Originally published January 1996
The medical device packaging community has recently made major strides in the direction of globalization with the completion and balloting last year of two new standards designed especially for the international marketplace. Together, these standards establish a new state of the art for device packaging that is likely to have an effect both internationally and within the United States.
The first of the two new standards was compiled under the auspices of the International Organization for Standardization (ISO). Titled Packaging for Terminally Sterilized Medical Devices and designated ISO 11607, this standard was unanimously approved in balloting that ended last September.1 Comments from seven of the voting countries were reconciled at a meeting of the working group responsible for the document (WG7, packaging) when it met in Tokyo last October in conjunction with its parent technical committee (TC198, sterilization). The revised version was subsequently approved for forwarding to the ISO central secretariat for publication as an international standard. As approved, ISO 11607 focuses on the development and production of device packaging; it provides requirements and guidance for the selection of materials, for the development of packaging processes, and for the validation of those processes.
The second standard was compiled by the European Committee for Standardization (CEN). Titled Packaging Materials and Systems for Medical Devices which Are to Be Sterilized, Part 1: General Requirements and Test Methods and designated prEN 868-1, this standard was opened for balloting last February, and is now undergoing revisions pursuant to the comments of the voting nations.2 It is the first of eight standards focused on sterilizable packaging materials; the remaining seven deal with requirements for specific types of materials or applications (e.g., paper bags, heat-sealable pouches, adhesive coated paper). As currently written, prEN 868-1 focuses on the selection and testing of materials to be used in device packaging. Unlike ISO 11607, it does not include guidance on process development or validation.
The approval of ISO 11607 provides the international packaging community with an agreed-upon standard that can be used to guide the formulation of harmonized national requirements. Thus, for individual device companies, the considerable effort required to implement all aspects of the standard will be repaid in the acceptability of their device packaging in many national and regional markets.
ISO 11607 is divided into six major sections dealing with the scope of the standard's application, normative (i.e., mandatory) references, definitions, packaging materials, package forming and sealing, and the final (product) package. An additional four annexes are devoted to a normative test method for measuring the resistance of impermeable materials to the passage of air; methods for evaluating performance in distribution, storage, and handling; a method for conducting dye-penetration testing; and a bibliography.
The introduction of ISO 11607 sets the tone for the future of global packaging with four key statements:
* The device components and the package system should combine to create a total product which performs efficiently, safely and effectively in the hands of the user.
* The specific nature of the medical device, the intended sterilization method(s), and the intended use, shelf life, transport and storage all influence the package design and choice of packaging materials.
* The development and validation of packaging operations are crucial to assure package integrity to the users of sterile medical devices. There should be a documented process validation program demonstrating the efficacy and reproducibility of all sterilization and packaging processes.
* The microbial barrier properties of packaging materials, together with suitable forming and sealing, are critical for assuring packaging integrity and product safety.
The CEN standard, prEN 868-1, is divided into eight major sections, including an introduction, statement of the standard's scope, normative references, definitions, requirements, test methods, documentation, information, and the label. Nine informative annexes offer guidance on such topics as microbial barrier evaluation and the impermeability of packaging seals.
IMPLEMENTING THE STANDARDS
Each prospective user of these standards will require time to read them and consider how they apply to their company and their company's products. There are several key areas to which users should pay particular attention.
First, prospective users should read the scope of the standards and determine whether they apply to their company, their suppliers, or their customers. If the documents are applicable to their company, they should read the definitions carefully. In ISO 11607, for instance, the definitions of manufacturer and producer are particularly important: manufacturer refers to a device manufacturer that packages or sterilizes a medical device, while producer refers to a producer of medical packaging materials or systems. Without a clear understanding of these definitions, implementation of this standard would be subject to confusion.
Companies should also pay close attention to any appendices labeled "normative." A normative reference means that compliance with the information presented therein is mandatory. In ISO 11607, Appendix A is normative and describes a simple test for determining whether a material is considered to be impermeable to the passage of air. Manufacturers must satisfy these test requirements in order to comply with ISO 11607. However, other appendices are labeled "informative," indicating that the information presented therein is for guidance but is not required. For instance, Appendix B lists several methods for evaluating the performance of a package in the distribution environment; these specific methods do not necessarily have to be followed.
