Cleanroom Protocols

By an eHow Contributor

1. A clean room is an artificially created hyper-sterile environment used in medical and scientific research facilities. They are intended to create an environment as free of pollutants and impurities as possible during the course of delicate procedures. Clean rooms are strictly regulated, and have very clear protocols for exit and entry that must be followed, as well as proper clothing and environmental controls.

Personal Hygiene

2. Personal hygiene is extremely important when entering a clean room. Human beings cause 75 percent of the impurities found within a clean room and therefore the majority of the measures taken must affect them. Before even arriving at the clean room, a person must have showered before coming over. Any problems with dermatitis and dandruff must be controlled. Smoking before entering a clean room is prohibited. No chewing gum or tobacco can be taken into the clean room. No cosmetics can be worn in the clean room, and all facial hair must be covered.

Proper Attire

3. Proper attire is also extremely important. First off, everyone entering a clean room must wear shoes that cover their entire foot. All outer clothing, such as jackets, hats or fuzzy sweaters, must be removed. It is a good idea to generally avoid any clothing that sheds fabric in any way. No sleeveless shirts, shorts, skirts or jewelry that could potentially damage or puncture any of the specialized clean room garments are allowed.

Gowning

4. Once the person entering the clean room has the proper attire, they can undergo gowning. Every person entering a clean room must wear a hair cover, a hood, shoe covers, coveralls (or a "bunny suit"), gloves, a face mask and safety glasses. The subject must put the coveralls on first, followed by the shoe covers. Next, he puts on the safety glasses, the plastic gloves and the face cover, and then raises his or her hood.

Entering and Leaving

5. People must enter and leave the lab as quickly as possible. They must keep any sneezes, coughs or nose blows as discrete as possible, or even leave the room beforehand if they can. The amount of things inside the lab must be kept to an absolute minimum. Only one person should enter or exit the lab at a time. Everything kept inside the clean room must remain inside the clean room at all times. Nothing from outside the clean room that is not authorized can be brought into the clean room.

Chemicals

6. All chemicals used in the clean room must be properly stored. Users of chemicals must always read the MSDS for every chemical they use. Any large amounts of chemicals must be kept outside the clean room.
   
   The following materials are not considered proper for a clean room: wood pulp- based products, styrofoam, powders, erasers, pencils or felt-tipped pens and anything that easily shreds or dissipates.

Requirements for a Class 100 Cleanroom

A clean room is a room with air that meets federal standards for cleanliness set forth by the United States Federal Standard 209. The standard is called the Cleanroom and Work Station Requirements, Controlled Environments. It was originally published in 1963 but has been revised several times since then. Air can be contaminated by hair, skin, particles from machines and equipment, bacteria and cleaning agents. Clean rooms are required for a variety of purposes including scientific experiments and manufacturing of pharmaceuticals and some machines and electronic equipment.

Class 100 Standard

For a room to qualify as a class 100 clean room, there must be fewer than 100 particles that measure greater than 0.5 micrometers per cubic foot of air. This is the equivalent of an International Organization for Standardization or ISO class 5 rating.

Cleaning Procedures

In order to maintain clean air at a class 100 standard, the room must be cleaned regularly. High Efficiency Particulate Air, or HEPA, filters are used to maintain air cleanliness. In addition, according to the Coastwide Laboratories website, the room must be mopped and trash taken out daily. Wiping down the walls and vertical surfaces must be completed weekly. The tacky mats at the entrance to the room must be pulled every two hours.

Dress code

According to the Fermi National Accelerator Laboratory website, individuals entering a class 100 clean room must step on a sticky mat prior to entering the dressing room to prevent bringing contaminants in on their shoes. A lab coat or coveralls should be worn and booties should be worn to cover shoes. Finally, hair should be secured in a hair net and approved gloves should be worn.

Other Regulations

In addition to the dress code, individuals may not have food, drink or gum in the clean room. Make-up, hair products, lotion and fingernail polish is also prohibited and jewelry must be removed prior to entering the clean room. Paper and fabric towels are not to be used; rather the room should be equipped with a hand drier.

Cleanroom Entry Procedures

The Pre-Change Zone

This area contains things like lockers for outerwear clothing, and cleaning mats for your shoes. This is where you should remove all jewelry, watches and items like cigarettes, wallets and keys. All cosmetics should be removed, and a disposable hairnet should be put on to keep stray hair from sticking out from the cleanroom hood. There are even beard covers, should they be needed. Depending on the facilities, there may be over-shoe coverings to put on, or they may have specific footwear dedicated to use in the cleanroom. There may also be a sink or hand washing system in this area.

The Changing Zone

Sometimes the handwashing area will be located in this area instead of in the prechanging zone. Either way, wash your hands thoroughly before changing into the cleanroom garments.

In this area you will put on cleanroom outer garments. Here you may find a hood, face mask, coveralls and overboots or a cap, gown and over-shoe coverings, depending on the type of cleanroom and the facilities. For either of these, changing requires that the garments be put on top to bottom. Put on the face mask or hood first, and then the coverall (or gown). It's important that the gown does not touch the floor at any point. If a coverall and hood are used, the hood should be tucked into the collar.

The Cleanroom Entrance

There is often a bench marking the crossover point between the changing area and the cleanroom entrance. This is to allow for the proper fitting of the overboots or over-shoe coverings. Once the overboot is on, it should not touch the floor of the changing room, and so you should sit on the bench, fit one foot with the overboot, put it in the cleanroom entrance area, and then do the same with the other foot. Put on the cleanroom gloves now, gripping them at the cuffs to keep them uncontaminated while they're being put on. If necessary, this is also the time to put on protective eyewear.

Injection Molding under Cleanroom Conditions

What must be an unexpected trend for many injection molders is the growing demand for plastic articles that must be produced under cleanroom conditions. Inquiries are being received from medical, pharmaceutical, and cosmetics manufacturers; the bio-technology industry; and electrical and electronic equipment makers. The realistic size of the investment required depends on the product specifications. Although these plastic materials are processed using a variety of methods, particular ambient conditions must be met in almost every case. For example, GMP guidelines and other requirements govern production under cleanroom conditions of articles destined for medical or pharmaceutical purposes.
Cleanroom installation located at Createchnic AG (Nürensdorf, Switzerland). Photo courtesy of Dittel Cleanroom Engineering
This article is the first in a two-part series on the use of injection molding techniques for medical device production under cleanroom conditions. The first part focuses on design considerations. The second part will identify issues related to facilities qualification and process validation.
BASIC REQUIREMENTS FOR DEVICE PRODUCTION
Appendix I of the Medical Devices Directive contains the fundamental manufacturing requirements for all medical products marketed in Europe. Among other things, the directive states that microbiological and particulate cleanliness, and the surrounding conditions under which medical devices are manufactured, must be guaranteed. These requirements point out clearly that the air in premises where medical products are being made must be free from germs and particles.
For pharmaceutical or medical engineering enterprises, a commitment to maintaining appropriate cleanroom technology is obligatory as part of complying with normal regulations, such as the GMP requirements. Changes that occur in market conditions can also demand respective precautions from other industries. Under such circumstances, the extent of the commitment to cleanroom processing needed by injection molders depends on the product specifications. Optimal cleanroom solutions adapted to suit individual specifications must be cost-effective and leave room for expansion.
ENVIRONMENTAL SPECIFICATIONS FOR CLEANROOMS
When planning a cleanroom operation, particular attention must be paid to dust sources. Of course humans are the largest individual source of dust. Dust particles are produced by human beings and their activities in vast quantities, even though most particles produced are smaller than 0.5 µm. The number of particles measuring 0.3 µm or less produced per minute is subject to the speed and kind of movements being made. Table I illustrates the typical amount of particulate matter produced by humans making typical movements.

