Dr. D promises this will be the last article on the debacle that occurred at a sterilization facility in Illinois. The third significant piece associated with this supplier, as premised on the FDA Form 483 observations were concerns raised over effective production controls or lack of. However, the doctor is quick to point out that if data was being intentionally altered, was the data alteration a controlled process documented by procedure? Just kidding folks. No amount of production and process controls can be successfully employed if the output is intentionally being altered or as FDA stated in multiple observations; “falsified.” If management had been “diffident” (look-it-up), then just maybe the outcome for this facility would have been different (not to be confused with diffident). Enjoy!

FDA Warning Letter – 22 May 2014

Dr. D kind of chuckled when I read through observation number seven (7); “Failure to adequately establish process control procedures.” Seriously? There was documented evidence of record falsification. If the falsification of records process was not part of a procedure and the doctor seriously doubts that it was, then of course process control issues should be cited.

7. Failure to adequately establish process control procedures that describe any process controls necessary to ensure conformance to specifications, as required by 21 CFR 820.70(a). Specifically, your firm’s procedures for analyzing dosimeter and dosimetry data are deficient in that:

a. Your firm does not distinguish between dirty or damaged dosimeters when citing the reason for re-reading dosimeters.

b. Procedures do not specify to document imperfections in the (b)(4) piece ((b)(4) dosimeter) when imperfections or scratches are present after initial inspection.

c. Dosimeters are not routinely cleaned before analysis.

d. On November 5, 2013, an operator was observed performing readings on 16 dosimeters and was observed placing his un-gloved thumb on the face of the dosimeter to position it in the laser thickness gauge introducing a fingerprint on the dosimeter.

e. The (b)(4) Series laser micrometer thickness gauge is not checked for reproducibility and drift before, during, or after a set of dosimeters are read.

f. Laboratory records do not include documentation to show when the spectrophotometers are blanked/zeroed during or prior to analysis of dosimeters to calculate dose for an irradiation run. Since November 4, 2011, your firm has had approximately 2,328 re-reads where the reason for the re-read is listed as “instrument not zeroed”.

We have reviewed your responses for sub-points (a) through (f) and have determined that the adequacy of your responses cannot be determined at this time because although your responses indicate that PROC-00036, “Routine Use – (b)(4) Dosimetry System” was revised on February 28, 2014, the revised procedure was not included with the updated responses to allow for FDA review. We also acknowledge your firm’s decision to change to (b)(4) dosimeters as your new dose measuring technology as part of a continuous improvement initiative. A follow-up FDA inspection will evaluate the implementation of the (b)(4) dosimeters.

8. Failure to adequately validate software used as part of production and the quality system for its intended use according to an established protocol, as required by 21 CFR 820.70(i). Specifically, actions were not taken to ensure that computer errors would not result in the loss of dosimetry and run dose data from the Dosimetry Measurement Application (DMA) module of (b)(4). For example,

a. The inspection found that 2,900 records were missing from the main table of the DMA module of (b)(4) between the time that it was installed at the Libertyville North facility on November 4, 2011 and November 6, 2013. Each missing record represents an attempt at creating a dosimeter record.

b. Of the 2,900 missing records, 1,623 records/dosimeters (representing (b)(4) irradiation runs) contained dosimetry data and were intentionally deleted from the DMA module. These records contained a calculated dose when they were deleted, and 192 of the dosimeters (representing (b)(4) unique runs) were out-of-specification low (under-dosed).

c. The (b)(4) and DMA systems are set up to automatically discard any dosimeter absorbance readings outside the set operating range of (b)(4) to (b)(4) absorbance units.

We have reviewed your responses to sub-points (a) through (c) and have determined that the adequacy of the responses cannot be determined at this time because your firm’s corrective actions are either on-going or documentation was not provided to allow for FDA review. For example, your responses indicated that the (b)(4) software and system documentation will be remediated, and a full revalidation of the (b)(4) system will be performed; however, this is not complete. In addition, your responses indicated a number of corrective actions to address the specific issues listed above; however, no documentation was included with the responses to verify these actions.

21 CFR, Part 820 §820.70 – 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.

Compliance for Dummies

The good news is that production and process control is not a difficult section of the QSR to comply with, in Dr. D’s humble opinion. However, it does take some work scripting procedures that delineate the production process. For example, most device establishment employ:

(a) work instructions (WIs);

(b) manufacturing process instructions (MPI);

(c) test procedures (TP);

(d) inspection instructions (II);

(e) assembly instructions (AI); and

(f) travelers/job routers to support production activities.

Additionally, production equipment must been properly installed and validated, including the manufacturing environment if it is located in a cleanroom or similar controlled environment. Furthermore, the regulation requires that appropriate steps be taken to ensure contamination control, preventive maintenance for production equipment, control of manufacturing materials; and documented evidence of effective change control be maintained.

For example, if a finished medical device is going to come into contact with the patient’s blood path, then manufacturing the finished medical device or critical components in a garage located in San Jose, CA is probably not going to be an acceptable environment. Please don’t laugh, it can happen. The best advice Dr. D can offer on the manufacturing side is start with establishing an appropriate manufacturing environment suitable for the type of medical device your organization is going to manufacture. For example, if the device is a U.S. FDA Class 3 electrophysiological catheter, you better start building and scripting the validation protocol for the Controlled Environment Room (CER) now. If you are planning to manufacture electronic systems, better read-up on ESD protection. As you can see this is not rocket science.

Please do not forget about validation activities. Process validation commences with the installation of new equipment, e.g., installation qualification. Funny story, several years ago Dr. D was involved in the transfer of a manufacturing line from the United States to the EU. The receiving end of the equipment installed the equipment and immediately put it into use. When the doctor inquired about the IQ, I was informed they leveraged the previous one executed in the United States. Are you kidding me? Seriously folks, IQ, OQ, PQ, and PPQ should be considered salient elements associated with establishing effective production and process controls.

Takeaways

For this week’s guidance, the doctor will leave the readers with just one thought. Always do the right thing. Please remember that the devices that you manufacturer or provide a service for (e.g., sterilization) may be used on you or a loved one someday. You want the device to be safe and effective in its intended use, don’t you? For those of you out there that have a broken moral compass, beware. A pair of shiny stainless-steel bracelets and an orange jumpsuit may be in your future.

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 – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. FDA’s enforcement page. (2014, May). FDA.gov Website. Retrieved June 4, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm399011.htm.