Additionally, manufacturers should pay attention to sentences in which the term shall appears. "Shall" indicates a requirement that is mandatory. In ISO 11607, there are more than 120 "shall statements" that apply to manufacturers and producers. In order to comply with this standard, all applicable requirements in those statements must be met. By contrast, sentences that use the term should indicate a recommendation that ought to be taken into consideration but is not mandatory.
Occasionally ISO 11607 indicates that the user "shall consider" a particular factor or course of action. For example, the standard states, "The suitability of the packaging for use in protecting the particular medical device shall be determined by the manufacturer. This shall include consideration of particular protection required by the medical device (e.g., protection against static discharge for electronic components) as well as the stresses which will be imposed during sterilization and subsequent transport and storage" (126.96.36.199).
At first glance, this language can be a bit confusing. However, the requirement is to consider the possibilities--and the standard assumes that it is the manufacturer that is most qualified to determine what particular protection is required. If a device is sensitive to moisture, then the manufacturer would have to include moisture resistance as a factor in determining the suitability of the packaging.
Taken together, the requirements of ISO 11607 and prEN 868-1 offer manufacturers substantive guidance for the design and development of medical device packaging. Following are some of the key elements covered by the two standards.
Properties of Packaging Materials. Manufacturers must demonstrate and document the fact that their packaging materials are nonleaching, nontoxic, and odorless, and that they are safe for use both before and after sterilization. The materials must be free of holes, cracks, tears, and creases. In their construction, they must possess the thickness or average mass specified by the manufacturer and be free of localized thickening or thinning that might impair their function. For such materials, the manufacturer must establish specific or minimum physical properties, which may include tensile strength, thickness, tear resistance, porosity, and burst strength. All materials must meet cleanliness requirements with regard to the shedding of particulate matter.
To establish minimum properties of their materials, manufacturers should assess those properties using materials from several different lots. Although it is not required by either the ISO or CEN standard, manufacturers should be aware that material orientation can also affect the integrity and performance of the package.
Control of Packaging Materials. The source, history, and traceability of raw materials for packaging must be known and controlled. The manufacturer must control and document the conditions under which packaging materials are produced, stored, transported, and handled, and must ensure that those conditions are suitable for the maintenance of the materials' performance characteristics and compatible with the use of the materials. Factors to be tracked and evaluated for material and system integrity and stability include: temperature, pressure, and humidity ranges and their maximum rate of change; exposure to sunlight and ultraviolet (UV) light; cleanliness; and bioburden levels. Where applicable, manufacturers should consider the use of protective wrapping during storage and transport.
Classification of Packaging Materials. The manufacturer is responsible for determining the permeability or impermeability of all materials, closures, and seals. Once the package system has been classified in this way, the manufacturer should confirm that it meets appropriate performance requirements. The CEN prEN 868-1 standard includes an informative annex with a decision tree that can be used to classify package systems.
Microbial Barrier Properties. Manufacturers must ensure that the packaging materials and finished package system possess adequate microbial barrier properties. The package must be effective, must meet specified design criteria, and must maintain the stated properties after undergoing environmental stresses. The manufacturer must also consider the permeability of the package to air and to specified sterilizing agents, to ensure that it will meet requirements for sterilization and removal of sterilants. ISO 11607 Annex A provides a normative test method for the resistance of impermeable materials to the passage of air. If the material is determined to be impermeable, no other microbial barrier testing is required.
Package Compatibility. Manufacturers must ensure that the materials and design of their packages are compatible with the devices they contain. Evaluation of the package-device interaction must include consideration of the device's mass and configuration, including edges and protrusions; the device's susceptibility to such risks as moisture, shock, and static discharge; the potential for abrasion or transfer of contaminants from the packaging materials; and the capability of the package to hold the device in its proper orientation.
