In this week’s edition of Devine Guidance (DG), the doctor continues with his prolegomenon (look-it-up if you need to) examination of the Quality System Regulations (QSR) while continuing to provide insight and guidance for compliance.
Inspection, measuring, and test equipment, in the opinion of Dr. D, forms a significant part of the quality-system foundation for successful medical device manufacturers. At the end of the day, device manufacturers need effective tools to gage adherence to approved product specifications; and the vehicle employed for doing so, is the performance of acceptance activities utilizing inspection, measuring, and test equipment.
Warning letter violation
Nothing raises the doctor’s hackles more than compliance issues associated with calibration, or rather, lack of calibration. This week’s warning letter extraction depicts procedural issues, execution issues, the utilization of equipment with expired calibration, equipment with documented functional performance issues, and to top it off, these are repeat violations from this device manufacturer’s previous inspection. Hello! What are you thinking?
Calibration is the foundation for acceptance activities and the effective employment of inspection, measuring, and test equipment. Every single investigator, auditor, internal auditor, customer auditor, and hopefully, mechanical inspector understands the significance of calibration and the employment of calibrated equipment as part of acceptance activities.
Warning letter (May 2010): Observation 7 of 12. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained to include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained, as required by 21 CFR 820.72(a). This is a repeat observation from FDA 483 issued on 11/20/07. For example:
a. The Lyophilizer Maintenance and Calibration Procedure (Q56-P14, Revision 02) specified that lyophilizers are to undergo quarterly preventative maintenance by a licensed contractor. However, quarterly preventive maintenance has not been executed for the VirTis and Hull Lyophilizers. Additionally, the firm admitted that quarterly maintenance procedures have not been performed by a licensed contractor.
b. A product technician at the firm admitted that the chart recorder used on the VirTis Lyophilizer to document lyophilization parameters has not been functioning since mid December 2009. No service work order had been initiated to repair the broken recorder.
c. The digital caliper (Equipment ill # (b)(4) used in receiving inspection activities is overdue for annual calibration. Last calibration was performed in 10/30/08.
FDA Response to Observation 7 of 12. We have reviewed your response and concluded that it is not adequate. You stated that you completed a review of your maintenance schedule and reminders have been entered into Outlook. However, you did not state if the lyophilizers and calipers would be immediately calibrated. Also, you stated that the VirTis operator was retrained but did not provide documentation of the training.
Quality system regulation – 21 CFR, Part 820
QSR – Subpart G – Production and Process Controls: Section 820.72 Inspection, Measuring, and Test Equipment
(a) Control of inspection, measuring, and test equipment. 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.
(b) Calibration. Calibration procedures shall include specific directions and limits for accuracy and precision. When accuracy and precision limits are not met, there shall be provisions for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device’s quality. These activities shall be documented.
(1) Calibration standards. Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or international standards. If national or international standards are not practical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard.
(2) Calibration records. The equipment identification, calibration dates, the individual performing each calibration, and the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.
Inspection, measuring and test equipment
I must admit, the doctor struggles to fathom the logic behind device manufacturers not having robust procedures and processes in support of inspection, measuring, and test equipment. Process control, acceptance activities, engineering studies, validations (IQ, OQ, PQ), product design and development, and even more important, ensuring finished medical devices are safe and effective, are premised on the application of effective inspection, measurement, and test equipment practices. Remember, the entire approach to inspection, measuring, and test equipment fails when calibration practices are inadequate or completely ignored. Calibration is an expensive and time-consuming investment. However, the costs associated with calibration activities can be unequivocally categorized as mandatory and considered part of the price for admission into the medical device industry.
