Smart, Connected

Packaging Series

Regulatory Considerations
in Medical Device Packaging
Key Concepts & Considerations
A detailed regulatory compliance review as it pertains to medical
device packaging operations for terminally sterilized products
Contents
2 Executive Summary

3 Introduction

3 Regulatory Environment

4 ISO 11607 & Sterile Packaging Requirements

6 Packaging System Process Validation

7 Conclusion
EXECUTIVE SUMMARY
Although all aspects of medical device materials, processes, and internal production policies are subject to global
regulations, compliant product packaging of terminally sterilized devices have enjoyed substantial new visibility in
recent years. That’s because packaging – once an afterthought to the product itself – has become a major innovation
factor for Medical Device Manufacturers (MDMs). New materials, processes, and market demands for improved
point-of-use convenience and reliability have elevated packaging’s role to that of “differentiator” in this rapidly growing
market segment. Packaging can impact many facets of product design, including traceability, but in this context it’s the
sterile barrier guarantee that makes it subject to rigorous testing and validation. In the United States, FDA adoption of
applicable consensus-based standards is consistent with a world-wide effort to harmonize country-specific requirements
that ensure global product availability by ameliorating the cost impacts of competing country standards. ISP 11607, parts
1 &2 deliver primary guidance, however, a variety of associated standards detail testing and materials standards as they
relate to specific types of packaging processes.

US Healthcare costs are under enormous pressures, making packaging of volume-driven Class I and Class II medical
devices such as syringes, intravenous (IV) administration kits and catheters, a target for cost and risk containment.
Packaging helps ensure devices are delivered contaminant-free, safe to use, and able to withstand a wide range of
shipping and storage conditions (CFR 820.130). While packaging and sterilization are mostly mature technologies
that rely on proven methods, the emergence of smaller, more complex devices and kits combined with cutting-edge
barrier materials and flexible films is challenging the status quo of legacy packaging solutions. Poorly designed and/or
validated sterile packaging (or labels) can be costly – a recent study found that outside of the product defects, the next
top two causes of recalls were sterility concerns (37 products), followed closely by labeling errors (30 products). ISO
11607 stipulates alignment of process and materials choices with the nature of the device itself, the intended sterilization
method and use, expiration date, transportation and storage considerations. ISO 11607 also defines requirements for
testing integrity, shelf life, and establishes sterility assurance protocols for seal and material integrity, distribution testing,
and package aging. It also stipulates printing and labeling compatibility with the entire terminal sterilization processing
system, including label adhesive shelf life / aging performance and Unique Device Identification (UDI) traceability
requirements.

ISO 11607-2 addresses development of forming, sealing, and assembly process requirements, and the packaging
validation process. The Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification
(PQ) phases assure the effectiveness of the packaging process for producing a consistent and stable sterile barrier
system. Together, they ascertain that the packaging process equipment operates as intended (EQ), that those
requirements will be consistently fulfilled during production (OQ), and that the process produces a consistent sterile
barrier under operating conditions (PQ).

While MDMs are ultimately responsible for validation, a capable supplier can help and perform many validation tasks.
Producers seeking to deliver more innovative, fit-for-purpose product packaging that is properly validated can realize
dramatic improvements in time-to-market performance by developing a validation plan in concert with their packaging
equipment OEM and installation team. Specialized packaging and high-value items are now increasingly common.
Packaging OEMs that offer manufacturers innovative, flexible solutions, designed to easily integrate into existing
production and software systems can help ease the cost and complexity of regulatory compliance while accentuating
competitive brand differentiation.

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 INTRODUCTION
When we consider the impact of medical device regulation, of medical device regulators from around the world that builds on
the product typically gets top billing, with packaging playing a the strong foundational work begun by the Global Harmonization
supporting role. But the truth of that relationship, as they say, is Task Force on Medical Devices (GHTF) to accelerate international
“complicated”. Consider that few markets have been so tightly tied medical device regulatory harmonization and convergence. A
to their packaging suppliers. That’s partly because in this highly detailed library of the output from both organizations is provided on
regulated industry the laborious and costly validation process can the IMDRF website, and is available to the general public.
hinder change. Once packaging has been tested and validated,
it often takes a major event or disruption to reconsider existing As we noted, those involved with medical devices tend to
processes or partners. Since packaging can touch many facets of concentrate on the device itself in their efforts to address
product design, is subject to rigorous testing, and plays a key role regulatory concerns. Is it safe, is it sterile, does it perform its
in traceability, it’s not surprising that medical device manufacturers function? However, medical packaging is equally important to the
(MDMs) tread lightly when it comes to packaging solution decisions. device safety, efficacy and performance. As such, medical device
Collaborating with experienced packaging professionals who manufacturers must consider and understand medical device
understand the global regulatory landscape and can help MDMs packaging regulations as well as they understand the design of
cost-effectively innovate to meet rapidly evolving market demands the product itself. As reference, a more detailed list of applicable
and rules can be a strategic advantage. consensus standards recognized by the FDA are presented in table
1 on page 4.

