As promised, in the week’s edition of Devine Guidance (DG) Dr. D will continue with analyzing the requirements associated with 21 CFR, Part 820 – Section 820.70; subsections (c) environmental control, (d) personnel, and (e) contamination control. As stated in the previous edition of DG, “production and process controls, are in the opinion of Dr. D, salient requirements that warrant significant attention by medical device manufacturers.” Remember pursuing the path of compliance, in regards to the Quality System Regulation (QSR) is the preferred route; versus exhibiting supercilious gasconade (look-it-up time) claiming compliance, while the agency rips apart your weakly compliant or non-compliant approach to production and process controls during one of their friendly visits.
Warning Letter Violation
Once again, identifying an offender of 820.70, from the FDA’s enforcement website, was child’s play. FDA noted violations of this requirement are frequent. Additionally, most violations are rooted in the lack of procedures or adequate procedures reflecting compliance to the requirements for production and process controls. Furthermore, compliance to my frequently quoted DG Rule # 6; “All procedures, work instructions, drawings, specifications, etc. must be written, well-documented, and controlled within a defined document control system,” would result in a significant reduction in Form 483 observations and subsequent warning letters issued by the agency. Moreover, responding correctly and fully to Form 483 observations can save an organization from the pain of receiving a warning letter, and the business interruptions that accompany these enforcement actions. Can you say interruption of new product approvals? Finally, if you really want to endear your organization to the FDA, feel free to partake in the practice of repeat observations, similar to this week’s offender.
Warning Letter (May 2010)
Observation One (1) 12 observations
8. Failure to establish and maintain adequate procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e). This is a repeat observation from the previous FDA 483 issued on 11/20/07. For example, your procedure for cleaning and maintenance of the manufacturing areas (Q53-P03, Revision 02) did not identify a schedule for routine cleaning of air vents in the dry room areas where product is assembled. During the inspection on 1/13/10 the vents were covered in dust and debris in Dry Room#(b)(4)
FDA’s Response to Observation One (1)
We have reviewed your response and concluded that it is not adequate because although you stated that a procedure was written to define and schedule air vent cleaning, you did not state if the air vents would be immediately cleaned or provided the written procedure for FDA’s review.
Observation Two (2)
11. Failure to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality, as required by CFR 21 820.70(c). This is a repeat observation from FDA 483 issued on 11/20/2007. For example, the firm does not have temperature and humidity controls in the VirTis Lyophilizer Room, Room &(b)(4) where mini-batch lots are stored and require controlled temperature and humidity conditions.
FDA’s Response to Observation Two (2)
Your response to this observation appears to be adequate.
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.
(c) Environmental Control
For starters, environmental control is much more than ensuring work surfaces are clean, the production floor swept, and the manufacturing area sustained at a comfortable 72-degrees Fahrenheit. Believe it or not, the FDA requires effective environmental controls that have been documented in a procedure. Surprised? Additionally, employees and contractors, including the janitorial staff need to be trained to the environmental control procedure(s). Surprised? Furthermore, the training shall be documented. Surprised? Finally, if your organization lacks procedures, training, and records of training in support of environmental control, or any QSR requirement, the FDA will issue a Form 483, which should not be a surprise. If compliance transgressions are deemed egregious, the look of surprise, on the faces of the management team, as they read the warning letter, will probably be priceless; and no – Dr. D does not like surprises.
Therefore, what does the FDA expect in regards to environmental control? In actuality, the agency would like to see a Class 1000 clean room in accordance with FED- STD-209 (just kidding). The regulation requires that the manufacturing environment be appropriate for the medical devices being manufactured. For example, manufacturing non-sterile devices or assembling pieces of capital equipment may warrant a reduced level of controlled environment, i.e., a clean work environment, manufacturing floor maintained at room temperature, with operators wearing lab coats. Manufacturing sterile devices such as catheters will probably require a controlled environment equal to or potentially better than a Class 10,000 environment, along with all of the trimming. If your organization is manufacturing implantable devices, the Class 1000 crack made in the previous paragraph may not be too far from the truth. The decision as to the required level of environment control is up to the device manufacturer; however, be prepared to defend your rationale.
For medical device manufacturers, a controlled environment is required for assembling medical devices. Wow – real rocket science right Dr. D. Some of the requirements that should be considered when writing the procedure and establishing the controlled environment are:
- No food or drink consumption (pizza & beer is ok – just kidding);
- No smoking or chewing of tobacco, gum, etc.;
- A well-maintained HVAC system (including calibration), with High Efficiency Particulate Air (HEPA) Filtration capable of maintaining positive pressure, reduced particulate (<10,000 parts-per-million), while sustaining stable temperature and humidity;
- A gowning procedure for all personnel entering the controlled environment;
- Gowns, hair nets, beard and moustache covers, booties;
- Detailed work instructions for cleaning all work areas;
- The 24/7 monitoring of temperature and humidity, employing calibrated chart recorders;
- Controlled pass-through areas for moving material into and out of the controlled environment;
- The infamous sticky mats at the entrance of the controlled environment;
- Hot water and soap capable of removing layers of skin (just kidding);
- Laminar flow hoods, when warranted for specific work areas;
- Non-particulate generating wipes, finger cots, gloves, etc.; and finally,
- Broken record time – all activities documented and reviewed. 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.
Remember, you will need to validate the controlled environment prior to its use. You will also have to sustain the environment 24/7; and have records available to prove compliance to the agency.
Dr. D. categorizes the personnel requirement under the “No Brainer Category.” Unfortunately, I see way too many violations of the QSR, by device manufacturers, for failing to establish requirements, including training of personnel working in controlled environments. For starters, having personnel entering the controlled environment with varying degrees of “toe jam” will quickly draw the attention of an FDA investigator during one of their friendly visits. Now granted, no one appreciates wearing flip-flops and cargo shorts more than Dr. D (except maybe Jimmy Buffett); however, this California business casual look is not appropriate for controlled environments.