Type of Movements	Numbers of Particles Produced per Minute
Seated or standing (not moving)	100,000
Seated (making slight movements)	500,000
Seated (moving arms or trunk)	1,000,000
Moving from sitting to standing	2,500,000
Walking slowly	5,000,000
Walking swiftly	7,500,000
Walking up steps	10,000,000
Athletic activity	15,000,000 – 30,000,000

Table I. Particulate matter produced by human activities.
In a room devoid of air currents, the human body emits dust particles continually in a radial direction. In this instance, however, dust particles larger than 5 µm are numerically unimportant, because they can be removed by appropriate cleaning methods. All the same, they must not be neglected, because their high speed of descent generally causes them to come to rest on horizontal surfaces and on or near the floor. Ultimately, they are raised as dust repeatedly by people walking around the area.
Because the constant production of dust is unavoidable, the overall number of particles must be reduced to a specified minimum using a suitable means. Subject to specific requirements, the lower the percentage of dust that will be permitted in a planned production plant, the higher the required investment for the design of the room and the selection of construction materials will be, and the more complex the instructions governing the conduct of the people who work there.
High categories of cleanliness are always associated with high investment costs. When planning, it is therefore important to ensure that the cleanroom conditions not only meet the specification profiles of the articles to be produced, but also those of the various production stations. Skillful planning can achieve different degrees of air purity at significantly reduced air volume inside a room. This will save on investment and utilization costs. After all, forward-looking planning offers a chance to design a flexible production layout. In most cases, expansion or organizational changes of a flexible layout can be put into practice at justifiable costs.
In Europe, cleanrooms of Class 6 (100,000 particles/cu ft) and those of Classes 5 to 3 (10,000 to 100 particles/cu ft) are generally specified for injection molding.
FUNDAMENTAL DESIGN CONSIDERATIONS
Cleanroom design, including the technical aspects of the premises and room, is generally a function of the cleanliness category and subsequently is subject to regulatory oversight. In order to prevent mistakes in planning, a project team should be established as early as possible. Apart from cleanroom experts and the customer's or user's representatives as well as those of the molder, the team should include specialists from the machinery manufacturer, mold maker, and material supplier. Subject to a planned production budget, it may also be expedient to consult experts from the raw materials, processing, packaging, and handling fields.
Modifying Injection Molding Machines for Device Production inside Cleanrooms. To integrate injection molding machines in a cleanroom-installed production line of Class 6 or better is comparatively easy in most cases. Machines can be equipped with either a horizontal or vertical clamping unit. Smooth, clean surfaces are required. Surfaces with nonslip or antislide coatings that cover walk-on surfaces must be removed because dirt particles will adhere to them. Connections for electrical supply lines should be installed in the machines' lower sections, close to the floor. All moving parts, particularly column bushes, should be self-lubricating and maintenance free.
Before installation and commissioning, the injection molding machine must be subjected to complete and thorough cleaning. To accomplish this, any contamination must initially be removed with conventional cleaning agents, followed by washing the machine down with cleaning spirits. From that time on, all persons working within that area must wear the apparel prescribed for that cleanliness level. For some levels, they must be dressed in special working clothes. This also applies to visitors, such as the machinery manufacturer's technicians. It is self-evident that all other cleanroom regulations must also be observed--such as absolutely no smoking within the room.
Ideally, the air-conditioning layout dictates machine installation in the production area. An optimum location for the clamping unit is directly underneath an air outlet to achieve a flow of cleaned air that is as uniform as possible over the mold.
Injection Molding Machines for Cleanroom Class 3. Injection molding machines must meet more extensive requirements for operating under Class 3 cleanroom conditions, with their outfitting governed by the products to be molded. Specifications for production plants manufacturing articles for the medical, biotech, or pharmaceutical industries are considerably more restrictive than those for other technical products. Application of a coat of antistatic paint and enclosure of the clamping unit may be necessary. Dead corners must be avoided to prevent dirt from collecting unchecked. Window frames and windows in covers must fit flush with the sheet metal on the inside to prevent dirt from collecting on protruding edges. In addition, all rubber hoses must be sheathed in plastic, and any tapped holes not used for mold retention in the platens should be closed.
In general, an almost laminar airflow is conducted through the clamping unit and thus the mold for a Class 3 cleanroom. The less obstructed the airflow through the machine, the easier it is to achieve and maintain the desired quality. That is why machine covers have to be smooth on the inside and tight at the sides. The introduction of air in a Class 3 cleanroom also affects the design of the clamping unit. In principle, an injection molding machine with a vertical clamping unit would also be suitable. In such a configuration, however, air introduction and extraction would become considerably more elaborate and therefore more expensive because the airflow must be conducted horizontally across or through the mold for extraction at the opposite side. It is possible that a different solution might be more cost-effective.
Such considerations are also of importance for the machine installation sites. If a complete molding shop is to be established in a Class 3 cleanroom, the machine siting plan must be determined in conjunction with space planning. A modular room-in-room solution is the most cost-effective and allows great flexibility. For that purpose, the machine hall can be established to conform to a lower cleanroom category, such as Class 6. On the injection molding machines, only the clamping units and any existing handling units must be enclosed by modular cabinets, if necessary. The cabinets must contain a ceiling filter for Class 3 and fans to supply precleaned air from the surroundings.
Electrical supply lines to the machines must be run as a function of the building's structural solution. If the entire shop is to be a Class 3 cleanroom, the lines must either be routed up through the floor for direct connection to the machines or enclosed and sealed within appropriate ducting. If the machines are enclosed, including partial enclosure in cabinets, lines must be run outside these cabinets. The actual connections must be close to the floor, which means below the mold area.
Before a machine intended for production in a Class 3 cleanroom may be installed, it must be given an overall, thorough cleaning outside that zone. Machine enclosure follows, if necessary, and another thorough cleaning is performed to achieve the "clean" status. From that point on, personnel must don regulation protective clothing, including hoods. Acceptance measurements that have also been specified can now be carried out.
Machine and Mold Maintenance. The maintenance of machines employed in cleanroom production is particularly important. Regular maintenance performed on the machines must be differentiated from cleaning jobs that must be completed just as frequently.
Machine maintenance is important because almost every malfunction can result in contamination of the machine, mold, or surroundings. Machine stoppages are considerably longer in these cases because of the necessary overall cleaning. It therefore makes sense to comply strictly with the maintenance intervals stipulated by the machine's manufacturer, including replacement of seals before they cause breakdowns through aging. Both machines and plants must be subjected to a weekly general cleaning to remove precipitation, dust particles, and other contamination. Depending on the article produced, cleaning may need to be more frequent. Gross contamination must be removed immediately, and if contamination should occur regularly, its source must be found and rectified.
The training of operators and maintenance personnel is also important. Experience has shown that the customary single instruction session is woefully inadequate. It is essential that employees receive follow-up instruction so that the necessary understanding is maintained and extended under difficult working conditions.
Injection Molding Tools for Cleanroom Production. The production of injection molding tools that meet relevant cleanroom specifications can be described as a specialty discipline mastered by only a few mold makers. One of the main difficulties is the restriction of lubricant use. In cases where this requirement is insurmountable, the lubricant must not be permitted to enter the mold cavity area under any circumstances; the lubricant must be diverted to the mold's inside by applying an appropriate pressure difference.
For obvious reasons, release agents are not allowed in cleanroom production. Pneumatic cylinders operated with cleanroom air are permitted for ejector movements; however, article demolding as such must not be supported by air blasts. Strippers actuated either mechanically or by pneumatic cylinders should be employed for that purpose. The positively guided mechanical version is preferred because it is more reliable, and ensures controlled demolding. With most of the other methods, a molding can stick in the mold and get deformed during subsequent mold closing, requiring the mold to be cleaned completely.
It is self-evident that sprue must be avoided. This can be achieved with pin-gating, for instance. Hot-runner molds are not always expedient because nozzles tend to leak, allowing contamination through melt or gases.
With cleanroom production, mold changes can be time-consuming and costly--particularly so in classified cleanroom areas. This becomes apparent with the preparations. Initially, the mold must be dismantled completely and cleaned under cleanroom conditions. A laminar-flow box that stands outside the cleanroom would be suitable for this purpose. The box can also be used for subsequent reassembly of the mold. After that, the mold is either encapsulated in a triple layer of film, which is then sealed by welding, or it is packed in a special transport box. The outer layer of film may only be removed in the cleanroom antechamber. The second wrap is taken off in the air lock between the two different clean zones. The inner, third wrap is only removed at the machine.
Raw Materials and Raw Material Supply. For the production of articles in classified cleanroom areas, only those plastic materials that have been produced under particularly clean conditions are allowed to be used. The characteristic profile of the molding materials employed is subject to the user's or customer's specifications, as well as the planned application for the finished articles. Some of the criteria for plastics used in medical applications are listed as: cleanliness, good rheological properties and physiological performance, biological compatibility, and color tolerance. Materials should be delivered in appropriate containers that have been sealed airtight by welding.
It is expedient for processing material to be fed to the machines by a centralized enclosed conveying system with an integrated, special extraction system. Alternatively, vacuum-operated feed systems attached to machines are feasible. All metering units must be operated with clean air. Even pipeline installations must conform to cleanroom conditions because abrasion fines must not be allowed to contaminate the plastic material. Pipe systems must be grounded to prevent them from becoming electrostatically charged.
Before they are processed, hydrophilic plastics must be dehydrated in special dryers outside the cleanroom. Under certain circumstances, it may be necessary to apply clean, dry air to the dehydrated granulate in order to remove any dust particles.
Molding and Downstream Processing. Once the machine has been equipped and the raw-material feed system has been set up, production can start. Depending on individual cases and particular regulations in force at the time, articles can either free-fall out of the machine on demolding or be removed by a handling unit. In a cleanroom production situation, a handling unit is usually mandatory. The reason: despite special protective clothing and every precaution, human beings are still the greatest source of generated dust and contaminants. Either special containers that can be sealed gas tight, gas tight bags, or pneumatic tubular conveying systems are suitable for catching free-falling articles. If bags are used, three of them must always be employed, nesting one inside the other. Each bag must be individually weld-sealed before being transported to areas outside the production zone. Pneumatic or vacuum conveying systems can be used where articles are conducted directly to workstations for finishing. These finishing stations are subject to the same basic conditions as those governing injection molding machines in cleanrooms.
Production Monitoring and Documentation. Cleanroom production without documentation would be unthinkable. The extent to which documentation needs to be applied ultimately depends on the actual use of the completed component, and the customer's specifications. All cleanroom production monitoring is, in principle, based on optimum aspects, in the interest of trouble-free operation alone.
Aside from the material-specific, article-related monitoring and checking actions, other forms of control are also required with cleanroom production. These concern regular analysis of the cleanroom air, for instance, to ensure that purity class is maintained, or special random checks of machine and article surfaces when producing moldings for the medical industry.
The correct attitude of factory employees should not be underestimated as an important criterion for quality-conscious production. This also expressly includes top management, which must comply with the same strict regulations that will become self-evident for the operators after appropriate and regular training.
Rules of Conduct for Personnel. Cleanroom working conditions cannot be compared with those maintained at normal workstations. Apart from the special rules of conduct and statutory regulations, the strain on personnel health must not be underestimated. Climatic and other conditions in cleanrooms, such as the continuous draft, can increase stress.
Cleanrooms are restricted areas and access must only be allowed to authorized persons. In general, people entering cleanrooms must be wearing protective clothing. Under no circumstances should this clothing be worn outside cleanrooms, and the clothing must be changed immediately after becoming contaminated. Naturally, smoking and the presence of food in cleanrooms is prohibited.
The mental attitude of all employees is of great importance, including the top echelons. Teams employed in cleanrooms must be prepared to accept without objection the specific demands that cleanroom operations entail. It is essential in cleanroom facilities to develop and strengthen a distinctive cleanroom conscientiousness. Accordingly, all other areas in the factory must be considered as contaminated, and for personnel to be aware of contamination is important.

