Let Dr. D begin this edition of DG by stating that labeling and what constitutes being a label can be confusing for device manufacturers. Labeling collectively consists of multiple components, depending on the device manufacturer’s packaging configuration. As a minimum, labeling comprises of the outer-most label on a packaged device, the Instructions for Use (IFU), information imbedded into the artwork on a carton or pouch, a pouch label, or even something as benign as a flash label, e.g. “New and Improved.”
To complicate matters further, outside of the United States, the Medical Device Directive (MDD) dictates a requirement for labeling to be multi-lingual, e.g., in English plus 50 other languages (just kidding, but someday a possible reality). Regardless, FDA wants to ensure device labeling employed in the U.S. is clear, concise, legible, and accurate. For example, if a carton label for a catheter depicts a working length of 105 cm, and the actual length of the device is 90 cm, the device manufacturer now has a problem. Can you say, “Misbranded product?” Can you say, “RECALL?” Yes, Dr. D has done it again, throwing around that ugly six-letter word. Seriously, the doctor cannot place enough emphasis on ensuring device labeling is accurate. The doctor has suffered through far too many field actions (code name for RECALLS) due to product labeling issues.
Warning letter violations
Dr. D broken-record time again, as this warning-letter extraction reflects another device manufacturer’s failure to establish and maintain procedures. Week after week, violations of the QSR, as evidenced by the warning letters issued by FDA, reflect a growing trend within the device industry. And that trend continues to be rooted in the lack of procedures required to support compliance with the QSR. It is my personal belief, regardless of regulatory path 510(k), IDE, or PMA, device manufacturers need to have their quality systems reviewed, certified, and approved, by a recognized regulatory body, to circumvent their inerrable (look-it up) policies preventing compliance to the QSR. Now granted, it is my belief FDA just does not have the resources to accomplish this task of policing, as the number of device manufacturers grows substantially; however, the onus should be placed onto the backs of the device manufacturers to select and pay for a notified body, capable of certifying a quality system. Dr. D is appalled that device manufacturers continue to rack up Form 483 observations and warning letters, while being allowed to distribute devices within the United States. This negative compliance trend needs to be reversed and this will happen only when device manufacturers begin pursuing a veridical (look-it up) approach to compliance.
Warning letter (February 2010): Observation 3 of 6 – Failure to establish and maintain procedures to control labeling activities, as required by 21 C.F.R. § 820.120. FDA 483 Item 3. Specifically: Your firm has not established written procedures for identifying labeling information, printing and applying labels on the carbon and D1 resin tanks, inspecting the labeling for accuracy, and documenting the labeling inspection results in the device history record. For instance, your firm applies a gray-color label on the mixed-bed resin tanks to prevent mixups with the other resin tanks intended for industrial applications, and a (b)(4) day installation sticker to control bacterial growth in the resin tanks. Your firm has not documented these requirements, and labeling inspections in the batch records (regeneration logs and exchange orders). Another instance, the installation date on the two resin tanks (Tank S/N (b)(4) and (b)(4)) at a hospital occurred a day before the tanks were actually filled at your firm as documented in their batch record.
Quality System Regulation – 21 CFR, Part 820
QSR – Subpart K – Labeling and Packaging Control
Section 820.120 Device Labeling:
Each manufacturer shall establish and maintain procedures to control labeling activities.
(a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary conditions of processing, storage, handling, distribution, and where appropriate use.
(b) Labeling inspection. Labeling shall not be released for storage or use until a designated individual(s) has examined the labeling for accuracy including, where applicable, the correct expiration date, control number, storage instructions, handling instructions, and any additional processing instructions. The release, including the date and signature of the individual(s) performing the examination, shall be documented in the DHR.
(c) Labeling storage. Each manufacturer shall store labeling in a manner that provides proper identification and is designed to prevent mixups.
