Friday, January 20, 2012

Ask the Facilities Guy: How do I produce a Disaster Recovery Plan?

By Richard Bilodeau, PEA question has arisen about terminology. Whether called a “disaster recovery plan” or a “crisis plan” or a “business continuity plan,” the end game is the same. Your goal is to resume manufacturing operations and fiscal stability, as quickly as possible, after a disruptive event. Some facilities and operations professionals believe that abandoning the term “disaster recovery plan” in favor of “business continuity plan” is more effective in procuring funding and support from senior management, and more palatable to the investment community. While the substance remains the same, the impression created by an undertaking titled “business continuity plan” is a focus on the future, generating product and profits. There is also a move afoot in some sectors to use the label BC/DR (business continuity / disaster recovery), suggesting the dual purpose of the process. You’ll need to decide what’s best for your organization, and facilitating your end goals.
This month in Round 2, I’ll guide you through some of the specifics of producing a disaster recovery plan tailored to the requirements of your manufacturing needs, including content. Pour that cup of Joe and settle in—those of us in facilities like nothing better than to write a plan, or read about writing one. But the pain you’ll feel today is miniscule compared to the pain of being unprepared for an unexpected disaster that impairs your manufacturing.
THE BEGINNING
You’ve completed the spadework: management is on board and has funded the effort; risk assessments are completed and prioritized regarding both probability of occurrence and damage potential; key team members are identified and recruited. Now what?
Before drafting the plan, make sure that all key departments of the organization are surveyed to a level appropriate to both their risk exposure and the potential financial impact a business disruption would produce. Rank and prioritize the information you glean and build it into your plan.
Following are some key components of the plan that will ensure its functionality. Consider using graphs, flow charts, and bold/bulleted text to convey the information as concisely as possible.

• Executive summary: not a bad place to outline the plan’s objectives, assumptions used in the process, and the scope of the plan.
• Statement of purpose: Make sure everyone reading the document understands what it is, and what it is not.

o Outline the conditions under which the plan will be implemented and clear chains of responsibility to make the call declaring an emergency and invoking the plan.
o Clearly outline notification triggers, processes/procedures, and recording requirements.

• Clearly delineate the names, contact information, and roles of the disaster recovery team members. Make sure each person has one, if not two, designated backups— depending upon your company’s travel schedules. Back-ups must be qualified individuals who are fully trained and can command the role for which they’re designated. It’s critical that this section of the plan be scrupulously updated.

o For companies with multiple locations, consider developing both a corporate team and site specific teams at each of your locations. Work hard to develop a sense of camaraderie and teamwork.
o Depending on the risks contemplated by the plan and your company’s organization structure, you will likely have several or all of the following teams: Emergency Management Team (including management, finance, logistics, procurement etc.), Crisis Communications Team, Incident Response Team and/or Emergency Response Team, Technical Services Team, Services Restoration Team. Some plans roll each of these groups under the Disaster Recovery Team mantle, with sub-groups with specific responsibilities selected from the list above.
o Make sure applicable outside emergency response and governmental agencies are listed, including a lead contact and their back-up. It’s critical that the emergency management team develop strong relationships, and undertake joint training, with local government officials and emergency response personnel.

• Keep a clear record of revisions chart near the front of the document. Make sure the plan is reviewed frequently, updated, and the new information is distributed to all team members. Do NOT wait for a scheduled review to update business changes, new personnel, or new risks. Ensure that any revisions are integrated in all copies of the plan.
• Extended team member roles, responsibilities, and authority: the heat of a crisis is no place for turf wars or lack of clarity in execution.
• Communications authority guidelines: Clearly designate who has the authority to speak with the press or other outside parties or governmental agencies, your investors (if applicable), customers, suppliers, and employees.

o Develop a strong communications protocol guide. Remember, in worse case scenarios, loose lips sink ships; in even the best cases they create confusion, conflicting information, and reputation damage.

• Emergency management standards and procedures: this is the heart of your plan. Many companies categorize potential disasters and develop specific protocol for each type, or for individual scenarios within these categories. Some broad categories include: natural disasters, workplace violence, key employee deaths or resignations, IT systems crises, chemical spills and release issues, supply chain disruption, fire, strikes, accidents, acts of terrorism, and criminal investigations.

o For each scenario, outline trigger thresholds for invoking the plan, escalation factors, notification requirements, and procedures.

• Checklists: Develop checklists that your teams can use to ensure a complete response and to organize actions during a crisis.

Focus on developing a draft document—don’t get caught up in the pursuit of perfection. Once you’ve developed a draft, make sure it’s thoroughly vetted— preferably in workshop forums set up with operations groups and members of the team. Encourage an open, constructive review format—your goal is not to collect kudos but to be sure everything is covered, clear, and structured in a way that will be most efficient in a crisis.
Scrupulously record the comments and suggestions and resolve any edits. Go back for a rewrite and then distribute the second draft for individual review and comment with a firm deadline for replies. Integrate any corrections into the final draft—the emphasis here is on the word “draft.” Business recovery plans are organic documents that must be constantly updated and amended to align with changing information and business conditions.

Pharma Facility Quality Audits: A Primer for Design Teams

By Scott Overton

Here is a familiar demand: “Show me where in the regulations it says to do that!” If you’ve spent any time in Quality, working on a facility or equipment project in the pharmaceutical industry, you have certainly had that put to you at some point. And why not?
Far and away, what most people (including our industry engineers, technicians, and operators) think about when they think “Quality” is “Compliance with Regulations.” Compliance is certainly an issue of vital importance, but Quality does not stop there, and there is no time when that is more clear than during a Quality Audit. This article will show that understanding the potential audit outcomes in the future can serve as powerful design criteria today.
For many companies today, the majority of their external quality audits will not be performed by regulatory agencies, but by other companies. This company auditor has a day or two to assess the overall “quality culture” of a potential supplier or contractor. Unlike the FDA that has a free pass into all FDA-regulated facilities in the U.S. at any time, a company auditor performs the audit at the discretion of the company being audited. After this audit is complete, and provided that the auditor says everything is okay to link his company to the manufacturing processes of the other, the auditor’s company will have little to no direct experience with day-to-day processing. In short, that’s a couple of days to make a full assessment of all quality systems in a unique facility that will have to be valid for a year or more. This is a challenge for non-sterile raw material suppliers, which only grows more challenging as cleanrooms and sterility claims are added to the mix.
With so little time to assess a facility and a manufacturing process (or many of them!), how is it that auditors can effectively and thoroughly measure the strength of all Quality Systems? It is here that a large part of non-Quality personnel would answer something along the lines of “directly measure the facility against the regulations using a checklist or other tool.” Though compliance with regulations is absolutely required, measuring against regulations is a very small part of an audit. Furthermore, it is difficult to do so “directly.” How would one measure “Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another”¹ directly? And how would it be done for every possible combination of personnel, materials, and products in a contract formulation and sterile liquid filling company, for example? In short, it can’t happen. Alternatively, there must be a way to achieve solid and defensible results.
The alternative is this: in order to be effective, auditors focus on two things:

How is the system controlled?
How is the system monitored?

