What are the major challenges that pharmaceutical end users experience with their packaging systems?

There are a couple of significant challenges that pharmaceutical manufacturers may experience in selecting and implementing packaging systems. One of these challenges is posed by the growing trend toward prefilled syringes for liquid injectables. Prefilled syringes offer a much higher degree of performance than traditional vials by eliminating the dosage preparation necessary at the hospital. However, the implementation of prefilled syringes expands the validation process for the drug manufacturer.

Jerry Martin, pharmaceutical and life sciences consultant to PMMI, The Association of Packaging and Processing Technologies

Another challenge stems from the new standard on the qualification of materials for packaging systems with regard to extractables and leachables. Chemicals that can migrate out of the packaging materials and into the dosage form are a concern. With advancing analytics technology, there is a push from the FDA to understand what risks are posed by packaging ingredient migration. U.S. Pharmaceutical Convention (USP) is actively working on revising its standards for qualifying plastic packaging materials from the raw material to the final format. It's in the process of being finalized and it will be helpful for the industry to follow those standards. The goal is to establish standard evaluation methods and eventually, threshold limits, out of a consensus of experts.

Can you elaborate more on the revision of standards by the USP?

USP has formed an expert committee of volunteers from different reaches of the pharmaceutical and biotech sectors — including testing laboratories, drug manufacturers and component or equipment suppliers — to assess the risks and establish an updated, standardized approach to qualifying materials and packaging systems. The first two new standards published late last year addressed the qualification of component materials and final containers made from those materials. The next standards will address the process equipment side — upstream of filling the final packaging. These are currently in draft form and will be finalized by the end of this year. The next step, slated for 2017, is to generate standards for the suitability of packaging in the final dosage form.

When will drug manufacturers be expected to comply with these new standards?

No deadlines are set for compliance. These standards are voluntary. The USP sets the reference standards for the U.S. Food and Drug Administration (FDA). Therefore, pharmaceutical manufacturers that follow the USP standards will not have to go through any extra steps to meet FDA approval. However, pharmaceutical manufacturers that opt not to abide by USP standards will be held accountable by the FDA to provide other proof that the methods of analysis utilized are at least as effective. The USP's guidelines are treated as expectations. If an FDA reviewer questions a practice that complies with USP standards, pharmaceutical manufacturers have a strong scientific basis to stand on.

At this particular juncture in time, what is driving the need for these new USP standards?

Packaging systems are becoming more and more complex. I recently read about a biological that is packaged in an automatically timed, self-injection device that patients can wear on their stomachs. When a packaging system was just a vial in a box, there were far fewer components to evaluate. We're moving into a domain where the drug and the device are a package deal, but assessed by different teams at the FDA. The trend toward more complex delivery systems just doesn't always fit into the organizational structure of that agency. The FDA addressed this through the Office of Combination Products and new guidance. Creating a standardized set of expectations will make oversight of these increasingly complex packaging systems easier for all parties.

How has this trend toward complex packaging systems affected the general supply chain?

Pharmaceutical manufacturers certainly want to ensure that drugs, especially biologicals, are kept at the right temperature through the course of the supply chain. While we haven't seen many instances where temperature control of the drug has compromised the delivery device, temperature control is becoming more sophisticated with tracers that monitor the temperature and maintaining it through electronic signal so that the operators detect any deviation before the product goes bad. The added complexity is bound to necessitate greater utilization of the Internet of Things (IoT) to provide a higher sense of security and environmental control. These methods are being investigated now. On the topic of track-and-trace, sophisticated monitoring devices can help serve to authenticate original products when the threat of counterfeits loom over a drug.

Establishing a Root Cause Failure Analysis Program at a Pharma Facility

By Anil Agrawalla, CMRP, Life Cycle Engineering

Your clean steam generator system stops and alarms. Production halts; operations quickly calls maintenance. Maintenance jumps into action and determines that the bearing seized in the feed water pump. A bearing order is expedited through procurement, maintenance efficiently makes the repair the next morning, and the production team runs tests before putting the system back into operation. Corrective actions are created to ensure that the bearing is stocked in the MRO storeroom, and to double frequency of the pump’s preventive maintenance. The senior leadership team is satisfied with the response and corrective actions, and praises the team for limiting the production delay to just 24 hours.

Does this scenario sound familiar? A critical piece of equipment fails and the facility scrambles to get the system back to operation. Corrective actions are implemented to reduce future failures, but are done without asking why the equipment failure occurred. Resources aren’t allocated to identify the root cause on a significant failure like this, yet resources are dedicated to other issues that don’t seem as important to the business. This gap creates the opportunity to implement a Root Cause Failure Analysis (RCFA) program.

