Study Protocol – Stage 2 - PQRI

1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group Issued and Effective September, 2011 Study Protocol Stage 2 Experimental Protocol for Simulation Study of Blow-Fill-Seal (BFS) PODP Container Closure Systems PODP Issued and Effective Leachables and Extractables Working Group September, 2011 Experimental Protocol for Simulation Study , Stage 2 TABLE OF CONTENTS 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 I.

2 INTRODUCTION 3 II. PURPOSE AND SCOPE OF WORK ( Study Protocol Stage 2) 5 III. REGULATORY STATUS 6 IV. SAFETY AND ENVIRONMENTAL IMPACT 6 V. TEST SYSTEM 7 VI. CHEMICAL S AND EQUIPMENT 7 A. Extraction Solvents 8 B. Additional Chemicals 8 C.

3 Extraction Equipment 8 D. Analytical Instrumentation 8 VII. EXTRACTION PROCEDURES 9 A. Simulating Extraction Solvents 9 B. Accelerated Extraction Conditions 9 C. Exaggerating Factors 9 VIII. ANALYTICAL METHODS 10 A. General 10 B. System Suitability 10 B. Gas Chromatography (GC) 18 1. General 18 2.

4 Sample Preparation 18 3. Operating Conditions 22 4. General Comments 22 C. High Performance Liquid Chromatography (HPLC) 22 1. General 22 2. Sample Preparation 22 3. Operating Conditions 22 4. General Comments 23 E. Headspace GC/MS Analysis 23 1. General 23 2. Sample Preparation 23 3. Operating Conditions 24 4.

5 General Comments 24 - 1 - PODP Issued and Effective Leachables and Extractables Working Group September, 2011 Experimental Protocol for Simulation Study , Stage 2 F. Inductively Coupled Plasma Atomic Spectroscopy (ICPAS) 25 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 1. General 25 2. Sample Preparation 25 3. Operating Conditions 25 4.

6 General Comments 26 IX. DATA EVALUATION AND REPORTING 26 A. Qualitative Analysis 26 B. Semi-Quantitative Measurement 26 X. GLOSSARY 27 XI. REFERENCES 27 - 2 - PODP Issued and Effective Leachables and Extractables Working Group September, 2011 Experimental Protocol for Simulation Study , Stage 2 I.

7 Introduction 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 It has been well established that substances extracted by drug products from their container closure systems can affect the drug product s safety and efficacy. Regulatory guidance has provided some recommendations regarding the analysis and toxicological safety assessment ( , qualification) of such substances. Thus, for example, the FDA issued Container Closure Systems for Packaging Human Drugs and Biologics Chemistry, Manufacturing and Controls (CMC) documentation Guidance for Industry in May 19991. In addition, the European Medicines Agency (EMEA) issued its Guideline on Plastic Immediate Packaging Materials in May Specific Guidance for Orally Inhaled and Nasal Drug Products (OINDP) is contained in two CMC Guidances addressing OINDP1: (i) the draft Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products, Chemistry, Manufacturing, and Controls Documentation (November, 1998); and (ii) the Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing, and Controls Documentation (July, 2002).

8 In September 2006, the Product Quality Research Institute (PQRI) issued a Recommendation entitled Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products 3. This Recommendation provided a scientific rationale and process to identify, quantify and establish the biological safety ( qualify) of leachables and/or extractables where appropriate, in OINDP. Included in this Recommendation were experimental protocols, and the results thereof, for establishing Best Demonstrated Practices for the performance of Controlled Extraction Studies, specifically relevant of the OINDP dosage forms. The PQRI Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group is developing, executing and reporting experimental studies as the means of establishing Best Demonstrated Practices for the performance of Chemical Assessments specifically relevant for PODP container closure systems and dosage forms.

9 Figure 1, The Chemical Assessment Triad, illustrates the Chemical Assessment Process. The PODP Stage 1 Study considered the process of Material Characterization; specifically the processes by which a Controlled Extract is generated, by which a Controlled Extract is analyzed and by which the test results are evaluated and interpreted. This Stage 2 Study considers the process of performing a Simulation Study , specifically establishing the extractables profile of an experimental container closure system constructed from some of the materials that were characterized in the Stage 1 Study . This experimental container closure system specifically mimics a Blow-Fill-Seal (BFS) packaging system, such as those used with many ophthalmic products, consisting of a BFS bottle, its associated cap, a closure gasket and an affixed printed label.

10 This experimental Protocol will be used by all participating laboratories and investigators. 1 Available at 2 Available at 3 Available at - 3 - PODP Issued and Effective Leachables and Extractables Working Group September, 2011 Experimental Protocol for Simulation Study , Stage 2 Figure 1. Generalized Chemical Assessment, The Chemical Assessment Triad. A simulation Study may be an appropriate and effective bridge between the material characterization process, which establishes extractables that are tentative leachables and product assessment, which measured confirmed leachables.