therapist was 44.  This is another contributing

 

 15   factor to the difficulty of reading the content of

 

 16   the medication vial.  While I may have just

 

 17   emphasized that the current relative age of the

 

 18   respiratory therapist and the difficulty the older

 

 19   therapist experiences in reading the labels, I want

 

 20   to clarify to you that deciphering respiratory care

 

 21   medication labels is a problem that cuts across all

 

 22   age groups of respiratory therapists.  The problem

 

                                                                81

 

  1   is how the medication is labeled or not labeled

 

  2   appropriately.

 

  3             The work flow of the respiratory therapist

 

  4   I think is probably most important for you to

 

  5   understand.  The therapist typically includes

 

  6   delivering medications and treatments to a number

 

  7   of patients for a local geographic region in a

 

  8   hospital.  The patients that are assigned have a

 

  9   very wide variety of medications that are being

 

 10   delivered to them.  Once the medication is checked

 

 11   by the pharmacist for drug interactions, the

 

 12   therapist typically carries medication with them as

 

 13   they begin rounds.  It would not be unusual for a

 

 14   therapist to carry between 14 and 15 different

 

 15   vials of medication.  The medications must be under

 

 16   control so that therapists either carry the

 

 17   medication in a fanny pack or they carry the

 

 18   medication in a locked draw on a cart they carry

 

 19   with them.

 

 20             In some institutions, medications are in a

 

 21   Pyxsis system.  In this situation, the medication

 

 22   can either be placed in a single patient medication

 

                                                                82

 

  1   labeled drawer or they come from stock supply.  So,

 

  2   again, multiple vials in a stock drawer.

 

  3             I just wanted to give you a view of what's

 

  4   in somebody's pocket typically.

 

  5             Another concern that faces the respiratory

 

  6   therapist is the lack of bar coding on the vial.

 

  7   Many hospitals are moving toward the scanning of

 

  8   medication bar codes.  The driving force for this

 

  9   use of technology is to identify the correct

 

 10   patient, identify the correct medication, confirm

 

 11   the correct dose of medication, confirm the correct

 

 12   route of medication, and record the time of the

 

 13   medication delivery.

 

 14             I want to share with you a few comments

 

 15   that I picked up from some respiratory therapists

 

 16   in just the most recent weeks.

 

 17             Staff have complained about the inability

 

 18   to see clearly the medication information.  For

 

 19   this reason, we switched to a different product

 

 20   that is individually wrapped in clearly labeled,

 

 21   color-coded foil packaging.  The current situation

 

 22   with the raised-letter labeling is an accident

 

                                                                83

 

  1   waiting to happen.  I know you talked earlier about

 

  2   underreporting.  It's because we've given the dose

 

  3   and never know we gave the wrong one in some cases.

 

  4             This is a second therapist:  I complained

 

  5   bitterly when the look-alike vials came out.  We

 

  6   did not leave them for any nurses to confuse.  We

 

  7   do not know of any medication errors beck of the

 

  8   look-alikes.  Doesn't mean it didn't happen.  We

 

  9   just don't know.

 

 10             So, again, a little bit more emphasis on

 

 11   the fact that we are seeing probably underreporting.

 

 12             This is a third one:  We have had problems

 

 13   with the unit-doze Xopenex and Atrovent looking

 

 14   alike and labeled in the same clear package.  We

 

 15   use Pyxsis and it's still a problem.

 

 16             So even moving the medication into a more

 

 17   controlled environment continues to be a problem

 

 18   for the therapist who's on the floor.

 

 19             This is a fourth therapist:  One

 

 20   encouraging thing that I have seen is differing

 

 21   shapes and sizes on a very few of the medications. 

 

                                                                84

 

  1   Since the death of the multi-dose vial of

 

  2   Albuterol, we have a supplier who sends us

 

  3   unit-dose vials of Albuterol that have a very

 

  4   distinctive teardrop shape  and a much smaller size

 

  5   for medication.  I give that a Bravo.  A similar

 

  6   thing has happened with the octagonal unit-dose

 

  7   vials of Pulmicort.

 

  8             And I think if you look at the very end of

 

  9   this, that small round is the Pulmicort.  But this

 

 10   is what's in the pocket of the therapist, and all

 

 11   they have to read on most of those are just that

 

 12   clear lettering.

 

 13             I was at a program, I did a program in

 

 14   Cincinnati last week, and I mentioned this in a

 

 15   patient safety presentation that I did to

 

 16   therapists.  About 600 were there, and what was

 

 17   interesting about it is several of them came up to

 

 18   me afterward and said, Can you imagine what the

 

 19   night shift therapist goes through trying to read

 

 20   these?

 

 21             Now, low light--it's bad enough, you know,

 

 22   with the age, but the low light.

 

                                                                85

 

  1             There's a couple more comments from

 

  2   therapists in there.  I think that you've probably

 

  3   got those.  You get the gist of what we're trying

 

  4   to say.  So on behalf of the American Association

 

  5   of Respiratory Care, I really appreciate the

 

  6   opportunity to share the association comments.

 

  7             I have one more slide that I want to share

 

  8   with you, and it's this one.  What you're seeing

 

  9   here are just the different medications.  One of

 

 10   those happens to be Tobramycin.  One of them--two

 

 11   of them are bronchodilators.  Two of them are

 

 12   exactly the same medication in different doses.

 

 13   Just to really emphasize what the packaging is

 

 14   doing to the therapist at the bedside.

 

 15             Thank you.

 

        x                   DR. GROSS:  Okay.  Thank you very much.            

16

 

 17   We will not have the committee ask some questions

 

 18   of the speakers, and you can ask questions of any

 

 19   of the speakers that have presented this morning.

 

 20             Leslie?

 

 21             DR. HENDELES:  I have two questions for

 

 22   Karen.  First, is there any Joint Commission

 

                                                                86

 

  1   requirements in terms of how respiratory therapists

 

  2   are supposed to handle medication?

 

  3             MS. STEWART:  There's been--

 

  4             DR. HENDELES:  And I have a second

 

  5   question, which is:  Would respiratory therapists

 

  6   mind carrying these single-unit dose vials wrapped

 

  7   in foil in their pockets?

