DESIGN
Perfecseal, Londonderry, Northern Ireland
Protection
The role of medical packaging is to deliver a clean, sterile, protected medical device to the point of use and to allow aseptic presentation. The packaging must be compatible with the method of sterilisation and should protect the device during handling, distribution and storage. ISO 11607 Packaging For Terminally Sterilised Medical Devices describes the primary packaging as the “sterile barrier system,” that is, the minimum packaging to allow sterilisation, provide an acceptable microbial barrier and to allow for aseptic presentation. The “protective packaging” protects the “sterile barrier system” and together they form the “packaging system.”1,2
Packaging combination products
In recent years, combination products have emerged. A successful combination product creates a product that has efficacy greater than the sum of the parts.3 Combination products are at the interface of pharmaceutical and medical device research. Examples include antimicrobial catheters, drug eluting stents, prefilled syringes and anti-biotic bone cement.
For combination products, the fundamentals of medical packaging still apply, but there are new challenges facing the packaging designer involving not only protecting the device, but also maintaining the safety and effectiveness of the drug or biologic. There is, therefore, often much more emphasis on the internal environment of the pack. The designer must consider what affects there may be on the drug/biologic: biocompatibility, photostability, moisture sensitivity, reaction to gases such as oxygen, leachables that may migrate into the drug/biologic and hence into the patient, or any loss of drug/biologic efficacy due to its migration into the packaging. The designer must also consider temperature stability and its effect on the safety and effectiveness of the product.
Drug eluting stents
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Figure 1: DES single pouch concept.
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The drug eluting stent (DES) is a classic example of a combination product, where the stent and drug are “combined” to provide a better therapeutic effect. DESs are used in the treatment of coronary artery disease (CAD), which is the leading cause of death in the developed world for men and women. The DES market is influenced by population demographics: approximately 84% of people who die from CAD are 65 or older.4 The concept of stenting grew directly out of cardiologists’ experience with angioplasty balloons in the late 70s and 80s.5 In a small percentage of cases, the artery would collapse after the balloon was deflated, which required emergency bypass graft surgery to repair the problem. With the advent of the bare metal stent (BMS), the artery could remain open after balloon deflation. The long term success of coronary bare metal stenting is limited by in-stent restenosis, which has led to the development of stents coated with a pharmaceutical ingredient that reduces restenosis.6–10
The DES market
The safety of DESs has been called into question by studies suggesting a predisposition to late stent thrombosis, an uncommon but potentially fatal complication.11–15 However, it has been suggested that drug eluting stents have “recovered from the bad press of 2006.” The United States (US) market is approximately 70% of the global market and Chris Cooley, analyst for FTN Midwest Securities Corporation (www.ftnmidwest.com), estimates the US market to be worth just under US$2 billion in 2008. However, the market is not standing still. Two new devices entered in 2008 to compete with the Taxus and Cypher stents. Boston Scientific (www.bostonscientific.com) and Johnson & Johnson (www.jnj.com) share the US market with the Taxus paclitaxel eluting stent and the Cypher sirolimus eluting stent, respectively. Endeavor, the zotarolimus eluting stent from Medtronic (www.medtronic.com) and Xience V (www.xiencev.com), Abbott’s (www.abbott.com) everolimus eluting stent were both approved by the US Food and Drug Administration and are now commercially available. There are currently approximately one million DESs sold globally and each one must be packaged safely to maintain sterility and efficacy.
Development of DES packaging
Typically, packaging for a DES employs two separate pouches: a primary sterile pouch that allows ethylene oxide sterilisation (EtO) and a secondary nonsterile high barrier pouch. The primary pouch must have a porous membrane to allow gas flow during the sterilisation cycle. The secondary pouch must have excellent barrier properties because, as a precaution to remove the risk of adverse reactions, the stent’s drug coating is protected from oxygen and moisture during its inpack shelf life. After sterilisation, the primary pouch containing the DES is placed inside the secondary pouch, which is gas flushed with a nonreactive gas such as nitrogen, and then sealed. To sequester any residual oxygen and moisture, a desiccant/oxygen scavenger may be used. The design team’s aim was to provide a single pouch concept and commercial solution that would perform the same function as the two pouches described above.
Porous and high barrier
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Figure 2: Medical device manufacturer’s seals.
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The major design challenge for a single pouch concept is how to allow EtO sterilisation, and then provide oxygen and moisture barrier during storage. The packaging designers solved this problem by creating a premade Tyvek– (DuPont de Nemours, Luxembourg, Luxembourg) polyethylene–Tyvek insert sealed inside a foil pouch in such a way to create two separate pockets: one to hold the DES and the other to hold the scavenger. The insert and basic pouch seal configuration is shown in Figure 1.