(d) Labeling operations. Each manufacturer shall control labeling and packaging operations to prevent labeling mixups. The label and labeling used for each production unit, lot, or batch shall be documented in the DHR.
(e) Control number. Where a control number is required by 820.65, that control number shall be on or shall accompany the device through distribution.
Section 820.130 – Device Packaging: Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.
Dr. D broken-record time again: written procedures are a fundamental requirement for compliance with the QSR, as stated by DG Rule # 6 – All procedures, work instructions, drawings, specifications, etc., must be written, well-documented, and controlled within a defined document control system. The QSR, for device labeling, clearly states, “Each manufacturer shall establish and maintain procedures to control labeling activities.”
Frankly, I am not sure how FDA could make this statement any clearer or easier to understand. Shall, in FDA speak, means the requirement is not optional, as reflected in the Nike™ commercials, “Just Do It.” Establish, in FDA speak, equates to actually developing a well-documented approach to compliance, a.k.a. written procedures. Maintain, in FDA speak, delineates the need for device manufacturers to constantly monitor the effectiveness of their written procedures, review the quality outputs associated with their written procedure, and revise (as appropriate) to ensure written procedures continue to be effective. Remember folks, this not rocket science.
What is the value of a label if it does not remained affixed to a product carton or pouch during normal distribution conditions? To ensure labels do not fall-off or peel- back, due to adhesion issues, device manufacturers are expected to qualify their label stock and validate its use, including adhesion. In fact, device manufacturers should be validating their entire labeling and packaging schemes employing EN ISO 11607-1:2009, EN ISO 11607-2:2006, and ISTA-2A principles. Ensuring the label remains affixed is only part of the problem. The printed information on the label must be accurate, and the label needs to remain legible throughout the entire distribution cycle; including storage, handling, and where used. That is why tests, such as the Sullivan Rub Test are important.
Ensuring the correct information makes its way onto the product labeling is mission critical. The information on the label should reflect key characteristics, as depicted within the product specification (e.g. working length), user information, regulatory information (e.g. California Proposition 65), recognized symbols, shelf life, batch number, storage and handling instructions, warning statements (e.g. contains Latex or DEHP), single-use, manufacturing address, country of origin, and any additional information deemed appropriate by the device manufacture and/or mandated by law.
Although the QSR is U.S.-centric, unless you plan on developing special labeling for markets outside of the U.S., e.g. the European Union (EU), Dr. D strongly recommends that EN 980:2008, CE Marks, Language Requirements, the use of SI Units, etc., be considered when creating product labeling. Additionally, the doctor recommends a robust approach to the label content review and approval process to ensure label content is accurate. For new product approvals, FDA will want to review the labeling as part of the initial submission, as will the notified bodies in the EU. Once the label information is deemed accurate, a label specification can be approved and a copy placed in the labeling and boxing area located on the manufacturing floor. Why? Read the next paragraph.
The approved label specification can be employed by the quality organization or designee for label inspection. The QSR clearly states, “Labeling shall not be released for storage or use until a designated individual(s) has examined the labeling for accuracy.” As part of determining label accuracy, the information depicted on the label, the legibility of information depicted on the label, and the quantity of labels received, printed, and retained need to be verified. Evidence of this verification step shall be retained in the Device History Record (DHR), including (a) the signatures of the individuals performing the inspection, and (b) the date the inspection was performed. A copy of the printed label should also be retained in the DHR. Dr. D recommends creating a label inspection sheet so a copy of the label can be affixed to the backside of the sheet for retention purposes.
Labeling storage begins with batch numbers assigned to the label stock, pre-printed labels, flash labels (Dr. D hates flash labels because it is difficult to control their use), etc. Employing effective line clearance in the labeling area will result in the prevention of potential label mix-ups. Dr. D. has witnessed the perils associated with an operator loading the wrong label stock onto a Zebra Xiii Printer (no, Dr. D is not a paid spokesperson for Zebra), the labels subsequently printed and affixed to the cartons of finished medical devices, and the devices placed into distribution. Can you say RECALL? Yes, there goes Dr. D invoking that nasty six-letter word again – stop.