 

  8             MS. STEWART:  There are recommendations

 

  9   around the delivery of medications from JCAHO, and

 

 10   most of that is surrounding the control.  It is

 

 11   first the pharmacist's review of that medication to

 

 12   see if there are any other interactions, and the

 

 13   second being that that medication is always under

 

 14   control.  And you'll see as you go across the

 

 15   country a number of different ways that hospitals

 

 16   are handling the medication control issue.  Some of

 

 17   them--the folks that I talked to last week, some of

 

 18   them have a cart where they carry all their

 

 19   plastics and other things that they need with a

 

 20   locked drawer, and their medications are in that

 

 21   drawer.  Other ones are using Pyxsis, and some are

 

 22   still carrying it physically on their person in a

 

                                                                87

 

  1   side pocket or a fanny pack.

 

  2             Your second question is, if they were

 

  3   individually wrapped, I think that therapists would

 

  4   use those either in any of those devices under

 

  5   control.  The problem is that they open, for

 

  6   example, a packet of Xopenex with 12 vials in it.

 

  7   That's just too much for them to carry when they've

 

  8   got so many different types to carry.

 

  9             DR. HENDELES:  If it's just one, they

 

 10   would be able to?

 

 11             MS. STEWART:  I think they would be able

 

 12   to carry it, yes.

 

 13             DR. GROSS:  Yes, Stephanie?

 

 14             DR. CRAWFORD:  Thank you.  This question

 

 15   is for Patrick Poisson, but, Ms. Stewart, don't go

 

 16   too far just in case you want to add to it.  I

 

 17   thank each of the speakers for their presentations.

 

 18             Mr. Poisson, with respect to your

 

 19   presentation, the sixth slide was talking about the

 

 20   advantages and disadvantages--I'm sorry, the

 

 21   advantages and limitations.  Each of the advantages

 

 22   from my interpretation were in the manufacturing

 

                                                                88

 

  1   process.  As you presented, each of the limitations

 

  2   was from the clinical use.  So my question is:

 

  3   From the recommendation--potential alternatives

 

  4   that you suggested, have you conducted, your

 

  5   company, or performed any studies using clinical

 

  6   groups such as the respiratory therapists to see

 

  7   acceptability of each of these options?

 

  8             MR. POISSON:  One thing I probably failed

 

  9   to mention is that Cardinal Health is a contract

 

 10   manufacturer, and the products that we manufacture

 

 11   are distributed by our customers.  And it's

 

 12   difficult for us to step in front of them and ask

 

 13   for this type of work to be done.

 

 14             Now, we have done some work with the

 

 15   shrink wrap sleeve label, and the feedback from

 

 16   that was very positive.  However, that was a very

 

 17   unique opportunity for us to get involved with

 

 18   that.

 

 19             In regards to the recommendations, yes,

 

 20   some of them are manufacturing--are good for the

 

 21   manufacturing process.  However, one that maybe

 

 22   wasn't explained as well is the sterility of the

 

                                                                89

 

  1   product.  Using a blow-fill-seal technology to

 

  2   manufacture products is recognized as providing a

 

  3   better microbiological quality of product out to

 

  4   the market versus a conventional process.

 

  5             DR. GROSS:  Michael?  I'm sorry.

 

  6   Stephanie, another question?

 

  7             DR. CRAWFORD:  Thank you.  Just one quick

 

  8   follow-up.  One of your recommendations was

 

  9   increase text size.  You mentioned that, of course,

 

 10   something would have to come off if that were

 

 11   happening--would come off if--

 

 12             MR. POISSON:  I think we'd have to

 

 13   undertake those discussions with the agency as to

 

 14   what could come off.

 

 15             DR. GROSS:  Michael?

 

 16             DR. COHEN:  I've been looking at these

 

 17   LDPE plastics for several years, actually, and

 

 18   trying to come up with solutions.  And actually the

 

 19   best thing I've ever seen is that shrink wrap, that

 

 20   overwrap, or sleeve, or whatever you want to call

 

 21   it.  Is that a proprietary system, or is that

 

 22   available to any manufacturer?  And can you foresee

 

                                                                90

 

  1   the actual use across the entire spectrum of LDPE

 

  2   containers, even the parenterals?

 

  3             MR. POISSON:  Well, we're very pleased

 

  4   with the progress we've made on the sleeve label.

 

  5   It did involve some development that we regard as

 

  6   intellectual property.  So regarding availability

 

  7   to the whole industry, I really can't speak on

 

  8   that.

 

  9             There will be potentially some leachable

 

 10   extractables even from that system.  There is ink

 

 11   on that label.  So that has to be evaluated for

 

 12   each product that it's used for.  It still may not

 

 13   work for every product.

 

 14             MR. SCHINDEWOLF:  If I could just make a

 

 15   comment on the proprietary nature, what's

 

 16   proprietary about that vial is the rounded end.  A

 

 17   lot of the vials that you'll see and I think some

 

 18   that were presented earlier can be on a flat end as

 

 19   well.  And we found that the rounded end helped the

 

 20   legibility.  As the sleeve shrinks, there tends to

 

 21   be some--what's the word I'm looking for?  The

 

 22   print can be--

 

                                                                91

 

  1             MR. POISSON:  It can be distorted.

 

  2             MR. SCHINDEWOLF:  Yes, "distortion,"

 

  3   that's the word.  So this was to help the

 

  4   readability of the bar code label itself, so that's

 

  5   what's proprietary in that particular design.

 

  6             DR. GROSS:  Yes, Henri?

 

  7             DR. MANASSE:  In terms of patient safety,

 

  8   one of the biggest issues that I think most

 

  9   practitioners confront is the kind of work-arounds

 

 10   that people utilize to make things convenient for

 

 11   them, and this notion of carrying drugs around in

 

 12   your pocket is a very good example.  But it seems

 

 13   that the sleeve is a pretty critical issue with

 

 14   respect to the capacity of adding more information

 

 15   coupled with bar codes, symbologies, et cetera.