Medical devices range from commodity products to high-tech

REGULATORY ENVIRONMENT instruments patented for their unique and specific design
Medical device packaging is regulated across the world. Products features. Packaging can affect various aspects of medical device
that affect the health and safety of people are regulated by the FDA performance, so the standards listed above should be applied
in the United States, and various other country-specific agencies judiciously and conscientiously. It can affect storage efficacy and
around the world. Standards demand that packaging equipment appearance, preserve device sterilization, and even determine
must be set up and maintained in a validated state, then measured ease of use. For example, if the end user has trouble opening a
and monitored over time for performance to specification. Several package, it may rip or tear, exposing the device to contamination
packaging standards are in place today, but the type of regulations and rendering it unusable.
that apply will depend on the kind of packaging required, i.e. if the
packaging is for a sterile device or for manual non-active device, or But in today’s rapidly growing and highly competitive market,
for an active device. packaging can also present a strategic advantage. Healthcare
brands are seeking responses to end-user demand for better,
These include: easier-to-open, easier-to-use, and easier-to-dispose of packaging
solutions. Interest in disposable, environmentally friendly flexible
ISO 11607 Packaging for terminally sterilized medical films is growing, but as of today few suitable MDM alternatives
devices exist. Down-gauging (thickness) commonly used films is still the
most widely implemented approach, as it reduces waste and
EN 868 Packaging materials and systems for medical cost (through decreased weight) without compromising barrier
devices to be sterilized, general requirements
and test methods functionality. Still, new, cutting-edge barrier materials and flexible
ASTM D1585 Guide for Integrity Testing of Porous Medical
films used in the food packaging sector are gaining traction in the
Packages medical industry. Food film producers have begun introducing
specialized medical production versions using advanced coextruded
ASTM F2097 Standard Guide for Design and Evaluation and multi-layered cast films, delivering on the promise of innovation
of Primary Flexible Packaging for Medical
Products in packaging sustainability. While alternative film materials present
unique challenges and opportunities for barrier, sterilization, and
ASTM F3475-11 Standard Guide for Biocompatibility
Evaluation of Medical Device Packaging migration considerations, the powerful combination of market
Materials interest and vendor innovation is sure to help them penetrate this
market at an increasingly faster rate.

While packaging and sterilization are mostly mature technologies

Luckily for medical device manufacturers, an effort by all countries that rely on proven methods, the emergence of smaller, more
to standardize or harmonize regulations is helping medical device complex devices (including combination products that incorporate
manufacturers comply with regulations more easily and cost drugs or bioresorbables) also challenge the status quo. Such
effectively. This effort, originated by the Global Harmonization Task products are more difficult to sterilize with standard methods
Force (GHTF), has evolved under the banner of the International such as gamma irradiation (Cobalt 60 radiation) and ethylene
Medical Device Regulators Forum (IMDRF). It is a voluntary group oxide (EtO), forcing MDMs to explore newer packaging and

