Have you ever had the misfortune of ordering an item over the Internet, having it shipped to your home, and upon opening the box, finding the item badly damaged? Let’s face it ladies and gentlemen, regardless of the carrier, USPS, UPS, or Fedex, products take a beating during the rigors of “routine shipping and handling.” In this edition of Devine Guidance (DG), Dr. D will provide guidance for 21 CFR, Part 820, Subpart – L (Handling, Storage, Distribution, and Installation), specifically (820.140 – Handling and 820.150 – Storage).
Back in April, Dr. D was about to be the proud owner of a new 57” flat-screen television. The second my eyes focused on the condition of the shipping container, I knew I was going to have issues. Sure enough, the screen was shattered. The moral of the story is that the packaging scheme employed by the manufacturer was not suitable for a routine distribution environment, regardless of potential handling issues.
Now granted, receiving a damaged TV and waiting for the replacement is nothing more than a minor inconvenience; however, with medical devices, this is not so minor. The expectation of healthcare providers is that the procured medical device is useable, right out of the box, while being safe and effective during its intended use. If the device does not work, the device manufacturer will receive a complaint. If it is determined that a damaged device has resulted in patient injury or death, the device manufacturer can expect to receive a Form 3500A (Mandatory Reporting for an adverse event). This form is required by law as part of the FDA’s Medical Device Reporting (MDR) process. Receive enough of these forms (a.k.a., MDRs); the device manufacturer can expect a visit from the agency.
Warning letter violations
The first warning letter observation falls into the category of the proverbial truth in labeling category. As Dr. D depicted in the previous edition of DG, the labeling must be accurate. No doubt pursuing a Sisyphean (look-it up) task of providing obviously inaccurate handling information on the label is problematic for this device manufacturer; however, it can be quickly resolved. The device manufacturer, depicted in the first warning letter can (a) commence delivering devices via the Good Humor Ice Cream Truck, keeping the storage temperature between 2 and 8 °C; (b) correct the labeling to reflect the proper handling and storage conditions; (c) actually test the packaging scheme and determine the appropriate handling and storage information; or (d) answers b and c. If you choose answer d, you must be a frequent reader of DG.
Now the second warning letter recipient has simply failed to invoke DG Rule # 6 – All procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled within a defined document control system. Remember, in the medical device industry, compliance to the QSR is mandatory and dictated by Federal Code (a.k.a., LAW) not optional (DG Rule # 1). Dr. D broken-record time, all aspects of a device manufacturer’s quality/business system shall be defined by procedures.
Warning Letter One (November 2009): Observation 2 of 5 – Failure to ensure that deterioration or other adverse effects to product do not occur, as required by 21 CFR § 820.140. Specifically, the labeling for all media states to store the product at 2°C to 8°C. Your firm does not ship the product at 2°C to 8°C as required by the labeling and has no justification documented for shipping the product under non-refrigerated conditions.
Warning Letter Two (May 2010): Observation 9 of 12 – Failure to establish and maintain adequate procedures that describe the methods for authorizing receipt from and dispatch to storage areas and stock rooms, as required by 21 CFR 820.150(b). Specifically, you have no procedure in place to specify who is authorized to retrieve mini-batches of product found in Room (b)(4).
FDA Response to Observation 9 of 12 – We have reviewed your response and concluded that it is not adequate because although you stated that you will create a procedure for controlling in-process materials in Room. You did not provide a copy of the procedure for FDA’s review.
Observation 10 of 12 – Failure to establish and maintain adequate procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed, as required by 21 CFR 150(a). For example, the mini-batch materials (optimized gold/membrane combinations) stored in Room (b)(4) are labeled “quarantine”; however, these materials are used to manufacture product.
FDA Response to Observation 10 of 12 – Your response to this observation appears to be adequate.
Quality system regulation – 21 CFR, Part 820
QSR – Subpart L – Handling, Storage, Distribution, and Installation
Section 820.140 Handling:
Each manufacturer shall establish and maintain procedures to ensure that mixups, damage, deterioration, contamination, or other adverse events to product do not occur during handling.
Section 820.150 – Storage:
(a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. 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.
(b) Each manufacturer shall establish and maintain procedures that describe the methods for authorizing receipt from and dispatch to storage areas and stock rooms.
