A Critical Assessment of Factors Effecting Blister Pack Formation In
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A Critical Assessment of Factors Effecting Blister Pack Formation in the Pharmaceutical Industry By Keith W Allen A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University Aug 2010 Department of Materials Supervisor: Dr G.W.Critchlow Acknowledgements I would like to thank my friend and colleague Dennis O’Reilly for reviewing the technical content and Mark Nicholls a Senior Analyst in the Physical Properties group at GlaxoSmithKline Research and Development Site in Harlow, in assisting in analysing the surface and material properties of the blister films discussed as part of my research studies. I would also like to thank my supervisor Dr Gary Critchlow for his support and advice in the preparation of this report, and Keith Yendall from the IPTME Department of materials at Loughborough University in assisting in analysing the surfaces of blister strips. A special thanks also to my wife Maria and my Daughter Kayleigh for their patience and support in typing sections and proof reading my entire Thesis. 2 Abbreviations AES – Auger Electron Spectroscopy APS – Alcan Packaging Singen AFM – Atomic Force Microscopy bpm – Blisters Per Minute BSI – British Standards Institute CEN – European Committee for Standardisation CLF – Current Lidding Foil COCs – Cyclic Olefin Co-polymers cpm – Cycles Per Minute DMF – Drug Master File DSC – Differential Scanning Calorimetry EMEA – European Medicines Evaluation Agency EU – European Union EP – European Pharmacopeia FDA – Food and Drugs Administration FTIR – Fourier Transform Infrared GC – Gas Chromatography GSK – GlaxoSmithKline GPTD – Global Packaging and Technical Development GRAS – Generally Recognised As Safe HDPE – High Density Polyethylene HSL – Heat Seal Lacquer ICH – International Conference Harmonisation IR – Infrared IPCs – In Process Controls JP – Japanese Pharmacopeia LDPE – Low Density Polyethylene MDPI – Multi-dose Powder Inhaler MHRA – Medicines Health Regulatory Association MSG – Mont-Saint Guibert MVTR – Moisture Vapour Transmission Rate NLF – New Robust Lidding Foil NCEs – New Chemical Entities NDA – New Drug Application OPA – Orientated Polyamide OPP – Orientated Polypropylene OTC – Over The Counter PA – Polyamide PCTFE – Polychlorotrifluoroethylene PE – Polyethylene PEL – Packaging Evaluation Laboratory PET – Polyester PLA – Poly Lactic Acid PMA – Polymethylacrylate 3 Abbreviations - Continued PP – Polypropylene PS – Polystyrene PVA – Polyvinyl acrylate PVdC – Polyvinylidene Chloride PVC – Polyvinylchloride R&D – Research and Development RFID – Radio Frequency Identifications RH – Relative Humidity SIMS – Secondary Ion Mass Spectroscopy SEM – Scanning Electron Microscopy SOP – Standard Operating Procedure SPM – Strips Per Minute UPVC – Un-plasticized Polyvinylchloride USA – United States of America USP – United States Pharmacopoeia µm – Micrometres VAPT – Variable Angle Peel Tester WVTR – Water Vapour Transmission Rate WHO – World Health Organisation XPS – X-Ray Photoelectron Spectroscopy 4 Abstract Blister packing is a very complex process, incorporating many areas of science and technology. To date there have been many studies carried out evaluating various types of blister materials, sealing and forming processes and heat sealable adhesives. However, there has never been a reported study pulling together all of the critical factors involved in achieving optimised blister packing. There is also very little on this topic in terms of published literature. The aim of this study is to evaluate all critical aspects of blister packing to resolve ongoing machine and material issues by enabling the introduction of alternative materials and processes. Further to a critical evaluation of the available literature and studies on the various types of blister sealing equipment and tool design, the alternative types of materials used to produce the blister packs were also evaluated to identify the critical features and parameters required to achieve a totally sealed hermetic pack. More recent studies have evaluated the seal quality of new and existing Multi- Dose Powder Inhalation (MDPI) lidding and base foils. These novel studies have utilised techniques such as Scanning Electron Microscopy (SEM) and calculated peel strength data using developed test protocols. Moisture ingress determination based upon both theoretical and actual calculations have also been deduced. A further study has also been carried out to determine the heat transfer from the heated sealing tools to the product for platen type blister sealing. This study set out to give an overview of the packaging requirements of the pharmaceutical industry, the purpose being to highlight the critical aspects of a heavily regulated industry and to explain the various stages of the packaging process to identify any areas of development and improvements that could be made as part of any subsequent studies. 