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13 PACKAGING
INTRODUCTION
PACKAGING DESIGN CONTROLS
User Preference
PACKAGING MATERIALS
PACKAGE VALIDATION
PROCUREMENT, ACCEPTANCE, AND STORAGE
PACKAGING PROCESS
EXHIBITS
Product Specification: Pouch
Header Bag (Specification Form)
The packaging industry is continuously evolving
as medical product companies institute changes in the design,
development, and manufacture of packaging systems. Thus, this
chapter is not aimed at providing an all-inclusive list of packaging
procedures and/or materials. Rather the goal is to instill an
awareness of important packaging issues involving both design
and manufacture. This chapter will also provide a basic understanding
of the importance of validating processes and equipment, and the
continuing need to maintain control of established packaging processes.
The result should be a package that protects the device during
handling and shipping, and from the environment and microorganisms
until the package is opened. This includes allowing for any necessary
sterilization. Packaging contains the product identification and
other information as described in Chapter 11, Labeling. Packaging
may also contain integral labeling and instructions for use or
these instructions may be in a manual or package insert. Finally,
when the consumer is ready to use this product, the package should
be easy to open without compromising the quality of the device.
In the end, a well designed package facilitates use of the device
and contributes substantially to the overall appeal of the product.
It makes sense for the manufacturer to invest in the development
of a safe, user friendly package.
The design of the device, the labeling,
the packaging and the manufacturing processes form the design
output [820.3(g)]. These should be integrated. Manufacturers should
consider the needs of the user as required by 820.30, Design Controls.
Manufacturers should document these design outputs in the device
master record then, procure, handle, store, and use the specified
materials according to the device master record. FDA regulations
are compatible with this total systems approach to device process
design, production, packaging, and labeling.
Finally, manufacturers should perform quality
assurance tests or acceptance tests on samples of the finished
packages and, if sterilized, repeat the tests after sterilization.
These tests should be based on a statistically valid sample to
insure confidence that the packaging is capable of maintaining
the integrity of the finished product. Where the device is very
expensive, or only available in small quantities, the packaging
tests may be performed on labeled, controlled packages that contain
identified, rejected or simulated devices, as appropriate. The
results of testing and/or inspection should be recorded in the
device history record. Correctly performing these activities can
reduce or prevent customer complaints, recalls, and product liability
actions.
Package design should be an integral part
of the product development program. Waiting until the end of the
development process to design packaging can result in severe delays
in getting the product into distribution. The whole idea is to
"build quality in." The total device and package system should be considered with
respect to: device characteristics, sterilization process if any,
sealing, labeling, secondary packaging, handling, shipping, environment,
storage, federal regulations, and end use.
Defective packaging and seals have been
a major cause of medical device recalls. This type of recall can
often be avoided by correct package design including validation
of the packaging and sealing processes. Packaging and sealing
machines should be set up according to written procedures that
are based on the known capability of the manufacturing system.
It is important to be aware of the state-of-the-art in sealing
methods and packaging materials, including their physical, chemical,
biological, and compatibility characteristics and, of course,
cost. "Wet" devices require high-barrier package materials
and sealants with impermeability; resistance to solvents, grease,
chemicals, and heat; and the ability to contain wetting agents,
reagents, oils, or fragrances. Thus, the ability to seal in the
presence of liquid components, if spillage occurs in the seal
area, is important. Some peelable adhesives are highly solvent-resistant
and also remain intact during radiation sterilization. If necessary,
obtain guidance from suppliers, technical literature, and consultants.
After the process has been developed and validated, the packaging
aspect of production should be performed according to GMP requirements
in order to maintain a state of control.