Superficially, these two questions appear to provide a very narrow perspective. On the contrary, they comprise a far more expansive view of facilities and processing than most, including the normal view of design, for example, which is to design for a specific production volume. The first clear outcome of designing a facility or process with these two questions in mind is that design decisions will be made knowing that the final design must be auditable. A simple example would be to imagine an airlock that does not have any sort of air pressure gauges. The original design intent may be to have 10 Pa over each door, but without data provided by monitoring devices, how could it be proven that the airlock is behaving as designed? Without data, how could adjustments to controls be justified to an auditor? The fact that an audit trail must be available may be very influential, which will be seen through some examples below.
Now it is great that we understand that systems of control and monitoring will be the way an auditor approaches the facility once it is built and the process is running, and it’s also great that we understand that the final facility or process must be auditable. But these facts are not very useful to design engineers and architects if they cannot be leveraged to inform design of projects in specific ways up front. Having a holistic, “eyes of the auditor” type quality influence in the design phase of a project would be incredibly valuable since all projects in the pharmaceutical industry will eventually be production facilities or manufacturing systems, which will go for Pre-Approval Inspection and then biennial inspections by the FDA and international regulatory bodies, and also countless supplier audits for as long as that that facility or process exists.
Some people may balk at the notion of using the potential results of future audits as design criteria as it is commonly held that “regulations keep changing.” I deny that. What happens most often is that over time, the rest of society continually develops more sophisticated technologies like computers, advanced materials, and precision equipment. As the rest of society keeps progressing (or in production lingo, “continuously improving”), our industry is expected to do the same. Thirty years ago, a daily monitoring of room pressure on a written log was the norm. Today, it is very common to see Building Management Systems monitoring room pressures constantly. Physics didn’t change. Air itself didn’t change. Over time, technology advanced and the Pharmaceutical Industry just kept up with it.
Furthering that idea, better data monitoring reduces business and quality risk overall, so these advancing technologies are implemented as companies’ assessment of risk changes. The written regulations also change—usually pretty slowly—to keep up with changing technology and risk perceptions. As an example, consider a smartphone. These devices have incredibly simple user interfaces and are powerful enough to let the user do almost everything a laptop does. With that level of simplistic technology available to anyone, why should a confusing Operator Interface on a process skid be acceptable?
What does it really mean to focus on systems of control and monitoring? Said another way, it means an auditor will focus on systems that will assure product will continuously meet specifications, that any issues with that production are identifiable, and that all activity is traceable. So the auditor focus on control and monitoring systems is truly a focus on “assurance” and “reliability.” Here, it seems that the goal of the design team and the auditor are the same. In project development, no design team aims to create a facility or a process that is unreliable; an auditor merely seeks to validate those efforts. Approaching design from this perspective of “assurance” and “reliability” is obviously constructive and helps projects in our life-saving industry come to the best decisions for our products and our patients. The area where this is most clear is cleanroom design, which will be the focus of the examples below.
Consider a situation in two different ways. In each of these scenarios, the product has some specific requirements, such as sterility throughout the process as the product cannot undergo any downstream sterilization steps. Also, for clarity, these processes are in a single-product facility:
SCENARIO 1: AN OPEN PROCESS
In an open process for a sterile product, the space required is a Grade A with a Grade B background. Personnel in that space are fully gowned. In Grade A, there is continuous particulate monitoring, minimal per-process microbial monitoring, and a lot of air being pumped into the space (laminar in Grade A to boot!).
SCENARIO 2: A CLOSED PROCESS
In a closed process for a sterile product, operations are in Grade C, D, or maybe even unclassified (depending on risk and the way the process is set-up). Personnel are wearing dedicated clean-area clothes and shoes, EM is radically reduced from an aseptic area, and the air change rate is maybe half of that in aseptic areas.
Now, both of these process scenarios have the potential to be completely compliant. For one, though, compliance is far more costly, challenging, time consuming, labor-intensive, and complex, which means that there are many more tools required to control the environment, many more items to monitor, and far more opportunities for failure. Each of these additional failure modes adds another parameter to the process that must be auditable and increases the number of people required to audit. There is nothing in the regulations that would state one of these approaches is completely wrong. And maybe with more information available, the system with fewer parameters to control and monitor is actually the best choice for the production material. What if the product in question here is experimental, unproven, and therefore in need of the developmental flexibility that comes with multi-use Grade A areas? What if product volumes are so vanishingly small that product hold-up (potentially greater in the closed system) is critical? This may come into greater relief with another example:
POTENTIAL SYSTEM A:
The production system is fully stainless steel. Everything was engineered, with measured and exact slopes for all piping. In between uses, all parts must be washed and, before that, the cleaning cycles had to be validated. Their control is automatic and also validated, so repeatability is almost certainly assured.
POTENTIAL SYSTEM B:
This is a completely disposable system. The disposable components can be purchased from multiple vendors (some of which are not as reliable as others), have some potential variability in tubing length, and since they come coiled in sterilized bags, the tubing often sags when outstretched, leading to variability in holdup in the system. The disposable components need no cleaning validation or cleaning cycles. These systems are sterilized by an outside vendor, but are never put through a validated cleaning cycle to remove any particles introduced during assembly at the vendor.
Knowing that outcomes like purity and yield are critical parameters, which system should be selected? What if the product is moderately sensitive to materials used in a disposable system? What if cleaning chemical residues have an exponential negative effect on potency? Again, understanding the way the entire process will be audited quickly digs into many details not always at the forefront of a facility design.
Similarly, across the industry, room air quality must be monitored. But monitoring a Grade A space means continuous particle monitoring, whereas Grade C monitoring may be only weekly or even monthly. For a critical product-contact utility, an auditor will review every document from Design Qualification through routine monitoring over the previous year or two in detail. For a Grade C EM program, the procedure will be reviewed and enough data to show compliance will be reviewed.
In all of these examples, different teams will come to different final selections and it is highly unlikely that any selection will be “wrong.” The unfortunate potential is that for either path taken, the selection will be made, designed to, and built from a single perspective: the perspective that comes with budgets and schedules, that moves in one direction from original concept to construction and validation, and that is ultimately inflexible because it was scoped and designed to meet a specific need (throughput or production volumes, for example) without including the need to control or monitor the process and be fully transparent in an audit, regardless of the volumes.
This is perhaps the best case for viewing projects from an auditor’s perspective. Ten years from the initial build, an auditor will be in that facility. In those ten years, dozens of changes will have happened, production volumes would have increased (hopefully), and systems would have been updated. Cleanrooms designed to hold one production lot at a time might now hold multiple lots. It is here where controlling and monitoring systems for multiple quality systems come together to form an overall quality assurance program. It is here where an auditor could look at the initial design and aid in recognizing how, over the long term, systems to control and monitor different aspects of production can be stressed to the point of failure.
At a minimum, the products of the Pharmaceutical Industry improve the quality of life and, in many cases, save lives or prevent disease entirely. Competition in this field is inevitable and tenacious. Increasing production and lowering cost cannot result in products of lower quality with unreasonable risk to patients.² For successful products, processes and facilities are asked to increase production over time as demand increases and lower costs as patents expire and competitors come to market. These pressures are as inevitable for a production facility as is the fact that it will be audited dozens of times. We would all do well to employ the tools of an auditor in the design of facilities and processes.
References:

FDA Guidance for Industry / ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Section D(4.4), August 2001
See Eudralex, Annex 11, Principle section

Why Static-Control Flooring Is So Important - And How to Find Solutions to Keep You Grounded

By Dave Long

Selecting the right kind of ESD (electrostatic discharge) flooring is always a challenge, and in controlled environments, the stakes are particularly high.
While cleanroom environments are known for the exacting standards used to control contaminants, it’s ironic that their anti-static flooring doesn’t always meet industry specifications. This is a critical concern on several levels:

First, the ESD problem is intensifying as electronic devices continue to become smaller and more powerful. Miniaturization, also known as device scaling, reduces the room for on-chip protection, increasing vulnerability to ESD and accenting the need for static-control, fault tolerant flooring.
In addition, recent and proposed changes to ESD standards, including ANSI (American National Standards Institute), increases challenges to manufacturing facilities seeking ISO certification. These changes address the need to comply with revised static-prevention performance parameters, with failure to do so exposing companies to potential lost business due to non-compliance.
Floors installed in cleanrooms have enormous bottom-line implications if you consider the potential costs of installing a new, correctly specified, floor after your facility is operational.