 

 16             Have you all thought about how you can

 

 17   eliminate the dissociation of the sleeve from the

 

 18   package itself?  Because the work-around, people

 

 19   are tearing off the sleeves and then carrying the

 

 20   package by themselves.  And is there a way that you

 

 21   can avoid that other than at the direct point of

 

 22   care?

 

                                                                92

 

  1             MR. POISSON:  I'll try and address that.

 

  2   One of the ways that these are used is that the cap

 

  3   is actually twisted off of the vial.  And one of

 

  4   the problems I see with individually foil

 

  5   overwrapping is the removal of that foil could

 

  6   potentially damage the vial in that process.  So

 

  7   it's a difficult thing to overcome.  We could

 

  8   tighten the foil potentially around the vial, but

 

  9   it just opens it up for damage in the transfer

 

 10   process from the location within the hospital to

 

 11   its use point.

 

 12             You know, there are a lot of advancements

 

 13   going on in packaging.  Certainly five years ago I

 

 14   don't think we would have all the options that we

 

 15   have now.  Maybe at some point in time we can get

 

 16   to a better alternative with the foil.

 

 17             DR. GROSS:  Robyn?

 

 18             MS. SHAPIRO:  I have two questions.  One

 

 19   is actually Henri's.  And this is to the agency.

 

 20   What factors, if any, are considered currently in

 

 21   the approval process with respect to these

 

 22   problems?

 

                                                                93

 

  1             And the second question is:  It seems to

 

  2   me that this morning we have much more information

 

  3   about the potential error, problem, than the

 

  4   leachability and contamination problem, and much

 

  5   more potential risk.  Has there been--maybe this is

 

  6   for Karen.  Has there been litigation over this?

 

  7   And, if so, what has happened?

 

  8             MS. STEWART:  I can't speak to any

 

  9   litigation, and I think one of the concerns that we

 

 10   have as therapists is that this probably goes underreported.

 

 11   The therapist delivers that care

 

 12   and leaves the bedside to treat the next patient.

 

 13   So they may not see an adverse effect or, as stated

 

 14   earlier by Dr. Sullivan, I believe, the patient

 

 15   does not get the potential relief of the

 

 16   medication.

 

 17             In other words, if you have Tobramycin and

 

 18   a bronchodilator in your pocket, they both look

 

 19   alike, you give the Tobramycin to the patient who

 

 20   needs the bronchodilator, you may not see the

 

 21   effect.  So it becomes underreported.

 

 22             MS. SHAPIRO:  And the patient may not

 

                                                                94

 

  1   either.  I mean, they may not realize--the patient

 

  2   or the family or whomever, the error may not be

 

  3   disclosed to anyone.

 

  4             MS. STEWART:  Except the patient's

 

  5   therapeutic treatment regime is going to be longer

 

  6   with a longer length of stay because they didn't

 

  7   get the proper--

 

  8             MS. SHAPIRO:  Sure, but they may not know

 

  9   why.

 

 10             MS. STEWART:  Right.

 

 11             DR. GROSS:  Are there any other questions?

 

 12             MS. SHAPIRO:  Can I have the first

 

 13   question answered by Paul or somebody about what

 

 14   currently is considered?

 

 15             DR. SHAH:  You are talking about in terms

 

 16   of the quality controls?

 

 17             MS. SHAPIRO:  In the approval process for

 

 18   any new drugs, what, if any, is considered with

 

 19   respect to safety relating to this possibility for

 

 20   error?

 

 21             DR. SHAH:  Let me just try to briefly

 

 22   summarize.

 

                                                                95

 

  1             When we get an application and we have

 

  2   these kind of packaging components, then usually

 

  3   the applicant may provide this information for all

 

  4   the components of each and every packaging

 

  5   component into the NDA, or they may choose to

 

  6   provide that information, if it proprietary,

 

  7   through a Drug Master File.  Then we review the

 

  8   chemical composition of each and very packaging

 

  9   component in a Drug Master File, but we cannot

 

 10   relay that information to the applicant.

 

 11             Once we know from the composition that

 

 12   there is a potential for volatile chemicals to be

 

 13   present in the component and they may permeate

 

 14   through the LDPE vials, then we ask the applicant

 

 15   indirectly, without revealing the other

 

 16   information, Have you studied any legibility or

 

 17   extractable--have you found any extractable, what

 

 18   kind of solvent conditions you have used to extract

 

 19   this leachable?  And we encourage them to contact

 

 20   the DMF supplier, work with them, and develop some

 

 21   procedures to find out what can be present and

 

 22   establish a profile.  Once you establish a profile,

 

                                                                96

 

  1   then you may identify, okay, these are the typical

 

  2   components present into a component, packaging

 

  3   component, and we are going to use that as a basis

 

  4   for screening the incoming packaging material.  And

 

  5   then you may have some kind of acceptance criteria.

 

  6   That may be a GC profile.  Or if you have

 

  7   identified a particular component by its chemical

 

  8   structure, then you may say, okay, it is extracted

 

  9   at, say, one milligram per ml or something like

 

 10   that, okay?  So then you will conduct some kind of

 

 11   a study for the shelf life, over the shelf life,

 

 12   whether that particular extractable gets into the

 

 13   drug product or not.  If it does not, then at least

 

 14   you have established that if I control the amount

 

 15   of incoming acceptance criteria, I have established

 

 16   incoming packaging material, then I do not see the

 

 17   leachable into the drug product.  So then you don't

 

 18   have to have a test for leachable into the drug

 

 19   product, but you have to establish that

 

 20   relationship.

 

 21             So we go through a series of steps to

 

 22   establish that, and once we are satisfied, then we

 

                                                                97

 

  1   may decide, okay, you are going to control or

 

  2   minimize this particular component at acceptance

 

  3   level in incoming packaging material.  Or you will

 

  4   have to carry out the leachable testing.

 

  5             MS. SHAPIRO:  What about the analysis with

 

  6   respect to the possible safety problems on account

 

  7   of the error issues?