The design controls established by 21 CFR
820.30 and, particularly 820.3(g), define packaging as part of
the device design output. This means the design phase of packaging
shall include the application of quality systems requirements
and the documentation of these applications. Control over package
design shall be performed according to 820.30 for any Class II
or Class III devices, devices automated with computer software,
and the following Class I devices:
| Device | Section |
| Catheter, Tracheobronchial Suction | 868.6810 |
| Glove, surgeon's | 878.4460 |
| Restraint, Protective | 880.6760 |
| System, Applicator, Radionuclide, Manual | 892.5650 |
| Source, Radionuclide Teletherapy | 892.5740 |
Manufacturers of other Class I devices should
establish and maintain procedures for ensuring that their device
design is correctly translated into production specifications.
They may use 820.30(h) as guidance. For these Class I devices
that require design controls, packaging design is performed according
to 820.130. The nature of the device as well as the sterilization
method(s), intended use, shelf life, transport, and storage all
affect package design.
The following activities are important to
maintain control of package design:
1. Planning for the design and development
of packaging; and defining responsibility for implementation of
design activities and controls. These plans should identify the
different groups and activities providing input into the design
process. Periodic review and approval is necessary as the package
design evolves.
2. Establishing design input and output
procedures, including review, documentation, signature, and date,
that are appropriate for the intended use and the needs of the
user and the patient. The procedures shall include safeguards
for addressing concerns about the proposed designs.
3. Ensuring that design review procedures
for all appropriate stages of the design development are conducted
by qualified individual(s) and include an individual not directly
responsible (NDR) for the design stage under review. This NDR
person could be one of several people on the design review committee.
The design identification, review results, reviewers, and date
shall be documented in the design history file [820.30(j)].
4. Documenting design verification/validation
to confirm that the design output meets the design input requirements
in the design history file. This documentation must include the
reviewers and date of review.
5. Establishing and maintaining design transfer
procedures that insure that the package design is correctly translated
into production specifications. The correct translation, of course,
may be directly done as part of the design output.
6. After the package design is accepted,
controlling changes according to company change control procedures.
The manufacturer shall establish and maintain procedures for the
identification, documentation, validation or where appropriate
verification, review, and approval of design changes before their
implementation. A significant part of this control is achieved
when design controls are followed.
7. Establishing a design history file to
demonstrate the design was developed and approved according to
plan. This, of course, should show that the design output meets
the design input -- a fact which should be obvious from data presented
during the final design reviews.
Design controls require that a packaging
design undergo considerable validation, review, and documentation.
However, the end result is a smooth transfer into production with
increased package safety and efficacy, resulting in greater customer
satisfaction and cost savings and reduced liability.
In addition to the GMP requirements, manufacturers
should always study current packaging practices for products similar
to theirs to determine current favorable practices and to prevent
user packaging problems. For example, customary use may dictate
the use of double primary packaging for some sterile devices.
Finally, any packaging used for medical devices should satisfy
the end user or customer requirements, which automatically satisfies
one of the design GMP requirements. This is a key point to be
considered during the design phase.
User Preference
In the Medical Device and Diagnostic Industry
magazine, the article, "Hospital-User Preference in Sterile
Device Packaging,"
reports the results of a survey of nurses from operating room
and central services areas of hospitals. Several conclusions from
the test results are listed below that should be of interest to
sterile device manufacturers.
Package features that might favorably influence
practitioners in the selection of a sterile medical device include:
The nurses believe that being able to see
and clearly identify a device is a "very important criterion
of user preference."
Also, as stated above, double primary packaging is preferred for
some sterile devices.
Fulfilling the design control procedures
discussed above should include using the most appropriate packaging
materials available for the device. Although requirements for
components, device master records, environmental control, etc.,
that affect the selection and use of packaging appear throughout
the Quality System (QS) regulation, the specific requirements
for packaging are in section 820.130. Also the design requirements
for Class II, Class III, and the few Class I devices that require
design control extend to the broad requirements in 820.30. Device
packaging and shipping containers should be designed and constructed
to protect the device from adulteration or damage during the customary
conditions of processing, storage, handling, and distribution.
Closely related label integrity requirements are in section 820.120.