Implementing an RCFA program at a pharmaceutical manufacturing site can be a large undertaking, especially for failures that don’t affect product quality. Site resources and priority are given to investigations for quality-related issues due to the strict nature of FDA and regulatory requirements for issues that can impact a patient’s health. Non-quality-related investigations can significantly impact business but often don’t get the same scrutiny as quality investigations. 

Including non-quality-related failures in a well-planned RCFA program can bring substantial value to the company. Three factors are key to program success when implementing an RCFA program in a pharmaceutical environment:

• Having a well-defined process that provides a strong foundation / framework
• Aligning the RCFA program with the existing quality investigation process to help ease the introduction to the site and reduce the resources required for implementation
• Communicating the program value to senior leadership and the rest of the site to achieve site-wide adoption and ensure persistency.

A six-step RCFA process will provide the needed framework. Alignment with the existing quality investigations occur within each step. 

STEP ONE: NOTIFICATIONThe notification step is a pre-defined set of triggers that initiate an RCFA investigation whenever a failure event results in significant loss to the facility. As a general note, an RCFA program can investigate any type of significant event. For the scope of this program, events are intended for equipment-related failures. Although the initial failure symptoms experienced are equipment-related, these failures may end up having root causes that are not directly attributed to the equipment.

The triggers used to initiate an RCFA investigation should encompass all aspects of the business including major safety incidents, environmental violations, product quality issues, high maintenance costs, and production downtime events. The triggers should look for single, significant failure events as well as smaller, repetitive failures that occur frequently. Though a single, smaller failure would normally not be investigated, the chronic and repetitive nature can lead to a significant cumulative cost to the company. The type of trigger and its trigger level need to be customized for each company. The triggers should be set so that the cost of the root cause investigation is less than the business cost experienced by the company.

The Quality, Safety, and Environmental departments may already have their own investigation triggers for failure events that have a quality or safety effect. Since the process, tools used, and goals of those investigations are similar to ones used in an RCFA program, a separate analysis is generally not needed. A maintenance or reliability employee trained in the site’s RCFA program should join the existing investigation process to help with identifying and mitigating the root causes. High maintenance repair costs and production downtime can have a significant financial impact, so both of these can be triggers for an investigation. Triggers for chronic events can include repetitive causes that are trended in the CMMS’s failure coding, or excessive stoppages noticed on the production floor during production runs. 

A process map of the Notification step, shown in the figure below, displays an example set of triggers. As the figure shows, there is a clear definition and level for each trigger, which reduces the ambiguity of when an RCFA should be triggered. The success factor for this first step of the RCFA program is to ensure that the rest of the facility is aware of the RCFA program and its triggers. All employees, from operators to directors, are responsible for identifying equipment failures that trigger an RCFA investigation and notifying the RCFA process owner.

STEP 2: CLARIFICATIONClarification entails the gathering of information necessary to analyze the failure events. Once an RCFA is triggered, an RCFA facilitator should be quickly assigned to gather any evidence or data related to the triggered event before the evidence disappears. The evidence can range from physical parts, data logs, manufacturing batch records, or interviews from employees involved in the event. It is critical for the RCFA facilitator to be skilled in investigation techniques, particularly those involving interviewing personnel. The facilitator should be able to gather factual event information without alienating the interviewees. These techniques are often taught through the Quality department for quality investigations, and can be utilized to train the RCFA facilitator.

Three Laws of HVAC Optimization

HVAC systems hold the key to energy efficiency in pharma

By Alaina Bookstein, Optimum Energy

Oct 05, 2016

Pharmaceutical manufacturing facility executives increasingly face demands to cut operational costs and drive down energy and water use to meet corporate sustainability goals. Heating, ventilation and air conditioning (HVAC) systems are a natural place to look for such savings: these systems typically account for 65 percent of the energy used in pharmaceutical manufacturing facilities, according to research by Lawrence Berkeley National Laboratory, and chilled water plants consume large amounts of water every day. Optimizing HVAC systems to minimize energy and water use clearly has enormous financial and sustainability benefits.

HVAC efficiency projects, however, often fail to deliver on their promise. In environments where maintaining precise ambient conditions is essential to product quality, even new, state-of-the-art HVAC systems lose operational efficiency after installation. System operators, faced with pressing operational needs, understandably will take control, overriding set points and sacrificing efficiency.

The HVAC efficiency upgrades that succeed aim for system-level optimization (mechanical systems working at peak effectiveness, all the time) rather than simple individual component efficiency. The engineers at Optimum Energy have broken down this approach into three laws of optimization:

1. Measurement comes first. Without an accurate measure of energy use by each piece of equipment in the system, it is impossible to accurately predict and report the impact of varying conditions on the system. In other words, if you can’t measure it, you can’t optimize it.