 

  8             DR. SHAH:  Okay.  Once we get that, we see

 

  9   that, okay, it is present into the drug product at

 

 10   a certain level.  And if we know the identity of

 

 11   that chemical, then we ask our pharmacology and

 

 12   toxicology person to review that data and decide

 

 13   whether that will have any safety issue.  And if

 

 14   they decide that it may have a safety issue, then

 

 15   they may ask the applicant to qualify that

 

 16   particular material or chemical at that level.

 

 17             MS. SHAPIRO:  Okay.  And all that has to

 

 18   do with the leachability question.  But what about

 

 19   the question having to do with the confusion

 

 20   problems on account of the labeling and its impact

 

 21   on safety?

 

 22             DR. SELIGMAN:  For all drug products that

 

                                                                98

 

  1   are approved by the agency, we look at the accuracy

 

  2   of the label, whether it's misleading or not,

 

  3   whether it's nonpromotional in nature.  We look at

 

  4   the name for potential confusion.  We look at the

 

  5   packaging regarding dose and frequency.  And if at

 

  6   the time we find, either at the time of approval or

 

  7   even subsequent to approval, that there is such a

 

  8   potential for either name confusion, for misleading

 

  9   dose, or any kind of misleading information that

 

 10   might lead to medication error, we make a

 

 11   recommendation to the manufacturers to try to--to

 

 12   alter that.

 

 13             I think the reason we're bringing this

 

 14   particular issue to this committee is that this is

 

 15   a particularly vexing issue.  But for the vast

 

 16   majority of products that we review, when we find

 

 17   such potential for confusion or potential error, we

 

 18   recommend to the manufacturer that that be

 

 19   addressed prior to approval of the product.

 

 20             MS. SHAPIRO:  Have you ever, with

 

 21   containers like this, sent it back and said, no,

 

 22   this doesn't--this won't do given these sorts of

 

                                                                99

 

  1   problems?

 

        T2B                 DR. SELIGMAN:  I'm not aware of any.  Some         

    2

 

  3   of them go through generics.

 

  4             Carol, did you want to respond to that?

 

  5             MS. HOLQUIST:  Yes.  Actually, our office

 

  6   in Office of Drug Safety, we only get whatever--we

 

  7   only see the packaging material that comes in with

 

  8   new products.  A lot of these products have been on

 

  9   the market for years and years.  So if indeed one

 

 10   of these products came in today with this packaging

 

 11   labeling, yes, of course, that would be one of our

 

 12   recommendations in our review that, based on

 

 13   post-marketing reports and evidence, we wouldn't

 

 14   recommend this.  But then the agency's hands are

 

 15   kind of tied because of the ingress issue.  So

 

 16   until we find an alternative packaging, it's a

 

 17   conundrum we're in.

 

 18             DR. GROSS:  Gene, did you want to comment?

 

 19             DR. SULLIVAN:  Yes, I just wanted to

 

 20   follow up on a couple things that have been said so

 

 21   far:  one, to just make sure the categories of harm

 

 22   to patients are in the right column.  There's the

 

                                                               100

 

  1   harm that the legibility issue brings in, so the

 

  2   harm that a patient suffers if he or she doesn't

 

  3   receive Tobramycin but instead receives Albuterol.

 

  4   And then what I was trying to touch on and the

 

  5   thing that's hard to get your hands around is the

 

  6   harm from the actual presence of these chemicals,

 

  7   and that it's well known that a patient may come to

 

  8   the emergency department and receive a few

 

  9   treatments of Albuterol and recover and be

 

 10   discharged.  Another patient may come in and not

 

 11   seem to respond and end up mechanically ventilated.

 

 12   And to what extent that could be related to

 

 13   contaminants in the drug product would be anyone's

 

 14   guess and impossible to day.  So I just wanted to

 

 15   make sure we consider those two sort of as they're

 

 16   the competing harms.

 

 17             The other issue I just wanted to talk

 

 18   about a little bit was the issue of the use of the

 

 19   flange or labeling that's not directly applied to

 

 20   the actual body of the nebule, be it with a shrink

 

 21   wrap or an applied label and so forth; that there

 

 22   is some intrinsic appeal because it seems to be

 

                                                               101

 

  1   less in contact with the LDPE, but keep in mind

 

  2   that if these are then put into an overwrap, a foil

 

  3   overwrap, perhaps for other

 

  4   reasons--light-sensitive products and so

 

  5   forth--that then you have sort of a micro

 

  6   environment, you know, like a little humidor with

 

  7   these chemical vapors that could then make their

 

  8   way--even though they're here on the flange, they

 

  9   could easily make their way into the product, and

 

 10   that's sort of evidenced by that case where we had

 

 11   the cardboard carton and that chemical made its way

 

 12   in.  So it's not, you know, a complete solution.

 

 13   We have to keep that in mind.

 

 14             DR. GROSS:  Arthur, you had a question?

 

 15             MR. LEVIN:  One is just a point of

 

 16   information.  Mike, is that the packaging with that

 

 17   label, that's what you are referencing when you say

 

 18   so far that's the best--

 

 19             DR. COHEN:  Not necessarily.

 

 20             MR. LEVIN:  Okay.

 

 21             DR. COHEN:  This is certainly acceptable

 

 22   as a way to identify a container.  But the ones

 

                                                               102

 

  1   I've seen have actually had a similar type of film,

 

  2   but it's been around the body of the ampule device.

 

  3   And there was a tear-off so that you would

 

  4   literally pull the tab and tear off the top part of

 

  5   the plastic.  It was a total overwrap.

 

  6             MR. LEVIN:  But it's something more than

 

  7   that.

 

  8             DR. COHEN:  Leaving the identify, even

 

  9   though this was exposed.

 

 10             MR. LEVIN:  Okay.  So the whole thing is

 

 11   shrink wrapped to something.

 

 12             DR. COHEN:  That's correct.

 

 13             MR. LEVIN:  Right, okay.  I didn't think

 

 14   we had seen one of those.

 

 15             DR. COHEN:  We didn't.

 

 16             MR. LEVIN:  Yes, okay.  So that clarifies

 

 17   that.

