The Quality System Regulation (QSR), for production and process controls, (21 CFR, Part 820 – Subpart G, Section 820.70) is in the opinion of Dr. D one of the more salient requirements of the regulation. In fact, the FDA has frequently focused their efforts on production and process controls during their friendly visits. If you have any reservations in regards to the agency’s resolve, I recommend a quick trip to the FDA’s website; specifically, enforcement actions and look at the number of warning letters issued for the lack of or ineffective production and process controls. Similar to design control, the requirements for production and process controls are substantial, so it is not possible, nor could Dr. D lend credence to the material by attempting to cover the requirements in just a single edition of Devine Guidance (DG). Having said that, I will spend the next few weeks breaking down production and process controls into smaller sound bytes that; hopefully, will make sense to the reader. Remember, if Dr. D. exhibits some level of asperity in his prose, it is because too many 483’s and warning letters, issued by the agency, could have been prevented. Remember, compliance is the key (broken record time), compliance is the key; (again) and compliance is the key to success in this industry, along designing and manufacturing a medical device that is safe and effective. In this week’s edition of DG, section (a) general, and section (b) production and process changes will be explored.

Warning Letter Violation
It took Dr. D all but a New York minute; or is it a New York second, to find an offending party for this edition of DG. This warning letter was the very first one depicted on the FDA’s website. It was at the very top of this week’s list, so how fortunate for Dr. D, appropriate for this week’s diatribe, and unfortunate for the warning letter recipient. As you will quickly be able to ascertain, after reading the excerpts from the warning letter, the FDA was thoroughly impressed with this organization’s approach to production and process control, or should I say lack of an approach. In fact, the FDA was equally impressed with the initial Form 483 responses put forth by this medical device manufacturer. Yes, I know – enough of the sarcasm Dr. D.

Warning Letter (May 2010)
Observation One (1)
3. Production processes were not adequately developed, conducted, controlled, and monitored to ensure that devices conform to their specifications. 21 CPR §820.70(a). Specifically, you have failed to adequately develop, monitor, and control production processes in order to ensure reliability and repeatability of the manufacturing process.
For example:
A) Your firm’s procedure for testing the quality of your water (SOP 036, Revision F)which is used to process products requires root cause investigations and re-testing to be performed immediately for water samples that fail action limits. On December 24, 2009, your contract laboratory reported to you that the conductivity test result (198 uS at 25 degrees Celsius) for port 10 did not conform to specifications. Your firm failed to perform a retest or investigate the OOS result as per your written procedure.
B) Your firm’s Routine Product Bioburden Testing SOP 046, Revision B. describes random sampling (b)(4). However, your firm has no documentation to show that (b)(4) final samples were taken from a (b)(4) manufacturing technician during the January 11, 2008, July 15, 2008, and July 31, 2009 bioburden testing as required by your written procedure.
C) Your Routine Product Bioburden Testing SOP 046, Revision B, specifies jncreased limits when compared to your 2008 and 2009 quarterly Artegraft product bioburden test results. There was no scientific data provided during the inspection to demonstrate the appropriateness for the limits set in your written procedure

FDA Response to Observation One (1).
We have reviewed your response pertaining to FDA-483 observation 5 (A2, B, C) and have concluded that your response was not adequate because of the following:
a) Your response does not provide any evidence that the failing water results for port 10 were erroneous. Your firm has failed to follow your own written procedure which requires root cause investigations and re-testing to be performed immediately for water samples that fail action limits. It is your responsibility to ensure that manufacturing processes remain in a state of control in order to produce devices that conform to their specifications.
b) No evidence of training was provided to show implementation of routine sampling which would include quarterly bioburden samples to be submitted per operator.
c) No evidence was provided in your response to support your new alert and action limits for bioburden.

Observation Two (2)
4. Failure to establish and maintain adequate procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality and failure to periodically inspect environmental control systems to verify that the system is adequate and functioning properly. 21 CFR§ 820.70(c). For example:
A) Your firm’s “Environmental Monitoring, Sampling and Corrective Action for the manufacturing Facility and Personnel”, Revision H, does not require your firm to monitor the positive pressure even though your validation report for Artegraft’s manufacturing facility, dated May 3, 1999, requires positive pressurization in (b)(4) from the (b)(4) and to (b)(4).
B) Your firm’s “Environmental Monitoring, Sampling and Corrective Action for the manufacturing Facility and Personnel”, Revision, H, requires swab sampling of the Artegraft and D-Clot manufacturing rooms and personnel sampling to determine the microbial burden within the manufacturing , environment and on the operator’s gloves. However, at the time of this inspection no alert and action limits had been established by your firm for swab sampling and personnel sampling.
C) Your firm’s “Environmental Monitoring, Sampling and Corrective Action for the Manufacturing Facility and Personnel”, Revision H, requires trend analysis to be performed on all resultant data in order to determine increases in all areas for microbial and non-viable particulate activity. However, at the time of this inspection no trend analysis was performed by your firm.