What is a clean room?

What is a clean room?
Generally speaking, a "Clean Room" is an enclosed room that has equipment which controls the amount of particulate matter in the air by using air pressure and filters. To meet the requirements of a "Clean Room" as defined by Federal Standard 209E and newer ISO standards, all Clean Rooms must not exceed a particulate count as specified in the air cleanliness class.

What are the room classes?
Standards have changed in the last few years. Federal Standard 209E classified rooms in numbers: Class 1, Class 10, Class 100, Class 1,000 Class 10,000 and Class 100,000. This method is simple, the number assigned to the class is the classification that the room must be designed to. Class 1 was the cleanest. The new ISO 14644-1 (or British Standard BS5295) has changed these numbers to simple classes: Class 3, Class 4, Class 5, Class 6, Class 7 and Class 8. Class 3 is the cleanest.

The difference? Generally speaking, federal standards are measured in cubic feet and the ISO standards are measured in cubic meters.

What is measured in the air? Class 3, 4 and 5 are based on the maximum number of 0.1 and 0.5 micron particles that are permitted in a cubic foot of air approaching any work operation within the room. Class 6, 7 and 8 are based on the number .5 micron particles.

What is a micron? To give you an idea of what is being measured, one micron is one-hundredth the width of a human hair. The smallest particle seen with the naked eye is a 10 micron particle. Clean rooms can control .01 and .05 particles!

Where do these particles come from? The clean room is under positive pressure, keeping out new particles from coming in. So where do they come from? Micro-organisms come from people in the room and other particulates from the processes in the room. Microbes come from skin cells of humans. We shed our outermost layer of skin every 24 hours, that is 1 billion flakes every 24 hours! One flake is about 35 microns.

Class limits (amount of particles allowed)
Federal 209B Standards:

• Class 100,000: Particle count not to exceed a total of 100,000 particles per cubic foot of a size 0.5 micron and larger or 700 particles per cubic foot of a size 5.0 micron and larger.
• Class 10.000: Particle count not to exceed a total or 10,000 particles per cubic foot of a size 0.5 micron and larger or 65 particles per cubic foot of a size 5.0 micron and larger.
• Class 1,000: Particle count not to exceed a total of 1000 particles per cubic foot of a size 0.5 micron and larger or 10 particles per cubic foot of a size 5.0 micron and larger.
• Class 100: Particle count not to exceed a total of 100 particles per cubic foot of a size 0.5 micron and larger.

ISO or BS 5295 Standards:

• Class 1: The particle counts shall not exceed a total of 3000 particles/m3 of a size of 0.5 micron or greater. The greatest particle present in any sample shall not exceed 5 micron.
• Class 2: The particle count shall not exceed a total of 300,000 particles/ m3 of a size 0.5 micron or greater: 2000 particles/m3 of a size 5 micron or greater: 30 particles of a size 10 micron or greater.
• Class 3: The particle count shall not exceed 1,000,000 particles of a size of 1 micron or greater: 20,000 particles/m3 of a size 5 micron or greater: 4000 particles/m3 of a size 10 micron or greater; 300 particles/m3 of a size 25 micron or greater.
• Class 4: The particle count shall not exceed a total of 200,000 particles/m3 of a size 5 micron or greater: 40,000 particles/m3 of a size 10 micron or greater: 4000 particles/m3 of a size 25 micron or greater.

