FOOD AND DRUG ADMINISTRATION


















                       ADVISORY COMMITTEE (DSaRM)


                           COMMITTEE MEETING















                         Wednesday, May 5, 2004


                               8:18 a.m.










                CDER Advisory Committee Conference Room.

                           5630 Fishers Lane

                          Rockville, Maryland



                        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.




      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.



                            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



                      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




  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.




  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.




  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




  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




  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




  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.




  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         



 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




  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




  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




  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




  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,




  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




  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.




  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.




  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




  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




  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




  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




  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




  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.




  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




  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. 




  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




  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.




  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




  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




  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




  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




  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




  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




  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?




  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.




  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




  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.




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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




  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. 




  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




  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




  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




  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




  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.




  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




  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




  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?




  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




  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?




  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




  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




  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




  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




  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            



 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




  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




  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




  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




  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,




  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




  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            



 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




  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




  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




  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




  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




  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




  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




  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




  1   individual vials.  Add a tactile symbol for generic


  2   identification based on the following advantages:


  3   quick approach, no impact on product chemistry or


  4   stability, and no impact on patient cost.  For


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


  6   label to accommodate bar coding.


  7             Thank you.


  8             DR. GROSS:  Thank you very much.


  9             Our next speaker is Karen Stewart of the


 10   American Association of Respiratory Care.


        x                   MS. STEWART:  Good morning.  Thank you for         



 12   giving me the opportunity to present today.  I


 13   think in your packets you have my written


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


 15   I want to share with you.


 16             I've been a registered respiratory


 17   therapist since 1971, and I am here as the


 18   spokesperson for the American Association for


 19   Respiratory Care representing respiratory


 20   therapists both nationwide and internationally.


 21             Respiratory therapists, like all other


 22   health care professionals, are very concerned about




  1   medication errors.  In recent years, since the


  2   elimination of most paper labels on unit-dose vials


  3   of medication, it has become increasingly difficult


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


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


  6   the therapist typically has on their person as


  7   they're making rounds.


  8             Not only is the print on the vial


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


 10   vial contributes to this difficulty.


 11             In 2001, the American Association for


 12   Respiratory Care completed a human resource survey,


 13   and at that time the average age of a respiratory


 14   therapist was 44.  This is another contributing


 15   factor to the difficulty of reading the content of


 16   the medication vial.  While I may have just


 17   emphasized that the current relative age of the


 18   respiratory therapist and the difficulty the older


 19   therapist experiences in reading the labels, I want


 20   to clarify to you that deciphering respiratory care


 21   medication labels is a problem that cuts across all


 22   age groups of respiratory therapists.  The problem




  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




  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




  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. 




  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.




  1             There's a couple more comments from


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


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


  4   to say.  So on behalf of the American Association


  5   of Respiratory Care, I really appreciate the


  6   opportunity to share the association comments.


  7             I have one more slide that I want to share


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


  9   here are just the different medications.  One of


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


 11   of them are bronchodilators.  Two of them are


 12   exactly the same medication in different doses.


 13   Just to really emphasize what the packaging is


 14   doing to the therapist at the bedside.


 15             Thank you.


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



 17   We will not have the committee ask some questions


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


 19   of the speakers that have presented this morning.


 20             Leslie?


 21             DR. HENDELES:  I have two questions for


 22   Karen.  First, is there any Joint Commission




  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




  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




  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




  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




  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--




  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?




  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?




  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




  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.




  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,




  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




  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




  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




  1   problems?


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



  3   of them go through generics.


  4             Carol, did you want to respond to that?


  5             MS. HOLQUIST:  Yes.  Actually, our office


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


  7   only see the packaging material that comes in with


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


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


 10   of these products came in today with this packaging


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


 12   recommendations in our review that, based on


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


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


 15   kind of tied because of the ingress issue.  So


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


 17   conundrum we're in.


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


 19             DR. SULLIVAN:  Yes, I just wanted to


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


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


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




  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




  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




  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




  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?




  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




  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            





  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




  1   with your attendance at the meeting.  Likewise, FDA


  2   encourages you at the beginning of your statement


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


  4   financial relationships.  If you choose not to


  5   address this issue of financial relationships at


  6   the beginning of your statement, it will not


  7   preclude you from speaking.


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



  9   have no financial ties or interests in any


 10   pharmaceutical company or any other company or


 11   organization that would be interested in the


 12   proceedings before the committee today, so I think


 13   I'm okay with that.


 14             DR. GROSS:  Thank you.


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


 16   I'm here today to represent the United States


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


 18   for Information and Standards Development.  We do


 19   have an expert committee that deals with safety


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


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


 22   would like to give you some background about the




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


  2   us and also to have it in the record.


  3             The USP is a nongovernmental organization


  4   that promotes the public health by establishing


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


  6   medicines and other health care technologies.


  7   These standards are developed by a unique process


  8   of public involvement and they're accepted


  9   worldwide.  Many other countries around the world


 10   recognize the USPNF standards as their own


 11   standards in terms of regulatory procedures within


 12   those countries.


 13             USP is a not-for-profit organization that


 14   achieves this goal through the scientific


 15   contribution of volunteers, and the volunteers


 16   represent pharmacy, medicine, and many other health


 17   care professions.  These individuals work in


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


 19   international.  In fact, there are many FDA


 20   scientists who serve as volunteer to USP.  They


 21   also come from the pharmaceutical industry and


 22   consumer organizations.  In addition to standards




  1   development, USP's has several other public health


  2   programs that focus on promoting optimal public


  3   health care delivery.


  4             In our mission statement, it says the


  5   mission is to promote the public health, and I


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


  7   also basically to promote the public health.  So I


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


  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.




  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,




  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




  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




  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?




  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




  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




  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.




  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




  1   legibility and address the problem of ingress of


  2   chemical contaminants and at the same time not


  3   create additional problems.


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


  5   thinking caps and consider if there are stakeholder


  6   groups, such as manufacturers, practitioners,


  7   consumers, and others, who might best advise FDA


  8   about possible new packaging configurations that


  9   might resolve some of these issues.


 10             And then given what you've heard today and


 11   based on our discussion, describe and advise us on


 12   an appropriate course of action to address not only


 13   the problem of ingress of contaminants but also


 14   medication errors due to legibility and similar


 15   packaging issues.


 16             So those are the issues before us.  Peter?


 17             DR. GROSS:  We share in your perplexity.


 18             DR. SELIGMAN:  Thank you.


        x                   DR. GROSS:  This is a difficult issue.            



 20             Thank you very much for the questions,


 21   Paul, and we will initiate the discussion.  The


 22   agenda allows two hours for discussion, so why




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


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


  3             MS. JAIN:  Lunch is on its way.


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


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


  6   begin the discussion now.


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


  8   this in an orderly fashion and take the issues as


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


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


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


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


 13   comments by saying that nebulization of


 14   bronchodilators is an obsolete way of treating


 15   acute bronchospasm, and part of whatever we do


 16   needs to focus on an educational program designed


 17   at using the meter-dose inhaler through a valve


 18   holding chamber, which is far more efficient,


 19   causes fewer side effects, less expensive way, and


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


 21   asthma.  The United States has a fixation on


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




  1   some reason, especially pediatricians, but there's


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


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


  4   that there are much more efficient ways and it


  5   would, of course, circumvent this problem for


  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?




  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




  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




  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




  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