Acceptance activities, especially receiving inspection (RI), are near and dear to Dr. D’s heart. In pursuit of my doctorate, I spent the better part of two years collecting and analyzing data associated with the execution of RI. The data and subsequent analysis, depicted within my doctoral dissertation (Exploring the Effectiveness of Defensive-Receiving Inspection for Medical Device Manufacturers: a Mixed-Method Study), arrived at one conclusion: While there is limited value in performing old-school RI, there is substantial value in developing your strategic-supplier base by providing these suppliers with the tools needed to develop robust processes. The goal is to collaborate with suppliers capable of manufacturing products that meet your specifications.
Additionally, these suppliers are capable of providing meaningful inspection and statistical data that can be employed in support of reducing the burden of RI. The end-result is RI resources can quickly analyze the data provided with, or shipped ahead of, received product. The reduction in inspection burden allows these valuable resources to be allocated to other activities such as First-Article-Inspection (FAI) in support of product development. Finally, there are fiscal savings associated with reducing the RI burden, with the most notable being the reduction in the number of inspectors required to support the RI function.
Warning letter violation
For this week’s edition of DG, Dr. D has extracted violations from recently awarded warning letters. In this example, I think award is the appropriate vernacular as the agency is legally able to award warning letters for bad, or should I say, non-compliant behavior. In general, FDA frequently cites violators of section 820.80.
The recipients of this week’s warning-letter extractions have violated two of the doctor’s cardinal rules; (a) DG Rule # 6 (having written procedures), and (b) DG Rule #3 (documenting the results). Trust Dr. D. when I say, “not having robust procedures or documented results, in support of acceptance activities, will result in an intense colloquy (look-up-time) between management and the FDA, prior to the investigator issuing the user-friendly Form 483.”
Another Dr. D watch out is the correct way to respond to a Form 483 observation or warning letter. An offending device manufacturer cannot simply reply by stating; “the problem has been fixed or a procedure has been generated.” Why? Although supposedly there are no dumb questions, this particular “why” question should be categorized as dumb. A Form 483 or warning letter, when issued, are the precursory steps taken in pursuit of additional enforcement action pursued by the agency. FDA requires OBJECTIVE EVIDENCE to support the closure of observations noted within the Form 483 or warning letter. Repeat after me, “objective evidence” good.
Warning Letter One (June 2010): Observation 3 of 6 – Failure to establish and maintain procedures for acceptance of incoming product as required by 21 CFR § 820.80(b). Specifically, your firm has failed to establish a written procedure for incoming product to be inspected, tested, or otherwise verified as conforming to specified requirements. This was a repeat violation from a previous inspection.
Warning Letter Two (May 2010): Observation 4 of 12 – Failure to adequately document acceptance activities to include the results, as required by 21 CFR 820.80(e)(3). For example:
a. Packaging Specification Sheets for a Foil Pouch (POU-055 – D03-ES123 – Revision 03) and the Raw Material Specification Sheet for Temperature Indicator (TEM-001 – D03-DS182 – Revision 04) listed the acceptable dimensions and functional testing requirements, however, the receiving inspection records did not include the measurements taken or the results of the functional testing performed on these materials by the QC inspector.
b. Raw Material Specification Sheet for a Urine Cup (UCP-009 – D03-DS78 – Revision 02) listed acceptable dimensions for the cup, but the receiving inspection records did not include the measurements taken to demonstrate that the incoming cup met the documented raw material specifications.
c. Specialty Chemical Specification Sheet for a Methadone BSAJBTG Antigen Conjugate (9MAD-01 – D03-BS074 – Revision 02)) required that the material had a minimum purity of (b)(4) but the raw material inspection records did not contain any evidence that this purity was met.
FDA’s Response to Observation 4 of 12 – We have reviewed your response and concluded that it is not adequate because you did not provide any documentation of the corrective action. You stated that specifications on raw materials needed to be reviewed and updated to reflect actual testing performed and new documents will be created to record the results. You stated that the process, and presumably, the documents will be completed by 2/28/10.
Observation 5 of 12 – Failure to establish and maintain procedures for acceptance of incoming product. Incoming product shall be inspected, tested, or otherwise verified as conforming to specified requirements. Acceptance or rejection shall be documented, as required by 21 CFR 820.80(b). For example, you do not have a procedure in place to test the purity of Methadone BSAJBTG Antigen Conjugate and the specification sheet provided by the vendor does not specify the purity level of the material.