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 TABLE 1
concern, evaluating packaging and product design simultaneously
Title of Standard Number Org helps ensure product performance is supported – and perhaps
enhanced – by packaging.
Standard Test Method for D3078:1994 ASTM
Determination of Leaks in Flexible The pressure to hold down healthcare costs puts enormous
Packaging by Bubble Emission pressures throughout the MDM supply chain, from original
Standard Practice for Performance D4169:1999 ASTM equipment manufacturers (OEMs) and their suppliers to end-users.
Testing of Shipping Containers and One area impacted is packaging material choices and related
Systems sterility concerns. This is particularly true in volume-driven Class
Standard Test Method for Seal F88:1999 ASTM I and Class II medical devices such as syringes, intravenous (IV)
Strength of Flexible Barrier Materials
administration kits and catheters. While sourcing cost-effective
Standard Terminology Relating F1327:1998 ASTM materials is important, packaging integrity and sterility maintenance
to Barrier Materials for Medical remain essential.
Packaging
Standard Test Method for F1929:1998 ASTM
Determining Integrity of Seals ISO 11607 & STERILE PACKAGING REQUIREMENTS
for Medical Packaging by Dye
Penetration Packaging and sterilization are critical to ensure devices are
Standard Test Methods for Internal F1140:2000 ASTM produced contaminant-free, safe to use, and able to withstand a
Pressurization Failure Resistance of wide range of shipping and storage conditions (CFR 820.130).
Unrestrained Packages for Medical Many standards are concerned with proving packaging
Applications
effectiveness as a sterilized barrier. Poorly designed sterile
Standard Guide for Integrity Testing F1585:2000 ASTM
of Porous Barrier Medical Packages packaging introduces costly problems and possible recalls for
medical device companies and their customers. It must arrive at the
Standard Test Method for Microbial F1608:2000 ASTM end-user site in a sterile condition – free of holes, tears and broken
Ranking Porous Packaging Materials seals. It may have to withstand sitting in inventory without breaking
(Exposure Chamber Method)
down. Or consider the financial impact of improperly designed and
Standard Guide for Accelerated Aging F1980:2002 ASTM validated packaging discovered during a product launch – a very
of Sterile Medical Device Packages
real scenario that while unusual, can be quite costly. In fact, the
Standard Test Method for Burst F2054-00 ASTM Cureus Journal of Medical Science published a 2018 recall study of
Testing of Flexible Package Seals 161 medical implant products from 33 companies. The study, which
Using Internal Air Pressurization also highlighted the manufacturer’s recall reasoning, found that
Within Restraining Plates
outside of the product defects, the next top two causes of recalls
Standard Test Methods for Pressure F2095-01 ASTM
Decay Leak Test for Nonporous were sterility concerns (37 products), followed closely by labeling
Flexible Packages With and Without errors (30 products). According to the study’s authors, “Sterility
Restraining Plates issues are often related to packaging which may not have been
Standard Test Method for Detecting F2096-01 ASTM determined through a different testing protocol.” In fact, FDA reports
Gross Leaks in Porous Medical
Packaging by Internal Pressurization that packaging and labeling issues constituted nearly 13 percent of
(Bubble Test) all medical device recalls. Packaging-related issues accounted for
Standard Guide for Design and F2097-01 ASTM nearly 380 Class 2 medical device product recalls during a recent
Evaluation of Primary Packaging for 10-year period. In 2015 ~17, 000 units of five different implant
Medical Products devices were recalled over their packaging integrity, and related risk
Packaging for terminally sterilized ANSI/AAMI/ ANSI/ of device damage during transit.
medical devices ISO 11607-97 AAMI/
ISO
Any number of sterilization methods may be deployed on a
packaging line, including gamma, electron beam, ethylene oxide
and autoclaves (heating). Each method requires testing and
validation to ensure the packaging material allows the sterilant to
sterilization technologies (or to find new ways to use existing penetrate the product. ISO 11607 stipulates that the packaging
technologies). Packaging solution providers that know how to solution development process and materials choices reflect the
leverage the latest packaging innovations within the bounds of nature of the device, the intended sterilization method and use,
regulatory requirements, have the in-house capabilities to support expiration date, transport and storage. The resulting packages must
such innovation, and can cost-effectively manage the phases pass a variety of quality assurance checks that target seal integrity
of validation process (IQ/OQ/PQ) stand to enhance an MDM’s (seal strength), material integrity (bubble leak), distribution testing,
competitive position and probability of success. So, while the and package aging.
product itself will always be the centerpiece of any MDM regulatory

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These standards define requirements for testing integrity,
shelf life and establishing sterility assurance levels:

1 A manufacturer must be able to consistently form and seal a package, meeting requirements for the strength and seal of
the bond after heat-sealing, the seal’s visual aesthetics and the ability to open the package

2 The package design must withstand shipping through all types of climates and a variety of physical hazards
(cold, hot, humid, dry conditions, dropping, compression, vibration, impacts and altitude changes)

3 A package must be able to maintain its integrity over time. For a sterile, disposable device package, that’s usually two years
– which can be simulated using acceleration techniques.