Once the device manufacturer has validated a packaging scheme capable of surviving the rigors of normal and sometimes, not so normal distribution channels, the correct device must make it into the hands of the physicians. Sounds pretty simple right? Wrong! Device manufacturers can write and train to procedures that support effective handling practices. Device manufacturers can successfully validate packaging schemes. However, without effective line-clearance practices in place and adequate final inspection, the potential for device mix-ups will occur. Trust Dr. D when I say “Murphy is always lurking in the corner.” If the device entering into the distribution cycle is placed into the wrong package or affixed with the incorrect label, you can expect to invoke an exercise in the ancient art of RECALL (yes, that nasty six-letter word again)!
Not wanting to end the handling aspect on a sour note, good handling practices, including effective line clearance, accurate label information in regards to handling and storage, can be successfully implemented with well-written procedures, training, validation testing, and sustained vigilance by all. Over the years, I have always taught my direct reports to handle medical devices with great care. Why? Because the recipient of the therapy provided by one of these devices could very easily be a family member. In fact, it might even be you.
Similar to the handling requirement, device manufacturers, “shall establish and maintain procedures for the control of storage areas and stock rooms for product to prevent mix-ups, damage, deterioration, contamination, or other adverse effects.” The caveat here is that the environment and location come into play versus just the handling. For example, if the storage temperature requirement, depicted in the first warning letter, were a valid requirement, the devices would need to be stored in that cold environment with evidence of effective temperature control.
One of Dr. D’s favorite storage requirements, as placed on labeling is, “Store in a Cool Dark Place.” I guess that means storing devices in bat caves is an option. Remember – if storage information on the label, e.g., temperature, has not been validated, it should not be on the device label. What the agency is really searching for, when evaluating the storage requirement, is assurances that device manufactures are not shipping damaged, discrepant, or expired devices into distribution.
Additionally, if devices have the potential for performance degradation, while sitting on the shelf in a distribution center, stock room, or similar environment, the devices shall be adequately protected from damage and the influences of the environment. For example, if a polymer is employed in a catheter shaft, and exposure to UV light can accelerate the breakdown of molecular chains; then special packaging (recommended foil pouches) and other protective steps should be employed. Regardless, the storage life for finished medical devices shall be determined through validation testing and the results documented. Remember, the useable shelf life is important data that will need to be placed onto the label of the finished medical device.
Stock rotation, another important aspect
Another important aspect of device storage is stock rotation. With a variety of ERP and MRP systems readily available, e.g., SAP™, batch management, including expiration dates, can be assigned and controlled systemically. In fact, once an expiration date is reached, an electronic gate should keep product from shipping. Dr. D strongly suggests adding at least a 3-month buffer to the expiration date and potentially longer, premised on inventory turns. Your supply chain folks can help make that determination.
Equally important, in regards to storage location, is the access and responsibilities of individuals being granted access. FDA feels so strongly about the control of product entering and leaving the stock rooms that they require device manufacturers to create procedures to delineate the practices for authorizing material receipts and material being dispatched to storage locations and stock rooms. The message that really needs to be understood is that all aspects of handling and storage must be effectively controlled. You can take it to the proverbial bank, when FDA arrives on your doorstep for a friendly visit, they will spend time in the stock room.
There are two ways to make a lasting first impression. The first, have the stockroom in complete disarray with clear evidence of ineffective inventory control and poor handling and storage techniques. The reward for this effort is simple: Can you say Form 483? The alternative is to have a well-organized and clean stock room, with every item in the room identified, with a batch number, expiration date (if appropriate), part number, etc. Remember, a first impression, regardless of the path chosen, is a lasting impression.
Takeaways: Accurate, effective and robust handling and storage processes
For this week, Dr. D will step down from the soapbox and not preach about the importance of written procedures and documented evidence. That said, there are two takeaways from this week’s guidance. For starters, the accuracy of handling and storage information, depicted on labeling, affixed to medical devices, should be considered mission critical. As depicted in this week’s warning letter extraction, inaccurate handling and storage information was cited, as an observation, in a warning letter. If a device manufacturer does not require the storage or shipment of product at a specific temperature, they should not place specific temperature information on the device label.
Secondly, effective and robust handling and storage processes, for medical devices, need to be sustained throughout the entire distribution cycle. Shipping expired product or damaged product is unacceptable. That is why FDA holds device manufacturers to task in regards to the proper validation of device packaging schemes, capable of surviving routine and not so routine handling and storage practices, including the potential influences for adverse environmental conditions.
In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG, when I evaluate Subpart – L (Handling, Storage, Distribution, and Installation), specifically 820.160 (Distribution) and 820.170 (Installation) – cheers from Dr. D. and best wishes for continued professional success.
- Code of Federal Regulation. (2009, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
- Devine. C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ.
- FDA – U.S. Food and Drug Administration Website. (2010). Warning letters. Retrieved September 3, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/