 

 18             The second thing is we seem to be sort of

 

 19   entirely focusing in inpatient and, you know, the

 

 20   issue of outpatient is certainly significant.  And

 

 21   I'm just wondering from, you know, what you've done

 

 22   to look at how well these kinds of solutions work

 

                                                               103

 

  1   in the outpatient pharmacy setting as opposed to

 

  2   inpatient settings where it's really--making sure

 

  3   that the respiratory therapist who administers the

 

  4   drug is clear on the right drug and the dosage et

 

  5   cetera.  What about an outpatient pharmacy?

 

  6             MR. POISSON:  Well, one of the reasons

 

  7   why--and someone may question why there's 12 vials

 

  8   in a pouch or even 28 or up to 60.  A lot of the

 

  9   reason behind that is because of the use period in

 

 10   the outpatient--outside of the hospital.  And based

 

 11   on feedback we've received, they view that as an

 

 12   advantage to have that type of packaging in that

 

 13   particular environment.  And the possibility exists

 

 14   that maybe some of these options we've presented

 

 15   today, such as the symbol on the vial would help

 

 16   them in that area from using the wrong product.

 

 17             So I think, you know, there's

 

 18   opportunities for a number of these options to be

 

 19   implemented based on the setting that they're used

 

 20   in.

 

 21             DR. GROSS:  Okay.  Henri, you have a

 

 22   question?

 

                                                               104

 

  1             DR. MANASSE:  I just want to follow up on

 

  2   Art's point in terms of outpatient use.  I can't

 

  3   imagine given the size of these containers, given

 

  4   the unreadability of these containers, and the

 

  5   obvious confusion that is brought to bear to those

 

  6   problems, that outpatients, particularly elderly

 

  7   outpatients, can manage this on their own.  I think

 

  8   somehow we've got to contemplate where we go with

 

  9   that because the increasing number of people who

 

 10   are using these on an outpatient basis and the

 

 11   increasing aging of the population presents us with

 

 12   an incredible challenge.

 

 13             DR. GROSS:  Okay.  Marci would like to

 

 14   make a comment.

 

 15             DR. LEE:  Thank you.  I just wanted to add

 

 16   to that.  Based on the medication error reports

 

 17   that we have received most recently, there are many

 

 18   comments about the elderly population using these

 

 19   drugs.  There are several reports from a pharmacist

 

 20   saying that his patients are expressing that

 

 21   they're afraid to use the product because they're

 

 22   afraid that they're going to double their dose

 

                                                               105

 

  1   accidentally because they're not sure what is in

 

  2   each ampule.

 

  3             Then, also, the letter in the background

 

  4   package that was sent to Senator Harkin, that also

 

  5   involved a woman who was writing in about her

 

  6   elderly mother that was having the same problem

 

  7   also from a mail-order pharmacy.  So in addition to

 

  8   a regular outpatient pharmacy where there's direct

 

  9   interaction with the pharmacist, you have people

 

 10   who are unable to get out of their home and receive

 

 11   their medications by mail having the same

 

 12   experiences.

 

 13             Carol wants to add something.

 

 14             MS. HOLQUIST:  Also, just in relation to

 

 15   the letters at the top of the vials themselves, we

 

 16   actually have gotten some reports as well where

 

 17   there's a question as to what the actual letter

 

 18   stands for, like A, is it for Albuterol or for

 

 19   Atrovent.  So some simple fixes, sometimes you also

 

 20   have to think beyond, that there's more than one

 

 21   product that begins with that letter.

 

        x                   DR. GROSS:  Okay.  We are a little bit            

22

 

                                                               106

 

  1   ahead of schedule, and we will proceed at this time

 

  2   with the open public hearing.  Dr. Eric Sheinin

 

  3   will present.  First I need to--

 

  4             MS. JAIN:  We need to read a statement

 

  5   first.

 

  6             DR. GROSS:  Both the Food and Drug

 

  7   Administration and the public believe in a

 

  8   transparent process for information gathering and

 

  9   decisionmaking.  To ensure such transparency at the

 

 10   open public hearing session of this Advisory

 

 11   Committee meeting, the FDA believes that it is

 

 12   important to understand the context of an

 

 13   individual's presentation.  For this reason, FDA

 

 14   encourages you, the open public hearing speaker, at

 

 15   the beginning of your written or oral statement to

 

 16   advise the committee of any financial relationship

 

 17   that you may have with any company or any group

 

 18   that is likely to be impacted by the topic of this

 

 19   meeting.

 

 20             For example, the financial information may

 

 21   include a company's or a group's payment of your

 

 22   travel, lodging, or other expenses in connection

 

                                                               107

 

  1   with your attendance at the meeting.  Likewise, FDA

 

  2   encourages you at the beginning of your statement

 

  3   to advise the committee if you do not have any such

 

  4   financial relationships.  If you choose not to

 

  5   address this issue of financial relationships at

 

  6   the beginning of your statement, it will not

 

  7   preclude you from speaking.

 

        x                   DR. SHEININ:  Thank you, Dr. Gross.  I              

8

 

  9   have no financial ties or interests in any

 

 10   pharmaceutical company or any other company or

 

 11   organization that would be interested in the

 

 12   proceedings before the committee today, so I think

 

 13   I'm okay with that.

 

 14             DR. GROSS:  Thank you.

 

 15             DR. SHEININ:  My name is Eric Sheinin, and

 

 16   I'm here today to represent the United States

 

 17   Pharmacopeia.  At the UPS, I am the Vice President

 

 18   for Information and Standards Development.  We do

 

 19   have an expert committee that deals with safety

 

 20   issues, and much of what I'm going to say today is

 

 21   a direct result of work that they have done.  But I

 

 22   would like to give you some background about the

 

                                                               108

 

  1   USP for those of you who may not be familiar with

 

  2   us and also to have it in the record.

 

  3             The USP is a nongovernmental organization

 

  4   that promotes the public health by establishing

 

  5   state-of-the-art standards to ensure the quality of

 

  6   medicines and other health care technologies.

 

  7   These standards are developed by a unique process

 

  8   of public involvement and they're accepted

 

  9   worldwide.  Many other countries around the world

 

 10   recognize the USPNF standards as their own

 

 11   standards in terms of regulatory procedures within

 

 12   those countries.