4 The Sterility Assurance Level (SAL) reflects the probability that the packaging will keep the device sterile
• The “bioburden” addresses the volume of allowable bacteria produced during the manufacturing process, expressed as
various levels of probability.
• The standard most hospitals require when purchasing medical devices is 10-6 – which is the probability that 1 device out
of a million packaged will become non-sterile.

Another sterilization consideration is package size. The “Goldilocks” Label substrate testing for adhesive shelf life (aging) performance is
rule of thumb prevails – i.e., a package that is neither too small particularly important since some glue adhesives react over time to
nor too large. While the smallest possible shipping containers can the material’s surface energy (dyne) and plastic surface treatments
provide logistic and costs benefits, they may compromise package may be affected by surface chemicals “blooming” over time.
integrity. The raw materials used must support an effective microbial
barrier (as well as be traceable and safe). It is a recommended While not directly related to sterilization procedures, packaging
best practice to conduct an engineering feasibility trial prior to labels’ role in medical device recall warrants mention. MDM
undertaking validation studies – using prototype devices with traceability requirements (Unique Device Identification or UDI)
identical size and weight of the proposed finished product can help regarding devices, device components and packaging, are
avoid costly mistakes by identifying packaging issues for resolution addressed in 21 CFR 820 and ISO 13485 for both devices
during product development. A recent revision of ISO 13485, themselves and labels. The UDI system helps identify medical
published in 2016, now embraces the entire device life cycle, devices post-distribution and use (in human and machine-readable
including sterile barrier systems, storage, distribution, and disposal form), placing an increased emphasis on packaging material’s
– increasing the focus on the work environment in which the sterile printability. While full UDI enforcement will be phased in over years,
packaging effort is conducted. regulatory bodies are noting that too many MDMs are still hesitating
to take compliance actions. Packaging OEMs that have adapted
Labeling is the final piece of the sterility puzzle. ISO 11607, part 1 their machines to meet data acquisition and storage requirements
stipulates printing and labeling compatibility with the entire terminal for marking and tracking products (including coding and vision
sterilization processing system. That means all printed components inspection systems) can help accelerate compliance. Retrofitting
or labeling must be qualified as part of the sterile barrier system for compliance can require a significant investment in equipment
validation. Aside from obvious requirements (easily understood, and software. Developing a UDI-compliant label strategy and
well-placed, inclusive of variable information such as lot code dating methodology prior to validating and deploying any device packaging
and expiry), labels need to remain intact and legible until the point solution represents an economic advantage.
of use. This lifespan includes shipping, handling and storage over
the stated shelf life – essentially the entirety of your terminally
sterilized product life cycle. This introduces other variables and
considerations, including:

The environment Procedures for

where the product label application
will be used
Adhesive choices Printing stock
for labels (e.g. (paper, plastic),
glues, pressure web stock &
sensitive labels) release liner

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PACKAGING SYSTEM PROCESS VALIDATION
Terminally sterilized medical devices are subject to a complex testing (real-life conditions) and can extend to focused simulation
validation process that begins in the packaging design phase and (very data intensive) in unique circumstances. Testing parameters
is executed across the Installation Qualification (IQ), Operational may address climatic exposure, compression, vibration, shock,
Qualification (OQ), and Performance Qualification (PQ) phases. low pressure, and concentrated impact. Products are physically
The goal is to demonstrate packaging process effectiveness for inspected for any damage and sterility. Output from this phase
producing a sterile barrier system that’s consistent and stable. includes documentation of ongoing process control and monitoring.
In the design phase quality systems, test methods, material
choices, and user inputs are assembled and used to prototype
the packaging system and process. Some typical examples of
packaging processes subject to validation include: IQ Phase
Check equipment
• form/fill/seal automated processes
& software operate
• kit assembly and wrapping
as intended
• rigid and flexible blister formation
• pouch, reel or bag formation and sealing
• tray/lid sealing
• filling and closing of reusable containers