2. Focus on the system. If an optimization plan focuses on installing the most efficient pieces of equipment without considering how to maximize performance of the whole system, it won’t capture the total available efficiency. Holistic, automatic optimization of HVAC systems typically increases energy efficiency by an additional 10 to 25 percent over just installing new equipment.

3. Optimization must be automatic, dynamic and continuous. To achieve maximum efficiency, optimization must be a real-time dynamic process, not a static set-and-forget process. Operational control of a pharmaceutical manufacturing plant or research laboratory must be based on real-time inputs and adjustments. Without that data and automation, you cannot fully optimize the HVAC system while maintaining strict environmental conditions.
Following these laws can lead to impressive results. For example, Amgen’s Thousand Oaks campus in southern California improved its average efficiency rating by 33 percent and saved $990,000 and 11 million kWh annually by optimizing three chiller plants and upgrading its building automation system (BAS).

The facility installed Optimum Energy’s OptimumLOOP technology, which works through the BAS to continuously and dynamically adapt the chilled water plant’s operations to conform with fluctuating loads, weather and occupancy conditions. A connection to the cloud-based OptiCx software platform increased visibility into plant operations, which revealed that a lead plant was operating extremely inefficiently.

Pharmaceutical facility directors can wring savings out of even the most demanding environments — with new or existing equipment — by following the laws of optimization.

cell and Gene Therapy Manufacturing 2016

Contributor: Miss Chanice Henry

Posted: 09/20/2016

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Earlier this month, Industry members gathered to tackle challenges and contribute to the discussion surrounding cell and gene therapies and their manufacture.

The dominant notion that emerged from the conference was the emphasis on the management of the product’s starting material in the manufacture of cell and gene therapies. The transit of these therapies should be perceived not as merely shipping but in fact mapping out a chain of identity and custody to ensure materials are fully preserved. Also, considering and planning for scaling-up early on in the process.

A range of topics were addressed on site including, scalability, gene modified t-cells, regulatory requirements, closed system processing and AAV based gene therapy vectors. The logistics of transporting a cell therapy to the patient with a reasonable cost of goods was examined. The reasonable cost of goods is understood as being the total price of all services and goods within the process of the therapy and its delivery. It was noted that logistics costs can extend up to 60% of the overall costs of the therapy.

Many experts at the event stressed that going commercial needs to be considered in the initial outset rather than just when the scaling up is needed.  System integration is vital to uplifting volumes.

Questions were asked on whether the patients should be brought to the therapy at the production site rather than vice versa due to the added controls needed. However, it was noted that this isn't always suitable in some cases as patients can be critically Ill, therefore international travel is not always an option.

Another key subject posed by speaker Dawn Hiles, Senior Biomedical Scientist, Production Manager for Cellular Therapies, Newcastle University was the focus on sterility assurance challenges in the manufacture of advanced therapeutic medicinal products. The entire whole production process needs to be designed to ensure that the product has the most minimal risk of contamination. Contamination can occur at any stage and the initial materials themselves need to be assessed.

Other experts onsite included the likes of, Sascha Sonnenberg, President of Global CTS Sales and Operations, Marken, Elena Meurer, Head of Pharmaceutical and Technical Development at Apceth, Miguel Forte of TXCell and Antoine Heron of Merck Life Sciences.

Companies present included Cell & Gene Therapy Catapult, Plasticell, World Courier and Cellular Therapeutics.

Crystal Clear Imaging for Nanoscale Molecular Arrangements

Fri, 10/14/2016 - 12:38pm

by Glenn Roberts Jr., Berkeley Lab

Infrared light (pink) produced by Berkeley Lab’s Advanced Light Source synchrotron (upper left) and a conventional laser (middle left) is combined and focused on the tip of an atomic force microscope (gray, lower right), where it is used to measure nanoscale details in a crystal sample (dark red). Image: Berkeley Lab, CU-Boulder

Detailing the molecular makeup of materials — from solar cells to organic light-emitting diodes (LEDs) and transistors, and medically important proteins — is not always a crystal-clear process.

To understand how materials work at these microscopic scales, and to better design materials to improve their function, it is necessary to not only know all about their composition but also their molecular arrangement and microscopic imperfections.

Now, a team of researchers working at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has demonstrated infrared imaging of an organic semiconductor known for its electronics capabilities, revealing key nanoscale details about the nature of its crystal shapes and orientations, and defects that also affect its performance.

