Dr. Kevina O'Donoghue (Microbiologist with SSE) has written a Chapter Entitled "Validating and Monitoring Cleanrooms" for the "Handbook for Critical Cleaning" (Revised Edition)
These Articles have been co-authored by Dr. Kevina O'Donoghue
Contamination Control In and Out of
the Cleanroom: Contamination Control and CGMP
Barbara Kanegsberg
and Ed Kanegsberg
February 2008
Controlling the fabrication environment is not an end in itself.
Manufacturers who process and assemble their product in controlled
environments know that the clean-room or mini-environment must be
appropriately designed and must also be maintained clean and contamination
free. However, cleanliness of the product itself is the ultimate goal.
This goal applies whether the application is from aerospace, military,
medical device, pharmaceutical, or other disciplines.
Much can be modeled from those who process pharmaceuticals. High
standards, many with the force of law, govern pharmaceutical and medical
device production. The U.S. Food and Drug Administration (FDA) issues
ever-increasing regulations to control the processes by which
pharmaceuticals are manufactured and packaged. The regulations that appear
in Title 21 of the Code of Federal Regulations, Section 210 (21CFR210) and
in subsequent sections are referred to as Current Good Manufacturing
Processes (cGMP). The word “current” emphasizes that knowledge of
processes evolves and that a process that was “golden” 20 years ago may
not be acceptable today. Similar medical device regulations are defined in
other sections of 21CFR. Even those not governed by pharmaceutical or
medical device requirements would profit by becoming familiar with the
principles of cGMP practices.
CGMP HISTORY
The first GMP regulations from the FDA appeared
back in 1963. A major revision in 1978 produced most of the regulatory
language in use today. An axiom is that good manufacturing processes be
documented and validated. Validation is defined as:
“Establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality attributes.” 1
In 2002, the FDA announced an initiative, Pharmaceutical Current
Good Manufacturing Practices (CGMPs) for the 21st Century, to enhance
and modernize the regulations. A key aspect of this initiative is to adopt
risk management approaches in quality management systems. We have
previously discussed the risk management approach for validating
cleanliness of medical devices.2
Risk management inherently involves process understanding; so rather
than being an expense, risk management can enhance productivity and
profitability. In a report generated as a result of the initiative, the
FDA states:
“Quality and productivity improvement share a common element —
reduction in variability through process understanding (e.g.,
application of knowledge throughout the product lifecycle). Reducing
variability provides a win-win opportunity from both public health and
industry perspectives.” 3
CROSS CONTAMINATION
The recall of a pharmaceutical product
due to cross-contamination led to increased FDA awareness of the
importance of validation and control of cleaning procedures.4 Drums containing recycled solvent used for pharmaceutical production had
previously been used for solvent recycled from pesticide manufacturing. As
a result of inadequate cleaning procedures for the drums, pesticide
residues were inadvertently transferred to the pharmaceutical product. The
example also illustrates the need for well-documented acceptance and
monitoring programs for process chemicals and storage containers.
SUPPLY CHAIN INTEGRATION
The incident involving cross
contamination of drums brings to mind the need to control and monitor
activities of the entire production supply chain. Manufacturers must be
confident that raw materials, process chemicals, biologics, and components
provided by suppliers are appropriately processed, packaged, and stored.
Sub-vendor and supplier processes and certifications must be documented.
Requirements, acceptance criteria, and audit policies and findings must be
both available and supportable. As noted previously, if suppliers use
commercial cleaners, formulations may change without notice or
documentation. Such changes can compromise efficacy of cleaning 5 and adversely impact performance of the assembled product.
IQOQPQ
The concept of IQOQPQ (Installation Qualification,
Operation Qualification, Performance Qualification) is often part of cGMP.
IQOQPQ is employed to verify and validate process equipment. Installation
Qualification (IQ) involves verifying that equipment is installed
according to manufacturer specifications (i.e., the wiring is hooked up
correctly). Operation Qualification (OQ) verifies that the equipment
operates to manufacturer specifications (i.e., it does what the spec sheet
says it should do). Maintaining equipment calibration is an aspect of OQ.
However, correct installation and operation does not insure that the best
or even suitable equipment has been selected for the task. Performance
Qualification (PQ) verifies that not only is the equipment performing but
that the process is working. Analytical testing may be required to verify
that the product is sufficiently clean.
PROFITABLE CGMP
To achieve efficiency, quality, and
profitability, cGMP should not be tacked on as a list of rules for
assembler training; cGMP should not be implemented in a pro forma manner.
Profitable cGMP involves understanding the process. Achieving profitable
cGMP can require a paradigm shift. A developer of cGMP training programs
in Ireland says,
“It is difficult to make workers aware of contamination issues.