Dr. D Story Time – Once upon a time, in a land called the United States, Dr. D was visiting a new supplier candidate. On this particular business trip, the good doctor had been in an automobile accident on the morning of the scheduled audit. Dr. D unceremoniously ended the life of one of Bambi’s relatives on Interstate 80 in Pennsylvania. Needless to say, the deer lost this battle but inflicted some serious pain on the doctor. Eventually, Dr. D made it to the doorstep of this supplier, a day later than expected, and extremely sore from the accident (airbags leave nasty marks, bruises, and an occasionally broken rib or two). My sense of humor, which I needed desperately for this visit, was void, lost in the pain. During the initial walk through, besides not having a recognizable quality system, Dr. D observed that most of the inspection, measuring, and test equipment, employed by this potential supplier, had expired calibration but was still in use. The calibration stickers depicted over-due calibration dates approaching two-years. My scheduled two-day visit was over before lunchtime, on the first day. Can you say – not approved? My parting gift to this potential supplier was the awarding of just one deviation. Yes, Dr. D felt like being generous. As I recall the deviation was worded; “no identifiable or cohesive quality system exists. Please provide a detailed plan, delineating a path toward establishing a quality system that is in compliance with EN ISO 13485.”
Story Epilogue – A year later, the supplier contacted Dr. D and asked if they were still being considered for the project. I was compelled to ask if the installment of a recognizable quality system had occurred. The answer absolutely floored the doctor; “No, we are waiting for the purchase order before we start!”
Control of inspection, measuring and test equipment
So what is the agency looking for in regards to control? For starters, rocket science time again, the expectation is that inspection, measuring, and test equipment, employed as part of the device manufacturing process, is suitable for its intended use. The results obtained, from the employment of test equipment, must be capable of producing repeatable, reproducible, and valid results.
The only way to achieve repeatable, reproducible, and valid results is through the application of verification and validation activities for all inspection, measuring, and test equipment. A Dr D watch out – be very careful about claiming the results obtained are self-evident, because other than death or taxes, very few things in the medical device industry fall into the category of self-evident; and if they do, a written rationale will be required to justify the self-evident claim. Additionally, the expectation is that some resemblance of a maintenance and calibration system exists, with the system documented by written procedure(s).
Furthermore, the handling, preservation, and storage of equipment is not only important, it needs to be captured in a procedure. For example, if your organization is storing microscopes, oscilloscopes, or similar pieces of equipment in the janitor’s closet, along side the mops, mop-buckets, and the brooms; FDA will probably take exception to the practice. Finally, all activities associated with this requirement shall be documented because the QSR clearly states the documented activities requirement; and documented evidence is always your best defense during a friendly visit, by the agency.
As with all requirements associated with the QSR, strict adherence to DG Rule # 6 – “All procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled with in a defined document control system” – is mandatory. In fact, the procedures for calibration need to be prescriptive in regards to determining and verifying limits for accuracy and precision.
Additionally, if during the execution of routine calibration, it is determined that a piece of equipment is no longer within published operating specifications, remedial action shall be pursued. In short, at least two actions will need to be pursued. One, the piece of equipment must be repaired, calibrated, adjusted, etc., to ensure it is once again operating within established parameters or the manufacturer’s specification. If equipment cannot be repaired, it needs to be indentified, tagged, and removed from service. It is a bad practice to leave out-of-tolerance or broken inspection, measuring, and test equipment on the manufacturing floor, without some type of label or tag (preferably red), informing the entire world that, “this piece of equipment shall not be used.” The best practice is to remove the piece of equipment; whenever possible, from the manufacturing floor.
Two, formal corrective action needs to be pursued to ensure devices manufactured during the time-period between when the last documented calibration was performed and when the out-of-specification condition occurred, are still acceptable for use (a.k.a., safe and effective for their intended use).
Furthermore, if the quality influence on finished medical devices, resulting from an out-of-tolerance condition relating to inspection, measuring, or test equipment cannot be determined; be prepared for that ugly six-letter word, RECALL! That is why batch control is so important. Effective batch management can limit the exposure due to operating anomalies such as calibration and equipment non-conformances.
Finally, yes – all activities associated with this requirement should be documented. This is always your best defense during a friendly visit from the agency.