To achieve this imaging breakthrough, researchers from Berkeley Lab’s Advanced Light Source (ALS) and the University of Colorado-Boulder (CU-Boulder) combined the power of infrared light from the ALS and infrared light from a laser with a tool known as an atomic force microscope. The ALS, a synchrotron, produces light in a range of wavelengths or “colors” — from infrared to X-rays — by accelerating electron beams near the speed of light around bends.

The researchers focused both sources of infrared light onto the tip of the atomic force microscope, which works a bit like a record-player needle — it moves across the surface of a material and measures the subtlest of surface features as it lifts and dips.

The technique, detailed in a recent edition of the journal Science Advances, allows researchers to tune the infrared light in on specific chemical bonds and their arrangement in a sample, show detailed crystal features, and explore the nanoscale chemical environment in samples.

“Our technique is broadly applicable,” says Hans Bechtel, an ALS scientist. “You could use this for many types of material — the only limitation is that it has to be relatively flat” so that the tip of the atomic force microscope can move across its peaks and valleys.

Markus Raschke, a CU-Boulder professor who developed the imaging technique with Eric Muller, a postdoctoral researcher in his group, says, “If you know the molecular composition and orientation in these organic materials then you can optimize their properties in a much more straightforward way.

“This work is informing materials design. The sensitivity of this technique is going from an average of millions of molecules to a few hundred, and the imaging resolution is going from the micron scale (millionths of an inch) to the nanoscale (billionths of an inch),” he says.

The infrared light of the synchrotron provided the essential wide band of the infrared spectrum, which makes it sensitive to many different chemicals’ bonds at the same time and also provides the sample’s molecular orientation. The conventional infrared laser, with its high power yet narrow range of infrared light, meanwhile, allowed researchers to zoom in on specific bonds to obtain very detailed imaging.

“Neither the ALS synchrotron nor the laser alone would have given us this level of microscopic insight,” Raschke says, while the combination of the two provided a powerful probe “greater than the sum of its parts.”

Raschke a decade ago first explored synchrotron-based infrared nano-spectroscopy using the BESSY synchrotron in Berlin. With his help and that of ALS scientists Michael Martin and Bechtel, the ALS in 2014 became the first synchrotron to offer nanoscale infrared imaging to visiting scientists.

The technique is particularly useful for the study and understanding of so-called “functional materials” that possess special photonic, electronic, or energy-conversion or energy-storage properties, he notes.

In principle, he adds, the new advance in determining molecular orientation could be adapted to biological studies of proteins. “Molecular orientation is critical in determining biological function,” Raschke said. The orientation of molecules determines how energy and charge flows across from cell membranes to molecular solar energy conversion materials.

Bechtel says the infrared technique permits imaging resolution down to about 10 to 20 nanometers, which can resolve features up to 50,000 times smaller than a grain of sand.

The imaging technique used in these experiments, known as “scattering-type scanning near-field optical microscopy,” or s-SNOM, essentially uses the atomic force microscope tip as an ultrasensitive antenna, which transmits and receives focused infrared light in the region of the tip. Scattered light, captured from the tip as it moves over the sample, is recorded by a detector to produce high-resolution images.

“It’s non-invasive, and it provides information about molecular vibrations,” as the microscope’s tip moves over the sample, Bechtel says. Researchers used the technique to study the crystalline features of an organic semiconductor material known as PTCDA (perylenetetracarboxylic dianhydride).

Researchers reported that they observed defects in the orientation of the material’s crystal structure that provide a new understanding of the crystals’ growth mechanism and could aid in the design molecular devices using this material.

The new imaging capability sets the stage for a new National Science Foundation Center, announced in late September, that links CU-Boulder with Berkeley Lab, UC Berkeley, Florida International University, UC Irvine, and Fort Lewis College in Durango, Colo. The center will combine a range of microscopic imaging methods, including those that use electrons, X-rays, and light, across a broad range of disciplines.

This center, dubbed STROBE for Science and Technology Center on Real-Time Functional Imaging, will be led by Margaret Murnane, a distinguished professor at CU-Boulder, with Raschke serving as a co-lead.

At Berkeley Lab, STROBE will be served by a range of ALS capabilities, including the infrared beamlines managed by Bechtel and Martin and a new beamline dubbed COSMIC (for “coherent scattering and microscopy”). It will also benefit from Berkeley Lab-developed data analysis tools.

Other contributors to the work include Benjamin Pollard and Peter van Blerkom, both members of Raschke’s group at CU-Boulder.

The work was supported by the National Science Foundation. The ALS is a DOE Office of Science User Facility.