The hardest job is changing their attitudes and behaviors. A program
that just presents ‘how to’ will not be as effective as one that also
discusses ‘why.’ It is very important that all aspects of GMP are
supported from the top management through to the workforce on the
ground. It is a culture that should be planted and maintained throughout
the business. A high standard of GMP should be not be an ‘extra’ part of
the working day but should be part of the work ethic of all
personnel.” 6
Quality management is a crucial part of the manufacturing process. The
receiver of a manufactured item, your customer, performs their own version
of IQ and OQ. As a manufacturer, it is your responsibility to insure that
for your customer there will be no surprises either on incoming inspection
or in subsequent utilization. By incorporating cGMP as part of the work
ethic, you can minimize the occurrence of such surprises and quickly
resolve any that happen.
Acknowledgement: The authors thank Dr. Kevina O’Donoghue,
Specialised Sterile Environments, Galway, Ireland for helpful comments and
suggestions.
References
- “Guide on General Principles of Validation”, U.S Food and Drug
Administration, May 1987. Available at http://www.fda.gov/CDER/GUIDANCE/pv.htm.
- B. Kanegsberg, E. Kanegsberg, and D. Albert. “Toxicological Risk
Assessment For Medical Devices-What is it?” Controlled Environments,
October, 2005.
- “Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach —
Final Report”; Department of Health and Human Services, U.S Food and
Drug Administration, September 2004.
Available at http://www.fda.gov/cder/gmp/gmp2004/GMP_%20finalreport2004.htm.
- “Guide to Inspections of Cleaning Validation”, U.S Food and Drug
Administration, July 1993. Available at http://www.fda.gov/ora/inspect_ref/igs/valid.html.
- B. Kanegsberg, “The Joyful Dawn of a New Era”, Process Cleaning
Magazine, May 2007. Available at http://www.processcleaning.com/magazineArchive.cfm?article=060107.
- K. O’Donoghue, personal communication.
Barbara Kanegsberg and Ed Kanegsberg are independent consultants in
critical and precision cleaning, surface preparation, and contamination
control. They are the editors of The Handbook for Critical Cleaning, CRC
Press. Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; http://www.bfksolutions.com/.
Copyright © 2009 Vicon Publishing, Inc.
Contamination Control In and Out of the Cleanroom: Keeping Product Clean In and Out of the Cleanroom -- (Part 1) The Interface
Barbara Kanegsberg and Ed Kanegsberg with Kevina O’Donoghue
February 2009
Are you aware that incorrect materials transfer could pose one of the biggest potential sources of contamination within a cleanroom? How many of you can say that while performing the transfer of materials into the cleanroom environment you are fully aware of your actions, practices, and methods?
KEEP THE PRODUCT CLEAN
Paperwork, raw materials for manufacturing the product, tools, and equipment must be successfully transferred to the cleanroom. The goal of a materials transfer program is to keep contamination from the outside world from entering the cleanroom. Benefits of investing effort in a materials transfer program include higher quality product, lower costs, and an enhanced competitive position.
Some materials are double bagged, some single bagged, and may be stored for long periods of time in cardboard boxes in warehouse environments. Other materials such as tools may not be bagged at all and are likely to have come from an uncontrolled environment.
Contamination control protocols for material transfer are vital. Materials brought into the cleanroom that have not been cleaned effectively during the transfer process are an immense source of particulate and thin film contamination. Inadequately cleaned materials can be a huge source of spore forming bacteria, extremely resistant bugs that are very difficult to eradicate from a cleanroom environment. Manufacturers of all critical product should be concerned about the impact of biological contamination, not just those producing medical devices and pharmaceuticals. Many people are not aware that biological contamination will dramatically affect particulate counts which are required in every cleanroom industry. At the same time, sterility is not enough; “dead dirt” can wreck havoc with critical devices. Water soluble lubricants and near-neutral pH processes can provide water, warmth, and nutrients, a favourable environment for biological contamination.
ROOM DESIGN
Materials transfer may be through a hatch leading directly from an unmonitored manufacturing area to a cleanroom or a transfer hatch between two cleanrooms. Is this an optimal arrangement for your process? With a hatch, employees are tempted to stand on either side, engaging in lively conversation, even enjoying their morning coffee. Such behaviour increases the likelihood of contamination. For new construction, consider a material transfer room.
Material transfer rooms should function like gowning rooms with a ‘clean’ side and a ‘dirty’ side. Very often a line of tape separates these areas. In practice, a “line in the sand,” does not keep personnel from crossing over to the ‘clean’ side inadequately gowned or in street clothes. Too often we see issues with high levels of contamination on the ‘clean’ side of the material transfer room where the root cause is the ‘dirty’ side.