Additionally, some level of personal hygiene is expected. Furthermore, make- up can be problematic, so if eyeliner and eyebrow liner are not permanently tattooed to the face of the person entering the controlled environment (Michael Jackson style), or somehow capable of flaking off onto the work surfaces, it should not be worn. Moreover, open sores, cuts, etc. must be covered. In fact, employees that are in ill health should not be permitted to enter the controlled environment. Besides, why risk getting fellow employees sick. Finally, clothing that generates particulate, jewelry, and the wearing of hats, ball caps (especially LA Dodger caps – as Dr. D. is a Giants fan) needs to be included into the procedure for proper controlled environment etiquette. Remember, the regulation is very specific; “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.”
(e) Contamination Control
Dr. D would like to tell you a brief story. Once upon a time, at a medical device manufacturer, in a faraway land known as California, the weekly surface contamination reports were placed upon the good doctor’s desk. Typically, the weekly sampling of work surfaces with contact plates would yield 25-colony forming units (CFU) or less. In this particular report, the number was greater than 1,000 CFUs for one specific microorganism, with the notation of to many to count. When I asked the laboratory to perform a detailed assessment and identify the species, the investigation determined the offender was fecal matter. Are you kidding me? That being said, the moral of this story is to ensure all personnel entering the controlled environment are adequately trained in the ancient art form of hand washing, and not just with water.
It is now time for another Dr. D and his broken record time, “as with all aspects of production and process controls and the QSR, as a whole, procedures are required.” In the case of contamination control, medical device manufacturer’s need to prevent the induction of contamination into the manufacturing area. Additionally, device manufacturers need to test and monitor work surfaces, the surrounding air, and water for monthly bioburden and pyrogen levels.
So what does Dr. D. recommend as a baseline program for contamination control? It really does commence with good hygiene, appropriate operator clothing, gowning, hair covers, facial hair covers, sanitizing soap and water, finger cots, gloves, non-particulate generating clean room supplies, the frequent cleaning of work stations, a first-class janitorial service, etc. Of course, the approach to contamination control needs to be placed into a well-written procedure, and all personnel entering the controlled environment must be trained to the procedure. Just on a side note; when the agency does visit, ensure the FDA investigator is properly trained on gowning procedures, prior to allowing the investigator admittance into the controlled environment. Also, remember to document the training of the investigator. Additionally, ensure material moving into the clean room is free of particulate and enters through a restricted pass-through (positive pressure portal).
In the previous three paragraphs, Dr. D. expanded on the prevention of contamination; however, monitoring for contamination is equally critical. Dr. D does not claim to be an expert on contamination other than to state; “germs are bad in the clean room.” That being said, I came across an outstanding Internet site, while researching this week’s edition of DG. The Microbiology Network contains multiple white papers pertaining to the topic of contamination control. It is a great site and well worth the visit. Dr. D also suggests becoming familiar with EN ISO 14644-1:1999, EN ISO 14644- 2:2000, EN ISO 14644-3:2005, EN ISO 14644-4:2001, EN ISO 14644-5:2004, EN ISO 14644-6:2007, EN ISO 14644-7:2004, and EN ISO 14644-8:2006. Collectively, these standards delineated the requirements for establishing, maintaining, and monitoring clean room environments. That being said, Dr. D. recommends the following monitoring steps be considered as part of sustaining effective contamination control.
- Pyrogen and bioburden testing of waste water;
- Pyrogen and bioburden testing on manufactured products (retains);
- Establishing acceptable levels, alert limits, and action limits for contamination testing( aerobic bacterial and fungal) and particulate counts;
- Monitoring particulate counts at randomly selected locations;
- Random surface monitoring employing specially designed contact plates, e.g., Trypticase Soy Agar (TSA) or Sabouraud Dextros Agar (SDA); and
- Random air sampling employing settling plates.
You will need to retain all of the records associated with environmental controls and contamination controls. Rest assured, the agency routinely reviews these records during their friendly visits, including the training records. Additionally, ensure all of the training records for personnel are current in regards to environmental controls and contamination controls. These records should include contractors entering the controlled environment. Finally, Dr. D. strongly recommends that environmental control and contamination control data be presented as part of management review.
In closing out this week’s edition of DG, three words come to mind, “compliance is mandatory.” Remember sustaining a controlled environment, providing appropriate training for employees and contractors entering the controlled environment, and keeping contamination from encroaching upon the controlled environment – specifically the medical devices being manufactured, is the proverbial low hanging fruit. Yes, it does take time and money to develop a fully functional and compliant controlled environment. However, in the medical device industry the cost of compliance is in reality the price of admission. 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), focusing on (f) buildings, and (g) equipment – 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 June 29, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/
Sutton, S. (2006, September). Counting Colonies. The Microbiology Network. Retrieved July 4, 2010, Fromhttp://www.microbiol.org/white.papers/WP.count.colony.htm
Sutton, S. (2009, August). Qualification of an environmental monitoring program – selection and justification of sampling sites. Pharmaceutical Microbiology Forum Newsletter, 14(8), Retrieved July 4, 2010, from http://www.microbiologyforum.Org/PMFNews/PMFNews.14.08.0808.pdf
Tierney, P., Burke, R., O’Donnell, B., & McAteer, J. (2010, May). Environmental monitoring – maintaining a clean room. Pharm Pro Magazine. Retrieved July 5, 2010, from http://www.pharmpro.com/articles/2010/06/clean-rooms-Environmental-Monitoring-Maintaining-a-Clean-Room/