Air quantity
A properly designed clean room must have a high rate of air changes to scrub the room of particulates. A Class 5 room can have an air change rate of 400 to 600 times per hour while a Class 7 room can change at 50 to 60 changes per hour.

Testing and certification
Once the room is completed, most specifications call for testing and certification. Some requirements state that the room should be test annually also. Testing is usually conducted by an independent testing agency using the ISO Standards. It is also imperative for the owner to purchase a clean room monitor in order to determine the daily status of the room.

Filter Bleed-Through, the Myth, the Reality and the Solution:

Filter Bleed-Through, the Myth, the Reality and the Solution:

Preface:

Filter “Bleed-Thru” is a condition existing primarily in the Bio-Pharm marketplace within Class A areas (fully filtered ceilings). Although a Band-Aid is not required, the outcome of such encounters, when dealing with end users that have a cleanroom off-line, can literally be “bloody” (possibly the real history for the term “Bleed-Thru”). Filter “Bleed-Thru” can be defined as: the measurement of background filter penetration exceeding the leakage specification during field certification.

For example: If the percentage (%) penetration over the entire face of a filter measures 0.02% and the maximum percentage (%) penetration leakage specification is 0.01% , you are experiencing “Bleed-Thru”. This is extremely troublesome to end users where down-time can very quickly translate into tens of thousands of dollars in lost production.

There are several key factors that can have an effect on and/or result in filter “Bleed-Thru”:

*
Inappropriate Filter Specifications
*
Filter Face Velocity
*
Test Particle Size

There are misconceptions within the industry concerning the true cause of filter “Bleed-Thru”. This article will review these misconceptions (myths), provide insight on the true mechanisms resulting in “Bleed-Thru” and recommend solutions.
"Bleed-Through", The Myth:

There is a general opinion, within the industry, that filter or media manufacturers have made a substantive change that has caused “Bleed-Thru. In most cases, the blame is directed towards the media. The claims being made are:

*
The filter manufacturers are using cheap media
*
New medias are thinner than MIL-SPEC media resulting in higher penetration.

Certainly, the newer standard medias are less expensive and thinner than MIL-SPEC media. The standard media grades utilized by Camfil Farr typically have the same percentage (%) penetration specification as the MIL-SPEC media grades *(Remember: percentage (%) penetration is percentage (%) penetration regardless of how you measure it). In identical configurations, these different media grades would perform the same, with respect to percentage (%) penetration. Therefore, media thickness, in this case, has no impact on penetration performance. It does, however, have an impact on pressure drop and its capability to stand-up to very harsh conditions.

As a consequence of higher tensile strength, MIL-SPEC grade media has a pressure drop penalty of nearly 20%!
"Bleed-Through", The Reality:

What is the reality or true causes of filter “Bleed-Thru”? As mentioned earlier, the primary causes are related to Inappropriate Filter Specifications, the Filter Face Velocity and/or the Test Particle Size. Let’s explore each of these possibilities to understand how they impact filter “Bleed Thru”:

Inappropriate Specifications: This is the start or origin of most filter “Bleed-Thru” problems. The typical Face Velocity specified to filter manufacturers for HEPA filters being used in Class A application areas is 90 or 100 FPM. These specifications do not usually set the maximum utilization velocity that the filters will be subjected to in their actual application (in-situ). Since velocity has a significant impact on penetration, the maximum utilization velocity should be the actual test velocity used at the filter manufacturer to guarantee compliance to field testing conditions. Another specification issue is attributed to the efficiency and leakage specification. Most specifications are written referring to industry recommended practices such as IEST (Institute of Environmental Science and Technology) or utilizing the verbiage contained within such a document. Most, if not all Bio-Pharm facilities specify a “type C” or performance indicative of a “type C” filter. The performance level hence specified is a minimum global efficiency of 99.99% on 0.3 micron particles and a fully leak tested (scanned) filter with a maximum leakage rate of 0.01% (which is identical to the global efficiency minimum penetration). The recommended practice of IEST recommends laskin nozzle generated aerosols for leak testing due to this issue of the maximum leakage penetration value being identical to the minimum efficiency value. This helps because the mass mean particle size diameter of a laskin nozzle generated oil aerosol is in the order of 0.7 micron in diameter. This eliminates problems with background penetration and allows you to look only for leakage *(Note: a leak is not particle size selective). If thermal aerosols are utilized, the mass mean particle size becomes much smaller resulting in potential filter “Bleed Thru” problems by design. Since more of these ‘smaller’ challenge aerosol particles will ‘penetrate’, the filter will, therefore, have a lower filter efficiency versus these smaller particles when tested in-situ.

Specifications do not address this issue and leave the field testing requirements up to the certifier. The reality is such that in many cases, field testing requires the use of thermally generated aerosol (which generate smaller challenge aerosol particles by design) to achieve sufficient concentrations which in turn will lead to a higher penetration/lower efficiency filter when tested in the field.

Filter Face Velocity: As stated above, Filter Face Velocities are typically specified at 90-100 FPM in Bio-Pharm applications. However, the actual velocities in-situ are usually significantly higher. It is not unheard of to see Filter Face Velocities at 120, 140, 150 or even as high as 180 FPM in the field. This upward shift in velocity has a rather dramatic negative impact on filter efficiency.

As an example, on the following chart:

Face Velocity vs. Efficiency

As you can see in the table, if the in-situ application subjects the filter to a higher than specified velocity, the filter efficiency drops below the 99.99% level and the result is “Bleed-Thru” in the field. Keep in mind, that if a laskin nozzle generated challenge aerosol is utilized, the possibility of “Bleed-Thru” due to a high application velocity is greatly diminished!!

Test Particle Size: As stated previously, most, if not all Bio-Pharm facilities specify a “type C” or performance indicative of a “type C” filter. The performance level hence specified is a minimum global efficiency of 99.99% on 0.3 micron particles and fully leak tested filter with a maximum leakage rate of 0.01% (which is identical to the global efficiency minimum penetration). The “type C” requirements specify efficiency testing with 0.3micron diameter thermal DOP. In Class A areas (fully filtered ceilings), field certifiers utilize portable thermal generators in order to achieve sufficient upstream concentrations. The problem with these generators, is that they are generating a particle size in a size range very close to or at a typical filter’s MPPS (Most Penetrating Particle Size). If a factory tested filter just meeting the 99.99% @ 0.3 micron efficiency specification is then tested with thermal aerosol in the field, it will likely exhibit “Bleed-Thru” since the efficiency in the field tested MPPS range will always be lower than at the 0.3 micron factory efficiency testing *(likely in the range of 99.996% -99.98%). This is typically not a problem for Bio-Safety Cabinets or Terminal Housings since a laskin nozzle generator is utilized.

*NOTE: you significantly compound the “Bleed-Thru” issue when testing in-situ at higher face velocities utilizing smaller sized (MPPS range) particles.
Filter “Bleed-Through”, The Solution:

The solution is quite simple. The filter specified/purchased by end users should be rated at an efficiency/particle size and maximum velocity to guarantee acceptance when tested with a thermal generator in the field. Simply stated, Camfil Farr would recommend a filter efficiency purchasing specification of H14 per EN1822 (a minimum efficiency of 99.995% @ MPPS). This performance level would be specified at the maximum velocity to be encountered in-situ. The leakage threshold would be set at a maximum of 0.008% at the factory to guarantee 0.01% scanning results in the field.
Summary:
Although filter “Bleed-Thru” has been thought of as a mystery caused by Media and/or Filter Manufacturers, it is evident that the root of such a problem stems from many possibilities. It is clear that a key factor for filter “Bleed-Thru” is related to particle size. The particle size issue stems from the use of portable thermal generators. The use of these generators is typically restricted to Class A areas to achieve sufficient concentrations. “Bleed-Thru”, therefore, generally occurs in these applications and not in applications such as Terminal Housings or Bio-Safety Cabinets. It is vitally important that both end users and filter manufacturers develop an appropriate filter specification, as proposed in the solution section, to guarantee that all filters purchased will meet the field testing requirements.