ISO 11607-2 addresses development of forming, sealing,

and assembly process requirements, and the execution of
the IQ/OQ/PQ validation phases:
Equipment installation qualification (IQ) – Ascertain that
packaging process equipment operates as intended (within OQ Phase PQ Phase
design parameters). In a smart, connected packaging system Ensure packaging At least 3 samples of
this will include the software that is controlling and managing the process requirements separate packaging
equipment. IQ typically takes place at or replicates the installation will be consistently production runs are vetted
setting and the environmental conditions to ensure conformance fulfilled during production against system requirements
with producer specifications. In addition, operator training,
instructional material, or work instructions regarding routine
cleaning and maintenance will be evaluated. While the MDM is ultimately responsible for validation, a capable
supplier can help and even perform most tasks associated with IQ/
Operational qualification (OQ) – used to ensure that packaging OQ. As for PQ, since it must include the product, PQ should always
process requirements, as defined, will be consistently fulfilled by be MDM led and performed with support by the packaging and/or
the packaging system during production. This includes evaluating automation suppliers. Of course, future system changes (materials,
all relevant equipment parameters for the forming, sealing and/or equipment, process, effectiveness, etc.) that compromise prior
assembly process across all packaging materials and equipment validation results require revalidation. Periodic “spot” revalidation
(sans the device itself), and establishing a “worst case” operating is considered a best compliance practice. Packaging materials
window. This includes inspecting and verifying that all control vendors are required to validate expected “shelf-life” claims (seal
measures are in place and that the sterility barrier produced in the strength and package integrity). While this can be carried out in real
process will meet acceptance criteria. time (years), accelerated aging methods are an accepted approach
in the interim.
Performance qualification (PQ) – evaluates whether the
packaging process will consistently produce a sterile barrier under Developing a validation plan in concert with the packaging
specific operating conditions. Like OQ, PQ evaluation must be equipment OEM and installation team (if different) can help
conducted against all packaging material and equipment variations. optimize the validation spend. Design phase collaboration can
During PQ at least three samples of separate packaging production help identify custom specifications defined by the Design Failure
runs are vetted against system requirements for appearance, seal Mode Effects Analysis (DFMEA). This method highlights critical-to-
width, strength, tightness and more. Holistic system performance quality specs related to the product’s intended use and function.
includes such considerations as machine equilibrium, breaks It can help eliminate the complexities introduced by non-relevant
or shift changes, line start and stops, and lot-to-lot differences. or unrealistic generic specs, helping streamline validation and
Unlike OQ, PQ requires packaging include the medical device the associated impact on time-to-market. A packaging OEM that
itself during testing. Assessing packaging transportation and understands DFMEAs, industry trends, end-user needs, and
storage integrity may include non-simulation integrity testing typical validation challenges associated with IQ/OQ/PQ can offer
(suitability of use), partial or general simulation performance design phase insight and innovation that will help avoid mistakes

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 and produce effective specifications that rationalize the validation
process. Product design phase collaboration offers more than just
accurate and precise specifications; it can also enable creative
package solution development. Assessing emerging technologies
and materials in the context of production and supply chain
operations can help identify new methods that may reduce material
consumption, package footprint, sterilization methods, or even
labor and handling such as transportation, and storage costs.
Collaboration in this phase also helps the packaging design team
align automation settings to manufacturing processes, ensuring
that the solution works efficiently within the specified process.
MDMs seeking to deliver more innovative, fit-for-purpose product
packaging that’s properly validated based on relevant, custom
specifications can realize dramatic improvements in time-to-market
performance.

CONCLUSION
The rapid growth of the medical device market is pushing the
limits of legacy packaging systems. MDMs are seeking faster
production speeds or turning to smaller batch runs that engender
greater product diversity and more frequent changeovers.
Specialized packaging and high-value items are becoming the
norm. Automating physical processes and integrating software
systems are the key to keeping up with demand – and that
must include packaging operations. Packaging OEMs can be
a valuable partner by providing manufacturers with innovative,
flexible machines that are designed to integrate seamlessly into
production lines and software systems that offer less costly, easier
compliance with a maze of complex regulations. While the MDM is
ultimately responsible for the design, installation, and validation of
the packaging solution, a trusted partner can help implement new
packaging automation and data management solutions that allow
MDMs to compete in this fast-growing market.

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ABOUT HARPAK-ULMA
Harpak-ULMA delivers smart, compliant, validated medical device packaging machines that
handle all common films, pouches, and trays for sterile packaging solutions. The company helps
to mitigate medical device packaging concerns, while offering full-service automation capabilities
that follow GAMP5, and include IQ and OQ validation experience. Harpak-ULMA offers over
25 years of experience resolving packaging challenges through automation, integration, and
regulatory compliance.