Also, the quality of packaging should be considered in relation
to the 21 CFR Part 812, Investigational Device Exemptions (IDE's)
for clinical evaluations; Part 814, Premarket Approval (PMA) applications;
Part 807, Premarket Notification [510(k)] submissions and, of
course, customer requirements. Failure to meet these packaging
requirements renders a device adulterated and has resulted in
recalls of sterile devices.
The package and device should be designed
together so that all factors in the product and package system
can be considered, such as device sharp edges and severe vacuum
stresses. Some other factors to consider are:
| End use | Sterilization process |
| Temperature | Adhesives |
| Moisture resistance | Package porosity |
| Thermal capacity | Cling resistance |
| Device composition | Pressure |
| Device size and shape | Vacuum |
It is important that sterile devices and
their packaging material meet the requirements of the sterilization
process, package sealing method, and intended use. For example,
radiation sterilization may discolor packaging and sealing materials,
or reduce their functional capabilities. All plastics are somewhat
affected by radiation sterilization, occasionally positively,
frequently negatively. Consideration should be given to the effect
produced and the radiation dose needed to produce an effect. Complete
storage and stability data should be compiled for sterile device
packaging subjected to radiation or should be obtained from the
supplier.
Ethylene oxide (EO) sterilization requires
packaging material of sufficient porosity to allow air to leave
the package and the gas to rapidly permeate the package, sterilize
the product, and then leave the package. Adverse levels of EO
residues left on the device harm the patient. Air washing at the
end of the cycle reduces residues. Evacuation of the sterilization
chamber for air removal, gas fill, and air washing can induce
package stress, particularly when the cycle calls for high temperature,
pressure, and rapid pressure changes before and after the gas
exposure (dwell) period.
Package validation involves two separate
validations: 1) the design validation of the package as a component
of the device and 2) the process validation of the packaging process.
Design validation uses evidence to establish what design specifications
will conform with the user needs and the intended use(s) [830.3(z)(2)].
Process validation establishes by objective evidence that a process
consistently produces a result or product that meets predetermined
specifications [820.3(z)(1)].
The regulation, of course, refers to establishing
evidence that the manufacturing steps involved in packaging the
device will consistently produce packaging which meets specifications.
For example, the process capability of packaging and sealing equipment
should be determined during process validation and documented.
Validation of the package design shall be performed under actual
or simulated use conditions that show the package conforms to
its stated intended uses. Risk analysis shall also be included
where appropriate.
Design validation results shall include:
the design identification, name of the individual(s) performing
the validation, method(s) used, and the date. All of this information
should be recorded in the design history file. If any significant
change is made in the packaging or packaging operation after validation,
the new process will need to be revalidated.
One of the most difficult aspects of package validation is determining how many samples to test. The goal is not to over test because of cost considerations while still running sufficient tests to provide statistically valid sampling. Statistical methods of analysis are important in process validation. The following decision tree from Medical Device and Diagnostic Industry, "Streamlining Package-Seal Validation," October 1992, provides various methods of statistical analysis. The manufacturer is challenged with determining which statistical method is most applicable to their individual needs. See Chart 1 below for possible methods of analyzing data. The resulting validation plan should identify, measure, and evaluate the key processes and variables that will require assessment to complete a validation or revalidation of the packaging and the packaging process.
Chart 1 above shows various possible methods
for analyzing data. Source: Medical Device and Diagnostic Industry
periodical, October 1992.
PROCUREMENT, ACCEPTANCE, AND STORAGE
The packaging associated labeling, sealing
methods, acceptance tests, etc., are part of the design output.
These design output documents are part of the device master record.
The device master record (820.181) should contain appropriate
specifications so that the desired packaging components may be
purchased, properly stored, and properly used. Suppliers are selected
according to 820.50, Purchasing Controls. Manufacturers shall
have adequate procedures for approval or rejection of all incoming
packaging components such as adhesives, wrapping materials, corner
protectors, pouches, cartons, etc. (820.80, discussed in Chapter
10). The supplier may test these components and provide the manufacturer
with a protocol for testing and the test results for each batch
(i.e., certificate of conformance to purchase specifications).
