Management Tool ISO 13485 / FDA cGMP QSR... CMDCAS, MDD, frequently asked question (regarding certification, work environment, measurement, control, monitoring, prevention, sanitation, and contamination)

The information herein relates to work / manufacturing environments, while CMDCAS (MDSAP) | ISO 13485, FDA cGMPs QSR or 21 CFR 820, MDD 93/42/EEC... provides explicit requirements for the operational environments, the information that follows provides implicit requirements converting and or evaluating against the nature of the products and service activities.

Further, PMA 510Ks submission may provide committing and agreements (and guidelines) needed to be followed. Reviewing the PMA 510Ks and relevant documents may provide insight to the environment controls for product realization.

Specifically note that 21 CFR 820.70 from concept to product realization provides guidelines such that possible problems within the validation process can and must be simulate. This information needs be included within the range of conditions in written operating procedures (instructions and records) and needs be replicated assuring that the results are meaningful and consistent - realize that conditions and requirements may vary from country to country. This may include process induced variables propitiated  by upper and lower limits of an echelon of effects including; temperature, humidity, variations in electrical supply, vibration, environmental contaminants (biological, chemical and physical), purity of  water, light, and employee training as deemed necessary to achieve conformance within the boundaries of safe product and effectiveness.

    Note: [Process and product data should be analyzed to determine what the normal range of variation responds to normalized process output. Knowing what is the normal variation of output is crucial in determining whether a process is operating in a state of control and thus capable of consistently producing the specified output.]

Appropriate measures should be taken to eliminate controllable causes of variation (and support quality objectives). For example, installing heating and air conditioning can eliminate extreme variations in temperature; otherwise, natural environmental condition may be proper in some regions without micro climate controlling (including "positive pressure" environments to maintain a lower level of particulate in the micro-atmosphere).

Employee training, often seen as a "cure all" for generating non conforming product may be improved and perhaps conducted more frequently, and employees can be (as we observed) monitored / supervised more closely to assure that they are properly performing to the requirements of the established processes.

    Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree assuring that the output will consistently meet specifications - like the old adagio… "100%, or even 200%, inspection does not assure 100% defectives and defect free product".


Certification to QMSMDD ISO 13485

ISO 13485 is a tool helping organizations and management to control compliance to regulatory requirements for medical devices. ISO 13485 is NOT for the purpose to replace or substitute legal or regulatory obligations and the laws of sovereign nations. For list of ISO 13485 certification bodies. Further, our team of CYBERSECURITY Specialist can test and harden your medical devices.


The Work Environments, specifics

Controlling the environment means defining specifications for (micro) environment parameters which includes; temperature, humidity, colony forming units (CFU's), and particulate per cubic foot, etc. should be established. The regional national regulatory requirements, in the USA the FDA, may not provide specific guidance for the aforementioned parameters of operations. Thus, no requirements may presently exist for micro-environmentally-controlled areas such as clean rooms. However, you may want to obtain a copy of "Federal Standard Airborne Particulate Cleanliness Classes In Clean room and Clean Zones" (FED-STD-209E or National equivalent) where in provides informative guidelines for developing clean room standards such as particle counts per cubic foot. This equivalent to US Federal Standard 209E defines various levels of environmental control such as Class 1000. Reiterating, a "Class 1000" room contains no more than 1000 particles 0.5 micron diameter size (or larger per cubic foot of air). As we discussed, and these may not be keen in the issue, information can be obtained from manufacturers of clean room equipment.

    E.g. Maintaining "Class 100" during routine operations in production activities. It is common that manufacturers use a "Class 10,000" (or even "100,000") for the assembly and packaging of devices that will be subsequently sterilized and wherein a low particulate count on the devices is desired (may not be required). The specifications for such a room could be:


Maximum of 10,000 of 0.5 micron diameter or larger per cubic foot


45 +/­ 5 percent


22 +/­ 2 degrees F (75 F +/­ 2.5)

Air Velocity:

19.5 meters/minute +/­ 2 percent (90 ft/min)

Air Pressure:

measured as 0.05 inches water between the clean room and other areas

For assembly of (convenience) kits and relating assemblies of medical devices that need to be free of "visible" particles, manufacturers use an "industrially clean area or controlled environment area." Characterization of these "rooms" are controlling temperature and humidity through air conditioning... filters and, in some cases if required or agreed pre-filters of much finer porosity than furnace filters are also used (see micron sizing previously indicated). The temperature is controlled by a standard room thermostat - BULLTEK strongly recommend that electronic/digital technology is used in lieu of analogue Hg instruments, for thermostats. Humidity variations can effectively be controlled through climatization controls.