Source: Berkeley Lab

A Basic Introduction to Clean Rooms

               A cleanroom is a controlled environment where products are manufactured. It is a room in which the concentration of airborne particles is controlled to specified limits. Eliminating sub-micron airborne contamination is really a process of control. These contaminants are generated by people, process, facilities and equipment. They must be continually removed from the air. The level to which these particles need to be removed depends upon the standards required. The most frequently used standard is the Federal Standard 209E. The 209E is a document that establishes standard classes of air cleanliness for airborne particulate levels in cleanrooms and clean zones. Strict rules and procedures are followed to prevent contamination of the product.

            The only way to control contamination is to control the total environment. Air flow rates and direction, pressurization, temperature, humidity and specialized filtration all need to be tightly controlled. And the sources of these particles need to controlled or eliminated whenever possible. There is more to a clean room than air filters. Cleanrooms are planned and manufactured using strict protocol and methods. They are frequently found in electronics, pharmaceutical, biopharmaceutical, medical device industries and other critical manufacturing environments.

            It only takes a quick monitor of the air in a cleanroom compared to a typical office building to see the difference. Typical office building air contains from 500,000 to 1,000,000 particles (0.5 microns or larger) per cubic foot of air. A Class 100 cleanroom is designed to never allow more than 100 particles (0.5 microns or larger) per cubic foot of air. Class 1000 and Class 10,000 cleanrooms are designed to limit particles to 1000 and 10,000 respectively. 

             A human hair is about 75-100 microns in diameter. A particle 200 times smaller (0.5 micron) than the human hair can cause major disaster in a cleanroom. Contamination can lead to expensive downtime and increased production costs. In fact, the billion dollar NASA Hubble Space Telescope was damaged and did not perform as designed because of a particle smaller than 0.5 microns.

            Once a cleanroom is built it must be maintained and cleaned to the same high standards. This handbook has been prepared to give professional cleaning staff  information about how to clean the cleanroom.

 What is Contamination?

            Contamination is a process or act that causes materials or surfaces to be soiled with contaminating substances. There are two broad categories of surface contaminants: film type and particulates. These contaminants can produce a “killer defect” in a miniature circuit.  Film contaminants of only 10 nm (nanometers) can drastically reduce coating adhesion on a wafer or chip. It is widely accepted that particles of 0.5 microns or larger are the target. However, some industries are now targeting smaller particles.

            A partial list of contaminants is found below. Any of these can be the source for killing a circuit. Preventing these contaminants from entering the cleanroom environment is the objective. It requires a commitment by everyone entering the cleanroom to make it happen. Professional cleaning personnel need to be aware of the importance of controlling contaminants. Strict procedures should be followed whenever entering or cleaning a cleanroom. Compromise is not acceptable when cleaning in a cleanroom.

Sources of Contamination

            This is a partial list of some of the commonly known contaminants that can cause problems in some cleanroom environments. It has been found that many of these contaminants are generated from five basic sources. The facilities, people, tools, fluids and the product being manufactured can all contribute to contamination. Review this list to gain a better understanding of where contamination originates.

1.     Facilities

Walls, floors and ceilings

Paint and coatings

Construction material (sheet rock, saw dust etc.)

Air conditioning debris

Room air and vapors

Spills and leaks

2.    People

Skin flakes and oil

Cosmetics and perfume

Spittle

Clothing debris (lint, fibers etc.)

Hair

 3.   Tool Generated

Friction and wear particles

Lubricants and emissions

Vibrations

Brooms, mops and dusters

4.    Fluids

Particulates floating in air

Bacteria, organics and moisture

Floor finishes or coatings

Cleaning chemicals

Plasticizers (outgasses)

Deionized water

5.    Product generated

Silicon chips

Quartz flakes

Cleanroom debris

Aluminum particles

Key Elements of Contamination Control

              We will look at several areas of concern to get a better idea of the overall picture of contamination control. These are the things that need to be considered when providing an effective contamination control program.

HEPA (High Efficiency Particulate Air Filter) - These filters are extremely important for maintaining contamination control. They filter particles as small as 0.3 microns with a 99.97% minimum particle-collective efficiency.  

CLEANROOM ARCHITECTURE - Cleanrooms are designed to achieve and maintain a airflow in which essentially the entire body of air within a confined area moves with uniform velocity along parellel flow lines. This air flow is called laminar flow. The more restriction of air flow the more turbulence. Turbulence can cause particle movement.

FILTRATION - In addition to the HEPA filters commonly used in cleanrooms, there are a number of other filtration mechanisms used to remove particles from gases and liquids. These filters are essential for providing effective contamination control.