FDA Response to Observation Two (2)
We have reviewed your response pertaining to FDA-483 observation 5 (A2, B, C) and have concluded that your response was not adequate because of the following:
a) No evidence was provided to support that you will be able to adequately monitor continuous positive pressure in your Artegraft manufacturing facility (Requirement per your Artegraft’s manufacturing validation report). Manufacturers are required to establish and maintain adequate procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality. As a part of the requirement, manufacturers are required to periodically inspect environmental control systems to verify that the system, including necessary equipment, is adequate and functioning properly and these activities are documented and reviewed.
b) No evidence was provided in your response to support your alert and action limits for swab sampling and personnel sampling.
c) No evidence of training was provided in your response to support implementation of your QA Data Trending and Analysis (SOP 51) procedure.

Observation Three (3)

5. Failure to 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. 21 CFR § 820.70(g). Specifically, your firm failed to provide the FDA investigator with procedures for inspecting, monitoring, and maintaining a (b)(4) Refrigerator, ID # 00059, that is used for the temporary storage of raw materials and in-process vascular graft materials used for manufacturing.

FDA Response to Observation Three (3)
We have reviewed your response pertaining to FDA-483 observation 7 and have concluded that your response was not adequate because of the following:
a) Your proposed written procedure for transporting grafts in and out of the (b) (4) refrigerator, WI-MFG-011, Revision A, is not adequate since this procedure does not require maintenance schedules for the adjustment, cleaning, and other maintenance of your refrigerator in order to ensure that manufacturing specifications are met. Manufacturers must also conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. When maintenance activity is required, the manufacturer must document and follow procedures for inspection of maintenance activities to ensure that such activity is conducted according to schedule, that all activities have been completed, and that equipment specification requirements continue to be met.
b) Your firm must ensure that all equipment that is used in manufacturing meets specified requirements and it must be appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use. Your response does not provide us with any evidence that the (b)(4) refrigerator is suitable for the temporary storage of raw materials and in-process vascular graft materials which are used for manufacturing products. By not adequately maintaining and inspecting the refrigerator, products that do not meet specifications may be used in the manufacture of the devices, which could ultimately lead to the finished devices not meeting specifications.

Quality System Regulation – 21 CFR, Part 820
QSR – Subpart G – Production and Process Controls

Section 820.70

(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.

Production and Process Controls
Production and process controls, in the opinion of Dr. D., is where the proverbial “rubber meets the road,” in support of medical device manufacturing. All aspects of the manufacturing process, for medical device manufacturers, should be detailed in the processes and procedures employed. Additionally, conformance to defined specifications is an important takeaway. Furthermore, the QSR is very specific and states; “Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications.” Finally, remember there are serious ramifications for the failure of manufactured medical devices to meet their specifications or function in their intended use. Can you say RECALL?

(a) General
Broken record time – adherence to Dr. D’s Rule # 6 – All procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled within a defined document control system, is required.

(1) The path towards compliance begins with well-written procedures, manufacturing work instructions and quality inspection instructions in support of production. Remember, no matter how benign a manufacturing step, inspection step, or process, might appear to be, ensuring work or inspection instructions clearly spell out the steps and expected outcomes is mission critical. The word that comes to mind should be “precise.”

(2) Process and device performance characteristics need to be continuously monitored throughout the entire manufacturing process. Additionally, test results and inspection results should be documented and the results retained in the Device History Record (DHR). Furthermore, if warranted, special processes or critical processes that require special set-ups may require ongoing monitoring as part of the production environment. For example, tensile testing, ultrasonic welding, or similar processes may require special or precise setups and a set-up sheet or log book, for tracking process performance, while ensuring such critical processes remain in control. As depicted in this week’s warning letter extraction, bioburden just might be a good process to focus on, as the agency sure did. Do not forget about monitoring external processes as well, e.g., sterilization or even critical processes being executed by suppliers. All processes, regardless of the controls being internal or external, need to be evaluated and monitored. Finally, Dr. D recommends the employment of Statistical Process Control (SPC) wherever possible. The assignment of some level of process capability, a.k.a., Ppk, is always a valuable production tool employed for gauging process effectiveness. Can you say Six Sigma?

One important, no very important, no extremely important takeaway for production and process controls is the verification and validation of all manufacturing processes, including test methods. Dr. D. will cover Section 820.75, process validation later this summer.

