PACKAGING DESIGN CONTROLS
PROCUREMENT, ACCEPTANCE, AND STORAGE
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:
|Catheter, Tracheobronchial Suction||868.6810|
|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.
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.
- 96 percent of the nurses had become "increasingly aware of the importance of quality packaging to infection control."
- 90 percent said that packaging quality could influence their selection of a sterile medical device.
- 87 percent wanted at least one package side to be transparent.
- 95 percent preferred the adhesive to transfer from the lid to the lip of a tray when opened to indicate a broken seal.
- 89 percent wanted sterilization process indicators printed on packages for sterile devices.
- 99 percent said fiber-free opening of a sterile device package is important or very important.
- 55 percent believed larger, high-profile devices would be best packaged in a tray with a peelable lid.
- 55 percent preferred black printing on the package for easy reading.
Package features that might favorably influence practitioners in the selection of a sterile medical device include:
- clean, fiber-free opening,
- double packaging,
- printed process indicator,
- easy-open notches on chevron peel pouches, and
- lids with adhesive transfer.
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|
|Moisture resistance||Package porosity|
|Thermal capacity||Cling resistance|
|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.
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:
- Receiving, In-Process and Finished Device Acceptance, section 820.80; and
- Distribution, section 820.160.
These sections require adequate controls for components, processing, and test/inspection. The controls necessary for all devices should assure that:
- labeling, whether a separate label or printed on the package, properly reflects the package contents and other labeling requirements;
- the packaging materials meet the device master record specifications;
- only devices approved for release are packaged and released; and
- the packaging operations are performed according to established procedures.
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:
- environmental and personnel hygiene control;
- validated operating procedures for sealing equipment;
- inspection to assure package integrity and sanitation; and,
- stringent control of packaged devices marked "sterile" but not yet sterilized.
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.