In other words, it is paramount to get your ESD flooring right the first time, and there should be no room for compromising within the precious real estate of cleanrooms. Yet, problems persist. Why?
INITIAL CONSIDERATIONS
Understandably, many engineers and facility managers are frustrated and confused when it comes to selecting static-control floors for their factories. They typically don’t have the time nor the expertise needed to deal with electrical specifications and standards. Selecting a floor includes considerations like maintenance, durability, ergonomics, safety, installation procedures, and, most importantly, how the floor controls static charges on people based on their footwear.
In cleanroom environments, the process often requires the assistance of outside experts who specialize in ESD, contamination control, ion chromatography, material out-gassing tests, and particle analysis.
Overall, depending on the application and site considerations, ESD floors can be installed over old floors, over bare concrete, or on top of raised access-flooring panels. However, due to contamination and particle control considerations, only three forms of ESD flooring are generally considered suitable for cleanroom environments: rubber, vinyl, and epoxy.
With this as the backdrop, the following will focus on key factors to consider in the evaluation and selection process, including electrical resistance, footwear, cleanliness, mechanical properties, and ergonomics.
ELECTRICAL RESISTANCE
Rubber, vinyl, and epoxy floors can be produced in either the conductive or the static-dissipative ohms range. According to the ESD Association, a conductive floor measures below one million ohms (1.0 X 10 E6) when using test method ANSI/ESD S7.1-2005. Using the same test, a floor measuring between one million ohms and one billion ohms (1.0 X 10 E9) is defined as static dissipative. As a general rule, most experts believe that floors measuring below 10 million ohms (1.0 X 10 E7) offer the best static-control performance for electronic manufacturing and handling. Floors measuring above 10 million ohms drain static more slowly than floors measuring in the conductive or lower end of the static-dissipative range (< 1.0 X 10 E7).
Also, ESD floors that are too conductive may not be considered safe. Most safety engineers refer to NFPA 99 to define the minimum resistance of conductive floors. According to the 2005 version of NFPA 99, a floor should not measure below 25,000 ohms (2.5 X 10 E4). There is a caveat when referencing NFPA 99, however: This test requires measuring a floor’s resistance using an ohmmeter with a 500 volt output, and most of the meters used for testing conductive floors operate at 10 volts. Unfortunately, this creates a potential safety dilemma for specifiers because a floor measuring 25,000 ohms at 10 volts will measure far below the NFPA minimum of 25,000 ohms when tested at 500 volts. For this reason, we recommend setting the resistance minimum above 50,000 ohms to address the discrepancy caused by the two different test methods.
Upshot: Recommended floor range: greater than 50,000 ohms and less than 10,000,000 ohms (5.0 X 10 E4 – 1.0 x 10 E7).

FOOTWEAR
ESD floors should never be evaluated solely on electrical resistance parameters, since that is only part of the story. ESD standards like ANSI/ESD S20.20-2007 require testing of both the resistive properties (ohms) and the charge-generation properties (volts) of the floor. The ESD Association requires that the floor’s performance be evaluated in combination with static-control footwear. The first requirement in S20.20 evaluates a property called “system resistance,” which is determined using the ANSI/ESD S97.1 test method. In this test, the ohms resistance is measured from a person’s hand to the ground—through the body, the footwear, the floor itself, and the ground. As of November 2011, an acceptable reading requires a system resistance below 35 million ohms (3.5 X 10 E7). (Note that before writing this article, we interviewed several members of the ANSI/ESD S20.20 committee about possible changes in the system resistance requirement. We were informed that the requirement might be raised to a maximum of 1 billion ohms (1.0 X 10 E9). However, if this system resistance is increased, requiring body voltage testing at the same time will likely offset it.)
Body voltage generation is determined by measuring static charges using test method ANSI/ESD S97.2. With this method, subjects wearing special static-control footwear walk on ESD flooring while connected to an instrument that measures the amount of static charge the subject generates from the interaction of the footwear and grounded floor. To meet ANSI/ESD S20.20, a person wearing approved, grounded footwear cannot generate over 100 volts. Achieving this parameter may be difficult in cleanrooms, however, depending on the contamination-control footwear requirements. Standard cleanroom shoe covers generate static voltages in excess of 1,000 volts. Several suppliers offer disposable and permanent static-control shoe covers with conductive or static-dissipative material on the bottom side.
Regardless of the shoe cover specifications, they should always be tested with the grounded floor. Testing has shown that many conductive and static-dissipative vinyl and epoxy floors will generate well over the 100 volt maximum on test subjects wearing these types of booties and shoe covers. The same testing has proven that conductive rubber flooring will generate well under 100 volts combined with most static-control cleanroom footwear. This is because conductive rubber flooring generates significantly less static than vinyl or epoxy flooring, regardless of footwear.
Upshot: Current system resistance requirement: < 35 million ohms (3.5 X 10 E7). Proposed requirements: system resistance < 25 million ohms and body voltage < 100 volts.
CLEANLINESS
When determining the compatibility between construction materials like flooring and cleanroom processes, there are numerous considerations. Here, we will touch on the main factors: out-gassing and particle transfer. According to ESD and contamination-control consultant Carl Newburg, president of Microstat Laboratories and River’s Edge Technical Services in Rochester, Minnesota, “Out-gassing is a measurement of the quantity of volatile chemicals released from a material while it is heated. Condensable volatile residue (CVR), Static Headspace, and Dynamic Headspace are typical tests used to measure out-gassed materials. Test results offer an indication of the material’s tendency to contaminate surfaces in a controlled environment with airborne molecular compounds.”
Most vinyl flooring materials fail stringent, elevated temperature outgassing testing due to the inclusion of plasticizers in the flooring material. Plasticizers are problematic because they can migrate out of the flooring material and create significant contamination problems in cleanroom applications like optics and MR head manufacturing. We have all experienced plasticizer migration through what we refer to as “new car smell.” This smell is the result of airborne plasticizer out-gassing from all of the various plastics used in an automobile’s interior. Without thorough testing, this plasticizer migration would be difficult to identity and quantify. Many flooring manufacturers will state that their flooring will meet all out-gassing requirements at ambient temperature, but most contamination-control experts do not believe that ambient testing is adequate.
Before specifying any flooring for installation, we recommend discussing the application with an expert in contamination control and ESD. As a rule of thumb, conductive rubber flooring and conductive epoxy flooring will perform the best in elevated temperature out-gassing tests. Unlike vinyl, rubber and epoxy are made without plasticizers.
Upshot: Floors that pass elevated temperature outgassing tests: conductive rubber and conductive epoxy.

