Medical device manufacturing is a heavily regulated industry. The regulations and standards differentiate between the design and development of sterile barrier systems and packaging systems, and the development, validation, implementation and maintenance of the packaging process itself. Meeting these regulations and standards, and more effectively planning a medical device development project, includes recognising the distinction between the requirements of package design and packaging operations. Appreciating the difference requires a collaborative business model that presents each process as a discrete engineering entity with distinct skill sets and responsibilities, which is where a packaging operations engineer (POE), to support the proposed need for effectively focused efforts on the packaging operations side of the equation, comes in.

Approved suppliers

In today’s global business landscape, package design development may not happen where packaging operations will be carried out. The POE may need to support supplier selection for multiple manufacturing/packaging sites. The US Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart E (Purchasing Controls)) states that each manufacturer must "establish and maintain records of acceptable suppliers, contractors, and consultants". Supplier evaluation methods and audits must be properly documented. POE activities can include:

  • seeking suppliers that provide services or products needed
  • verifying approved supplier list(ASL) for supplier listing
  • considering suppliers familiar with FDA regulations
  • supplier site visits and audits
  • investigating customer service history
  • acquiring, verifying and validating supplier samples
  • determining routine audit schedules
  • signing supplier agreements
  • ASL updates.

Incoming inspection

Packaging material composition and compatibility verification may be required before use. This can be of particular concern for fluids or porous and coated products where packaging materials could have a detrimental effect on product form, fit or function. If so, verification at incoming inspection is conducted through testing or certificate of analysis review. As the subject matter expert on the packaging material and process, the POE supports the quality group in determining testing and sampling plans.

Inventory

Here we consider storage space, logistics, environmental requirements and shelf-life. The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart L (Handling, Storage, Distribution, and Installation)) lists the requirement for establishment and control of storage areas to "prevent mix-ups, damage, deterioration, contamination or other adverse effects". It further states: "When the quality of product deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its condition shall be assessed as appropriate." This also applies to the packaging material where the deterioration of its quality over time affects its fitness for use to preserve and protect the product. Some questions the POE helps to answer include:

  • How much inventory needs to be on hand? Input data can come from product sales forecasting, production capacity and supplier lead times.

  • How much space is available? Lean tools can assist in balancing demand with capacity.

  • What are the packaged unit quantities? Handling and dispatch time can be reduced by having suppliers pack inner shippers in production dispatch quantities.

  • How is the packaging material received? Supplier material packaging method must meet product and process environment requirements. For instance, sterile packaging material used in controlled environments should itself have been packaged in a controlled environment and double bagged to facilitate transfer to point of use.

  • Are special environmental controls required for storage? The effect of the environment on packaging material performance must be considered. This is particularly true when shelf life is conditional on the material being stored within a certain temperature and humidity range.

Equipment

Equipment is a key process component, from incoming inspection to the actual packaging process. The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) includes the following equipment guidelines:

  • "Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements, and is appropriately designed, constructed, placed and installed to facilitate maintenance, adjustment, cleaning and use."

  • "Each manufacturer shall ensure that all inspection, measuring and test equipment, including mechanical, automated or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results."

  • "Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked and maintained. The procedures shall include provisions for handling, preservation and storage of equipment, so that its accuracy and fitness for use are maintained. These activities shall be documented."

Packaging incoming inspection can include dimensional verifications, seal strength and/or material composition analysis. Such testing requires specialised equipment that must be acquired and validated for use. Work instructions and training must be provided to incoming inspection personnel on proper test methods and equipment usage. The POE supports these efforts.

The equipment as an aspect of the packaging process should be a part of the package design development. The POE works closely with the package design engineer during this phase. To avoid waste, it is critical that the existing capabilities of the packaging facility be taken into account during the package design phase. Designing a package that meets the requirements of the product and uses existing, available packaging technology is a golden path to follow.

Should the new package design necessitate the purchase of new equipment, requirements must be reviewed such as budget, available space, available facility/utility support, equipment performance needs, required labour skill and so on. The equipment purchase decision can also include strategic growth factors. Evaluating additional equipment utilisation opportunities before purchase can provide investment sharing across multiple product lines, which will maximise the return on the investment.