 

 13             USP is a not-for-profit organization that

 

 14   achieves this goal through the scientific

 

 15   contribution of volunteers, and the volunteers

 

 16   represent pharmacy, medicine, and many other health

 

 17   care professions.  These individuals work in

 

 18   academia, they work in government, both U.S. and

 

 19   international.  In fact, there are many FDA

 

 20   scientists who serve as volunteer to USP.  They

 

 21   also come from the pharmaceutical industry and

 

 22   consumer organizations.  In addition to standards

 

                                                               109

 

  1   development, USP's has several other public health

 

  2   programs that focus on promoting optimal public

 

  3   health care delivery.

 

  4             In our mission statement, it says the

 

  5   mission is to promote the public health, and I

 

  6   always liken that to the mission of CDER, which is

 

  7   also basically to promote the public health.  So I

 

  8   believe we're all interested in the same types of

 

  9   standards.

 

 10             At the USP, the volunteers, many of them

 

 11   serve on our Council of Experts and its expert

 

 12   committees.  The members of these committees are

 

 13   USP scientific decisionmakers, and they form our

 

 14   standard-setting body.  Council members are elected

 

 15   by USP's membership at our five-year convention.

 

 16   They're elected on the basis of their knowledge and

 

 17   expertise, and they serve five-year terms.  So even

 

 18   individuals who come from industry, from their

 

 19   companies, when they volunteer to work with USP,

 

 20   they represent themselves.  They do not represent

 

 21   their employer, their organization, or anybody else

 

 22   when they work on our standards.

 

                                                               110

 

  1             The 2000-2005 Council of Experts comprises

 

  2   62 nationally recognized scientists, academicians,

 

  3   and clinicians.  Each one of these individuals

 

  4   chairs an expert committee, and the expert

 

  5   committees are made up then in turn of

 

  6   distinguished experts.

 

  7             One of the committees is named the USP

 

  8   Safe Medication Use Expert Committee.  This

 

  9   committee is comprised of 18 members representing

 

 10   pharmacy, nursing, and medicine.  It includes an

 

 11   FDA liaison, Carol Holquist.  It includes Captain

 

 12   Jerry Phillips, who was formerly the Associate

 

 13   Director for Medication Error Prevention in FDA's

 

 14   Office of Drug Safety.

 

 15             For more than 30 years, USP has promoted

 

 16   the importance of collecting and sharing

 

 17   experiential data from health care professionals.

 

 18   In the last decade, particular emphasis has focused

 

 19   on medication error reporting and prevention as a

 

 20   way for USP to positively affect the public health.

 

 21   The data collected from two of our programs--the

 

 22   USP-ISMP Medication Error Reporting, or MER,

 

                                                               111

 

  1   Program and MEDMARX--are reviewed and analyzed by

 

  2   USP staff and USP's Safe Medication Use Expert

 

  3   Committee.

 

  4             In October of 2002, USP sent a letter to

 

  5   the chief of CDER's Compendial Operations staff,

 

  6   Yanna Mille, to inform her, on behalf of the Safe

 

  7   Medication Use Expert Committee, of the continuing

 

  8   concerns of the committee and of health care

 

  9   professionals and practitioners regarding both the

 

 10   difficulty in identifying drug products packaged in

 

 11   low-density polyethylene ampules and vials and the

 

 12   resultant medication errors from their misuse.

 

 13             Plastic ampule packaging is frequently

 

 14   used for respiratory therapy drugs.  The ampules

 

 15   often do not bear labels but are labeled by

 

 16   debossing or embossing the actual plastic

 

 17   container.  This debossing or embossing is

 

 18   described by health care practitioners who have

 

 19   reported to the USP reporting programs as being

 

 20   unreadable, causing difficulty in identifying the

 

 21   product within.  Because this packaging is now

 

 22   being used not only for respiratory therapy drugs

 

                                                               112

 

  1   but also for injectables and oral solution, it is

 

  2   even more important that the subject products be

 

  3   easily identified and readily distinguishable from

 

  4   each other.

 

  5             USP has provided the Compendial Operations

 

  6   staff, the Dockets Branch, and the Office of Drug

 

  7   Safety with more than 42 specific case studies

 

  8   where mediation errors occurred because of the use

 

  9   of these products.  We also have submitted copies

 

 10   of the actual product containers involved in the

 

 11   medication errors that were reported through the

 

 12   two USP reporting programs.

 

 13             In addition to providing comment on the

 

 14   concerns expressed to USP by health care

 

 15   practitioners, the USP Safe Medication Use Expert

 

 16   Committee unanimously voted to encourage FDA to

 

 17   establish an alternate method of labeling for the

 

 18   various drug products packaged in the plastic vials

 

 19   being discussed today.  This would be in order for

 

 20   these products to be clearly identifiable,

 

 21   hopefully thereby reducing the numerous medication

 

 22   errors that have occurred and likely will continue

 

                                                               113

 

  1   to occur.

 

  2             The expert committee also suggested that

 

  3   the FDA cease approval of products in these

 

  4   containers because their use continues to be the

 

  5   subject of numerous medication error reports.

 

  6             From April 20, 2002, through January 31,

 

  7   2004, an additional 26 reports of actual and

 

  8   potential medication errors have been received

 

  9   through USP's medication errors reporting programs

 

 10   regarding the similarity in the labeling of

 

 11   products in low-density polyethylene vials.  The

 

 12   problems with these containers continue, and the

 

 13   USP and the USP Safe Medication Use Expert

 

 14   Committee recommends that FDA take any necessary

 

 15   action to improve the labeling of low-density

 

 16   polyethylene ampules and vials.

 

 17             I thank you for your attention and your

 

 18   consideration of USP's concerns.  If you have any

 

 19   questions, I'll certainly try to answer them.

 

 20             DR. GROSS:  Thank you very much.

 

 21             Are there any questions from the panel?

 

 22   Jackie?

 

                                                               114

 

  1             DR. GARDNER:  I would just like to ask,

 

  2   Dr. Sheinin, does USP have a recommendation of one

 

  3   of these methods over another?