5 Once an overview had been undertaken, it was necessary to identify the current and new materials under development that are and will be used for blister packaging in future applications. It has also been neccessary to determine the required protection in terms of moisture vapour, light transmission, seal strength and seal integrity that the products require. Prior to any decisions on the areas to research as part of my studies it was essential to understand the types of blister designs and material construction with the necessary additives such as stabilising agents, stability agents and antiblock agents. The rationale being to avoid repetition of any previous developments and to use those developments and previous studies to further enhance the performance of the current materials, developing totally new concepts and blister structures. Once the materials were identified a study was carried out into two types of blister sealing equipment, namely rotary and platen sealers. This was essential in developing a good understanding of the process and technology available when introducing new materials and alternative blister designs. Furthermore, it was key in understanding the problems associated with blister packs and in resolving ongoing material and equipment issues. Further research was then directed towards other critical aspects of blister sealing, such as dwell time, temperature, pressure and the importance of the adhesive function. After which the types of testing that is carried out on the finished blister to ensure that a good hermetic seal is achieved was identified. This guarantees that the product will be preserved during its shelf-life and the required dose will be administered throughout. The study then focused on a number of operational improvements and introduction of new materials, such as alternative types of lidding and base laminates, new heat seal lacquers and new rotary blister sealing tools. 6 Index Chapter 1 Introduction into the Main Factors Effecting Blister Pack Formation in the Pharmaceutical Industry 1.1 Overview of Packaging for the Pharmaceutical Industry 1.1.1 Introduction 18 1.1.2 Child Resistant Packaging Legislation 20 1.1.3 Packaging Development 21 1.1.4 Advances in Technology 23 1.1.5 Innovation in Pharmaceutical Packaging 24 Chapter 1 Section 2 1.2 General Introduction into Blister Sealing 1.2.1 Problems Associated with Blister Packs 25 1.2.2 Pack Design and Blister Layout 27 1.2.3 Blister Sealing Equipment 27 1.2.4 Protection and Use 28 1.2.5 New Developments 28 Chapter 2 Section 1 Literature Review 2.1 Critical Aspects of Blister Packaging 2.1.1 Materials and Laminates used to Produce Blister Packs 30 2.1.2 Types of Blister Pack 34 2.1.3 Additives used in the Manufacturing Process of Blister Films 42 2.1.4 Types of Blister Sealing and Forming Equipment 44 7 2.1.5 Critical Aspects of the Blister Sealing Process 51 2.1.6 Problems Associated with Blister Sealing 68 2.1.7 Overall Conclusions on the Critical Aspects of Blister Sealing 73 Chapter 2 Section 2 Literature Review 2.2 Principles of Adhesion 2.2.1 Introduction 76 2.2.2 Factors required for Optimised Adhesion 79 2.2.3 The Influence of Pre-treatment on Adhesion 81 2.2.4 Surface Morphology & Joint Strength 83 2.2.5 Bulk Adhesive Properties 83 2.2.6 Hot Melt Adhesive 85 2.2.7 Properties of an Adhesive that effect Adhesion 86 2.2.8 Heat Seal Strength 89 2.2.9 Theories of Adhesion Relating to this Study 90 2.2.10 Stress Distribution 91 2.2.11 Stresses in the Adherened 91 2.2.12 Stresses within the Adhesive 92 2.2.13 Summary 93 Chapter 2 Section 3 Literature Review 2.3 Strength of Adhesive Joints 2.3.1 Introduction 94 2.3.2 Peel Test 94 2.3.3 Experimental Procedures in the Fixed Arm Peel Test 101 8 Chapter 2 Section 4 Literature Review 2.4 Material Characterisation and Surface Analysis 2.4.1 Introduction 104 2.4.2 Principle Techniques Employed in this Research Study 106 Chapter 2 Section 5 Literature Review 2.5 Heat Transfer into Blister Strips 2.5.1 Introduction 111 2.5.2 Basics of Heat Transfer 111 2.5.3 Introduction into Heat Flow Equations 114 Chapter 3 Experimental 3.1 Methodologies and Procedures used during this Study of Blister Sealing 3.1.1 Introduction 118 3.1.2 Protection against Moisture 119 3.1.3 Process Leak Testing 123 3.1.4 Seal (Peel) Strength Test 127 3.1.5 Device Indexing Force Testing (Torsion Hub) 128 3.1.6 Coating Weight of Heat Seal Lacquer 129 3.1.7 Accelerated Shelf-life Tests 129 3.1.8 Experimental Techniques used to Investigate Bond Formation 129 Chapter 4 Results 4.1 Modelling of the Heated Platen Sealing Process 132 4.1.1