MECHANICAL PROPERTIES
Most cleanroom floors are installed using methods that create a seamless floor, which can be achieved with epoxy coatings because the material is coated onto the floor in liquid form and allowed to flow across the surface. The downside to seamless epoxy coatings involves the difficulty and time required to make repairs in the event of damage from scratches or cracking. A typical cure time for an ESD epoxy floor is between 24 and 72 hours, depending on the number of layers. If a repair is performed in an operational cleanroom, the epoxy could create contamination or odor problems during the time it takes to harden from its liquid state. Additionally, epoxy repairs usually require some form of abrasive floor preparation to make the surface fit for recoating. Abrasive floor preparation could generate particles that contaminate fixtures and HEPA filters.
Rubber and vinyl can also be installed without seams using a technique called seam welding, which fills in and fuses gaps resulting from the interactions of sheet floor flooring or adjacent tiles. Both tiles and sheet floors can be seam welded (similar to caulking), but most specifiers prefer sheet flooring since there are fewer seams to weld. The welds in rubber sheet flooring are less visible compared with vinyl welds because, unlike vinyl, rubber does not shrink. Rubber and vinyl floors can be repaired more easily than epoxy using simple techniques that don’t require abrasive floor preparation techniques. Conductive rubber sheet flooring can be installed with fast-drying, pressure- sensitive adhesives that can usually be applied in an operational cleanroom. Pressure-sensitive adhesives allow for foot traffic within an hour of the repair.
ERGONOMICS
Of the three most common cleanroom flooring options, rubber offers the most slip-resistant walking surface, wet or dry. Rubber is also softer underfoot, and it absorbs ambient noise better than hard epoxy and vinyl surfaces. Even though it is much harder than generic rubber used in forms like anti-fatigue matting, rubber can become damaged from rolling heavy loads over it. Compared with epoxy, it is also more difficult to roll heavy racks weighing thousands of pounds over rubber. In some cases, epoxy may be the only practical flooring option due to its toughness and ability to handle rolling loads and chemical spills.
Upshot: Rubber offers the most ergonomically friendly solution.
SIMPLIFYING THE SELECTION PROCESS
Indeed, there is a vast amount of technical information to consider when selecting static-free flooring in controlled environments—and it would be short-sighted to look for shortcuts in the process. In the final analysis, the key concepts are prevention and protection.
To prevent ESD problems, select the flooring option that best meets current and anticipated industry specifications. While there are different variables, here is what industry sources recommend for cleanrooms and electronic manufacturing facilities:

Conductive Rubber the only ESD flooring certified as Class-0 Qualified is rated “ideal;” it also has low body voltage generation.
Conductive Vinyl Tile and Conductive Epoxy may also be suitable.
Other flooring options are not recommended.

As far as protection, if you plan wisely from the get-go, you can avoid costly liability issues later on. We encourage installation floor audits to determine if you are ground safe.

Failure Modes and Effects Analysis (FMEA)

By Scott Mackler

A tool to balance cost and schedule while maintaining facilities readiness.
In the October issue of Controlled Environments, Richard Bilodeau, “Ask the Facilities Guy” wrote about establishing an “Equipment Reliability” program. While clearly an important issue, it is one that often facilities departments have a hard time getting their arms around—as Richard points out. One tool that we have found quite useful in supporting high facility onstream time and process yield factors, as well as sustainability, is the equipment or hardware FMEA (Failure Modes and Effect Analysis). The FMEA exercise will provide the facilities team with a prioritized “risk burn-down” plan for ensuring readiness and can serve as a convenient basis for capital and operating expense budget creation and execution.
We have recently performed FMEA exercises for aerospace assembly, integration, and test facilities, aseptic filling laminar flow units and accompanying HVAC systems, thermal vacuum test chambers, powder metallurgy processing lines, precision cleaning equipment, and continuous web processing machinery. In many cases not only were predictive and preventive maintenance issues uncovered and addressed with corrective action plans developed as a consensus among customers, users, service providers, and subject matter experts, but in a few cases, serious life safety and product safety issues were brought to light and effectively dealt with before a catastrophe— likely one without warning—could occur.
An FMEA identifies the severity, occurrence, and detection of failure effects and then establishes priority- ranked corrective action plans. A cross-functional team including the customer or process owner, subject matter experts, facilities and maintenance specialists, quality assurance, and design engineering participate in a brain-storming exercise that identifies each potential failure and ranks the possible effects of each failure and develops a resulting RPN or “Risk Priority Number.” The RPN is the arithmetic product of the severity multiplied by the (probability of) occurrence multiplied by the (ability of) detection.
The objectives of the FMEA are to:

Ensure that potential failure modes and their effects are identified and ranked as to severity, occurrence, and detection.
Provide assessment as to risk ranking based on RPN (Risk Priority Number) and generate action register to burn down risk—thereby reducing life cycle costs, improving reliability and durability of systems.
Prioritize the engineering efforts and resources based on the assessment of potential failure impacts to the product and eliminate or minimize the impact of potential failures to the product.
Provide information for development of an efficient and effective preventive maintenance plan.
Establish closer links between production, quality, facilities engineering, and maintenance.

Examples of suggested scales for severity, detection, and occurrence might be:

Typically the deliverables of the FMEA include a Pareto Chart illustrating the number of failure items and risk effects that were identified and subsequently ranked by RPN during the brainstorming and analysis sections of the exercise, and then either a projected or an achieved burndown of the RPNs after development and execution of the Corrective Action Plan.

Point of View: An Apple To Apple Comparison on Cleanroom Proposals

By Kelly Barton

That’s a tough one, but for simple, relatively small cleanroom projects there are a few things that you can do to help ensure everyone bidding the job is “singing from the same song sheet.” No matter how simple, it’s very important to generate a specification sheet and conceptual drawing or sketch and make sure all the prospective bidders get it and reference it in their proposal. The sketch must include the ceiling height in the cleanroom and room sizes. Ask them to separately itemize any items that they feel are needed but are not included in the spec sheet. If you do not have anyone in your organization qualified to generate this document, hire an outside consultant with the understanding that all you need is a very basic scope statement. The time you spend trying to figure out the differences between bids will cost you more time, money, and frustration than the consultant will charge. Plan on at least two bid phases, initial and final bids. As you evaluate the bids you will get a better understanding of what is needed and can make better decisions regarding what to specify in the final bid phase. The evaluation phase of the bids can almost be an education on cleanroom design for your staff. Don’t be shy about asking contractors why one proposal is different than another. Make sure you are comfortable with their explanation.
Here are some very important specifications to include in your document that are critical for a contractor to determine cost. If everyone gets a spec sheet with these variables defined, your final bids will be more accurate and should be more consistent.