 

  4             DR. SHEININ:  A recommendation?

 

  5             DR. GARDNER:  For solving this problem?

 

  6             DR. SHEININ:  Not at this point, not that

 

  7   I'm aware of.  The obvious solution to me--and I

 

  8   actually worked at FDA for 30 years before I went

 

  9   to USP--would be to have a label on the containers.

 

 10   But there are concerns with migration through the

 

 11   low-density polyethylene.  I'm sorry I missed the

 

 12   end of the previous presentation where they were

 

 13   describing perhaps some way to help identify these

 

 14   products.

 

 15             DR. GROSS:  Robyn Shapiro?

 

 16             MS. SHAPIRO:  I just have a question about

 

 17   these report forms.  Was patient counseling

 

 18   provided?  And then, if yes, before or after error

 

 19   was discovered?  Does that mean about what the drug

 

 20   is, how to take it, how to read it?  What does the

 

 21   counseling refer to?

 

 22             DR. SHEININ:  I believe that the

 

                                                               115

 

  1   counseling is provided by the professional who's

 

  2   reporting the problem to us.  I don't believe USP

 

  3   does the counseling.

 

  4             MS. SHAPIRO:  So we don't really know what

 

  5   that refers to.

 

  6             DR. SHEININ:  Unfortunately, the Safe

 

  7   Medication Use Expert Committee is not under my

 

  8   area of responsibility.  But as far as I know, that

 

  9   counseling would not be provided by USP, and we

 

 10   probably do not know what the nature of that

 

 11   counseling was.  The form is asking if there has

 

 12   been any counseling.

 

 13             DR. GROSS:  Henri?

 

 14             DR. MANASSE:  Good morning, Eric.

 

 15             DR. SHEININ:  Hi, Henri.

 

 16             DR. MANASSE:  Two questions.  We've talked

 

 17   today about two major issues:  one is the leaching

 

 18   of chemical agents from various labeling techniques

 

 19   and embossments; the other having to do with the

 

 20   readability issues and the packages themselves.

 

 21             Has USP convened any technical experts on

 

 22   either one of those issues to contemplate what's

 

                                                               116

 

  1   the existing science, what do we know, what do we

 

  2   not know, as well as what our reasonable solutions,

 

  3   given what's known, in other industries or other

 

  4   options for dealing with this problem?

 

  5             DR. SHEININ:  Not that I'm aware of.  It

 

  6   certainly is a good suggestion, and I will take

 

  7   that back to the committee and to Diane Cousins,

 

  8   whom I think many of you probably know, and see if

 

  9   there is a way that we could proceed in that

 

 10   manner.  I think it's a very good suggestion and

 

 11   something that should be done.

 

 12             DR. GROSS:  Okay.  Thank you very much.

 

 13             DR. SHEININ:  Thank you.

 

        x                   DR. GROSS:  If there are no further              14

 

 15   questions, since we remain ahead of schedule, Dr.

 

 16   Paul Seligman will now introduce the issues and

 

 17   questions that he has for the Advisory Committee.

 

 18             DR. SELIGMAN:  You should all, members of

 

 19   the committee, have a one-page LDPE Discussion

 

 20   Points.  These, I believe, are in the packages as

 

 21   well for public distribution.  Why don't we simply

 

 22   refer to these rather than booting up the slides.

 

                                                               117

 

  1             You've heard this morning about the issue

 

  2   related to the ingress of volatile compounds as a

 

  3   problem with these particular containers and

 

  4   various approaches to deal with this issue as well

 

  5   as not only--to deal with both the preservation of

 

  6   the purity of the drug, as well as ways in which to

 

  7   improve the legibility of the label.

 

  8             What we've asked in the first question is:

 

  9   Given the various approaches that you've heard

 

 10   today, including embossing and debossing of

 

 11   containers, the use of unit package overwraps, the

 

 12   elongation of the bottom tab and using that as an

 

 13   place to print critical information, the use of

 

 14   paper labels, the use of ink directly on the vial,

 

 15   various potential approaches including tactile

 

 16   recognition, shrink wrap labels, and then we

 

 17   actually even saw the use of glass ampules or

 

 18   vials, what we're interested in the committee

 

 19   addressing first off is to discuss the potential

 

 20   advantages or disadvantages of these approaches and

 

 21   to identify in 1b any creative solutions or

 

 22   alternate packaging design that would improve

 

                                                               118

 

  1   legibility and address the problem of ingress of

 

  2   chemical contaminants and at the same time not

 

  3   create additional problems.

 

  4             We'd also like to have you put on your

 

  5   thinking caps and consider if there are stakeholder

 

  6   groups, such as manufacturers, practitioners,

 

  7   consumers, and others, who might best advise FDA

 

  8   about possible new packaging configurations that

 

  9   might resolve some of these issues.

 

 10             And then given what you've heard today and

 

 11   based on our discussion, describe and advise us on

 

 12   an appropriate course of action to address not only

 

 13   the problem of ingress of contaminants but also

 

 14   medication errors due to legibility and similar

 

 15   packaging issues.

 

 16             So those are the issues before us.  Peter?

 

 17             DR. GROSS:  We share in your perplexity.

 

 18             DR. SELIGMAN:  Thank you.

 

        x                   DR. GROSS:  This is a difficult issue.            

19

 

 20             Thank you very much for the questions,

 

 21   Paul, and we will initiate the discussion.  The

 

 22   agenda allows two hours for discussion, so why

 

                                                               119

 

  1   don't we do roughly an hour, and then maybe we can

 

  2   have lunch and then finish up, if that's okay.

 

  3             MS. JAIN:  Lunch is on its way.

 

  4             DR. GROSS:  Okay.  Well, whenever lunch is

 

  5   here, we will re-evaluate our timing.  But let's

 

  6   begin the discussion now.

 

  7             Anyone have any comments?  Why don't we do

 

  8   this in an orderly fashion and take the issues as

 

  9   Paul presented them, with 1a being the first.

 

 10   They're all sort of interrelated, but why don't we

 

 11   get specific and talk about 1a first.  Leslie?

