Clean Room Packaging

it is always interesting to share strategies in packaging development with others in the clean room industry. A common theme in discussions I have had over the years is the challenge packaging engineers face developing the best product for a particular application. What is the best product? Is it the item that perfectly matches a wish list of technical requirements?

In this age of modern technology almost anything is possible. We can design products and processes that produce the cleanest, toughest, lowest off gassing, purest, and highest barrier properties. It is easy for a packaging engineer to envision a product or process that perfectly addresses a set of technical requirements, and to totally absorb oneself in the details of what I call a “technical vacuum.” A “technical vacuum” is an engineering state of mind that focuses only on technical requirements and avoids reality, approaching technical challenges without anticipating market and cost considerations.

The real story of successful packaging engineers is their ability to scrutinize technical requirements, challenge those requirements, and finally condense them into products and processes that are affordable, marketable, and realistic. It is important for you to understand that initial technical requirements presented for packaging applications rarely perfectly match the actual end product of successful development efforts.

This case study is written to provide you some insight in how your packaging suppliers approach your product development needs. Before reading the case study, review the general outline, just below, of how a flexible packaging development team approaches a project.

* Find out what is desired in as much detail as possible. This includes:

* Physical properties and specifications. If specifications are not completely known, explore the customer’s process and help develop preliminary specifications.

* Determine a cost window needed by customer.

* Prioritize the customer’s needs with the customer and determine what is absolutely required.

* Every desired attribute that is not absolutely required should be addressed later in the process.

* Determine if the volume potential is worth the effort/cost involved.

* Determine if there is a skills and technology match. If you do not have the skills and technology to overcome the challenges involved, recognize it immediately and determine if those skills and technology are available elsewhere and their cost. If there is no match, end the project.

* Outline the best theoretical process and product that can provide solutions in the most cost effective way. Check and see if there are existing structures and processes that meet the need. If so, consider a patent search.

* Estimate costs of Step 4 and match them against the cost window needed. If there is not a match, review the goals with the customer. If the customer’s expectations and requirements do not meet their cost window, end the project.

* Develop and test substrates and processes for required attributes. Make sure you remain in the customer’s cost window. If after testing you are outside the cost window, regroup and communicate with the customer about the path forward.

* Test through customer’s process.

* After successful testing, review costs and determine if the nonessential but desired properties are viable and go back to 4.

Case Study

Our case study occurred several years ago when Fisher Container Corporation had several pharmaceutical industry steam sterilizing operations approach us looking for solutions to problems they were having with available packaging formats. These operations, although in different companies, and making different products, all had very similar process layouts. They were all clean room operations, secondary processing facilities,1 and sterilized with steam autoclave at temperatures of 121C. For those unfamiliar with steam autoclave sterilization, high temperature steam is pulsed through a permeable substrate with a pore size of 0.22 micron or less, that surrounds the item being sterilized. The steam is transferred through the substrate by differentiating the air pressure in an autoclave chamber. As the air pressure inside the permeable package and the surrounding chamber are different, increasing and decreasing in a cycle, steam transfers in and out of the permeable package, sterilizing the item inside. The item is finally dried, using sustained dry heat, to remove moisture left from the steam sterilization cycle.

In brief, their operations were taking items such as vials, containers, stoppers, plungers, etc., sterilizing them in permeable pouches, and then holding them in inventory for use in other final fill operations. Their concern was with the pouches during this process.

The challenges they listed were inconsistent cleanliness, the need for stronger seals, and a desire to reduce the amount of time taken to dry the items after the steam cycle. They desired permeable packaging certified to surface cleanliness Level 100 Mil Spec 1246C. The packaging currently available to them was manufactured with materials certified by the FDA, but was not certified to a specific surface cleanliness level. They needed to tighten surface cleanliness specifications due to anticipated changes in industry cleanliness and processing standards. The high differential pressures used during the autoclave cycles caused great stress on the seals of the permeable packaging currently available in the market. The sterilizing operations averaged 2% seal failures. The items in these packages had to be cleaned and sterilized again at great cost. Seal failures also left open the possibility that contamination could inadvertently occur. The sterilizing operations also wanted to reduce drying times to increase the efficient use of their autoclaves.