CLEANING - Cleaning is an essential element of contamination control. Decisions need to made about the details of cleanroom maintenance and cleaning. Applications and procedures need to be written and agreed upon by cleanroom management and contractors (if used). There are many problems associated with cleaning. Managers need to answer the following questions before proceeding with any cleanroom cleaning program:

1.    What is clean?

2.    How is clean measured?

3.    What cleaning materials can be used in the cleanroom?

4.    When can the cleanroom be cleaned?

5.    How frequent does it need to be cleaned?

CLEANROOM GARMENTS - The requirements for cleanroom garments will vary from location to location. It is important to know the local garment requirements of the cleanroom management. Gloves, face masks and head covers are standard in nearly every cleanroom environment. Smocks are being used more and more. Jump suits are required in very clean environments.

HUMANS IN CLEANROOMS - There are both physical and psychological concerns when humans are present in cleanrooms. Physical behavior like fast motion and horseplay can increase contamination. Psychological concerns like room temperature, humidity, claustrophobia, odors and workplace attitude are important. Below are several ways people produce contamination:

1.    Body Regenerative Processes-- Skin flakes, oils, perspiration and hair.

2.    Behavior-- Rate of movement, sneezing and coughing.

3.    Attitude-- Work habits and communciation between workers.

              People are a major source of contamination in the cleanroom. Look at the people activies listed below. Notice the number of particles produced per minute during these activities.

PEOPLE ACTIVITY	PARTICLES/MINUTE (0.3 microns and larger)
Motionless (Standing or Seated)	100,000
Walking about 2 mph	5,000,000
Walking about 3.5 mph	7,000,000
Walking about 5 mph	10,000,000
Horseplay	100,000,000

                                                                    

COMMODITIES - Care is taken when selecting and using commodity items in cleanrooms. Wipers, cleanroom paper and pencils and other supplies that service the cleanroom should be carefully screened and selected. Review of the local cleanroom requirements for approving and taking these items into the cleanroom are essential. In fact, many cleanroom managers will have approval lists of these types of items.

COSMETICS - Many cosmetics contain sodium, magnesium, silicon, calcium, potassium or iron. These chemicals can create damaging particles. Cleanroom managers may ban or restrict cosmetics in the cleanroom. This is usually dependent upon the threat to the product being made in the cleanroom. A recent mirror on a space telescope was fogged up from the cologne that was present in the cleanroom.

MEASUREMENT AND INSTRUMENTATION  - Some important measurements related to contamination control are particle count, air flow & velocity, humidity, temperature and surface cleanliness. Cleanroom managers usually have specific standards and/or instruments to measure these factors.

ELECTROSTATIC DISCHARGE (ESD) - When two surfaces rub together an electrical charge can be created. Moving air creates a charge. People touching surfaces or walking across the floor can create a triboelectric charge.  Special care is taken to use ESD protective materials to prevent damage from ESD. Cleaning managers should work with their personnel to understand where these conditions may be present and how to prevent them.

Cleaning Procedures for Clean Rooms

 What follows are some recommended procedures for cleaning cleanrooms. It is important to emphasize that these procedures are guidelines and not standards or rules. The procedures listed here are routine cleaning tasks. Local cleanroom cleaning procedures may supercede the ones listed here. It is important for cleaning managers to review all cleaning procedures to be used in a cleanroom with the cleanroom management. A detailed cleaning schedule should be prepared for every cleanroom. Here are some procedures to be completed when cleaning a Class 10,000 cleanroom:

Cleaning Procedures for a Class 10,000 Cleanroom

Housekeeping maintenance of the cleanroom and restricted areas is essential to assure quality. Cleaning of a cleanroom should be performed on a daily basis. Improper cleaning of the cleanroom can lead to contamination and a loss in end user product quality. Proper selection of equipment and materials is important for proper cleaning. Only products that have proven cleanroom performance records should be considered for use in cleanrooms. These products should be listed and all vendors should be informed about the strict policies of how products are qualified. All procedures should be strictly enforced. Below are some examples of how to organize the cleaning to be done in a cleanroom. These are NOT schedules or exact procedures. They are guidelines for preparing work procedures and schedules. Local requirements must be included in any cleaning program.

List of Some of Equipment and Supplies Needed to Clean the Cleanroom

(All supplies must meet the Class 10,000 minimum requirements)

                                    1.             Cleaning and disinfecting solutions

                                    2.             Cleanroom mops

                                    3.             Cleanroom vacuum cleaner (if allowed)

                                    4.             Cleanroom wipers

                                    5.             Cleanroom mop bucket and wringer

List of Cleaning Tasks to be Completed in the Cleanroom

(Frequency may vary depending upon local requirements) 

                                    1.             Cleaning of all work surfaces in the controlled environment.

                                    2.             Vacuuming (if allowed) of the floors and work surfaces.

                                    3.             Emptying of appropriate trash and waste.

                                    4.             Cleaning of the doors, door frames and lockers in the pre-staging                                     area and gowning areas using the approved cleaning solution.