Each Tyvek strip in the insert performs a separate function: the left-hand strip, and to some extent the right hand strip, allow the flow of EtO gas during sterilisation; the right hand strip allows the flow of residual moisture and oxygen between both pockets during inpack shelf life. This allows the desiccant–oxygen scavenger to absorb any residual moisture and oxygen.
In use, the medical device manufacturer places the DES inside the back pocket and makes seal 1 (see Figure 2). after sterilisation, the manufacturer inserts a desiccant–scavenger into the front pocket and gas flushes before making seal 2.
The left hand Tyvek portion is then redundant and can be trimmed away to improve aesthetics and reduce pack size, as shown by the dotted line. The insert’s polyethylene strip is required in seal 2 because Tyvek would hinder the creation of a hermetic seal, which is discussed later in more detail.
Materials
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Figure 3: SEM rendering of Tyvek (DuPont).
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Figure 3 shows a scanning electron microscope (SEM) rendering of Tyvek; this is the DuPont brand name for flash-spun high-density polyethylene that allows gas transfer by convection, whilst maintaining outstanding resistance to microbial penetration.16 The foil material is a white multilayer structure consisting of biaxially oriented polyamide, aluminium foil and a peelable sealant. The aluminium foil provides excellent barrier properties: nominally <0.02 g/m²/day moisture vapour transfer rate and <0.02 cm³/m²/day oxygen transfer rate. The nylon provides excellent strength and toughness, contributing to the structure’s tensile strength of more than 200 N/25 mm.
Seal permeability
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Figure 4: Seal configuration.
(click image to enlarge) |
Another challenge is how to ensure that the pouch’s perimeter seals maintain a high barrier to moisture and oxygen ingress. Testing had shown that if Tyvek was sandwiched between the two foil materials, there was sufficient porosity through the edge of the Tyvek to allow gas transfer.
The use of a polyethylene strip in the insert solved the problem for the manufacturer’s seal 2, but to avoid porosity through the insert’s right hand strip of Tyvek (shown dotted), the packaging design was modified to include additional seals, as shown in Figure 4. These seals are designed to allow EtO sterilisation of the channel between the “additional seals” and the main side seals.
Aseptic presentation and easy opening
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Figure 5: Opening feature.
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To allow easy access to the DES, the foil has a peelable sealant and a “corner opening” feature is designed into the seal profile, as shown in Figure 5. The peelable sealant opening system provides a consistent peel–seal highlighted by a white transfer showing evidence of pack opening. It is important to note that the pocket containing the desiccant is nonsterile, and therefore, the user must be guided by instructions and peel logos printed onto the pack to ensure that the pack is opened correctly.
Product safety and testing
Cytotoxicity and ageing data are required to support the medical device manufacturer’s decision to use specific materials and packaging formats prior to lengthy and expensive in-pack device stability testing.
Any materials used in medical packaging should be tested to ensure that there are no harmful extractables. Cellular toxicity is determined in accor- dance with ISO 10993-5, Biological Evaluation of Medical Devices, Part 5, Tests for In Vitro Cytotoxicity. To support the requirements of ISO 11607, the packaging materials must be compatible with the shelf life of the device and sterilisation method. The ageing process can be accelerated by elevating storage temperature in accordance with ASTM F-1980, Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices, based on the assumption that the chemical reactions involved in deterioration of materials follow the Arrhenius function. However, because accelerated ageing is based on assumptions, real-time ageing is also conducted in parallel. In both cases, the materials’ sealing characteristics and physical properties are monitored such as tensile strength, porosity, microbial barrier, puncture resistance and tear strength. Other requirements may be necessary depending on customers’ specific needs.
Validation
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Figure 6: DES pouch machine.
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The pouch is considered to be a “preformed sterile barrier system.” It is supplied partially assembled for filling and final sealing and thus falls within the scope of ISO 11607 Part 2.
Specifying, commissioning and testing of a new manufacturing machine require careful consideration. The guidelines for ISO 11607 provide directions for installation qualification, operational qualification and performance qualification (PQ) so that the process parameters are challenged to ensure that they will produce pouches that meet all defined requirements under all anticipated conditions of manufacturing. The PQ demonstrates that the process can consistently produce acceptable pouches under the specified operating conditions. In practical terms, the heat seals of the pouch have been validated to determine maximum, minimum and optimum settings that will reliably produce peelable seals to a statistical capability index greater than 1.33.