We began the development program with a series of justification meetings with potential customers, designed to determine exact specifications, volume potential, and cost window for a new package. The volume potential justified a research effort and we also determined a cost window for the potential package. Next, over a period of several weeks, we gathered a preliminary set of specifications for a new pouch. The following desired specifications were drawn up by the customers in order of priority:

* Surface cleanliness Level 100 Mil Spec 1246C. Substrates had to withstand temperatures up to 125C for 5 minutes and 121C for 45 minutes.

* Substrates used had to have low off gassing and leachables properties. In other words films that would not contaminate the items inside the pouch when autoclaved.

* The permeable substrates had to have a pore size 0.22 micron or smaller. (Microbial barrier had to be <0.22>

* Seal strengths should be as strong as possible. Data was not available on exactly what seal strength was required. We tested their current packaging and found seal strengths ranging from 3-4 lbs. per linear inch. Seals also had to be hermetic.

* There should be as large a permeable surface area as possible to reduce drying times.

* A clear window or face was necessary to allow visual inspection.

* A peelable seal format was needed to allow the pouch to be pulled open easily when the part inside was needed for primary processing.

We then took this priority list and began analyzing potential substrates and process technologies. We checked market sources for existing pouch formats that could fulfill the requirements and found none. Next we partnered with one of the sterilizing plants and did further seal testing in their autoclave to tighten the seal strength specification. Seal strength requirements had to be addressed before we could complete a theoretical product model. The reason we needed to do this is that seal strength requirements can exclude certain substrates being used together, and also determine what seal types and seal equipment can potentially be used. After eight seal test trials taken over a two month period we determined a minimum seal strength requirement of 5.5 lbs. per linear inch in the first autoclave trials.

With a firm seal strength specification in hand, and three months into the project, the development group set out to justify a theoretical process and pouch form that met the specification list. We quickly determined that the ideal permeable film type was spun bond high density polyethylene (SBHDPE). We had experience cleaning this film and had attempted to clean other permeable substrates to Mil Spec 1246C level 100 without success in the past. This made SBHDPE the only film type that could meet the cleanliness requirement. SBHDPE also had a pore size less than 0.22 micron, and could withstand 121C for sustained periods of time, and temperature spikes up to 121C. The film had great off gassing and leachables characteristics as well. Hermetic seals were easily achieved with this film type. Although SBHDPE was promising, we had several hurdles related to the use of this film type when matched against other specification requirements:

* The best seal strength that could be achieved in a peelable seal format was 3.5 lbs. per linear inch.

* The best seal strength we had ever achieved in any format with SBHDPE was 5 lbs. per linear inch.

* SBHDPE was expensive and it would not be possible to make a pouch completely with this film type and remain in the cost range needed. We determined that only one side of the pouch could be SBHDPE given the cost window set for the pouch. Also, if SBHDPE was 100% of the pouch, drying times could be reduced; but if the pouch were 50% SBHDPE this could not be achieved.

* We needed to develop another film type that was inexpensive, clean, pure, and had the ability to seal well to SBHDPE at strength levels above 5.5 lbs. per linear inch.

* The plastic resins that could theoretically produce this new film type (noted as film type PCHD from this point) would not produce crystal clear film. This would conflict with the desire for a clear widow or face.

This justification process lasted a month, taking us into the fourth month of the effort. Before proceeding we needed to present our conclusions to our customers and see if any of these findings would be an insurmountable hurdle. After several weeks of discussion we agreed on the following:

* That a clear window or face was not required. The customers had used a clear window in the past as a visual check for contamination. If we provided clean certified film this was no longer necessary. This meant a pouch made of 50% SBHDPE and 50% PCHD was a viable option.

* The minimum seal strength requirement remained 5.5 lbs. per linear inch. This eliminated the possibility of peelable seals, which was acceptable. This also meant we had to improve our seal process or seal technology as the highest seal strength we had ever achieved with SBHDPE was 5 lbs. per linear inch.

* Drying time reduction was not an absolute requirement when weighed against product cost considerations. Again, this made a 50% SBHDPE pouches a viable option.