Formed Packages. Formed packaging must comply with the manufacturer's specifications for seal width, and burst or seal strength. Peelable packages are to provide continuous and homogeneous peel characteristics without exceeding limits for delamination, tearing, or fiber shedding that might affect aseptic presentation.
Package Integrity and Stability. The entire package must be free of punctures and tears, material delamination or separation, and channels or open seals. For packaging systems that are sealed using methods other than heat seals, the closures must be continuous. Manufacturers must also institute a program for ensuring the stability of the package. This program should take into account specified storage conditions for the shelf life of the product.
Adhesives. To meet the requirements of ISO 11607 and prEN 868-1, adhesive coatings must be continuous in pattern, without voids, and consistent in weight. Manufacturers must establish a minimum, specified seal strength for such coatings, which should result in a uniform seal strength.
Labeling. The label and labeling system must not adversely affect the package's compatibility with the sterilization process, be rendered illegible, or otherwise be adversely affected by the manufacturing, transport, and storage environments. The inks to be used must not transfer, bleed, or strike through to the device or react with the packaging material in such as way as to impair the utility or graphic quality of the labeling.
To satisfy these requirements, it is a good idea for manufacturers to assess the safety of the inks used for both surface printing and "trapped" printing (between plies). In addition, they should establish a system for label control, such as differentiating labels by size, shape, color, or referenced procedures.
Sterilization Stability. Both ISO 11607 and prEN 868-1 require that manufacturers demonstrate and document the fact that their packaging materials are suitable for the prescribed sterilization process and that they will remain stable after sterilization. In practice, these requirements mean that the manufacturer should conduct research to determine the compatibility of the general class of the material with the sterilization process. Manufacturers may want to pay special attention to the following sterilization-related concerns that could affect the stability of their packaging materials.
* All samples should be sterilized to the maximum sterilization exposure prior to any physical or safety testing. Full exposure should consider the possibility that the product may be resterilized for multiple use, as specified in its design requirements.
* A number of cellulose-based materials can significantly react with the agents used in some of the newer methods of sterilization--such as vapor phase and plasma hydrogen peroxide, peracetic acid, and gaseous chlorine dioxide--thereby negatively affecting their integrity and limiting the access of sterilants to the device.
* When sterilization is to be accomplished by the use of gamma radiation, the manufacturer should take into account the fact that as cobalt 60 becomes depleted it may require increased exposure times to produce the same dose level. These longer exposure times can increase oxidative degradation on both the product and its packaging. Also, radiation sterilization samples should be aged for approximately four weeks prior to testing to allow for continuing free radical oxidative degradation.
* Some sterilization methods that formerly used Freon 12 as a diluent are now using diluents that include ethylene oxide (EtO) under increased cycle temperatures and rate of pressure change; this change in method can increase the stress on package seals.
* With EtO sterilization, the rate of elution (aeration) is dependent on the composition of the plastic materials. To a large extent, aeration time is thus determined by the composition of the device and its package, not by the porosity of the bacterial barrier material. Manufacturers should ensure that their analyses of EtO sterilization methods include the prehumidification portion of the EtO cycle.
Sterilization Indicators. If the package is to include a sterilization process indicator it must comply with the appropriate standards for such indicators, ISO 11140-1 and EN 867-2.
Standard Operating Procedures. The manufacturer must develop written procedures and specifications for control of the packaging process, and must incorporate these into the process performance qualification. For machine systems these procedures and specifications should include machine setup and process start-up. Sealing and forming procedures and specifications should include settings and tolerances for all such process parameters as temperature, pressure, torque, and dwell time. The procedures and specifications should also include valid methods for testing the quality of the finished package.
Package Testing. To meet the requirements of ISO 11607 and prEN 868-1, the manufacturer must conduct appropriate tests to establish the integrity of the completed packaging. Tests that should be considered include water, saline, and alcohol repellence; internal pressure; vacuum leak; gas sensing; and seal width, continuity, and integrity. Seal testing methods identified by the standards include dye penetration, and physical and burst strengths. Tests specific to paper materials include pH, chloride, and sulfate limits; brightness limits; pore size; water repellence; and minimum tensile, tear, and burst strengths.