The manufacturer could accept this specific data as sufficient
certification based on his assessment of the supplier along with
the review of the certificate or order his own testing.
Incoming components should be examined for
damage and identity before being used. At a minimum, this examination
should include visual inspection. Thereafter, the packaging should
be handled and stored in such a way that it is kept clean and
safe from damage. Packaging and devices to be sterilized should,
obviously, be kept clean before sterilization. For transfusion
and infusion assemblies, devices that come in contact with circulating
blood or cerebrospinal fluid, intraocular lenses and the surgical
instruments used in their implantation, and any device labeled
as "pyrogen
free"
or "nonpyrogenic,"
the manufacturer should carefully and appropriately control the
environment to which the associated packaging materials are exposed
in order to minimize bioburden and cellular debris from dead bacteria.
Pyrogens primarily arise from cellular debris of gram-negative
bacteria.
The packaging operation is a manufacturing
process as described in Section 820.70, Production and Process
Controls. Other GMP sections also apply to packaging including,
but not limited to:
These sections require adequate controls
for components, processing, and test/inspection. The controls
necessary for all devices should assure that:
The controls required will vary with the
type of device packaged. For example, when a sterile device is
packaged, a manufacturer's considerations should include:
For a product to be sterilized in-house,
either a physical quarantine area or label control should be used
to prevent shipment of devices marked sterile, but not yet sterilized.
The required level of control is very high. The stringent control
also extends to give-away samples not intended for actual use
on patients -- samples should be sterile if so labeled because
they might be used. One approach is to sell samples at zero cost
so that the samples are subjected to all of the company finished
product controls.
A written procedure is required by 801.150(e)
for interstate contract sterilization. The purpose of this
requirement is to help prevent the erroneous release of packaged
and labeled "sterile"
devices that are not yet sterilized even though they appear to
be sterile and ready for release. Regardless of whether 801.150(e)
applies, the QS regulation requires sufficient controls as necessary
to prevent mixups in complex situations such as contract sterilization.
For consistency, a contract is commonly used by manufacturers
for interstate and intrastate shipments. Such a contract, and
compliance with it, satisfies the applicable GMP requirements.
Section 820.181(d) requires that the device
master record include packaging methods and processes. Written
instructions should be provided to assure that the necessary controls
are understood and consistently implemented. The need for, and
the extent of, written instructions should be determined based
on the complexity of the operation and the nature of the product.
Some products such as radioimmunoassay test kits can deteriorate
during packaging if the process is not timed properly. In such
cases, written instructions should describe how the device(s)
should be handled and expedited during packaging in order to prevent
delays, and thus deterioration.
The procedure for testing and/or inspection
of finished packages shall be written [(820.80(d)]. To the extent
feasible, the testing of finished packages should be quantitative.
The packaging of sterile devices should be tested and/or inspected
before and after sterilization. This testing is done on a sampling
basis. Sampling plans are valid only when a process is in a state-of-control;
therefore, the device must be manufactured and packaged using
a quality system as described in this manual.
The examples that follow will aid a company
in preparing product packaging specifications and/or in purchasing
standard packaging.
Product Specification: Pouch
This form is used to purchase specific pouches
from a standard family of pouches. The finished device manufacturer
completes the form with the desired size, material, style, etc.
The form refers to other documents which define the technical
characteristics of the pouches.
Header Bag (Specification Form)
This specification for a header bag is set
up as a checklist with the specifications on the right-hand side
and a drawing of the bag on the left. The finished device manufacturer
completes the form with the desired technical characteristics,
assigns it a part number, and approves the finished document.
An interesting idea reflected in this form is the important information
block at the bottom of the form. This is a good way to remind
personnel of pertinent information that is not strictly a part
of the specification yet is vital to the control of this particular
item.
Updated 1/1/1997
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