FDA’s Response to Observation 5 of 12 – We have reviewed your response and concluded that is not adequate because you did not provide a procedure for testing the purity of the Methadone BSA/BTG Antigen Conjugate.
Quality System Regulation – 21 CFR, Part 820
QSR – Subpart H – Acceptance Activities Section 820.80 Receiving, In-process, and Finished Device Acceptance
(a) General. Each manufacturer shall establish and maintain procedures for acceptance activities. Acceptance activities include inspections, tests, or other verification activities.
(b) Receiving acceptance activities. Each manufacturer shall establish and maintain procedures for acceptance of incoming product. Incoming product shall be inspected, tested, or otherwise verified as conforming to specified requirements. Acceptance or rejection shall be documented.
(c) In-process acceptance activities. Each manufacturer shall establish and maintain acceptance procedures, where appropriate, to ensure that specified requirements for in-process product are met. Such procedures shall ensure that in-process product is controlled until the required inspection and tests or other verification activities have been completed, or necessary approvals are received, and are documented.
(d) Final acceptance activities. Each manufacturer shall establish and maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria. Finished devices shall be held in quarantine or otherwise adequately controlled until released. Finished devices shall not be released for distribution until:
- The activities required in the DMR are completed;
- The associated data and documentation is reviewed;
- The release is authorized by the signature of a designated individual(s); and
- The authorization is dated.
(e) Acceptance records. Each manufacturer shall document acceptance activities required by this part. These records shall include:
- The acceptance activities performed;
- The dates acceptance activities are performed;
- The results;
- The signature of the individual(s) conducting the acceptance activities; and
- Where appropriate the equipment used. These records shall be part of the DHR.
General requirements a no-brainer
The general requirement is a Dr. D no-brainer. Device manufacturers are required to write, maintain, train to, and comply with their procedures in support of all acceptance activities. Additionally, these acceptance activities should include physical inspection, testing, verification, data collection, analysis, and all other activities that can be remotely construed as acceptance. My recommendation is to invest some time, effort and of course money into establishing your organization’s approach to performing acceptance activities. Effective acceptance activities can be your first-line of defense against the introduction of defects into finished medical devices, while reducing the potential for expensive market withdraws, a.k.a., RECALLS. Yes, RECALLS are ugly; unfortunately, they continue to be a reality in the medical device industry.
Receiving acceptance activities
As I mentioned earlier, I find little value in the antiquated approaches many device manufacturers employ in support of RI. Remember, the fundamental requirement, as stated within the QSR is, “Incoming product shall be inspected, tested, or otherwise verified as conforming to specified requirements.” It does not state you must perform 100 percent visual or mechanical inspection on every-single product procured and received. That is why Dr. D supports a well-documented approach to reduced inspection activities, especially at RI. I am a big proponent of establishing a fundamentally sound and statistically-based approach to inspection, executed by the supplier, and verified by the procuring activity, in support of reducing the overall inspection burden.
As part of a series of articles, which I penned for Medical Device Summit earlier this year in January and February, Dr. D provided a significant amount of information and granularity in regards to reducing the inspection burden associated with RI. The doctor strongly suggests that you take the time and read these articles. Through the employment of an interactive approach to supplier management, with active supplier participation, using tools such as the collection and analysis of measurement data can result in a reduction in the amount of receiving acceptance activities pursued. In conjunction with the FAI process, it is a reasonable expectation that the specification creators glom the opportunity and work with the suppliers in determining critical features requiring monitoring and measurement data, in support of a Supplier Statistical Data Program (SSDP). Your suppliers should have the capability to identify the critical features and dimensions needed to gage the overall effectiveness of their manufacturing processes, and the sustainability of long-term process control.
For an effective SSDP to work there must by a collaborative approach pursued, between the supplier and manufacturer, for identifying the features and characteristics requiring inspection and measurement. Additionally, the determination of whether the data collected should contain attribute data or variable data; and targeted process capability indices (Ppk) occurs as part of the development process. Can you say Ppk of 2.0 (Six Sigma)?
Furthermore, risk indices need to be considered for all components placed into the program when establishing a SSDP. The FMEA (and I hope you are using them) should help determine the appropriate levels of risk. Finally, once agreement is reached on what should be included within the SSD Agreement (SSDA); the agreement should be reviewed, approved, and signed by both parties (supplier and device manufacturer).
One final thought, after launching a SSDP, you will need to keep your suppliers honest. What does that mean? It means you will need to occasionally inspect lots received as part of the SSDP and verify your measurement results match that of your suppliers. Regardless of the tools employed as part of complying with the receiving acceptance requirement, all of the results shall be documented and retained. Why? Because having documented results equates to supporting evidence, which is always your best defense during a friendly visit by FDA.
