Clinical Concerns on Permeability of LDPE Vials in Inhalation Drug Products

1. DSaRM Advisory CommitteeMay 5, 2004 Permeability of LDPE Vials: A clinical perspective Eugene J. Sullivan, MD, FCCP Division of Pulmonary and Allergy Drug Products

2. Overview: • Introduction • Drug Products • Patient Populations • Potential sources of contaminants • Potential adverse effects of contaminants • Difficulties monitoring for adverse effects • Summary and Discussion

3. Introduction 1/2 • The topic for discussion today is how best to minimize the potential for medication errors, given the clinical concerns regarding low density polyethylene (LDPE) containers. • This presentation will review these clinical concerns, in order to provide background for the discussions today.

4. Introduction 2/2 • The clinical concerns can be summarized as follows: • Many inhalation drug products are packaged in low density polyethylene (LDPE) containers • LDPE is permeable to volatile chemicals • Numerous volatile chemicals exist in the immediate packaging environment • Volatile chemicals may have irritant, as well as toxicologic effects • Because these effects may be poorly tolerated by patients, efforts should be made to minimize the potential for contamination of inhalation drug products

5. Drug Products • Examples of inhalation drug products packaged in LDPE containers include: • Albuterol sulfate • Ipratropium bromide • Albuterol/Ipratropium • Metaproterenol • Levalbuterol • Cromolyn sodium • Budesonide • Tobramycin

6. Drug Products • These are inhalation solutions (or suspensions) intended for delivery by nebulizer • Manufacturing processes are very carefully controlled in order to maintain a high standard of product purity • They may be used in a regular dosing schedule (e.g. QID) or as-needed, when symptoms flare • Bronchodilator inhalation solutions (albuterol, etc) are commonly used in the inpatient and acute care setting (hospital wards, ED, ICU)

7. Patient Populations • These inhalation drug products are used by patients with various pulmonary disorders: • asthma • COPD (chronic obstructive pulmonary disease: chronic bronchitis and emphysema) • cystic fibrosis • These diseases are characterized by: • fixed or variable obstruction to airflow • histologic abnormalities (e.g. airway inflammation) • allergic propensity (atopy) (asthma) • airway hyperresponsiveness

8. Patient Populations • Asthmatic patients are known to react adversely to chemical irritants • Acute bronchospasm (wheezing and SOB) • Patients with severe asthma may react to very low doses of inhaled chemicals/irritants • perfumes, cleaning agents, smoke • methacholine challenge testing • Many asthmatic patients also develop bronchospasm from inhaled allergens • Early and late phase responses

9. Potential Sources of Contaminants • Labels • Glues, inks, lacquers • Secondary bulk packaging (eg cartons) • Glues, inks • FDA analytical survey of approved inhalation solutions marketed in LDPE containers • 29 of 37 samples tested positive for volatile chemicals that were presumed to have originated in the packaging materials

10. Potential Adverse Effects • Irritant effects • Immunologic effects • Toxicologic injury • Carcinogenicity

11. Difficulties in Monitoring for Adverse Effects • Adverse effects may mimic symptoms for which the drug is being used (bronchospasm) • Therefore, adverse effects would not likely be recognized and reported. • Although modest bronchospasm related to irritant contaminant may lead to reduced efficacy, this may not be detected. • Even more significant bronchospasm related to irritant contamination would likely be attributed to refractory underlying disease.

12. Summary 1/2 • Many inhalation drug products are packaged in low density polyethylene (LDPE) containers • LDPE is permeable to volatile chemicals • Numerous volatile chemicals exist in the immediate packaging environment

13. Summary 2/2 • Various volatile chemicals have been identified in these products • Volatile chemicals may have irritant, as well as toxicologic effects • Because these effects may be poorly tolerated by patients, efforts should be made to minimize the potential for contamination of inhalation drug products

14. Discussion 1/2 • This line of reasoning led in part to the development of the Draft Guidance entitled “Inhalation Drug Products Packaged in Semipermeable Container Closure Systems” (July, 2002) • The Draft Guidance recommends that measures be taken to limit chemical contamination of these products • Alternative approaches to paper labels (e.g. embossing/debossing)

15. Discussion 2/2 • The move away from paper labels has introduced a new concern: medication errors. The issue of how best to minimize the potential for medication errors will be the topic for today’s discussion.