                                    5.             Mop gowning and cleanroom floors.

Cleaning Procedures for a Class 1000 Cleanroom

Below is a sample of a cleaning program in a Class 1000 Cleanroom. This is only a sample of a program. Local standards and requirements must be followed.

Area	Description of Work	Frequency
101	Change tacky mats	Every 2 hours
102	Wet mop with approved mop, cleaner & DI water	2 times per shift
103	Dust mop (if allowed)	2 times per shift
104	Remove trash, sweep, mop with appropriate cleaner wipe down tables and coffee area, clean walls and recycle cans	1 time per shift
105	Vacuum entry mats, sweep and mop floors	1 time per shift
106	Mop floor with pre-burnish cleaner and tap water	1 time per shift
107	Remove trash. Always wear gloves. Never take waste containers inside cleanrooms.	1 time per shift
108	Wet mop floors	1 time per shift
109	Remove acid and solvent trash	1 time per shift
110	Clean and replenish dispenser in all restrooms	3 times per week
111	Vacuum floor (if allowed)	2 times per week
112	Clean stainless steel pass throughs with s/s cleaner and appropriate wipes	1 time per week

The list above is a sample of some of the common tasks that need to be performed in a Class 1000 cleanroom. The list is not exhaustive. But gives some ideas of how to prepare work schedules and procedures. An assessment of the cleanroom in conjunction with cleanroom management will help define these tasks and frequencies.

Cleaning Procedures for a Class 100 Cleanroom

Zone	Procedure	Frequency
Zone 1a	Trash removal	Once daily
	Mop walkways	Once a week
	Wipe down horizontal surfaces	Once monthly
Zone 1b	Pull tacky mats	Every 2 hours
Zone 1c	Mop and trash removal	Once daily
	Wipe down walls and trim	Once a week
Zone 1d	Mop and trash removal	Once daily
	Wipe walls and trim	Once a week
Zone 2a	Mop	Twice a shift
	Wipe walls and trim	Once a week
	Vacuum	Once monthly
Zone 2b	Mop and trash removal	Once per shift
Zone 2c	Wipe down walls, windows, doors, trim, showers, passthroughs and fire extinguishers.	Once a week

The list above is a sample of some of the common tasks that need to be performed in a Class 100 cleanroom. The list is not exhaustive. But gives some ideas of how to prepare work schedules and procedures. An assessment of the cleanroom in conjunction with cleanroom management will help define these tasks and frequencies.

General Cleanroom Regulations

Below is a list of general regulations recommended as a minimum for the successful operation of a cleanroom. All professional cleaning personnel should be aware and follow these regulations at all times.

1.    All personal items such as keys, watches, rings, matches, lighters and cigarettes should be stored in the personal locker outside the gowning room.

2.    Valuable personal Items such as wallets may be permitted in the cleanroom provided they are NEVER removed from beneath the cleanroom garments.

3.    NO eating, smoking or gum chewing allowed inside the cleanroom.

4.    Only garments approved for the cleanroom should be worn when entering.

5.    NO cosmetics shall be worn in the cleanrooms. This includes: rouge, lipstick, eye shadow, eyebrow pencil, mascara, eye liner, false eye lashes, fingernail polish, hair spray, mousse, or the heavy use of aerosols, after shaves and perfumes.

6.    Only approved cleanroom paper shall be allowed in the cleanroom.

7.    Approved ball point pens shall be the only writing tool used.

8.     Use of paper or fabric towels are prohibited. Use of hand dryers equipped with HEPA filters are suggested.

9.    Gloves or finger cots should not be allowed to touch any item or surface that has not been thoroughly cleaned.

10.    Only approved gloves, finger cots (powder-free), pliers, tweezers should be used to
handle product. Finger prints can be a major source of contamination on some products.

11.    Solvent contact with the bare skin should be avoided. They can remove skin oils and increase skin flaking.

12.    Approved skin lotions or lanolin based soaps are sometimes allowed. These can reduce skin flaking.

13.    All tools, containers and fixtures used in the cleaning process should be cleaned to the same degree as the cleanroom surfaces. All of these items are a source of contamination.