Stability testing
Knowing that the packaging materials are “safe” and that the pouch is validated in accordance with ISO 11607, helps the medical device manufacturer to complete the rigorous stability testing necessary to determine that the product is safe and effective within its package. Drug/device stability testing is beyond the scope of the packaging engineer. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, to establish a retest period for the drug substance, and/or a shelf life for the drug product and recommended storage conditions.17–25
Risk free supply
Apart from the obvious and serious requirements that medical packaging should ensure absolute safety, there is also financial risk because of the high cost of the device. One DES costs approximately US$3000 compared with US$1000 for a bare metal stent. It is estimated that in the sterilisation chamber there could be as much as US$10 million worth of stents. If for some reason the packaging fails, the DESs cannot be resterilised. It is therefore important that the pouch is produced using the highest possible “risk free” manufacturing standards. The single pouch concept and manufacturing method were first developed and proven on a prototype machine, which led to commissioning the full-scale production unit shown in Figure 6, which is now operating in a clean room and part of a state-of-the-art medical packaging facility.
Challenges
The scientific and technological breakthroughs to improve health and lengthen the average human life span have accelerated the pace of medical innovation and resulted in a plethora of new medical devices with advanced features and superior performance properties.26 Each device must be packaged to ensure that it is functional and that pharmacological or biologic properties are protected until the point of use. This is the challenge for medical packaging. The development of a single pouch concept for drug eluting stents is just one example of how these challenges are being met by the health care packaging industry.
References
1. ISO 11607-1:2006 Packaging for Terminally Sterilised Medical Devices, Part 1 deals with Materials and Design, Requirements for Materials, Sterile Barrier Systems and Packaging Systems.
2. ISO 11607-2:2006 Packaging for Terminally Sterilised Medical Devices, Part 2 deals with Processes, Validation Requirements for Forming, Sealing and Assembly Processes.
3. M.A.Z. Hupcey and S. Ekins, “Improving the Drug Selection and Development Process for Combination Devices,” Drug Discovery Today, 12, 19–20, 844–852 (2007).
4. “Drug Eluting Stents – Technology and Market Forecast,” Medtech Ventures (2005) http://medtech-ventures.com
5. B. Meier et al., “25 Years of Coronary Angioplasty: Almost a Fairy Tale,” The Lancet, 361 (February 2003).
6. M. Valgimigli et al., “New and Old Strategies to Afford the Liberal Use of Drug-Eluting Stents in Real-Life Scenarios,” European Heart Journal Supplements (2005).
7. Clinica – World Medical Technology News, 1287, 28 December 2007.
8. I. Iakovou et al., “Incidence, Predictors and Outcome of Thrombosis After Successful Implantation of Drug-Eluting Stents,” JAMA, 293, 2126–2130 (2005).
9. A.T.L. Ong et al., “Sirolimus-Eluting Stents Remain Superior to Bare-Metal Stents At Two Years,” Journal of the American College of Cardiology, 47, 7 (2006).
10. H. Kelbæk et al., “The Stenting Coronary Arteries in Non-Stress/Benestent Disease (SCANDSTENT) Trial,” Journal of the American College of Cardiology, 47, 2 (2006).
11. D. Austin et al., “Drug-Eluting Stents: Do The Risks Really Outweigh the Benefits?” Heart, 94, 127–128 (2008).
12. I. Moussa, “Are Drug-Eluting Stents Cost-Effective When Compared With Bare-Metal Stents In a Real-World Setting?,” Nature Clinical Practice Cardiovascular Medicine, 3, 192–193 (2006).
13. U. Sigwart, “Drug-Eluting Stents Are Safe And Effective Right Or Wrong?” Journal of the American College of Cardiology, 47, 7 (2006).
14. S. Heuser, “What’s Next For Stents? Drug-Releasing Versions Have Limitations, Which Researchers Are Trying To Solve With The Next Generation Of Devices,” The Boston Globe, (5 December, 2005).
15. J.W. Hirstfeld and R.L. Wilensky, “Drug-Eluting Stents Are Here — Now What? Implications For Clinical Practice And Health Care Costs,” Cleveland Clinic Journal of Medicine, 71, 10 (2004).
16. DuPont Medical Packaging, “Technical Reference Guide For Medical Packaging,” www.medicalpackaging.dupont.com
17. Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products.
18. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics.
19. Guidance for Industry: ICH Q1B Photostability Testing of New Drug Substances and Products.
20. Guidance for Industry: ICH Q1C Stability Testing for New Dosage Forms.
21. Guidance for Industry: ICH Q3A Impurities in New Drug Substances.
22. Guidance for Industry: ICH Q3B Impurities in New Drug Products.
23. Guidance for Industry: ICH Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products.
24. Guidance for Industry: ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.
25. Guidance for Industry: ICH Q6B Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products.
26. “Healthy Prognosis for Healthcare Packaging,” Healthcare Packaging, J. Butschli, Ed, 25 December 2007.
George Mankel, MSc Pkg Technology, F Inst Pkg, is Product Leader – Films, at Perfecseal Ltd, Acorn Road, Campsie Industrial Estate, Londonderry BT47 3GQ, UK, tel. +44 2871 814 000, e-mail: gmankel@bemis.com, www.perfecseal.ie