With this feedback, our group outlined the potential costs associated with the development of the second film type, PCHD, and the development of new seal processes or seal equipment that could achieve seal strengths of 5.5 lbs per linear inch. We weighed this cost estimate against the market potential, and the product cost window, and determined we should still continue with the project.

Now in the sixth month of the project, we began focusing on the development of PCHD. We could not proceed with seal strength improvement efforts until we had our second film type. We had previously chosen a plastic resin base that theoretically could produce a pure, clean film with identical melt temperature characteristics to SBHDPE. Over a three month period we completed a series of justification trials on the PCHD resin base, testing off gassing, leachables and extractables, temperature, and cleanliness characteristics of film produced from the resin. All the tests were successful allowing us to begin seal tests in the ninth month of the project.

We began the seal tests using our current technology. The pouch was to be formed from two sheets of material, unwound from separate rolls that passed through clean processing units, and into a forming area that applied seals on three sides. We varied processing speed, dwell time, dwell pressure, and temperature in every conceivable combination. We were able to obtain seal strengths of over 6 lbs. per linear inch; however our process range of performance still produced pouches with seals below 5.5 lbs. per linear inch. After three months of analysis we determined that we needed to change the angle of attack on the sealing heads that heated and compressed the seal area. This would reduce the shear forces on the edges of the seals and tighten the range of seal strengths produced by the process. This required having new sealing heads designed and manufactured for our equipment. Four months later we received the sealing heads and now in the sixteenth month of the project began seal integrity tests again. The results were satisfying with seal strengths averaging 7 lbs. per linear inch, and a seal range of 6 - 8 lbs. per linear inch.

Over the next two months we ran several complete manufacturing runs testing the final product for purity, cleanliness, and seal strength. Next we arranged justification trials at our customers site, producing separate lots of pouches according to the inspection and justification regimens of each customer. This trial period took us into the twenty third month of the project and successfully concluded the project.

The final pouch format that was adopted by our customers clearly differed from their original specification request, but they were still thrilled with the outcome. This case study highlights again the need for you the customer, and your packaging partner, to clearly communicate about specifications and attributes that are absolutely required, and to work together to challenge your specification requirements. Our challenge in this case was to develop a pouch that met their primary needs in a target cost range, and that clearly required some compromises. The benefits for the customer were an increased level of quality assurance, and a reduction in processing failures. Our customers now knew off gassing, leachables, and cleanliness characteristics of all packaging used in their secondary sterilizing operations. This served them greatly when the FDA and the industry tightened quality assurance regulations several months after we began supplying product. We, as a company, also received several unintended benefits from this effort. We were able to use the new seal technology to manufacture 100% SBHDPE pouches, and other pouch styles with superior seals. We were also able to use the set of comprehensive test data from this project to apply successfully for a process patent for this style pouch under the title “Autoclavable Breather Bag.”

References:

1 A secondary processing facility concentrates on parts and processes that prepare items for internal use. These items would then be used for primary processing. Primary processing is the manufacture of items that would be sold.

Determining Particle Count in Clean Packaging Film

Given the lack of up-to-date standards and the importance of optimizing communication between vendors and users, the contamination control industry needs a universal procedure for the testing of clean film packaging. This article provides concise, definitive directions for doing that.

The procedure begins with ensuring that all parts, components, assemblies and subassemblies, systems, and related equipment required for the cleanliness testing of clean film packaging have been cleaned to the highest levels of cleanliness and inspected in accordance with testing procedures and testing parameters for the utmost cleanliness required. A minimum Class 100 facility for quality testing is essential; if a Class 100 facility is not available, a Class 100 laminar flow hood located within a Class 1000, 10,000 or 100,000 facility can be utilized. Before testing begins, a trained technician should ensure that the lab facility is clean and clear of any obstructions or non-essential equipment and articles. All apparatus should be pre-cleaned and assembled for ease of operations.

The technician should wear a static-shielding garment with the head fully protected by a full hood (eyes-only) or bouffant hat. If a full hood is not worn, a mustache or face covering of the highest quality should be worn. The technician’s hands should be covered with long or ultra-long vinyl or latex gloves overlapping the sleeve areas. The operator should wipe down the face, arms, and sleeves of the garment, as well as the gloves, prior to initiating the test.