Room Classification, either Fed Std or Iso spec should work here.
Temperature specification and tolerance. Example: 68 +/- 5 Deg.
Humidity specification and tolerance. Example: 50 +/- 10% RH. Let the bidder know if the temperature and humidity specifications are process critical or operator comfort. If humidity control does not affect your product, leave it out. It is the most costly specification to control for the HVAC system.
Amount of process exhaust in CFM. This is relevant since both outside air to generate room positive pressure and air removed from the cleanroom by the process has to be accounted for.
Process heat load in kilowatts (KW). Are there ovens, large process machines, or just operators in the cleanroom? If you are not sure about this item, list the connected electrical voltage and current draw (amps) to start with. This will ensure some A/C tonnage is dedicated to this specification.
Number of operators. This affects temperature and to some degree, humidity.
A brief definition of the manufacturing process or product in the cleanroom may also help.
A description of the host building is helpful since this may affect where the HVAC equipment can be placed.

Monday, January 9, 2012

Cleaning validation in the pharmaceuticals industry:

Good pharmaceuticals manufacturing practice requires from pharmaceuticals companies that rooms and apparatus such as centrifuges and other devices must be cleaned according to written methods (“Good Manufacturing Practice” or GMP).
The most suitable method must be validated by the respective pharmaceuticals company on the basis of regulatory requirements [1] and their own expertise and technological advances in apparatus engineering. This takes place as part of cleaning validation; and this is precisely where the innovations of Ferrum in the area of vertical scraper centrifuges offer further alleviations.
Not without “my” risk assessment
The word cleaning validation represents a real challenge to the pharmaceutical, apparatus and plant engineering industries. This does not just simply involve complying with regulatory standards. The safety of pharmaceuticals, feasibility and efficiency are main aspects.

At the start of every cleaning validation is the validation plan, which can be divided into three phases, see also [2], [3]. The providers of centrifuge technology solutions can make an essential contribution in all three phases towards realisation and efficiency. This can only be achieved by working together and harnessing all available relevant knowledge available.
The three phases can be briefly described as follows:
1)Internal status inspection of planned production line
This concerns the question of which active and inactive ingredients are to be produced or used? The product change frequency has a considerable influence on the efficiency. One must therefore know which cleaning agent and method should or can be used.

This is where the latest innovative VBC centrifuge technology comes in; based on the expertise of the machine supplier in apparatus engineering and construction in line with the latest advances in mechatronics as well as design aspects and process sequences of solids-liquid separation and cleaning. The machine supplier is not responsible for the active ingredients however.

2)Risk assessment of products and facilities
The internal pharmaceuticals status inspection must be followed by risk assessment for all products, the aim being to identify substances that are a particular hazard. Responsible is the pharmaceuticals company, see graphic “worst-case” analysis according to Borchert [6].
Centrifuge manufacturers can make a valuable contribution with their expertise and years of experience in the assessment of design-related cross-contamination (e.g. difficult to access or absorbent surfaces, dead ends in pipes and extraction points, etc.).
3)Determination of extent of validation
On completion of the internal status inspection and joint risk assessment (machine supplier and pharmaceuticals company), the extent of validation can (must) be determined by the pharmaceuticals company, see also [4].

In this phase, Ferrum is able to offer the possibility of validating design-related critical points in its own assembly halls following assembly and so reduce by this verification item, time-consuming validation within the pharmaceuticals company. By means of a so-called riboflavin test, for example, the effectiveness and wettability within the centrifuge can be verified or also the effectiveness of CIP cleaning of inert material at “critical points”.
It is therefore in the interest of the pharmaceuticals company to complete validation quickly and if possible in the phase prior to commissioning. This is only possible in cases where existing facilities are duplicated. As maximum flexibility in the manufacture of pharmaceuticals is of the essence today, apparatus such as centrifuges must be appropriately flexible in design.

Precisely this step was taken at Ferrum with the latest VBC vertical pharmaceutical centrifuge. The processes of rinsing, washing, spraying, measuring, analysing, scraping, blowing out and even flooding have been greatly improved in the new generation of centrifuges over that which was state of the art a few years ago. The special advantage of Ferrum centrifuge technology solutions is that many of the different function modules can be integrated flexibly both in the initial design of the machine as well as retrofitting. The cleaning process can be optimally adapted to the respective production sequence in a highly flexible manner.
It is therefore extremely important that the experienced and innovative centrifuge supplier is included in process selection already in the planning phase.

Cleaning procedure validation and selection
In order to locate fouling on machine parts, specific samples are taken before and after the cleaning procedure. In the PIC document PI 006, sampling procedures using the wipe or swab test and flush or rinse test are considered suitable. [5]

One advantage of the swab test is that it provides information on where the fouling is located, e.g. in bends or branches of pipe systems.

Useful is the inclusion of global analytical methods. An example is TOC determination for organic loading, conductivity measurement for ionic residues and ph measurement for cleaning agent residue detection. These analytical methods can be included as online measurements or installed in the centrifuge. Such analytical methods can be used for multifunction systems to provide maximum flexibility during commissioning, as all possible active and inactive ingredients are often not known. Offered is a retrofitting option; this is usually possible in the majority of cases without redelivery to the manufacturer’s workshop due to the modular design of the VBC.

Modularity in use

Passive contribution towards cleanliness in scraper centrifuges
It may sound simple, but good access to the centrifuge is a precondition for its cleaning and analysis, even when fully automatic CIP systems are usually installed. The modular design of the VBC vertical pharmaceutical centrifuge takes this into account. The design of the cover opening, the position of the outlet and the basket drive can be selected in a wide range of variants and combinations. This enables the machine to be optimally adapted to local space conditions at the site of installation without additional expenditure; this is something that will be appreciated by structural engineers and plant constructors as well as those responsible for maintenance.

Until now, only so-called horizontal centrifuges where considered suitable for installation in a clean room. With the introduction of the VBC, a vertical scraper centrifuge now meets all requirements for installation in a clean room concept, as the complete drive can be arranged below the vibrating plate. This allows the technical area to be separated from the clean room area by means of a membrane in the floor/ceiling.
This method of installation complies with the wishes of many pharmaceuticals companies as the entire production flow takes place gravimetric vertical. The VBC vertical scraper centrifuge thus requires less space than a conventional horizontal centrifuge, as this additional clean room area is required for opening the horizontal housing and positioning the pipes with respect to the vertical product flow into the horizontal machine.

A further important item in the design of the VBC is the one-piece concept of the housing and base plate, avoiding numerous edges and transitions with the advantage of less fouling.
Active contribution towards cleanliness in scraper centrifuges
The function modules that contribute towards active cleanliness include CIP nozzles. The principle applies: As much as necessary, as little as possible. Especially in the case of multifunction systems, the use of an additional CIP nozzle may be necessary. In the modular concept of the VBC centrifuge, this does not present a problem as the CIP nozzles are flanged and easily retrofitted (during production) without welding. It goes without saying that these flanges are all provided with GMP compliant seals.

Those responsible in pharmaceuticals companies can face a far greater problem if the cleaning process must subsequently be changed from CIP cleaning to flood cleaning with a change of product, see “worst-case” analysis. This is another problem that can easily be solved with the design concept of the VBC, as the complete bearing and sealing system is in a modular design. The so-called bearing cartridge can be prefitted as a floodable version and exchanged for the fitted cartridge (during production); and all this without removing the complete centrifuge and sending it to the manufacturer’s works. After the conversion, the complete centrifuge can be flooded up to the cover.