Filters are and will remain a critical part of the installation to maintain the cleanliness required in Bio-Pharm manufacturing and packaging facilities. Camfil Farr is proud to be the leading manufacturer supplying ‘clean air solutions’ to this industry.

Filter Classifications Table

Classifications Of Clean Rooms

Classifications Of Clean Rooms

Clean rooms are classified by the cleanliness of their air. The method most easily understood and most universally applied is the one suggested in the earlier versions (A to D) of Federal Standard 209 of the USA. In this old standard the number of particles equal to and greater than 0.5 m m is measured in one cubic foot of air and this count used to classify the room. The most recent 209E version has also accepted a metric nomenclature. In the UK the British Standard 5295, published in 1989, is also used to classify clean rooms. This standard is about to be superseded by BS EN ISO 14644-1.
Federal Standard 209

This standard was first published in 1963 in the US and titled "Clean Room and Work Station Requirements, Controlled Environments". It was revised in 1966 (209A), 1973 (209B), 1987 (C), 1988 (D) and 1992 (E). It is available from:

Institute of Environmental Sciences and Technology
940 East Northwest Highway
Mount Prospect, Illinois, 60056 USA
Tel: 0101 708 255 1561
Fax: 0101 708 255 1699
e-mail: iest@iest.org:

The clean room classifications given in the earlier A to D versions are shown in Table 1.
Table 1: Federal Standard 209D Class Limits

FS 209D Class Limits

In the new 209E published in 1992 the airborne concentrations in the room are given inmetric units, (i.e. per m3), and the classifications of the room defined as the logarithm of theairborne concentration of particles ³ 0.5 m m e.g. a Class M3 room has a particle limit forparticles ³ 0.5 m m of 1000/m3. This is shown in Table 2.
Table 2: Federal Standard 209E Airborne Particulate Cleanliness Classes

FS 209E Cleanliness Classes
British Standard 5295:1989

This standard is available from:

B S I Standards
389 Chiswick High Road
London W44 AL
Tel 0181 996 9000
Fax 0181 996 7400
e-mail: info@bsi.org.uk

Because of the imminent publication of EN ISO 14644-1 parts of this British Standard have a limited life. Parts will be superseded by the ISO standards as they appear as an EN standard.

The British Standard is in five parts. These are:

Part 0 - General introduction and terms and definitions for clean rooms and clean air devices. (4 pages)

Part 1 - Specification for clean rooms and clean air devices. (14 pages)

Part 2 - Method for specifying the design, construction and commissioning of clean room and clean air devices. (14 pages)

Part 3 - Guide to operational procedures and disciplines applicable to clean rooms and clean air devices. (6 pages)

Part 4 - Specification for monitoring clean rooms and clean air devices to prove continued compliance with BS 5295. (10 pages)

Part 1 of the standard contains ten classes of environmental cleanliness. Shown in Table 3 are the classes given in the standard. All classes have particle counts specified for at least two particle size ranges to provide adequate confidence over the range of particle size relevant to each class.
Table 3 BR 525 Environmental Cleanliness Classes
BS 5295 Environmental Clean...
BS EN ISO Standard

Because of the large number of clean room standards produced by individual countries it is very desirable that one worldwide standard of clean room classification is produced. The first ISO standard on clean rooms has been published (June 1999) as 14644-1 ‘Classification of Air Cleanliness’. It is about to be adopted as a European standard and hence a standard for all countries in the EU. This standard is available from standard organizations throughout the world and in the UK is available from the BSI. Shown in Table 4 is the classification that has been adopted. Table 4. Selected ISO 209 airborne particulate cleanliness classes for clean rooms and clean zones.

ISO 209 Cleanroom Classes

The table is derived from the following formula:

Cleanroom Classes Formula

where:

Cn represents the maximum permitted concentration ( in particles/m3 of air ) of airborne particles that are equal to or larger than the considered particle size. Cn is rounded to the nearest whole number. N is the ISO classification number, which shall not exceed the value of 9. Intermediate ISO classification numbers may be specified; with 0.1 the smallest permitted increment of N. D is the considered particle size in m m. 0.1 is a constant with a dimension of m m. Table 4 shows a crossover to the old FS 209 classes e.g. ISO 5 is equivalent to the old FS 209 Class 100.

The occupancy state is defined in this standard as follows:

As built: the condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present.

At-rest: The condition where the installation is complete with equipment installed and operating in a manner agreed between the customer and supplier, but with no personnel present.

Operational: The condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon. The standard also gives a method by which the performance of a clean room may be verified i.e. sampling locations, sample volume etc. These are similar to FS 209. It also includes a method for specifying a room using particles outside the size range given in the table 4. Smaller particles (ultrafine) will be of particular use to the semiconductor industry and the large (³ 5m m macro particles) will be of use in industries such as parts of the medical device industry, where small particles are of no practical importance. Fibers can also be used.

The method employed with macro particles is to use the format:

‘M(a; b);c’

where

a is the maximum permitted concentration/m3
b is the equivalent diameter.
c is the specified measurement method.

An example would be:

‘M(1 000; 10m m to 20m m); cascade impactor followed by microscopic sizing and
counting’.
Pharmaceutical Clean Room Classification
EU GGMP

The most recent set of standards for use in Europe came into operation on the 1st of January 1997. This is contained in a ‘Revision of the Annex to the EU Guide to Good Manufacturing Practice-Manufacture of Sterile Medicinal Products’. The following is an extract of the information in the standard that is relevant to the design of clean rooms:

For the manufacture of sterile medicinal products four grades are given. The airborne particulate classification for these grades is given in the following table.

Medicinal Cleanroom Classific...

Notes:
(a) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grades A, B and C.
(b) The guidance given for the maximum permitted number of particles in the "at rest" condition corresponds approximately to the US Federal Standard 209E and the ISO classifications as follows: grades A and B correspond with class 100, M 3.5, ISO 5; grade C with class 10 000, M 5.5, ISO 7 and grade D with class 100 000, M 6.5, ISO 8.
(c) The requirement and limit for this area will depend on the nature of the operations carried out. The particulate conditions given in the table for the "at rest" state should be achieved in the unmanned state after a short "clean up" period of 15-20 minutes (guidance value), after completion of operations. The particulate conditions for grade A in operation given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. Examples of operations to be carried out in the various grades are given in the table below. (see also par. 11 and 12).

Cleanroom Uses by Class

Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.

Microbial Contamination Limits

Notes:
(a) These are average values.
(b) Individual settle plates may be exposed for less than 4 hours.
(c) Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action.
Isolator and Blow Fill Technology (extract only)

The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing be at least
grade D.

Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non-viable limits at rest and the viable limit only when in operation. Blow/fill/seal equipment used for the production of products for terminal sterilization should be installed in at least a grade D environment.
Guideline on Sterile Drug Products Produced by Aseptic Processing

This document is produced by the FDA in the USA and published in 1987. Two areas are defined. The ‘critical area’ is where the sterilized dosage form, containers, and closures are exposed to the environment. The ‘controlled area’ is where unsterilized product, in-process materials, and container/closures are prepared.
The environmental requirements for these two areas given in the Guide are as follows:

Critical areas ‘Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations is of acceptable particulate quality when it has a per-cubic foot particle count of no more than 100 in a size range of 0.5 micron and larger (Class 100) when measured not more than one foot away from the work site, and upstream of the air flow, during filling/closing operations. The agency recognizes that some powder filling operations may generate high levels of powder particulates, which by their nature do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality within the one-foot distance and still differentiate "background noise" levels of powder particles from air contaminants, which can impeach product quality. In these instances, it is nonetheless important to sample the air in a manner, which to the extent possible characterizes the true level of extrinsic particulate contamination to which the product is exposed.

Air in critical areas should be supplied at the point of use as HEPA filtered laminar flow air, having a velocity sufficient to sweep particulate matter away from the filling/closing area. Normally, a velocity of 90 feet per minute, plus or minus 20%, is adequate, although higher velocities may be needed where the operations generate high levels of particulates or where equipment configuration disrupts laminar flow.

Air should also be of a high microbial quality. An incidence of no more than one colonyforming unit per 10 cubic feet is considered as attainable and desirable.

Critical areas should have a positive pressure differential relative to adjacent less clean areas; a pressure differential of 0.05 inch of water is acceptable’.

Controlled areas ‘Air in controlled areas is generally of acceptable particulate quality if it has a per-cubic-foot particle count of not more than 100,000 in a size range of 0.5 micron and larger (Class 100,000) when measured in the vicinity of the exposed articles during periods of activity. With regard to microbial quality, an incidence of no more than 25 colony forming units per 10 cubic feet is acceptable.

In order to maintain air quality in controlled areas, it is important to achieve a sufficient airflow and a positive pressure differential relative to adjacent uncontrolled areas. In this regard, airflow sufficient to achieve at least 20 air changes per hour and, in general, a pressure differential of at least 0.05 inch of water (with all doors closed), are acceptable. When doors are open, outward airflow should be sufficient to minimize ingress of contamination’.

Comparison of CR Standards

This information was compiled from various sources including the listed agencies and the handbook ‘Clean Room Technology’ as written by Bill Whyte.

Effect of protective coating of aspirin tablets with acrylatemethacrylate copolymers on tablet disintegration times and dissolution rates

An important area of application of polymeric film coating of tablets is to protect against moisture degradation [1] . Aspirin for instance is moisture degradable and therefore its tablets require protective coating. Polymer films for this area of application should have a high moisture resistance and should dissolve or swell and disrupt when in contact with aqueous fluids to allow disintegration and dissolution of the tablet, otherwise bioavailability will be compromised. A previous study [2] has indicated that film coating of tablets will invariably lead to increase in disintegration times.

The acrylatemethacrylates are water insoluble but swellable polymers. The presence of cationic (quaternary ammonium) groups in the polymer chemical structure confers the hydrophilic swelling property. Thus, the higher the cationic content the higher the porosity and permeability of resulting films [3] . The polymers have been investigated as binders in tableting [4] , microencapsulation of drug particles for controlled release application [5] .

The present study investigates their applicability in protective coating of aspirin tablets against moisture degradation. Pursuant to this objective the water uptake potentials of the tablets, their disintegration times and dissolution rates were determined.

Two analogous acrylatemethacrylate copolymers designated here as A and B were received under the trade names Eudragit RL and RS, respectively from Rhom Pharma, Darmstadt, Germany. A and B differ only in their cation content in the ratio 2:1(A:B) and have an average molecular weight of 1 50 000. Glycerol triacetate (Sigma-Aldrich, Italy) and ethanol (analar grade, BDH) were used as plasticiser and casting solvent respectively in the formulation of the coating fluid. Aspirin tablets BP were used as substrate (core) in the coating procedure.

A sample of the polymer A or B (5 g) was dissolved in ethanol (100 ml) by overnight stirring. In another aspect of the study, the polymers A and B were mixed in different proportions to form the coating fluid with intermediate cation content [Table - 1]. Glycerol triacetate was added as plasticiser in a concentration of 0.5% w/v to the coating fluid. Aspirin tablets (n=30) were placed in a laboratory-coating pan (Manesty, UK. Model 75096) whilst the tablets were rotating in the pan, the coating fluid was applied in three aliquots of 5 ml each allowing 5 min drying at 60 0 between each application and drying finally for 1 h also at 60 o .

The thickness of the tablets (n=10) were measured with a digital micrometer before and after coating. The difference divided by two gave the film thickness. The tablet thickness before coating was 3240 µm and after coating was 3300 µm (tablets coated with polymer A) and 3296 µm (tablets coated with polymer B). The calculated mean film thickness was 30±8 µm (A) and 28±6 µm (B). The tablet hardness (kg) was determined using a Monsanto hardness tester (Monsanto Chemical USA). Twenty tablets randomly selected were used and mean values are reported. Tablet disintegration test (DT) was determined in 0.1N HCL at 37±0.5 o by the British Pharmacopoeia method [6] . Six tablets were used in each determination. Mean values are reported.

A humidity chamber was created by placing a beaker of supersaturated solution of sodium chloride (500 ml) in a glass chamber giving a relative humidity (RH), 78% at the ambient temperature, 30 o . The weight of the tablets (previously equilibrated in a dessicator for 24 h) was individually determined using a sensitive electronic balance (Mettler Toledo B154, Switzerland) and then placed in a humidity chamber for various time intervals up to a maximum of 24 h. At pre determined time intervals the tablets were removed from the humidity chambers and re-weighed. The percentage (%) increase in weight was taken as the moisture uptake. Different humidity chambers were used for the different sampling intervals such that the tablets were not in contact with the external environment during the storage interval in the chambers.

The stirred beaker method described earlier [7] was followed. In the procedure, aspirin tablet (300 mg) was placed in a basket of mesh size 450 µm which was in turn immersed in dissolution medium i.e. 800 ml water at 37±0.5 o , which was stirred 100 rpm with a Gallenkamp single blade stirrer. At specific time intervals a sample (5 ml) was withdrawn from the leaching fluid. The sample was heated to 100 0 to allow for complete hydrolysis to salicylic acid. Freshly prepared ferric chloride solution (5% w/v, 1 ml) was then added. The sample was allowed to stand for 5 min during which a blue colour developed. Absorbances of the coloured samples were read at 'λmax 540 nm in a UV spectrometer (Unicam, Sp500). The experiment was carried out in triplicate; and the mean absorbances were used to obtain the amount of drug dissolved at the different time intervals.

The data in [Table - 2] shows that tablet hardness increases slightly after film coating compared with the uncoated tablets. For instance, the mean hardness of the uncoated tablets was 4.7±0.5 kg while that for polymer A coated tablets was 5.6±0.5 kg, and for polymer B coated tablets, 5.6±0.7 kg. The difference in tablet hardness was not statistically significant ( p >0.05).

The results of film coating on tablet disintegration time are presented in [Table - 2]. The uncoated tablets disintegrated within half a minute. Coating with polymer A increased the disintegration time to 16 min against the BP limit of 30 min for coated tablets. Coating with polymer B however prolonged the disintegration time considerably up to 115 min, completely outside BP specification. Thus protective coating with polymer B is not recommended while A is recommendable.

Mixing polymers A and B in different proportions gave a means of varying the cation content of the polymeric coating. The data in [Table - 2] indicated that as the cation content increased; DT decreased correspondingly. This finding is attributable to the potential of the cationic groups for promoting hydrophilic swelling of the films [3] , leading to their eventual rupture during disintegration test.