As stated in the previous paragraph, it is important to keep track of the number of labels printed. In a perfect world, an automated approach to printing and affixing labels is preferred; however, because of the varying sizes of labels, pouches, cartons, and the expense associated with automation, many manufacturers still apply the labels manually.
It is the strong opinion of Dr. D, “There is no better way to control mix-ups on the production floor then to employ an effective approach to line clearance.” The foundation for effective line clearance is the batch control of materials, i.e., labels, pouches, IFUs, and cartons. Obviously, all of the batch information associated with labeling and packaging shall be retained in the DHR, as should a copy of the label, as previously stated.
Another key influencer affecting line clearance, as with all manufacturing and inspection operations is employee training. Remember, pouching, boxing, and labeling are the final manufacturing steps prior to finished devices shipping to sterilization and distribution. The quality and manufacturing staff working in the labeling and boxing area must possess a keen eye for detail and be thoroughly trained in the execution of their duties.
As part of the control number requirement, the QSR invokes 820.65. A quick refresher for the folks that may have missed earlier editions of DG, Section 820.65 of the QSR, is the requirement for traceability. When the use of a control number is required by regulation, e.g., surgical implant, the assigned control number must remain with the finished device or devices throughout their entire life cycle. The entire life cycle concludes with the use of the device(s), or the scrapping of the device(s) – in short, the device is no longer in service and available for use. It does not end with the sale. Remember, traceability should be a salient requirement as device manufacturers will rely heavily on traceability, should a RECALL ever become necessary (I know, stop with the “R-Word” already!).
Dr. D has already expounded on the virtues of validating packaging schemes to ensure finished medical devices are adequately protected during the trials and tribulations associated with, as the QSR states, “customary conditions of processing, storage, handling, and distribution. Device manufacturers can have pretty boxes, eye-catching color schemes, and flash labels fit for use on laundry-soap cartons; however, none of these is worth a hill of beans if the packaging does not prevent damage to the device, or the sterile barrier.
That said, device manufacturers must validate packaging and the effectiveness of the packaging for protecting the finished medical device. The expectation of FDA and regulatory bodies around the world is that the packaging validation include packaged product that has been:
- Processed through the appropriate sterilization cycle (if applicable);
- Exposed to a reasonable distribution challenge (ISTA-2A); and
- Supported by aging studies to support shelf-life (accelerated to support initial product approval followed by real-time).
Packaging is an extremely important deliverable as part of the overall product design cycle. Remember, regardless of how good a device design might be; it is worthless if the device cannot be delivered to healthcare professionals ready for use. Device safety and device efficacy trumps speed to market any day of the week.
There are three takeaways from this edition of DG. One, the accuracy of device labeling is a mission-critical step for device manufacturers. If the information depicted on a device label is incorrect, device manufactures can expect to withdraw product from market (note – Dr. D did not use the word RECALL). Two, ensure product packaging and labeling are properly validated, including distribution cycles, storage conditions, and useable shelf life. Three, if product is going to be distributed outside of the U.S., become familiar with the MDD and EN 980. Designing labeling schemes for deployment in multiple markets can result in significant cost saving.
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 (820.140 – Handling and 820.150 – Storage) – 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.
EN 980:2008. (2010, May). Symbols for use in the labeling of medical devices. European Standard – Prepared by: Technical Committee CEN/CLC/TC 3.
EN ISO 11607-1:2009. (2010, March). Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems. International Organization for Standardization.
EN ISO 11607-2:2006. (2006, July). Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing, and assembly processes. International Organization for Standardization.
FDA – U.S. Food and Drug Administration Website. (2010). Warning letters. Retrieved August 30, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/
ISTA-Procedure 2A:2008. (2008). Packaged-products weighing 150 lb (68 kg) or less. International Safe Transit Association.