U.S. manufacturers should note that FDA commonly cites as deficient any testing that includes only the packaging, without the device. Where applicable, testing should be performed with the device in the package. FDA expects that package testing will include evaluation of the package's biobarrier, toxicity, physical and chemical properties, and porosity.
Sampling. Manufacturers must develop and implement sampling plans that will permit statistically significant evaluations of the packaging system.
Defects. Defects must be assigned to categories that define actions to be taken during normal production runs. The external package surface is to be inspected for defects such as the presence of foreign material as well as for dimensional accuracy; seal integrity; the presence of humidity, moisture, or staining; and irregularities in or on sterile barrier materials. The irregularity defect categories are to include tears, cracks, holes, and fractures. Opened samples are to be inspected for foreign material, irregularities, seal attributes, and unacceptable humidity, moisture, or staining.
Documentation. The manufacturer must develop testing documentation for the full packaging system. The system's mass and fragility with relation to the manufacturing and transport methods and environments must be taken into consideration. Testing documentation must be in the form of formal, approved protocols with pass/fail criteria. The testing sequence for the packaging system must also be identified. Process control documentation should also include materials related to the selection and verification of packaging materials, and any change authorizations.
PACKAGING PROCESS VERIFICATION AND VALIDATION
Although prEN 868-1 does not deal with issues related to process development verification and validation, ISO 11607 offers valuable guidance on these areas. Following are some of the key process-related requirements specified by that standard.
Installation Qualification. Although not mentioned in the ISO standard, installation qualification is an essential step in validating the packaging process. The equipment to be used in the process must be appropriate for its intended purpose, properly installed, and able to be calibrated.
Process Performance Qualification. The manufacturer must ensure that all processing equipment and ancillary systems consistently function over multiple runs within the established design operating limits and tolerances, and that they are capable of monitoring the key parameters related to the packaging system.
The manufacturer must also assess the packaging process in order to establish appropriate key operating parameters as well as upper and lower process limits. The upper and lower limits are to be safely within the range required to produce packages that consistently meet design specifications, as determined by package failure analysis. Physical performance testing is to be performed at the process limits.
An evaluation should be conducted to ensure that the complete package formation and assembly operation will provide an appropriate fit of the product into the package, and that the package will meet essential requirements for dimensions. To determine their effect on the final package, the manufacturer should evaluate materials characteristics and sealing parameters, including temperature, pressure or vacuum, dwell time or line speed, energy levels or frequency, and torque limits for lid/cap closure systems. Seal integrity, strength, and uniformity are to be assessed at the optimum, upper, and lower control limits.
The manufacturer must assess the effects of processing stresses on the package materials and package design. Although not specified by the standards, such assessments should include the effects of physical loading of the product into the package as well as subsequent handling procedures and equipment.
Product Performance Qualification. In addition to conducting materials qualification tests as part of the design and development process, the manufacturer must assess the package materials and design in relation to the mechanical and compatibility requirements of the device; the forming and sealing process; the label and labeling system; the full sterilization process at exposure extremes; the handling, distribution, and storage systems; aseptic presentation and other user requirements; and any limits to environmental conditions that will arise during use. This validation must include the full range of material and seal properties.
The manufacturer must verify that sterile package integrity is maintained under the rigors of distribution, storage, handling, and aging, for at least the claimed shelf life of the product. This verification should include package labeling.
Revalidation. The manufacturer must reverify and revalidate the packaging process if changes are made to the materials, product, equipment, or processes that might compromise the original validation and affect the sterility, safety, or efficacy of the device.
Documentation. All validation procedures and results are to be fully documented and maintained in accordance with applicable quality systems requirements. Documentation is to be provided for equipment calibration, preventive maintenance, and cleaning, and must include related specifications and schedules.
As a final verification and validation step, the manufacturer should submit all documentation to a formal review and approval process. The review should consider and provide documentation about the process that was used to develop the packaging system (with statistical results where applicable), references to the location of background technical data, and major problems and corrective actions taken to solve them.