Testing

Isopropyl alcohol (IPA) should be a prime solvent for test fluids. This should meet TT-I-735 Grade A. Other applicable solvents would be DI, UPW, or ethyl alcohol. Preparation of solvents should be the highest grade of solution, and should be primarily filtered into an ultra-clean solvent dispenser.

The initial filtration unit at the exit of the solvent dispenser should be a Pall type with an absolute filter of 0.2 micron efficiency, which is compatible with the solvent being used. The next filtration position would be at the dispenser end, with a clean, pressurized dispensing gun recommended. At the nozzle of this gun should be a 0.45 micron membrane filter. The combination of these two filtration units on the test solvent container, in conjunction with filtration of the solvent going into the dispenser, will ensure the utmost quality and purity of the test solvent.

Additional equipment would include the following:

> A stainless steel membrane funnel assembly, which will allow for capturing of any solvent during the test process

> A Pyrex-style flask suited to the funnel assembly and adapted for a vacuum system attachment

> 0.45 micron porosity, gray or black background gridded, membrane filters for observation

> Stainless steel scissors

> Tweezers

> 2 x 2-in. glass microscope slides

> 45 mm membrane petri dishes

> An oil-less vacuum pump

All apparatus and equipment should be pre-cleaned and laid out in an orderly manner on a pre-cleaned table in the Class 100 room or laminar flow hood. Using an appropriate tack cloth, the operator wipes down all garments, sleeves, and gloves prior to initiation of the test. All equipment is prewashed prior to the initiation of the testing, using the pre-filtered and pre-cleaned test solvent.

The first step in all testing is to run a solvent blank on the solution being used. A 0.45 micron, 45 mm membrane filter is removed utilizing pre-cleaned tweezers, placed on a pre-cleaned 2 x 2-in. glass slide, and rinsed off in an angled solvent wash to remove any contamination of the membrane filter. This is then placed on the pre-cleaned membrane funnel assembly, and the funnel assembly is put together. Approximately 100 ml of the test solvent is poured into the pre-cleaned funnel to be filtered through the 0.45 micron membrane filter. Vacuum is applied to the flask bottle, drawing a vacuum through the membrane filter from the funnel assembly to speed the flow of fluid or solvent through the membrane. Once the membrane appears to be dried, the vacuum pump is turned off. The membrane is removed and placed in a pre-cleaned petri dish. The petri dish is then covered with a pre-cleaned lid and placed on a microscope for inspection.

The inspection of the membrane is performed at 40 power through a binocular or trinocular microscope assembly, equipped with a certified and calibrated scale, or through a microscope video monitor setup that allows the viewing of the membrane not only through the trinocular microscope but also through a calibrated monitor and sizing assembly. Any particulate viewed is calibrated or sized at 100 power, either by changing the reticle setup of the binocular microscope or by resetting the monitor system to view particles at 100 power.

Once the entire surface of the membrane is inspected and any particulates are identified and sized, the solvent is then proven to be clean. The next step in the setup is to take a sample of clean film product for testing, isolating approximately 0.1 m² (1 ft²) of surface area, which is equal to a 6 x 12 in sealed area, or an assemblage of bags to equal 0.1 m² (1 ft² or 144 in²) of surface area. (The surface area of a bag includes both sides of the bag.) When sheeting is utilized, both sides are to be rinsed off to equal 0.1 m² (1 ft²) of surface area. In lay-flat tubing, an equal amount of tubing is to be utilized to equal 0.1m² (1 ft²) of surface area.

Once the surface area has been isolated or sealed on all four sides, the outside of the test sample is pre-cleaned by first wiping down, and then rinsed off with the pre-cleaned and pre-validated test solution. Utilizing the pre-cleaned stainless steel scissors, a corner of the bag or test sample is carefully slit (not cut), to make an opening. Slitting is performed by gently closing the scissors into the film, and then pushing through in a slicing action. This will prevent any contamination due to the scissoring or cutting action of the scissor against the film being tested.