(3) Compliance with specified reference standards or codes means compliance to FDA mandated standards or internally developed and validated standards may not be sufficient. The selection and application of appropriate standards must be all- encompassing. What in the heck does that mean Dr. D? For example, ISTA-2A may be a necessary standard to ensure product is packaged and protected while ensuring the manufactured medical device is delivered to the healthcare provider, through normal distribution stressors, undamaged. ISTA is the acronym for the International Safe Transit Association; and their standards are recognized as supporting compliance with EN ISO 11607-1 & -2. Other external standards such as those created by the Association for the Advancement of Medical Instrumentation (AAMI) may be required, depending upon the products being manufactured. Compliance to external codes is also a mandated requirement. For example, Proposition 65 (California) requires companies operating within the state or introducing products for commerce into the state to comply with requirements of the statute. Proposition 65 delineates specific requirements for the handling and disposal of toxic chemicals, the posting of warning – e.g., “carcinogen – may cause cancer in quality professionals and FDA investigators” (just kidding about the quality professionals), or the requirement for specific labeling requirements when chemicals, and materials – e.g., DEHP, are employed as part of the manufacturing process or inherent in the finished medical device.

(4) Employing approved processes and equipment (do not forget about software) for the manufacture of medical devices, are fundamental requirements for medical device manufacturers. As I stated earlier, process validation will be covered in a future edition of DG. That being said, ALL PROCESSES employed in the manufacture of medical devices require validation. Additionally, the expectation is that all equipment employed in the manufacture of medical devices be submitted to Installation Qualification (IQ), Output Qualification (OQ), and Process Qualification (PQ). Furthermore, all equipment employed as part of the manufacturing process should be calibrated, if warranted , and placed into a preventive maintenance program, as necessary. Just a friendly reminder from Dr. D, please ensure all manufacturing personnel are trained to approved and released processes and the operators are trained to verify the operational status of manufacturing equipment, including the calibration status. Finally, broken record time again – All training shall be documented!

(5) If your organization employs workmanship standards, ensure the standards are documented and released within your document control system. Manufacturing and quality personnel should be trained to the workmanship standards and just like the previous section, training must be documented. Additionally, your organization may select the use of samples to be employed as part of the workmanship standard. In fact, Dr. D loves the use of samples for inspection applications, providing the samples are controlled, and the samples are themselves evaluated and maintained as part of the equipment preventive maintenance and calibration system. In short, you do not want to employ samples that have the potential for significant degradation, over time.

(b) Production and Process Changes
Feel free to make all of the production and process changes that you want. The agency no longer cares about medical device manufacturers making changes. WHAT? Just kidding, Dr. D just wants to ensure I still have the attention of the readers. Changes to production or processes, regardless of how benign such changes appear, need to be assessed. For Class 1 and Class 2 products, e.g., 510(k), in the United States, the proverbial letter-to-file, should suffice. However, for Class 3 devices (PMA), a 30-day PMA Supplement may be in order, depending upon the changes. If the change to production or process is significant such as moving a product line, a 180-day review by the agency may be required. When in doubt, contact the FDA and ask. Regardless of the changes, verification and validation activities need to be pursued; and remember all changes need to be documented, reviewed, and approved, by the appropriate levels of oversight and authority (remember Section 820.40). Finally, if production and process changes are not managed in accordance with the regulation, let Dr. D refresh your memory with the extremely scary 6-letter word – RECALL! Rest assured, the agency can and will quickly ascertain if serious compliance issues exist; and begin issuing the famous Form 483, documenting observations of non-compliance, as a reward. Depending on the egregiousness of the violation or the quantity of violations noted, organizations may receive additional recognition, a warning letter! Conclusion

The primary takeaway from this week’s guidance is for the most part elementary. The FDA demands that medical device manufacturers exhibit complete control over production and process controls. Similar to the previous 21-editions of DG, procedures, documentation, execution, etc. are all salient requirements. Additionally, the expectation is that verification/validation activities support all released product and processes (internal and external); and subsequent changes to product and processes. Furthermore, external standards, applicable codes, workmanship standards, the employment of samples, etc., must also be considered, and their use validated; including manufacturing equipment (IQ, OQ, and PQ). Finally, written procedures and documented training are not only mandatory, but provide for your best defense when the agency decides to bless your organization with one of their friendly visits.

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 the evaluation of Subpart – G (820.70), specifically (c) environmental control, (d) personnel, and (e) contamination control, – cheers from Dr. D. and best wishes for continued professional success.

References

• AAMI – Association for the Advancement of Medical Instrumentation Website. (2010, June). AAMI homepage. Retrieved June 24, 2010, from http://www.aami.org/ about/index.html
• 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 June 22, 2010, from http://www.fda.gov/ICECI/EnforcementActions/ WarningLetters/
• ISTA – International Safe Transit Association Website. (2010, June). ISTA-2A Overview. Retrieved June 24, 2010, from http://www.ista-1a-2a-3a.com/index.html
• Prop 65 News. (2010, June). Your online guide to California’s unique environmental statute, proposition 65. Retrieved June 21, 2010, from http:// www.prop65news.com/pubs/brochure/madesimple.html