MARKETING IN EUROPE
The CEN standard prEN 868-1 will apply to products offered for sale in Europe, and is intended to complement the requirements of the European Union's medical device directives. As mentioned previously, the CEN standard considers only packaging materials and does not include package design and process validation, which are part of the ISO standard. While the CEN and ISO standards are not identical, neither are they mutually exclusive. By complying with prEN 868-1, manufacturers would also meet many of the requirements contained in ISO 11607.
For the European market, the key difference between the ISO and CEN standards lies in the way they are applied. For manufacturers seeking to market their products in Europe, conformity with the requirements of prEN 868-1 will be mandatory, while use of the additional requirements of ISO 11607 will remain strictly voluntary.
The rapid emergence of global markets for medical devices is hastening the harmonization of standards. Keeping abreast of such international standards can be a key factor in determining the success of a medical device manufacturer. The ISO 11607 and prEN 868-1 standards constitute either actual or de facto requirements for medical device packaging in the European Union and will therefore play an important role in determining the ability of a manufacturer to market or export medical devices to this region.
In the near future, ISO 11607 seems destined to attain broad influence. The United States delegates to ISO TC198/WG7 have indicated that the standard will be proposed to the American National Standards Institute (ANSI) for adoption as a U.S. national standard, and the prospects for its acceptance appear excellent. Japanese delegates have indicated that a similar effort will be initiated in Japan.
Manufacturers should consider developing an approach to their packaging processes that incorporates all the applicable requirements of the ISO 11607 and prEN 868-1 standards. By doing so, they will be well prepared to expand into global markets, wherever they appear. At the same time, complying with such international standards will provide the manufacturer with a definite structure that can be used in complying with FDA's proposed revision of the GMP regulation. Since the GMP regulation itself offers only the most general sort of guidance, the manufacturer is responsible for creating a program that will fulfill its requirements, and international standards can fill the bill nicely in this area.
In addition, FDA has expended considerable resources in the development of standards, and views them as state of the art. Consequently, the agency will in all likelihood view the ISO packaging standard in the same fashion, using it as a guidance with which manufacturers will be expected to demonstrate compliance. So while the ISO standard is voluntary, its existence will undoubtedly make it the reference document for FDA. Manufacturers should consider this likelihood in their future planning.
1. Packaging for Terminally Sterilized Medical Devices, ISO/DIS 11607, Geneva, Switzerland, International Organization for Standardization, 1995.
2. Packaging Materials and Systems for Medical Devices which Are to Be Sterilized, Part 1: General Requirements and Test Methods, prEN 868-1, Brussels, Belgium, European Committee for Standardization, 1995.
Denis Dyke is vice president for technical and regulatory affairs at PM Health Care Group (Philadelphia).
QUALITY SYSTEMS FOR GLOBAL PACKAGING
In keeping with the global trend toward a quality systems approach to manufacturing, ISO 11607 explicitly requires that each of its substantive sections "be carried out within a formal quality system" (4.1.1). While noting that third-party certification is not necessary for manufacturers to meet the requirements of the standard, ISO 11607 specifically references the ISO 9001 and ISO 9002 quality systems standards as "suitable" descriptions of such systems.
For U.S. manufacturers, establishment of a suitable quality system is also linked to the publication of FDA's proposed revision of the good manufacturing practices (GMP) regulation, which is expected to appear this spring. The revised GMP regulation incorporates many elements of ISO 9001, including new sections on design control.
Following are some other standards and draft standards that include quality systems information specific to medical device manufacturing:
ISO/CD 13485: Quality Systems--Medical Devices--Supplementary Requirements to ISO 9001.
EN 46001: Quality Systems--Medical Devices--Particular Requirements for the Application of EN 29001.
PrEN 724: Guidance on the Application of EN 29001/46001 and EN 29002/46002 for Non-Active Medical Devices.
PrEN 50103: Guidance on the Application of EN 29001/46001 and EN 29002/46002 for Active (Including Active Implantable) Medical Devices.