The amounts (%) of drug dissolving from the tablets at the various time intervals are plotted in [Figure - 1]. The dissolution rates were obtained from the slopes of the linear portions of the plot. These were (% h -1 ) 28.3 (uncoated tablets) 16.6 (tablets coated with polymer A), and 14.8 (tablets coated with polymer B). The dissolution rates of tablets coated with films of intermediate polymer cation content are presented in [Table - 2]. These results indicate that polymer B markedly retard dissolution rates, attributable to its effect on the tablet disintegration times noted above. This retarded dissolution rate will have serious implication for bioavailability.

The results are presented in [Figure - 2] which shows that the uncoated tablets absorbed moisture more rapidly than the coated tablets, attributable to the barrier property of the films against moisture transmission. Polymer B, exhibited a slightly stronger barrier property compared to A. The difference can be associated with the higher content of the hydrophilic cationic groups in A. As the cation content increased the extent of moisture uptake will also increase [Table - 2]. This is attributable to the higher cationic content, hence higher porosity and permeability of resulting films [3] .

In conclusion, film coating with the acrylatemethacrylate effectively protect the tablets against moisture uptake. However, polymer B impaired the disintegration and dissolution properties of the tablets. Hence, it is not applicable in the protective coating of the tablets. Whereas polymer A will be suitable for the protective coating of the aspirin tablets against moisture uptake. Polymer B is not considered suitable because of its effect on the disintegration and dissolution profiles of tablets.


References Top

1. List, P.H. and Kassi, G., Acta Pharm. Technol., 1982, 28, 21. Back to cited text no. 1
2. Sangalli, M.E., Maroni, A., Zema L., Busetti, C., Giordano, F. and Gazzanida, A., J Control. Release, 2001, 73, 103. Back to cited text no. 2
3. Okor, R.S., J. Pharm. Pharmacol., 1982, 34, 83. Back to cited text no. 3
4. Uhumwangho, M.U., Okor, R.S. and Eichie, F.E., Acta Pol. Pharm., 2004, 61, 255. Back to cited text no. 4
5. Eichie, F.E. and Okor, R.S., Tropical J Pharm. Res ., 2002, 1, 99. Back to cited text no. 5
6. British Pharmacopoeia, Her Majesty's Stationary Office, London, 1988, A 101. Back to cited text no. 6
7. Okor, R.S., J. Control. Release, 1991, 16, 349. Back to cited text no. 7

Effect of protective coating of aspirin tablets with acrylatemethacrylate copolymers on tablet disintegration times and dissolution rates

Aceclofenac, a non-steroidal antiinflammatory drug, is used for posttraumatic pain and rheumatoid arthritis. Aceclofenac fast-dispersible tablets have been prepared by direct compression method. Effect of superdisintegrants (such as, croscarmellose sodium, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in vitro release and stability parameters has been studied. Disintegration time and dissolution parameters (t_50% and t_80%) decreased with increase in the level of croscarmellose sodium. Where as, disintegration time and dissolution parameters increased with increase in the level of sodium starch glycolate in tablets. However, the disintegration time values did not reflect in the dissolution parameter values of crospovidone tablets and release was dependent on the aggregate size in the dissolution medium. Stability studies indicated that tablets containing superdisintegrants were sensitive to high humidity conditions. It is concluded that fast-dispersible aceclofenac tablets could be prepared by direct compression using superdisintegrants.

Keywords: Fast dispersible tablets, aceclofenac, croscarmellose sodium, sodium starch glycolate, crospovidone, disintegration time, dissolution

• Other Sections▼
  • Abstract
  • MATERIALS AND METHODS
  • RESULTS AND DISCUSSION
  • REFERENCES

Aceclofenac, (2-[2-[2-(2,6-dichlorophenyl)aminophenyl]acetyl]oxyacetic acid), a nonsteroidal antiinflammatory drug (NSAID) has been indicated for various painful indications¹ and proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment². Aceclofenac is practically insoluble. For poorly soluble orally administered drugs, the rate of absorption is often controlled by the rate of dissolution. Clear aceclofenac-loaded soft capsules have been prepared to accelerate the absorption³. The rate of dissolution can be increased by increasing the surface area of available drug by various methods (micronization, complexation and solid dispersion)⁴. The dissolution of a drug can also be influenced by disintegration time of the tablets. Faster disintegration of tablets delivers a fine suspension of drug particles resulting in a higher surface area and faster dissolution.

Of all the orally administered dosage forms, tablet is most preferred because of ease of administration, compactness and flexibility in manufacturing. Because of changes in various physiological functions associated with aging including difficulty in swallowing, administration of intact tablet may lead to poor patient compliance and ineffective therapy. The paediatric and geriatrics patients are of particular concern. To overcome this, dispersible tablets⁵ and fast-disintegrating tablets⁶ have been developed. Most commonly used methods to prepare these tablets are; freeze-drying/Lyophilization⁷, tablet molding⁸ and direct-compression methods⁹. Lyophilized tablets show a very porous structure, which causes quick penetration of saliva into the pores when placed in oral cavity^7,10. The main disadvantages of tablets produced are, in addition to the cost intensive production process, a lack of physical resistance in standard blister packs and their limited ability to incorporate higher concentrations of active drug⁵. Moulded tablets dissolve completely and rapidly. However, lack of strength and taste masking are of great concern^8,11. Main advantages of direct compression are, low manufacturing cost and high mechanical integrity of the tablets^9,12. Therefore, direct-compression appears to be a better option for manufacturing of tablets. The fast disintegrating tablets prepared by direct compression method, in general, are based on the action established by superdisintegrants such as croscarmellose sodium, crospovidone and sodium starch glycolate. The effect of functionality differences of the superdisintegrants on tablet disintegration has been studied¹³. The objective of the present work was to develop fast dispersible aceclofenac tablets and to study the effect of functionality differences of superdisintegrants on the tablet properties and to provide information on the storage conditions of these tablets.

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  • Abstract
  • MATERIALS AND METHODS
  • RESULTS AND DISCUSSION
  • REFERENCES

MATERIALS AND METHODS

Aceclofenac (Aristo Pharmaceuticals Ltd, Mumbai, India), croscarmellose sodium, sodium starch glycolate, and microcrystalline cellulose (Maple Biotech Pvt Ltd., Pune, India), aspartame (Ranbaxy, New Delhi, India). Crospovidone (Concertina Pharma Pvt., Ltd, Hyderabad, India). Talc and magnesium stearate were purchased from S. D. Fine Chem Ltd., Mumbai India.

Blending and tableting:

Tablets containing 100mg of aceclofenac were prepared by direct compression method and the various formulae used in the study are shown in Table 1. The drug, diluents, superdisintegrant and sweetener were passed through sieve # 40. All the above ingredients were properly mixed together (in a poly-bag). Talc and magnesium stearate were passed through sieve # 80, mixed, and blended with initial mixture in a poly-bag. The powder blend was compressed into tablets on a ten-station rotary punch-tableting machine (Rimek Mini Press-1) using 7 mm concave punch set.

TABLE 1 FORMULAE USED IN THE PREPARATION OF TABLETS

Evaluation of dispersible tablets:

Tablets were evaluated for weight variation, hardness, friability, thickness and disintegration time¹⁴, wetting time¹⁵ and stability¹⁶. In weight variation test, twenty tablets were selected at random and average weight was determined using an electronic balance (Shimadzu, AX200, Japan). Tablets were weighed individually and compared with average weight. The Pfizer hardness tester and the Roche friabilator were used to test hardness and friability loss respectively. Disintegration time was determined using USP tablet disintegration test apparatus (ED2L, Electrolab, India) using 900 ml of distilled water without disk at room temperature (30°)¹³. Thickness of tablet was determined by using dial caliper (Mitutoya, Model CD-6 CS, Japan). To measure wetting time of tablet, a piece of tissue paper was folded twice and placed in a small Petri dish containing sufficient water. A tablet was kept on the paper and the time for complete wetting of tablet was measured.