Bibliography
[1] EG-GMP Guide, Appendix 15
[2] Jörg Koppenhöfer; Efficient and cost-saving cleaning validation in the area of active ingredients and substances in multifunction systems, gempex, GmbH, Mannheim, Source: http://www.gempex.com/
[3] Dr. Bernd Köhler und Dr. Carsten Richling; Planing, implementation and documentation of cleaning validation in the pharmaceuticals industry, SWISS PHARMA 25 (2003) No. 9.
[4] FDA Guide for inspection of the validation of cleaning processes; http://www.fda.gov/ICECI/Inspections/default.htm
[5] PIC/S PI 006; Recommendations for validation master plan; GMP Consultant, GMP-Verlag, Schopfheim (2003)
[6] D. Borchert; Cleaning validation (Bd. 1, Chapter 8.B-8.K), GMP Consultant, GMP-Verlag, Schopfheim (2003

BRET - a new method for assaying protein-protein interactions in living cells

This method, called bioluminescence resonance energy transfer (BRET), takes advantage of a naturally occurring phenomenon, namely, the Förster resonance energy transfer between a luminescent donor and a fluorescent acceptor. BRET can be observed in the sea pansy Renilla reniformis. This organism expresses a luciferase, which emits blue light when it is purified. If the luciferase is excited in intact cells, green light occurs, because in vivo the luciferase is associated with the green fluorescent protein (GFP), which accepts the energy from the luciferase and emits green light.
The transfer efficiency depends on the degree of the spectral overlap, the relative orientation, and the distance between the donor and acceptor. BRET typically occurs in the 1-10 nm regions, which is comparable with the dimensions of biological macromolecules and makes BRET an ideal system for the study of protein-protein interaction in living cells.
BRET – the assay method
BRET is an advanced, non-destructive, cell-based assay technology that is perfectly suited for proteomics applications, including receptor research and the mapping of signal transduction pathways. The assay is based on non-radiative energy transfer between fusion proteins containing a bioluminescent luciferase and a GFP mutant.
In most applications the fused donor is Renillaluciferase (Rluc) rather than aequorin, to avoid any intrinsic affinity for Aequorea-derived GFP mutant; the acceptor is the Yellow Fluorescent Protein (YFP), to increase the spectral distinction between the two emissions. When the donor and acceptor are in close proximity, the energy resulting from catalytic degradation of the coelenterazine derivative substrate is transferred from the luciferase to the YFP, which will then emit fluorescence at its characteristic wavelength.
To demonstrate the clear discrimination between positive and negative control of the BRET assay technology, the luminescence and fluorescence signals of the BRET^2™demo kit (Perkin Elmer Life Sciences) were quantified on the microplate reader POLARstar OPTIMA (BMG LABTECH, Fig.1), allowing the monitoring of the kinetic curves and the calculation of the BRET ratio. The POLARstar OPTIMA´s internal reagent injectors for 384-well plate format combined with high-end simultaneous dual emission detection offer a unique advantage for fast kinetic assays where simultaneous emission detection at two wavelengths is required.
The BRET²™demo kit applies the cell-permeable and non-toxic coelenterazine derivative substrate DeepBlueC™ (DBC) and a mutant of the Green Fluorescent Protein (GFP²) as acceptor. These compounds show improved spectral resolution and sensitivity over earlier variants.
Fig 1: The POLARstar OPTIMA is perfectly suited for monitoring BRET assays due to its simultaneous dual emission detection system, which allows collecting 50 kinetic data per second, and its internal reagent injectors for 384-well plate format.
The BRET² kit was performed as described in the kit instructions. The reaction was measured in a white 384-well plate at two channels in simultaneous dual emission detection mode with the highest possible resolution of 0.02 s for every data point. Four sets of samples were run in triplicate, a blank (non-transfected cells), a positive control (Rluc-GFP²), a negative control (Rluc + GFP²), and a buffer control (BRET² assay buffer). Readings were started immediately after the automated injection of the luciferase substrate DBC.

The kinetic curves of the negative control are shown in Fig.2 for both channels. The low values of the 515 nm channel indicate that no resonance energy transfer occurred. Whereas the positive control shows reduced values at the 410 nm and elevated values at the 515 nm channel due to the BRET effect.
Fig 2: Resonance energy transfer is obvious for the positive control. No BRET occurs for the negative control.
The calculated BRET ratio indicates the occurrence of protein-protein interaction in vivo. This type of detection eliminates data variability caused by fluctuations in light output which can be found with variations e.g. in assay volume, cell types, number of cells per well and/or signal decay across the plate. In Fig.3 the blank corrected BRET² ratios for both, negative and positive control, are shown and were determined as:

The signal for negative and positive control here reveals a value of around 0.06 and 3.3 respectively, which leads to a factor of around 50 and a clear discrimination between these controls.

BRET - a new method for assaying protein-protein interactions in living cells

Category: BRET

The signal for negative and positive control here reveals a value of around 0.06 and 3.3 respectively, which leads to a factor of around 50 and a clear discrimination between these controls.
Fig 3: Ratio of negative and positive control.
The high factor between these controls is caused by the artificial fusion construct of the positive control (Rluc-GFP²) resulting in an extremely high BRET. Real assay samples will presumably result in lower ratios. Nevertheless, the large spectral resolution between donor and emission peaks in BRET² (115 nm) greatly improves the signal to background ratio over traditionally used BRET and FRET technologies that typically have only a ~50 nm spectral resolution.³
Advantages of BRET over FRET
The BRET technique is related to an existing method for monitoring biomolecular interactions and conformational changes, fluorescence resonance energy transfer (FRET). In FRET, the luminescent donor is replaced by a second fluorophore, which emission spectrum overlaps with the excitation spectrum of the acceptor fluorophore. By using two spectral mutants of GFP, it is possible to genetically attach donor and acceptor fluorophores to proteins, which allows the study of protein interactions in native organisms under physiological conditions.
The main disadvantages of FRET, as opposed to BRET, are the consequences of the required excitation of the donor with an external light source. BRET assays show no photo bleaching or photoisomerization of the donor protein, no photodamage to cells, and no light scattering or autofluorescence from cells or microplates, which can be caused by incident excitation light. In addition one main advantage of BRET over FRET is the lack of emission arising from direct excitation of the acceptor.
This reduction in background should permit detection of interacting proteins at much lower concentrations than it is possible for FRET. However, BRET requires the addition of a cofactor and for some applications, e.g. determining the compartmentalization and functional organization of living cells, the GFP-based FRET method is superior to BRET due to the much higher light output.
BRET applications
The BRET technology was first described in 1999 from Xu and colleagues¹ and has been used successfully for a wide range assay types including protein-protein interactions (e.g. interaction of cardian clock proteins¹), GPCR functional assays⁴ (incl. orphan receptors), receptor oligomerization², and protease activity assays in living cells². BRET has been further used for Ca^{2 +} detection. By fusing GFP directly to the luminescent jellyfish luciferase aequorin, which metabolizes coelenterazine in response to binding free calcium ions, a sensor was produced, that reports calcium ion flux by increases in GFP fluorescence.⁵
Conclusion
BRET is a new energy transfer based technique that offers the ability to directly study complex protein-protein interactions in living cells. There is no need for an excitation light source. Therefore photosensitive tissue can be used for BRET, and problems associated with FRET-based assays such as photobleaching, autofluorescence and direct excitation of the acceptor are eliminated. This powerful technology has been applied in a range of interesting applications in academia and drug discovery. Its homogeneous nature and the development of sensitive plate readers, which offers injection features, have made high-throughput screening using BRET in live cells possible.
References