Rather than a strip of tape, consider an “étagère,” a physical barrier such as racking or cabinets that allows expedited transfer of materials while discouraging personnel movement to the clean side. If racking or cabinets are on wheels, it is simple to move them to allow access of large equipment or bulky materials. Of course, because such barriers are not physically distinct rooms, the dirty side of the transfer room should also be fairly clean.
CONVENIENCE
Cleaning materials within the transfer area must be convenient. A wipe down station should always be visible in the material transfer room with a low-residue cleaning agent such as isopropyl alcohol (IPA) and low-lint wipes readily accessible. If there is a hatch rather than a room, consider wipe down stations immediately before and immediately after transfer. If no wipe down station is present, there is the temptation for personnel to pass material in without cleaning it.
TRANSFER VERSUS GOWNING
The changing/gowning areas should not be used for wiping down and transferring materials to avoid potential contamination of personnel and cleanroom clothing. Good practice within a cleanroom should generally allow clean materials to come in one way and used materials to exit by another area.
STAY TUNED
In Part 2, we will discuss techniques for cleaning during transfer, managing bulky materials, and automation.
Dr. Kevina O’Donoghue, is a Microbiologist at Specialized Sterile Environments, Galway, Ireland. She can be reached at kevina@cleanrooms.ie.
Barbara Kanegsberg and Ed Kanegsberg, “the Cleaning Lady and the Rocket Scientist,” are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, CRC Press. Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; http://www.bfksolutions.com/.
Copyright © 2009 Vicon Publishing, Inc.
Contamination Control In and Out of the Cleanroom: Keep Product Clean In and Out of the Cleanroom, Part 2: The Program
Barbara Kanegsberg and Ed Kanegsberg With Kevina O’Donoghue
March 2009
The first step in developing an effective precision cleaning process for the product is to determine where cleaning can be avoided. Keeping the product clean, particularly during transfer and storage, is an important part of your contamination control program.
Much effort is expended in keeping the cleanroom clean, in monitoring the cleanroom. Much effort is expended in developing, validating, and monitoring cleaning processes for both so-called "high-end" products and for industrial applications. It is critical to manage three major sources of contamination for products fabricated within the cleanroom. These contamination sources are:
- People
- Equipment
- Transfer
EFFECTIVE TRANSFER
Many items such as raw materials for use in the manufacturing of the product are supplied double bagged or triple bagged depending on the manufacturing process. The outer packaging could potentially be highly contaminated so careful removal of this packaging is of utmost importance.
Sometimes pallet trucks of cardboard boxes are loaded into the transfer area. How do you remove contamination from those parts when going from the dirty side to the clean side? How do you avoid particle generation? In general, it is wise to remove all cardboard packaging outside of the controlled environment. As we explained in the previous column,1 the material transfer room is a controlled environment that includes a 'dirty' side and a 'clean side.' However, contamination must be minimized even in the 'dirty side.' Therefore, remove the cardboard in an area outside of but proximal to the transfer area; then immediately move materials to the transfer area.
CLEANING
Set a cleaning protocol for surfaces, packaging, and product during transfer. We have observed people spraying isopropyl alcohol (IPA) on a part, then transferring it into the cleanroom. Simply anointing the material with IPA may not be adequate. Remember that effective cleaning typically involves both physical and chemical action. A more effective, but still convenient cleaning protocol is to use an alcohol spray, such as IPA, in conjunction with non-linting wipes. The IPA must be of high quality and free of residue. Large storage containers and benchtop dispensers must be made of materials that do not leach residue. While there is no perfect cleanroom wipe, the selected wipe must be optimal for the application.2
In the transfer room or area, first clean the benchtop and racking. As soon as material is transferred to the dirty side of the transfer room,1 clean the outer bag. Very often this outer bag is removed and not cleaned down. The risk of this technique is that contamination from this outer bag can get onto the inside bag and onto the gloves of the material handler who wipes the inside bag.
STORAGE
Once cleaned, the outer bag can be removed. The inside bag should then be wiped down and left on the pre-cleaned benchtop or racking fixture for cleanroom personnel to collect. If the material is left on this racking for a long period of time, then cleanroom personnel should wipe it again as a precautionary measure, before bringing it into the cleanroom environment. The definition of "a long time," analogous to a Clean Hold Time in pharmaceutical validation, is specific to the fabrication process and facility; you should determine and document a reasonable policy.