Stability studies:

The stability of selected formulations was tested according to International Conference on Harmonization guidelines for zone III and IV. The formulations were stored at accelerated (40± 2º/75±5% RH) and long-term (30±2º/65±5% RH) test conditions in stability chambers (Lab-Care, India) for six months following open dish method¹⁷. At the end of three months, tablets were tested for disintegration time, hardness friability, thickness, drug content and moisture uptake.

Dissolution Study:

In vitro release of aceclofenac from tablets was monitored by using 900 ml of SIF (USP phosphate buffer solution, pH 7.4) at 37±0.5° and 75 rpm using programmable dissolution tester [Paddle type, model TDT-08L, Electrolab, (USP), India]. Aliquots were withdrawn at one minute time intervals and were replenished immediately with the same volume of fresh buffer medium. Aliquots, following suitable dilutions, were assayed spectrophotometrically (UV-1700, Shimadzu, Japan) at 274 nm.

Statistical analysis:

Each tablet formulation was prepared in duplicate, and each analysis was duplicated. Effect of formulation variables on disintegration time and release parameters (t_50% and t_80%) were tested for significance by using analysis of variance (ANOVA: single factor) with the aid of Microsoft^® Excel 2002. Difference was considered significant when P <>

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  • Abstract
  • MATERIALS AND METHODS
  • RESULTS AND DISCUSSION
  • REFERENCES

RESULTS AND DISCUSSION

Since, the flow properties of the powder mixture are important for the uniformity of mass of the tablets, the flow of the powder mixture was analyzed before compression to tablets. Low Hasner`s ratio (≤1.32), compressibility index (≤24.68) and angle of repose (≤18.13) values indicated a fairly good flowability of powder mixture. As the tablet powder mixture was free flowing, tablets produced were of uniform weight with acceptable weight variation (≤4.68%) due to uniform die fill. Hardness (3.63-4.31 kg/cm²) and friability loss (0.15-0.72 %) indicated that tablets had a good mechanical resistance. Drug content was found to be high (≥96.2%) and uniform (coefficient of variation between 0.89-2.56%) in all the tablet formulations.

The most important parameter that needs to be optimized in the development of fast dispersible tablets is the disintegration time of tablets. In the present study, all the tablets disintegrated in ≤57.5 sec fulfilling the official requirements (<3>18. Fig. 1 depicts the disintegration behavior of the tablets in water. It is observed that the disintegration time of the tablets decreased (from 28.25 to 17 sec) (P<0.05)>P>0.05) on the disintegration times of the tablets. However, disintegration time increased (P<0.05)>19 might have formed a thick barrier to the further penetration of the disintegration medium and hindered the disintegration or leakage of tablet contents. Thus, tablet disintegration is retarded to some extent with tablets containing sodium starch glycolate. Comparatively, disintegration times of the tablets containing crospovidone20. Thus, these results suggest that the disintegration times can be decreased by using wicking type of disintegrants (crospovidone).

Fig. 1 Effect of concentrations of sodium starch glycolate (——), croscarmellose sodium (—Δ—) and crospovidone (—□—) on disintegration time and sodium starch glycolate (—•—), (more ...)

Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of dispersible tablets. Fig. 1 depicts the wetting times for tablets prepared with three superdisintegrants. Wetting times of the tablets did not change (P>0.05) with increase in the croscarmellose sodium from 2-4%. However, wetting times decreased (P<0.05)>P<0.05)>P<0.05)>

The influence of superdisintegrants on the dissolution of aceclofenac from the tablets is shown in figs. ​figs.22-​-4.4. The t_50% and t_80% (time for 50% and 80% of release) values decreased (P<0.05)>50% and t_80% values increased (P<0.05)>50% and t_80% values did not change (P>0.05) with increase in the level of crospovidone. These results indicated that dissolution parameter values of croscarmellose sodium and sodium starch glycolate containing tablets are in consistent with the disintegration time values observed. However, disintegration time values observed with crospovidone tablets are not predictable of dissolution of the drug. The rapid increase in dissolution of aceclofenac with the increase in croscarmellose sodium may be attributed to rapid swelling and disintegration²⁰ of tablet into apparently primary particles¹³ (fig. 5a). While, tablets prepared with sodium starch glycolate, disintegrate by rapid uptake of water, followed by rapid and enormous swelling²⁰ into primary particle but more slowly¹³ (fig. 5b) due to the formation of a viscous gel layer by sodium starch glycolate¹⁹. Crospovidone exhibits high capillary activity and pronounced hydration with a little tendency to gel formation²⁰ and disintegrates the tablets rapidly but into larger masses of aggregated particles¹³ (fig. 5c). Thus, the differences in the size distribution generated and differences in surface area exposed to the dissolution medium with different superdisintegrants rather than speed of disintegration of tablets may be attributed to the differences in the t_50% and t_80% values with the same amount of superdisintegrants in the tablets. Thus, although the disintegration times were lower in crospovidone containing tablets, comparatively higher t_50% and t_80% values were observed due to larger masses of aggregates.

Fig. 2 Effect of croscarmellose sodium level on the release of aceclofenac.

Fig. 4 Effect of crospovidone level release of aceclofenac.

Fig. 5 Photographs showing disintegration of tablets in water after 20 sec.

Fig. 3 Effect of sodium starch glycolate level on the release of aceclofenac

When tablets were kept at real time (30±2º/65±5% RH) and accelerated (40±2º/75±5% RH) storage conditions, both disintegration time and hardness values decreased significantly indicating that tablets have lost the mechanical integrity leading to more friability loss (Table 2). Increase in thickness of all tablets was noticed particularly pronounced in crospovidone tablets. These results indicate that, at higher relative humidity, tablets containing high concentration of superdisintegrants get softened and hence, must be protected from atmospheric moisture. As crospovidone tablets absorbed larger amount of moisture, tablets became fragile and developed cracks. After stability test period, some portion of the tablet edges was removed and hence, drug content, hardness, friability and disintegration tests could not be conducted on these tablets.

TABLE 2 STABILITY STUDY DATA OF THE TABLET FORMULATIONS

It is concluded that, although functionality differences existed between the superdisintegrants, the fast dispersible aceclofenac tablets could be prepared by using any of the superdisintegrants used. The dissolution parameters were consistent with disintegration times of croscarmellose sodium and sodium starch glycolate containing tablets. However, disintegration time values of crospovidone tablets were not correlating with dissolution profiles. Dispersible tablets prepared with superdisintegrants must be protected from atmospheric moisture.

Acknowledgments

Authors wish to acknowledge Maple Biotech Pvt Ltd, Pune, India for providing croscarmellose sodium, sodium starch glycolate and microcrystalline cellulose as gift samples. Authors are grateful to Aristo Pharmaceuticals Ltd, Mumbai, India and Ranbaxy, New Delhi, India for providing aceclofenac and aspartame respectively as gift samples.

• Other Sections▼
  • Abstract
  • MATERIALS AND METHODS
  • RESULTS AND DISCUSSION
  • REFERENCES

REFERENCES

1. Hinz B, Auge D, Rau T, Rietbrock S, Brune K, Werner U. Simultaneous determination of aceclofenac and three of its metabolites in human plasma by high-performance liquid chromatography. Biomed Chromatogr. 2003;17:268–75. [PubMed]

2. Legrand E. Aceclofenac in the management of inflammatory pain. Exp Opin Pharmacother. 2004;5:1347–57.

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