Calibration standards and records
Since FDA governs device manufacturers building finished devices for introduction into commerce within the Unites States and its protectorates, the expectation is that the calibration system shall be premised on a national standard. In the United States, that standard is the National Institute for Standards and Technology (NIST). Most device manufacturers probably maintain primary and/or transfer standards that are NIST traceable. Dr. D will also assume that most medical device manufacturers retain a metrology service to perform calibration on standards, and potentially on all inspection, measuring, and test equipment employed during the manufacturing process. If your organization is creating standards because no external standard exists, these standards need to be validated. The output of the standard must be repeatable, reproducible, and provide valid results.
Although record retention is important for all aspects of the QSR, calibration records should probably be elevated to a mission-critical status. Traceability, back to a national standard, for specific pieces of inspection, measuring, and test equipment is mandatory. Additionally, the calibration records, for each piece of inspection, measuring, and test equipment should reflect, as a minimum:
- The date calibration was performed;
- The name of the technician performing the calibration;
- The date the next calibration is due;
- A list of primary and secondary standards, including their calibration status, employed as part of the calibration;
- A printout / record of adjustments made;
- A printout / record of key operational characteristics verified;
- A notation of performance limitations; and
- A detailed analysis of out-of-tolerance conditions, including corrections.
Furthermore, all pieces of inspection, measuring, and test equipment shall be clearly identified with a unique serial number and a calibration sticker or label that reflects; (a) date calibrated, (b) name of technician performing the calibration, and (c) the date calibration is due. Make sure inspectors and operators are properly trained, so they never use equipment reflecting an expired calibration status.
Finally, although the QSR is not overly prescriptive in regards to what should be retained in the calibration files or what a procedure should reflect, the EN ISO 17025 is very prescriptive in regards to good calibration laboratory practices. Medical device manufacturers should refrain from employing metrology facilities and other outside testing laboratories that are not EN ISO 17025 compliant. Employing metrology labs that are certified to EN ISO 17025 is really the best practice to pursue.
Other procedural considerations
Now granted, the depth and detail required for supporting compliance with the inspection, measuring, and test equipment will vary depending on organizational structure, size, need, etc. Some of the bulleted items depicted below deserve consideration when drafting procedures to support calibration:
1. A policy for:
a. introduction of new inspection, measuring and test equipment into use;
b. removal of equipment;
c. lost equipment;
d. equipment storage;
e. addressing out-of-tolerance events;
f. expired / past-due calibration
2. An all-inclusive list of equipment, including the calibration status and location (aka, calibration-recall list};
3. Calibration intervals;
4. Calibration ranges and accuracies;
5. Storage of primary and secondary standards;
6. The calibration, identification, and employment of equipment owned by employees (note: common in machine shops; however, Dr. D believes this is a bad practice);
7. The assessment of metrology and other external labs (extremely important);
8. A definition and list of the records retained in the individual equipment files;
9. Inclusion of the calibration system into the internal audit function;
10. Individual procedures for each piece of equipment calibrated internally;
11. Employment of tamper-proof seals, when warranted;
12. Different classes of calibration, e.g., calibration required versus no-calibration required;
13. Equipment traceability;
14. Environmental conditions; and
15. Training (extremely important).
Once again, Dr D does not claim that this list is all-inclusive. However, if device manufacturers can wordsmith these bullet points into a procedure or series of procedures, the outcome will probably be viewed as favorable during an FDA visit; providing the procedures are being followed.
In wrapping up this week’s edition of DG, the takeaways are: 1. employment of an effective approach to calibration control, including procedures to support the inspection, measuring, and test equipment requirement delineated within the QSR; 2. calibration is one of the key building blocks supporting the foundation for an effective quality system; 3. accuracy of acceptance activities is premised on calibration and the accuracy of the inspection, measuring, and test equipment employed; 4. non-conformances associated with inspection, measuring, and test equipment can result in product recalls; and 5. documented evidence is your best defense during a friendly visit from FDA.
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 complete the review and provide guidance for the last subsection of Subpart – G (820.75), process validation – 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 ISO 17025 (2005, May). General requirements for the competence of testing and calibration laboratories-ISO/IEC 17025: 2005. Retrieved July 23, 2010, from http://ihs.store/spectstore
- FDA – U.S. Food and Drug Administration Website. (2010). Warning letters. Retrieved July 20, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/