Facilities

A determination of the facility’s capability to support equipment and process to be implemented must be carried out with POE guidance.

  • How much space is needed for the process? The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) states that "buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups and assure orderly handling".
  • What utilities are needed to operate the equipment? Equipment requirements must match facility support capabilities unless equipment or facility modifications are possible. Utility details can include electrical, purity-rated nitrogen for modified atmosphere packaging, and compressed air (may require a clean, oil-free system).
  • Are there special environmental support requirements? The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) states: "Where environmental conditions could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions." ISO 11607 (Packaging for Terminally Sterilized Medical Devices, Part 2) states the same risk-mitigation requirement referencing the packaging assembly of the sterile barrier system. Depending on the product requirements and the lead-in process, environmental requirements can be from Class 8 through to much more controlled (even aseptic) levels (see ISO 14644).

Validation

The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) states: "Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures." Further process validation guidance on installation qualification, operational qualification and performance qualification is covered in ISO 11607, Part 2.

"A poor seal of a sterile product pouch is most significant due to the breach of the sterile barrier in place to protect the patient from secondary infection."

The packaging equipment and process validation output demonstrates that the equipment and associated process can repeatedly and reliably (with predetermined confidence) produce a package that meets the specifications. Upper and lower specification limits serve as the criteria to accept or reject the equipment and associated process. Through packaging equipment/process validation, the POE evaluates the process variability and calculates capability. In addition, upper and lower process limits are determined to assure specifications are consistently met. The activities can either include or be preceded by characterisation studies that determine possible failure modes and define critical to quality (CTQ) features. Performance qualifications demonstrate the developed equipment/process capability under production conditions.

Process

The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) states: "Each manufacturer shall develop, conduct, control and monitor production processes to ensure that a device conforms to its specifications." This is supported by ISO 11607, Part 2, which states the process control and monitoring requirement to establish procedures to ensure the above is carried out during routine operation. The POE supports this requirement through validations and risk analysis, which helps determine where process controls are required in order to mitigate risk. Through failure mode effect analyses (FMEA) for medical device, non-conformances are classified based on patient risk.

For instance, a poor seal of a sterile product pouch is most significant due to the breach of the sterile barrier in place to protect the patient from secondary infection. A blemish noticed on that pouch may only be rated as a cosmetic issue but still investigated further to assure it does not exist as the precursor to a more significant issue.

Labour

What skill set is required for operation of the equipment and are those human resources currently available, or will new positions need to be created, recruited and hired for to support the process? The Code of Federal Regulations (CFR 21; Subchapter H; Part 820; Subpart G (Production and Process Controls)) states: "Each manufacturer shall ensure that validated processes are performed by qualified individual(s)." The POE supports the determination of operator qualification requirements and may even directly support the operator qualification process.

Process transfer

This refers to packaging process transfer to manufacturing. Proper transfer assures that standardisation is complete and the process control systems are designed in. This not only includes the POE design and hand-off of operations and quality control processes themselves, but operator qualifications and training of management/supervisor(s) to empower them to oversee the processes.

On-going support

Responsibility division is distinct for this point. The package design engineer provides quality and compliance support for investigation and resolution of packaging non-conformances associated with validated package designs. The POE provides quality and compliance support for investigation and resolution of packaging non-conformances to do with validated packaging processes. The POE will also participate in monitoring activities that periodically or continuously review process control and improvement opportunities as well as conduct or lead process change and revalidation activities. In ISO 11607, Part 2, it states the "periodic revalidation or reviews should be considered since multiple minor changes could cumulatively affect the validation status of the process".

Conclusion

Key to the proposal of POE as a discrete entity is its consideration as a standardised approach to the development and implementation of these medical device packaging and manufacturing-related challenges. The intention of doing so as a ‘standard’ is the assurance of repeatable, timely, high-quality results while meeting strategic goals, applicable regulatory requirements, and, most importantly, customer needs.