Replace A/C filters as part of a routine schedule maintenance-program. Any practices or factors from the list that follows is deemed appropriate and may be elected to use and specified as routinely performed or followed. Some factors to consider when planning and using a controlled environment schemes need to address

    • Clothing and basic dress code anteroom;
    • Controlled entry into production areas;
    • Prohibiting eating, drinking, smoking, or gum chewing;
    • Preventing the use of lead pencils (or otherwise carbon particulate);
    • Regulating the storage of glassware and containers;
    • Preventing or controlling the cutting, tearing or storage of cardboard, debris;
    • Cleaning the room and production equipment per documented procedure/instructions/checklist;
    • Maintaining original design and ongoing cleaning of work areas;
    • Selecting of furniture and eliminating the nonessentials (think 5S's);
    • Controlling room air "quality" (amount of particulate, pressure, velocity, and exchange rate), as agreed;
    • Reducing or eliminating the possibility of electrostatic charges (by controlling work surface composition or grounding, as deemed necessary);
    • Assure the cleanliness of materials, components and tools;
    • Controlling the purity, sterility, and - nonpyrogenicity of process water; and
    • Maintaining pre-filters, HEPA filters, and electrostatic precipitators.


Measurements, Controls and Monitoring

A measurement, surveillance or monitoring protocol should be implemented, in tune with requirements set forth by:

    • Contractual agreement
    • Regulatory mandate, specifically (not interpretative)
    • Internal agreements

Once setting this protocol apply to maintain measurements, controls and/or monitoring for each of the factors necessary controlled for given operations. This will ensure that requirements are been met and that equipment is performing adequately to requirements of the micro environment within agreed parameters. Whenever and if particulate count "Class" is required (as specified) monitoring of airborne particles including performing air samples (see ASTM or national equivalent methodologies). If required, monitoring of working surfaces for biological activity [colony forming units of microbes] may be accomplished applying various techniques - (Note: the higher the humidity the higher of biological activity).

Documented procedures/instructions provide guidance to sampling methods and methodologies for testing, and the resultant data must be recorded. Otherwise optional, services can be contracted for which applying clauses 4.6 of ISO 13485 / FDA cGMP QSR is a must.

And let it be that the protection of the community of patient under care from CYBERSECURITY vulnerabilities.

Prevention and Control

National regulations, in the USA FDA cGMP QSR regulation requires in 820.70(e), that every manufacturer implement and maintain procedural documents to prevent contamination of product or processing equipment. These documented procedural processes (with or relevant to specifications) are to be established by the manufacturer ensuring that finished devices/product meets quality claims (e.g. environment particulate). Typical devices, examples given: in vitro devices that are not contaminated with microbes, detergents or rodenticides; circuits that are not contaminated with (resin) flux residues; implants that are not contaminated with body oils and certain implants that are not contaminated with pyrogenics.

    Explanatory Note: Pyrogens are substances that cause feverish symptoms in humans and other life forms, and arise primarily from cellular debris of adverse bacterial activity. Certain implants such as orthopedic implants are not required or expected to be pyrogen free. Other devices are required to be non-pyrogenic including: transfusion and infusion assemblies, devices that come in contact with circulating blood or cerebrospinal fluid, intraocular lenses and the surgical instruments used in their implantation, and any device labeled as "nonpyrogenic". Manufacturers should carefully control the environment in which such devices are manufactured and processed to minimize contamination with bacteria or establish a procedure for cleaning the devices.

    An organization may wish to consider applying ISO 14971 to manage risk - Application of Risk Management To Medical Devices.

If necessary for the device to meet company product specifications or labeling claims, cleaning / sterilization procedures and schedules to meet the requirements of section 820.70 or national equivalent and may need to be written (at instruction level, responding to "the how to..."). Each process activity / operation should be analyzed in order to unload into appropriate instruction or determine that is not needed. For example, written instructions are usually not required for cleaning floors and workbenches in areas where non­sterile and non­growth promoting components or devices are processed and packaged. Records/instructions related to facilities, the environment and personnel practices need to be kept simple/agile. The record of cleaning may be an instruction in the form of a checklist , initiated, or signed. Where a checklist is used for repetitive work, it is advisable (for the medical and aerospace, minimum) sector that the person's name be on the record (at least once). The schedule for cleaning may be posted or filed as long as it is in a convenient location.

Sanitation in the Work Environment

Bathroom, dressing, storage, and waste facilities should be provided such that is sanitized, to the appropriate extend  [reference 820.70(d) or national equivalent]. Such facilities should be maintained clean/sanitized based on a regular schedule. Where necessary, such as in a clean room environment, special clothing and an area to safeguard or store garments (e.g. head sanitized protection) should be provided. Clean room clothing is not to be worn into uncontrolled rooms otherwise outside the facility.

When and where eating, drinking, or smoking could have an adverse affect on the devices' performance and fitness for use, procedures linked to instructions on how to prevent adverse effects [national or see USA 21 CFR 820.70(d)]. E.g. these activities could be confined to specially designated areas such as a lunch room and alike. Directions and containers or equipment should be provided for timely and safe disposal of trash, byproducts, effluents and others.

Contamination by Hazardous Substances and Prevention

If pesticides, insecticides, or other hazardous substances are in use, written procedures to limit their use or for their removal from work surfaces and devices need be establish... to prevent any adverse affect on the manufacturing process or the device [820.70(e)]. If contracting, add the clauses of elements of ISO 13485 7.4 (820.50 FDA QSR).




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