Xu Y, Piston DW, Johnson CH. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc Natl Acad Sci USA 1999;96:151-6.
Angers S, Salahpour A, Joly E, Hilairet S, Chelsky D, Dennis M, Bouvier M. Detection of b₂-adrenergic receptors dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc Natl Acad Sci USA 2000; 97:3684-9.
Mahajan NP, Linder K, Berry G, Gordon GW, Heim R, Herman B. Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence resonance energy transfer. Nat Biotechnol 1998; 16:547-52.
Ayoub MA, Couturier C, Lucas-Meunier E, Angers S, Fossier P, Bouvier M., Jockers R. Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer. J Biol Chem 2002; 277:21522-8.
Baubet V, Le Mouellic H, Campbell AK, Lucas-Meunier E, Fossier P, Brûlet P. Chimeric green fluorescent protein-aequorin as bioluminescent Ca^{2 +} reporters at the single-cell level. Proc Natl Acad Sci USA 2000; 97:7260-5

Fig 3: Ratio of negative and positive control.
The high factor between these controls is caused by the artificial fusion construct of the positive control (Rluc-GFP²) resulting in an extremely high BRET. Real assay samples will presumably result in lower ratios. Nevertheless, the large spectral resolution between donor and emission peaks in BRET² (115 nm) greatly improves the signal to background ratio over traditionally used BRET and FRET technologies that typically have only a ~50 nm spectral resolution.³
Advantages of BRET over FRET
The BRET technique is related to an existing method for monitoring biomolecular interactions and conformational changes, fluorescence resonance energy transfer (FRET). In FRET, the luminescent donor is replaced by a second fluorophore, which emission spectrum overlaps with the excitation spectrum of the acceptor fluorophore. By using two spectral mutants of GFP, it is possible to genetically attach donor and acceptor fluorophores to proteins, which allows the study of protein interactions in native organisms under physiological conditions.
The main disadvantages of FRET, as opposed to BRET, are the consequences of the required excitation of the donor with an external light source. BRET assays show no photo bleaching or photoisomerization of the donor protein, no photodamage to cells, and no light scattering or autofluorescence from cells or microplates, which can be caused by incident excitation light. In addition one main advantage of BRET over FRET is the lack of emission arising from direct excitation of the acceptor.
This reduction in background should permit detection of interacting proteins at much lower concentrations than it is possible for FRET. However, BRET requires the addition of a cofactor and for some applications, e.g. determining the compartmentalization and functional organization of living cells, the GFP-based FRET method is superior to BRET due to the much higher light output.
BRET applications
The BRET technology was first described in 1999 from Xu and colleagues¹ and has been used successfully for a wide range assay types including protein-protein interactions (e.g. interaction of cardian clock proteins¹), GPCR functional assays⁴ (incl. orphan receptors), receptor oligomerization², and protease activity assays in living cells². BRET has been further used for Ca^{2 +} detection. By fusing GFP directly to the luminescent jellyfish luciferase aequorin, which metabolizes coelenterazine in response to binding free calcium ions, a sensor was produced, that reports calcium ion flux by increases in GFP fluorescence.⁵
Conclusion
BRET is a new energy transfer based technique that offers the ability to directly study complex protein-protein interactions in living cells. There is no need for an excitation light source. Therefore photosensitive tissue can be used for BRET, and problems associated with FRET-based assays such as photobleaching, autofluorescence and direct excitation of the acceptor are eliminated. This powerful technology has been applied in a range of interesting applications in academia and drug discovery. Its homogeneous nature and the development of sensitive plate readers, which offers injection features, have made high-throughput screening using BRET in live cells possible.
References

Xu Y, Piston DW, Johnson CH. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc Natl Acad Sci USA 1999;96:151-6.
Angers S, Salahpour A, Joly E, Hilairet S, Chelsky D, Dennis M, Bouvier M. Detection of b₂-adrenergic receptors dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc Natl Acad Sci USA 2000; 97:3684-9.
Mahajan NP, Linder K, Berry G, Gordon GW, Heim R, Herman B. Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence resonance energy transfer. Nat Biotechnol 1998; 16:547-52.
Ayoub MA, Couturier C, Lucas-Meunier E, Angers S, Fossier P, Bouvier M., Jockers R. Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer. J Biol Chem 2002; 277:21522-8.
Baubet V, Le Mouellic H, Campbell AK, Lucas-Meunier E, Fossier P, Brûlet P. Chimeric green fluorescent protein-aequorin as bioluminescent Ca^{2 +} reporters at the single-cell level. Proc Natl Acad Sci USA 2000; 97:7260-5

Sustenance of Clean Room Conditions

By Rashmi Nagabhushan
Director, Thermadyne Pvt. Ltd., Faridabad
Rashmi Nagabhushan is an M.Tech from IIT Delhi and has over 20 years experience in various capacities in group companies of Continental Device India Ltd. She has been associated with Thermadyne Pvt. Ltd., the complete clean room company, for the last 13 years.

Lakhs of Rupees spent in installing a clean room can go down the drain if cleanliness levels are not maintained on a continuous basis. Personnel training and discipline are the key factors. Sustenance guide lines should be followed both in letter and spirit. Clean room discipline can make a success or a failure of a clean facility. People must be motivated and trained to achieve cleanwork habits and follow timely maintenance practices.

Indoor air quality is of paramount importance for human comfort and health. Similarly, indoor air quality of manufacturing facilities plays a vital role in the yield and quality of many products.
There has been a great deal of advancement in building clean rooms suitable for different applications. Many individual national standards and now international ISO standards are available which define cleanliness classes and measuring procedures for their compliance. Guide lines are also available on the cleanliness levels required for various manufacturing facilities. Expertise now exists to achieve even Class 10 and Class 1. But little is said as to how to sustain the built cleanliness. In fact, by and large, the contract between the customer and contractor is on satisfying the ‘as built’ or ‘at rest’ requirements. And in most cases it is found that cleanliness levels in operational conditions are considerably poorer and some times may lead to conflicts between the two parties. First and foremost, many factors are required to be taken into consideration before designing and installing clean rooms to ensure achievement and sustenance of clean room conditions. Some of the important ones are listed below

Factors to be Considered at the Design Stage

Type of industry (to determine class of cleanliness).
Contamination generation by process, abrasion or by constructional materials.
Occupancy and physical activity level.
Contamination level in the surrounding areas.
Presence of heated surfaces.
Equipment lay-out in the room.
Process exhausts.
Future expansion plan.
Statutory requirements

Having given due consideration to the above factors and achieving the desired conditions at start-up why do most facilities fail to sustain the desired cleanliness levels on a long term basis?
The reasons sound very trivial, but their impact is unbelievable. The unhappy situation can be largely attributed to lack of personnel discipline which results in many short comings and ultimately in the failure of the clean room. If however the following practices are followed we can save the situation.