In-process acceptance activities
Not unlike receiving acceptance activities, device manufacturers spend a significant amount of time and money in pursuit of in-process acceptance activities. Once again, the regulation does not state, “thou shall 100 percent inspect and test every-single device as part of the normal manufacturing flow.” What device manufacturers need to do is establish robust and validated processes, well-written manufacturing and inspection instructions, and pursue in-process inspection activities, that are premised on a documented statistical approach. Remember the agency is big on employing validation and verification.
For example, electrophysiological catheters are complex Class 3 devices (US) that contain a significant amount of wiring and electrical connections. A 100 percent in-process electrical test may be warranted due to device complexity. However, catheter-working length, with a wide tolerance may require only a sample inspection, maybe an AQL of 4.0. Regardless, each device manufacturer gets to establish an EFFECTIVE approach for pursuing in-process acceptance activities.
I underline effective because regardless of the approach pursued, it will need to be defendable as effective to FDA. For example, if the yields for catheter-working length are low, then justifying an AQL of 4.0 is going to be difficult to defend. Besides, effective in-process acceptance activities not only place the business at risk (Recalls), they can quickly erode margins due to excessive rework. One final thought, , the result of all in-process acceptance activities shall be what? Documented – right answer!
Final acceptance activities
The FDA no longer requires final acceptance activities. Just kidding! Final acceptance activities are considerably more complex than receiving or in-process acceptance activities (in Dr. D’s opinion). Upon completion of final acceptance, the device manufacturer is basically certifying that the finished medical device meets all requirements (product specification, market specification, etc.) and will be safe and effective for its intended use. Once all of the physical inspection and testing activities have been completed, the entire documentation package assembled as part of the manufacturing process, a.k.a. the Device History Record (DHR) needs to be reviewed.
In short, successful completion of the manufacturing process requires verification that finished devices were assembled, inspected, and tested in accordance with the requirements delineated within the Device Master Record (DMR). Until the final review process is completed, all finished devices or batches of finished devices shall be placed into a quarantine area and held until the review has been successfully completed.
As part of the final review process, the following activities need to occur.
- As previously stated, all manufacturing, inspection, and testing requirements, identified within the DMR, must be completed.
- All of the documentation and data collected and placed into the DHR must be reviewed for acceptability.
- A formal release of the finished devices or batch of devices must occur, including the name and signature of the individual authorizing the release, and the date the release occurred.
- Product cannot be released for distribution until formal approval has been achieved. Remember, if product sterilization is required post manufacturing, release cannot occur prior to the completion of sterilization and post-sterilization testing, as required.
Keeping with previous themes, the QSR does not specifically state what constitutes an acceptance activity. That is the job of the device manufacturers who need to be specific when writing procedures and creating processes, including identifying inputs, outputs, and the data needing to be collected as part of acceptance activities. With today’s state-of-the-art MRP/ERP systems, such as SAP, detailed manufacturing routers can be created that delineate data requirements throughout the entire manufacturing process. Regardless, the requirement is that all data collected, analyzed, and employed for ascertaining device acceptability, as part of the acceptance process, shall be retained. This data (records of acceptance) forms an integral part of the DHR.
What does the QSR require for acceptance records? As a minimum:
- The identification and description of the acceptance activity performed, e.g., final electrical test;
- Documenting the date the activity was performed;
- Documenting the results of the acceptance activities performed; hopefully, pass or fail;
- The name and signature of the individual performing the activity; and
- Documenting the list of equipment (name, nomenclature, serial number, etc.) employed as part of the acceptance activity, when appropriate.
The key takeaways for this week are straightforward. For starters, selecting suppliers capable of supporting an effective SSDP can result in a significant reduction in the RI burden, which results in actual fiscal savings being realized by device manufactures. Employing statistical tools when performing in-process acceptance activities can result in additional savings.
Final acceptance activities must be successfully completed before finished devices can be released for distribution. Finally, there are a few specific pieces of information that require collection and placement into the records supporting acceptance. And one final thought – the QSR does not dictate to device manufacturers how receiving, in-process, and final acceptance activities are to be performed; the QSR specifies that these activities (generically) are required.
In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Just a quick note, Dr. D purposely omitted 820.86. The doctor will be enjoying a four-day weekend and will not have time to pen a lengthy column for next week. Until the next installment of DG, when I provide guidance for Subpart – H, and specifically (820.86), acceptance status – 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 August 3, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/