Sometimes material is stored within the material transfer area or cleanroom environment itself until ready for use. In this case, the benchtop/racking surface and outer bag is wiped down thoroughly as described above and left on the surface for entry into the storage area. All materials stored for long periods of time within the material transfer or cleanroom should be left double bagged. It should be noted that if materials are stored within a cleanroom in totes or on racking, then these should be cleaned on a regular basis as part of the cleanroom cleaning schedule. When the material is required for use, then the outer bag should be cleaned again and removed and the inner bag cleaned before opening. Final packaging should be removed only just prior to use of the material.
CONTAMINANTS DEAD AND ALIVE
It is important to understand the source of particulate contamination, both viable and non-viable. If sterility is the only concern, then sterile materials, double or triple bagged, may not need to go through such rigorous cleaning of the packaging as each layer of packaging is sterile. However, care should be taken when removing the outer packaging to ensure it does not pose a threat to the inner packaging. Be aware that particle counts include both viable and non-viable particles.
LARGE ITEMS
Transferring bulky materials is particularly difficult. Sometimes, only parts of the assembly can be cleaned prior to transfer. In medical and pharmaceutical applications, cleanliness of large, bulky objects is typically determined by swabbing and testing for microbial contamination. Aside from the time factor in microbial analysis (perhaps three to five days), the absence of significant microbial contamination does not necessarily rule out non-viable contamination, particulate, and thin film. Sampling followed by particulate counting and/or non-volatile residue testing may be required.
Some items may have to be wheeled into the cleanroom on trolleys due to the weight or size of the material. These trolleys should be thoroughly cleaned before entering the cleanroom, in particular the wheels. Sticky mats may help to remove excess contamination from the floor area but this alone is not a good enough clean for entry into the cleanroom; the hubs and axles can also be contaminated. To minimize entry of contamination to the cleanroom, one trolley can be used to transfer the material from the warehouse to the ‘dirty' side of the material transfer room and another trolley that is dedicated for cleanroom use can be used to transfer the material into cleanroom from the ‘clean' side. This method however does involve an extra handling step. Unfortunately, more often than not, this extra desirable transfer step is judged to be consumption of valuable time. Setting up written justified policies for such activities may be helpful.
ACCOUNTABILITY
With larger assemblies there is also the issue of responsibility and accountability. The people in the warehouse may move materials into the transfer area without cleaning them, on the assumption that cleanroom technicians will take care of cleaning issues. Those in the cleanroom may assume that the parts have been pre-cleaned. Even worse, in the interest of supposed efficiency, management may tacitly support or even mandate an unwise policy of bringing materials into the cleanroom without cleaning them. If you are faced with such fallacious cost-cutting measures, and if logic does not prevail, tracking the failure rate may be the most compelling approach.
IS AUTOMATION THE ANSWER?
Not always. The assumption is made that people are the problem and that if you remove the people, there will be no contamination problems associated with materials transfer. Automation simply does things the same way each time; you may be automating a process that inherently generates particles.
The equipment itself can generate particles. We have observed transfer equipment, moving materials into a cleanroom, that had both particulate and nonparticulate contamination on the "tracks." The design and maintenance of transfer and process equipment must be considered, because equipment and fixturing can degrade. Sometimes, the same racks or trays are used in both early stages of production and in the cleanroom. It is important to separate and segregate the processes (Figure 1). People need to be involved in design, oversight, and monitoring of transfer processes.
KEY PROGRAM
The material transfer process should be a key element in the cleanroom contamination control program. Too often, the process of materials transfer is not given a huge amount of time, if any, in employees training programs. It is vital that personnel performing the material transfer process understand the responsibility and importance of their role and are fully aware of the impacts of their methods and practices. They must also understand the impact of their behaviors, particularly the negative impact of incorrect behaviours. Personnel awareness and understanding is crucial for this process to be performed effectively; for this to happen, there must be management support and understanding.
References:
- B. Kanegsberg, E. Kanegsberg, and K. O'Donoghue, "Keeping Product Clean In and Out of the Cleanroom, Part 1: The Interface," Controlled Environments Magazine, Feb. 2009.
- Siegerman, H., "Wiping Surfaces Clean," Vicon Publishing, 2004.
Our colleague, Dr. Kevina O'Donoghue, is a Microbiologist at Specialized Sterile Environments, Galway, Ireland. She can be reached at kevina@cleanrooms.ie
Barbara Kanegsberg and Ed Kanegsberg, "the Cleaning Lady and the Rocket Scientist," are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, CRC Press. Contact them at BFK Solutions LLC., 310-459-3614; info@bfksolutions.com; http://www.bfksolutions.com/.
Copyright © 2009 Vicon Publishing, Inc.
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