 

 12             DR. HENDELES:  I'd like to preface my

 

 13   comments by saying that nebulization of

 

 14   bronchodilators is an obsolete way of treating

 

 15   acute bronchospasm, and part of whatever we do

 

 16   needs to focus on an educational program designed

 

 17   at using the meter-dose inhaler through a valve

 

 18   holding chamber, which is far more efficient,

 

 19   causes fewer side effects, less expensive way, and

 

 20   it's the way the rest of the world treats acute

 

 21   asthma.  The United States has a fixation on

 

 22   nebulizer therapy that they won't let go of, for

 

                                                               120

 

  1   some reason, especially pediatricians, but there's

 

  2   clearly 10 to 15 double-blind, placebo-controlled

 

  3   trials, a Cochran review, et cetera, that indicate

 

  4   that there are much more efficient ways and it

 

  5   would, of course, circumvent this problem for

 

  6   asthma.

 

  7             Now, having said that, I really like the

 

  8   idea of having that foil pack, like the Nephron,

 

  9   with a single unit, and I think that would solve

 

 10   the problem.  It would allow for the bar coding.

 

 11   And according to Karen, respiratory therapists

 

 12   would be willing to carry that in their pocket.  As

 

 13   I understand it, the reason why they carry single

 

 14   units in their pocket is because when they open the

 

 15   foil pack, there's 12 of them there.  If there's

 

 16   only one, they would probably carry it.  And, of

 

 17   course, that could also be addressed through

 

 18   professional education as well.

 

 19             DR. GROSS:  Leslie, for myself and anyone

 

 20   else who is not 100 percent clear on what you said,

 

 21   would you contrast the two methods of medication

 

 22   delivery again?

 

                                                               121

 

  1             DR. HENDELES:  Bronchodilators as well as

 

  2   inhaled steroids can be delivered by a pressurized,

 

  3   meter-dose inhaler that's attached to a valve

 

  4   holding chamber with an age-appropriate connection,

 

  5   either a mouthpiece for older folks or a mask for

 

  6   preschool kids that seals around their nose and

 

  7   mouth, and you fire off a few puffs, such as four

 

  8   puffs, into this chamber and it's equivalent in

 

  9   efficacy to nebulizing a bronchodilator in the

 

 10   emergency room.  It causes fewer side effects.  It

 

 11   takes a minute or two to give the treatment instead

 

 12   of 15 to 20 minutes, and it's far more convenient

 

 13   for patients and cheaper.  They don't have to buy a

 

 14   compressor for $150.

 

 15             DR. GROSS:  Could someone from the FDA

 

 16   comment on whether or not they want to tackle that

 

 17   issue?

 

 18             DR. SULLIVAN:  That may not be an issue

 

 19   for the FDA really to address.  I don't think there

 

 20   would be any--the evidence being what it is, that

 

 21   MDIs may effect just as great a degree of

 

 22   bronchodilation as a nebulizer, it would be

 

                                                               122

 

  1   something that physicians should interpret and use

 

  2   in their clinical judgment.  I don't think there

 

  3   would be any rationale for the agency to pull

 

  4   nebulizer solutions off the market.  I think that

 

  5   would be very drastic.  So from our perspective, we

 

  6   have to deal with them.

 

  7             Now, if the medical community starts to

 

  8   learn that maybe they are overusing nebulizers

 

  9   through Dr. Hendeles' shaking the cage a little

 

 10   bit, that's just great.  But the issue will still

 

 11   remain for us.

 

 12             DR. HENDELES:  And, indeed, there are

 

 13   patients who might be unconscious, for example, or

 

 14   would need the nebulizer, and there are drugs such

 

 15   as Tobramycin that can't be delivered by MDI.

 

 16             DR. GROSS:  Arthur?

 

 17             MR. LEVIN:  I realize it isn't within the

 

 18   scope of authority of the FDA to dictate clinical

 

 19   practice, but part of the problem here is we're

 

 20   dealing with a tension between an issue of

 

 21   potential harm, which is the leaching of, you know,

 

 22   substances that don't belong in the solution into

 

                                                               123

 

  1   the solution and the documented potential harm of

 

  2   error.  And we're looking at a variety of

 

  3   solutions, none of which is perfect and each of

 

  4   which brings with it some question:  You know, does

 

  5   it solve the error problem entirely?  Or by solving

 

  6   the error problem entirely, does it still leave us

 

  7   open to the problem of possible impurity?

 

  8             In that context, I think the FDA does have

 

  9   something to say, and then when we move to the

 

 10   ambulatory setting particularly, where these issues

 

 11   I think get even more complicated--and we really

 

 12   haven't talked about it--that if there are better

 

 13   ways to deliver the product that relief us of the

 

 14   burden of trying to figure out the perfect solution

 

 15   on these two different potential harms, that's

 

 16   worthy of comment.  I mean, nobody expects you to

 

 17   be able to pull the product from the market, but in

 

 18   dealing with improving safety of products, I don't

 

 19   think it's entirely out of character for the FDA to

 

 20   make a comment that one of the solutions here is to

 

 21   use a different form of delivery that obviates the

 

 22   need to talk about all of this.  You may not be

 

                                                               124

 

  1   able to say, "You can't use the other," but you can

 

  2   certainly say, "Moving in this direction seems to

 

  3   be a way to solve the problem," and I would say

 

  4   particularly in the ambulatory populations.

 

  5             DR. GROSS:  Maybe we'll have one or two

 

  6   more comments on this particular issue.  Then we'll

 

  7   have to get back to the questions raised by Dr.

 

  8   Seligman in 1a.

 

  9             Brian?

 

 10             DR. STROM:  yes, I'd like to in my initial

 

 11   start be more provocative.  We're hearing, as

 

 12   Arthur is saying, between two safety problems,

 

 13   without good data on either side to quantify each

 

 14   of them.  We're using in one case physiological

 

 15   chemical tests and the theory that leaching might

 

 16   be a problem, and it's clearly understandable why

 

 17   it can't be quantified more than that.  And we're

 

 18   hearing on the other side about medication errors

 

 19   based on the spontaneous reporting system, which is

 

 20   grossly incomplete.  We don't know how many there

 

 21   are out there other than the fact that we're seeing

 

 22   a number, and there are clearly many more out there

 

                                                               125