Steps to be Taken after Clean Room Installation

Personnel training.
Proper maintenance of air conditioning systems and other clean air systems to ensure that required air quantity is supplied on a continuous basis.
Timely cleaning / changing of filters, again to ensure that designed clean air quantity is maintained.
Proper and continued use of change room entry equipment.
Proper gowning.
Clean room discipline.
Scheduled cleaning of clean rooms.
Strict observance of equipment maintenance practices for clean rooms.
Regular monitoring of clean room conditions.

Some guide lines are available on the above which have been highlighted at the end however due to lack of appreciation of cause and effect, people tend to take them lightly thus causing degradation of facilities.
Being a clean-room company, installing and validating clean rooms, we have first hand experiences on the main culprits which lead to problems of sustenance of air cleanliness. To give you an insight into some of the problems, a few case studies are listed below.

CASE STUDY - 1

A class 10,000 facility was successfully installed. On revalidation after 6 months, particle counts were found to be in the range of 2 to 3 lakhs. It was observed that clean-room gowning procedures were not being followed properly, specially in terms of shoes. The surrounding area of the building also had rubble and people were bringing in a lot of dirt. The situation was worsened by the constant movement of people inside the clean area.
A thorough cleaning-up of the area, proper gowning and proper changing of clean room slippers brought back the clean conditions. See Table 1.

Table 1 – See case study 1
Designed Class - 10,000 0.5μ and above particle count (Average)			Number of Hepa filters - 16
	Production Area	Change Room	Observations
At Startup	3220	3100	Within specified limits
After 6 months	210,000	350,000	Dirty shoes inside change room. Gowning improper. Air shower not used properly. Sleepers washed once in a month. Water tap inside change room.
After one year	170,000	294,000	Shoes outside change room. Rest same as above.
After 1.5 years	81,000	140,000	Dresses in garment storage cabinet, new dresses. Three times floor cleaning (wet). Worker discipline better.
After 2 years	14,000	34,000	Air curtain at change room entrance. Proper discipline.
After 2.5 years After 3 years	6600 4930	32000 14300	Filters not changed.

CASE STUDY - 2

In another case filters choked unevenly due to dampers not being provided independently for each filter. The choked filters i.e. four out of twelve were replaced. This resulted in most of the air coming through the new filters resulting in pockets of unclean area and also, generally a higher count due to turbulence caused by high velocity through clean filters. See Figure 1.

CASE STUDY - 3

One small company asked us to do their clean-room validation. We found the particle counts to be high. On investigating we found that out of four terminal Hepa filters two were replaced by fine filters after choking. Since the air discharge from the filters was through perforated grilles it took us some time to figure out the problem.

CASE STUDY - 4

Filters were choked and sufficient air quantity was not reaching the area, resulting in negative pressure inside the area. Each time the entry door was opened, dirty air was coming in. The problem was accentuated as an additional exhaust was fixed for a new process machine which was not taken into consideration in the initial design.

CASE STUDY - 5

An otherwise satisfactory facility failed miserably on start-up. It was found that machines were crowding the clean room very badly and not allowing proper air flow.
Besides, unclean compressed air was being used freely, resulting in a total collapse of the clean area.

CASE STUDY - 6

Window air conditioners were added subsequently to supplement cooling of an existing clean facility. Installation was done very poorly leaving gaps between the air conditioner and the window cut out. Also some unfiltered fresh air was getting added through the window air conditioner.

CASE STUDY - 7

In another case a good clean room (Class 10,000) deteriorated badly due to influx of additional people and machinery to cope with the sudden increase in production capacity.

CASE STUDY - 8

One laboratory which was near a railway line developed cracks in the ceiling due to vibration and resulted in high particle count. A patch up did help but ultimately the laboratory had to be shifted to another location.

CASE STUDY - 9

A satisfactory clean facility detiorated within six months. A thorough investigation revealed that the fan used in the air handling unit did not have the desired static pressure capability. Inadequate clean air supply resulted in negative pressure and ruining of the facility.

Other Observations

In some cases cracking and detaching of sealing compound in Hepa filters with time was found to be a major reason of failure.
In a number of cases, damaged Hepa filters were found to be in use in spite of the concerned people being aware that this would cause problems.
While choked filters are replaced, their installation does not get adequate attention due to inadequate training of maintenance staff. Thus we get either dirty clean rooms or quickly choked Hepa filters.
Validation is not done at regular intervals. If you don’t monitor the clean room, you can sit pretty without any warning till you collect losses due to rejection of products.
In many cases even at the first validation, initial results are poor. But a through cleaning of the area invariably results in the designed class of cleanliness.

Recommendations for Maintaining Existing Clean Room Conditions in the Clean Room Area

Only authorised personnel should enter the clean rooms. • No body should be allowed into the clean room without wearing clean room garments including cap and clean room shoes/chappals properly.
Always stay in the “air shower” for a specified time before entering clean rooms.
After the use of garments and shoes, these should be kept at a proper place. Never go into “nonclean” areas from change room with garments or shoes.
Do not walk into a clean room unless necessary.
Smoking in the clean room and change room is prohibited.
Do not take contamination producing material like tobacco, food, match boxes, purses, cosmetics, card boards and unnecessary papers inside the clean areas. Also do not apply cosmetics in the clean area.
Do not sharpen pencils in the clean room and use a ball point pen only. • Wear gloves and finger cots whenever required.
Do not touch contaminated articles or surfaces after wearing finger cots/ gloves.
Do not scratch your head or rub your nails inside the clean room or change room and keep finger nails clean.
Do not take personal items into clean room, keep them in lockers provided.
Keep your work table clean.
Clean / change filters in the air conditioning system as and when required.
Never sweep the clean room floor, vacuum them or wet mop them as per frequency specified.
Clean walls, ceilings and furniture as per frequency specified with wet mop.
Garments should be washed as per frequency specified.
Clean all furniture, equipment and raw material packages etc. properly before taking into clean room.
Do minimum maintenance of equipment inside the clean room. Take the equipment outside the clean room for maintenance.
Unpacking of the machinery required for the clean areas should be done outside the clean room.

Clean room discipline which covers all the points listed earlier and above can make a success or a failure of a clean facility. People must be motivated and trained to achieve clean work habits and follow timely maintenance practices

Pharmaceutical info

Friday, January 20, 2012

Ask the Facilities Guy: How do I produce a Disaster Recovery Plan?

Pharma Facility Quality Audits: A Primer for Design Teams

Why Static-Control Flooring Is So Important - And How to Find Solutions to Keep You Grounded

Failure Modes and Effects Analysis (FMEA)

Point of View: An Apple To Apple Comparison on Cleanroom Proposals

Monday, January 9, 2012

Cleaning validation in the pharmaceuticals industry:

BRET - a new method for assaying protein-protein interactions in living cells

BRET - a new method for assaying protein-protein interactions in living cells

Category: BRET

Sustenance of Clean Room Conditions

Factors to be Considered at the Design Stage

Steps to be Taken after Clean Room Installation

CASE STUDY - 1

CASE STUDY - 2

CASE STUDY - 3

CASE STUDY - 4

CASE STUDY - 5

CASE STUDY - 6

CASE STUDY - 7

CASE STUDY - 8

CASE STUDY - 9

Other Observations

Recommendations for Maintaining Existing Clean Room Conditions in the Clean Room Area

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