14.    NO tool should be allowed to rest on the surface of a bench or table. It should be place on a cleanroom wiper.

15.    Only cleanroom approved wipers are allowed to be used. The wipers must be approved for the Class of cleanroom being cleaned.

16.    ALL equipment, materials and containers introduced into a sterile facility must be subjected to stringent sterilization prior to entrance.

17.    NO ONE who is physically ill, especially with respiratory or stomach disorders, may enter a sterile room. This is a good practice in any cleanroom environment.

 Personal Actions Typically Prohibited in Cleanrooms

1.   Fast motions such as running, walking fast or horseplay.

2.   Sitting or leaning on equipment or work surfaces.

3.   Writing on equipment or garments.

4.   Removal of items from beneath the cleanroom garments.

5.    Wearing the cleanroom garment outside the cleanroom.

6.    Wearing torn or soiled garments.

Cleanroom Air Flow Principles

are facilities designed for conducting research or manufacturing products that require extremely clean environments. Typically, cleanrooms employ a broad range of techniques to prevent air particles, bacteria, and other contaminants from entering the workspace, often by means of employee dress code and washing, pass-thru lockers and chambers, and intensive detail to cleaning. However, one of the major forces keeping a cleanroom particle free is the air filter system. Cleanrooms employ many different types of filters, including HEPA filters and ULPA filters, but there are two standard air flow patterns that are consistently used: laminar flow and turbulent flow.

Cleanroom Basics 

Cleanrooms are necessary for various kinds of scientific research that require particle- and bacteria-free environments. For example, when scientists grow cultures, it is important to reduce the introduction of other bacteria so that results will not be compromised. Manufacturing various kinds of products like microprocessors also requires particle-free environment, because even a human hair contacting the small chips of a microprocessor can inhibit or destroy functionality.

Cleanrooms are either hard- or soft-walled. A hard wall cleanroom is a permanent structure or part of a larger permanent structure, while a soft wall cleanroom can be transported or augmented depending on requirements, and primarily exists within a larger, permanent structure. Modular, soft wall cleanrooms are needed for medical emergencies or when smaller runs of environment-sensitive materials are produced within a larger facility.

Cleanrooms are graded depending on how clean the air in the facility is. There are two standards used for this determination: the ISO and United States federal standards. ISO grades are numbered sequentially, advancing from 1. A cleanroom graded ISO 1 contains ten or fewer particles per 0.1 micrometer cubed area. A cleanroom graded ISO 2 contains 100 or fewer particles per 0.1 micrometer cubed area. The rest of the series feature the amount of particles rising by a factor of 10 per level. US federal standards are numbered 10, 100, 1000, etc., with the lower class number representing a cleaner facility. Class 1 cleanrooms have one or fewer particles per 0.5 micrometer cubed area. Class 10 cleanrooms have 10 or fewer particles per 0.5 micrometer cubed area. Ascending class grades rise by a factor of 10.

Because people often work in cleanrooms, they are required to follow dress and behavior guidelines to limit the amount of particles they will bring into a cleanroom or particles they will shed while working in the environment. Workers must change from street clothes into specially designed outfits, often with full hood coverings, gloves, and breathing masks. Workers must also enter through an air shower to eliminate remaining particles on the cleanroom suit, and then pass items into the cleanroom through a small chamber that prevents outside air from entering the clean environment.

Cleanroom Air Filtration

Cleanrooms employ air filtration to limit the particles in the environment air. Typically, this is through the use of either a highly efficient particulate air (HEPA) or ultra low particulate air (ULPA) filter. These filters can remove roughly 99.9 percent of all microparticles in room air by applying either laminar air flow or turbulent air flow techniques to the environment air.

Laminar air flow refers to air that flows in a straight, unimpeded path. Unidirectional flow is maintained in cleanrooms through the use of laminar air flow hoods that direct air jets downward in a straight path, as well as cleanroom architecture that ensures turbulence is lessened. Laminar air flow utilizes HEPA filters to filter and clean all air entering the environment. Laminar filters are often composed of stainless steel or other non-shed materials to ensure the amount of particles that enter the facility remains low. These filters usually compose roughly 80 percent of the ceiling space. Cleanrooms employing laminar air flow are typically referred to as Unidirectional Airflow Cleanrooms.

Non-unindirectional airflow cleanrooms utilize turbulent airflow systems to clean particulate air and maintain a clean environment. While laminar air flow filters are often a component of turbulent airflow systems, they are not the only systems employed. The entire enclosure is designed to use laminar flow and random, non-specific velocity filters to keep the air particle-free. Turbulent airflow can cause particle movement that can be difficult to separate from the rest of the air, but non-unidirectional airflow systems count on this random movement to move particles from the air through the filter.