In this week’s edition of Devine Guidance (DG), Dr. D will continue down the production and process controls path by examining the requirements for subsections (f) buildings, and (g) equipment. Buildings and equipment fall into Dr. D’s not rocket science category. Why? Because the investments made, by medical device manufacturers, into buildings and equipment, are in reality a down payment toward the price of admission into the medical device industry. Besides, ask your district office of the FDA if assembling a Class 3 device, for arguments sake an electrophysiological catheter; (a) in your backyard, (b) using tools just purchased from the Home Depot or Lowes, (c) while wearing cargo shorts and flip-flops, is an acceptable practice. Be prepared to step aside and listen to the hysterical laughter emanating from the district office. All kidding aside, the expectation is that a suitable facility, with equipment and tooling that has been verified, validated, calibrated, etc., be employed in the manufacturing of devices. A medical device manufacturer’s nescience (look-it-up) in regards to the quality systems regulation (QSR) will be rewarded, with a Form 483, and potentially a warning letter; if the violations are bountiful and egregious to these specific requirements, and the QSR, as a whole.
Warning Letter Violation
This week’s offender of the QSR was attempting to try for an agency record. In fact, the warning letter retrieved for this week’s edition of DG depicted 19-observations, documenting significant violations of the QSR. What – are you kidding me? Nineteen (19) observations, noted in the warning letter, are completely unacceptable. Can you say out of control? In fact, if Dr. D counted all of the subsections to these observations, and additional thirty-four (34) non-conformances were noted, expanding the grand total to fifty-three (53) observations identified. Yes, Dr. D possesses some basic mathematic skills, the doctor can add. Are you kidding me? Fifty-three notations for compliance issues – you have to be kidding. If Dr. D were the recipient of this warning letter, my two-biggest concerns, after I have provided an initial response to the agency, would be; (1) when are the doors to the facility going to be chained and locked, and (2) will I look good in an orange jumpsuit?
Warning Letter (March 2010)
Observation 9 of 19. Failure to validate computer software for its intended use according to an established protocol when computers or automated data processing systems are used as part of production or the quality system, as required by 21 CFR 820.70(i). For example, when requested no validation documentation to support the commercial off-the-shelf program (b)(4) used to capture complaints, returned merchandise and service requests was provided.
Quality System Regulation – 21 CFR, Part 820
QSR – Subpart G – Production and Process Controls
(a)General. Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications. Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications. Where process controls are needed they shall include:
(1) Documented instructions, standard operating procedures (SOP’s), and methods that define and control the manner of production;
(2) Monitoring and control of process parameters and component and device characteristics during production;
(3) Compliance with specified reference standards or codes;
(4) The approval of processes and process equipment; and
(5) Criteria for workmanship which shall be expressed in documented standards or by means of identified and approved representative samples.
(b)Production and process changes. Each manufacturer shall establish and maintain procedures for changes to a specification, method, process, or procedure. Such changes shall be verified or where appropriate validated according to 820.75, before implementation and these activities shall be documented. Changes shall be approved in accordance with 820.40.
(c)Environmental control. 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. Environmental control system(s) shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly. These activities shall be documented and reviewed.
(d)Personnel. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual.
(e)Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.
(f)Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mixups, and assure orderly handling.
(g)Equipment. 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.
(1)Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented.
(2)Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and individual(s) conducting the inspections, shall be documented.
(3)Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these adjustments.
(h)Manufacturing material. Where a manufacturing material could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures for the use and removal of such manufacturing material to ensure that it is removed or limited to an amount that does not adversely affect the device’s quality. The removal or reduction of such manufacturing material shall be documented.
(i)Automated processes. When computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol. All software changes shall be validated before approval and issuance. These validation activities and results shall be documented.
As previously stated in this edition of DG, “The building requirement falls into Dr. D’s category of not being rocket science.” According to the QSR, “Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups, and assure orderly handling.” Simply put, the building and building layout for manufacturing medical devices requires some intelligent design. For example, you want to ensure material flows efficiently through the manufacturing cycle. Not wanting to over simplify the approach; (a) raw materials enter the building at one location, (b) inspected (as necessary), (c) placed into stores or Kan Ban, (d) kitted,(e) released to manufacturing, (f) assembled into finished medical devices, (g) submitted to final inspection, (h) cleaned, (i) packaged, (j) released for sterilization, and (k) shipped to the sterilizer at a location that is segregated from the material receipts location. For the most part, the flow is sequential and capable of preventing, as the QSR reflects, “mix-ups.”
As part of the building requirement, device manufactures should also consider:
- Sufficient space available to support manufacturing operations;
- Defined area(s) for holding non-conforming product;
- Defined holding areas for material pending receipt and evaluation
- Clean and well-organized stockroom;
- Plan for pest control;
- Plan for disaster recovery (real important for areas prone to earth quakes, tornados, an hurricanes);
- Adequate electrical drops available on the manufacturing floor;
- Plumbing for compressed air, nitrogen, and other inert gases (as warranted);
- Water (city or DI);
10. Office space;
11. Building maintenance;
13. Lunch and break rooms; and
Please keep in mind, Dr. D’s list is not an all-inclusive one. My intent is to ensure device manufacturers take into consideration anything and everything in regards to the building that houses medical device manufacturing. Remember the old adage, “First impressions are lasting impressions.”
Time for another Dr. Story – once upon a time, the doctor was asked to visit a supplier that specialized in wiring grinding. The for-cause visit was due to food particles (Cheetos® residue) being found on wires upon receipt. Seriously, would you like some Cheetos® with that guide wire? Now granted, wire grinding can result in extreme challenges for facility managers in the pursuit of maintaining a clean facility. However, I am sure the look of surprise on Dr. D’s face, actually the look of shock on Dr. D’s face was priceless, when the plant manager handed the good doctor a pair of guilloches, upon entering the building. Are you kidding me? What part of suitable environment was not understood by this supplier? The entire facility was covered in machine oil. Needless to say, Dr. D’s visit was brief.
Can you say IQ, OQ, and PQ? If you cannot, you had better learn the meaning of installation qualification (IQ), output qualification (OQ), and process qualification (PQ). The regulation states; “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.” What the agency is requiring from device manufacturers is documented in the following bullet points.
- Ensure equipment and tooling, to be employed in the manufacture of medical device, is adequately documented. For example, if a piece of equipment is procured from an approved supplier, there should be a procurement specification. If equipment or tooling is manufactured internally, e.g., the model shop; the expectation is that a specification or drawing be created and given to the model shop for the project.
- After it has been determined that equipment meets specification, the design of the equipment is robust, and the equipment has been installed, including the IQ, the real fun begins. The piece of equipment must be maintained and cleaned, adjustments and settings locked in, and the operators and maintenance technicians trained.
- Additionally, operator and technician training, equipment operating instructions, maintenance, calibration, etc. shall be documented. Broken record time – DG Rule # 6 – All procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled within a defined document control system.
- Furthermore, please do not forget the IQ, OQ, and PQ. The FDA has become extremely process focused; and they will ask to review documentation associated with these activities.
There is a plethora of calibration and maintenance software, such as Blue Mountain, available for sale. Employment of software can really simplify the scheduling aspect of preventive and scheduled maintenance. All equipment will require some type of maintenance on a regular basis, daily, weekly, monthly, etc.; however, a subset of equipment will also require calibration and adjustments. Regardless, all activities associated with maintenance need to be documented. The documentation shall include a procedure defining the maintenance, cleaning, calibration, or adjustments being performed. Additionally, the records documenting the performance of these activities shall include the date, name, and signature of the person(s) performing the activities. Remember, DG Rule # 3 – Document the results of all events in writing, because if it is not documented in writing, the events did not occur.
The regulation requires periodic inspections to ensure equipment is being maintained in accordance with the published maintenance schedule. In short, verifying the effectiveness of the entire maintenance program needs to be incorporated into the internal audit program. Depending upon how the inspection activities are employed on the manufacturing floor, tollgate versus audit inspection, random audits of processes, and the equipment employed for the processes is strongly recommended. Once again, remember to document all of the audit and random inspection activities, including the date, name, signature, and the results of each inspection.
Frankly, Dr. D hates adjustable equipment on the manufacturing floor, especially if the equipment requires frequent adjustments. Regardless, if adjustments to equipment need to be made, I suggest that these adjustments, tolerances, limitations, etc. be placed into a released procedure or template. Ensure the procedure or template is located at each station and the operators are reading and utilizing this documentation. Additionally, operators making these adjustments shall be trained and the training documented – broken record, the Doctor knows.
The two primary takeaways, from this edition of DG, are (a) invest in and design a world-class manufacturing facility; and (b) invest in equipment capable of supporting device manufacturing. Remember, when the agency comes to visit your facility, and trust Dr. D when he states, “eventually an investigator will end up on your doorsteps,” the initial impressions made will be lasting impressions. Additionally, equipment maintenance, IQ, OQ, PQ, calibration, operator training, technician training, written procedures, records, etc. are basic requirements for compliance with section 820.70 of the QSR. Furthermore, written records of these activities are always your best defense, when sitting across form the FDA investigator, during one of their friendly visits. Finally, always remember FDA visits are formal investigations (collecting evidence) versus audits performed by notified bodies.
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 continue with the fourth and final part of evaluating of Subpart – G (820.70), focusing on (h) manufacturing material and (i) automated processes – 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 July 7, 2010, from http://www.fda.gov/ICECI/EnforcementActions/ WarningLetters/