Using pre-cleaned, gloved hands, the corner of the film that is slit is now pinched open carefully. Again, 100 ml of test solution is introduced into the packaging material. The opening is folded over to prevent any leakage of solution, and the product is then agitated with the solution inside for approximately 10-12 seconds. It is critical to agitate the solution long enough in all surface areas and crevices of the film, but not long enough to allow degradation of the film area or film material by the test solution. (See NASA’s KSC-C-123H Method I, Surface Cleanliness of Fluid Systems.¹)

The funnel assembly is reassembled using a second pre-cleaned 0.45 micron, 45 ml dark gridded membrane and pre-cleaned funnel assemblies as before. The solvent is then poured into this assembly. The vacuum is drawn through the funnel until the most of the solution has been pulled through the membrane. An additional amount of pre-cleaned and blanked test solution is then utilized to final rinse the funnel assembly.

Once again, the membrane is then dried slightly by the vacuum, removed carefully from the funnel assembly, placed into a pre-cleaned petri dish and covered. This pre-cleaned and covered petri assembly, with the membrane from the test procedure, is again placed under a binocular or trinocular microscope. The viewing of the membrane is done again at 40 power. The typical scanning process is to view the individual squared-off or gridded areas of the membrane, excluding the initial or intimate contacted squares on the petri dish. This means that the squares or grids around the lidded areas of the petri dish are excluded because of the possibility of contamination from the closure of the petri dish.

Starting from the upper left-hand corner, the gridded membrane is viewed in a lateral process from left to right or right to left, moving down row by row and viewing all grids. When particulate is identified, the operator will change the 100 power reticle viewing for sizing on a calibrated reticle in a binocular scope or for viewing across the monitor at 100 power via a calibrated sizing apparatus equipped with a trinocular video monitor setup.

Once the entire gridded surface of the membrane has been inspected and all particulate sized, based on groupings of 5-15, 15-25, 25-50, 50-100, 100-150 and 150+ microns, the total count should then be accumulated.

Particulates smaller than 5 microns are normally not sized in referencing Mil Standards, Mil Specs, NASA specifications, or customer specifications such as Lockheed Martin’s, since these particulates have not been determined to be a critical matter. It should be noted that in the smaller than 5 micron size range, if the membrane is obscured or covered with particulates, the test should be determined to be a failure. As technology has advanced, however, some companies are testing for particulate levels as low as 0.2 microns. Because this size range is extremely difficult to test by microscopic methods, liquid particle counters equipped with sensors are now in use.

Throughout the entire operation, care must be taken so that the operator’s or technician’s hands or garments do not enter the downstream area of the filtered air flow or cross over the testing apparatus, test samples, membranes, or petri dishes during any test. This is extremely critical because any such motion or cross-contamination may cause contamination in the test membrane.

Care must also be taken in sizing of particulate so that the longest dimension of a particle should be examined as the maximum length. In terms of fibers, anything more than 50 microns in length should be classified and identified as either a particle or fiber, with both cross and length dimensions noted. Once the entire membrane surface has been examined, particulates sized and counted, these numbers are cross-referenced to the appropriate specification. Determination of cleanliness relative to pass-fail criteria is then made.

During this process, if a membrane is identified as having too many particles to be counted, it should be classified as a possible reject. However, per ASTM F312-69, Standard Test Methods for Microscopical Sizing and Counting Particles from Aerospace Fluids on Membrane Filters,² a second method can be utilized. Again, by scanning the entire gridded surface, starting in one corner of the membrane, the number of gridded units and particulate by unit measure are recorded. When the numbers become too extreme for continued counting, an extrapolation of particle counts, or grid counts, can then be utilized, per the ASTM specification, based on percentage of grid units counted per entire gridded surface and the number of particles counted in the counted gridded units.

This extrapolation will therefore result in an estimated count on the total surface area. For utmost accuracy, however, the entire surface should be counted when possible and feasible. The quality control department should then review the test results against the required specification. When an extreme abnormal count is seen, a second microscopic inspection can be utilized to confirm the original numbers.

In conjunction with this, a similar method for testing can be utilized using many of the procedures and processes described above except for the replacement of the microscope and membrane units with the quantitative and qualified liquid particle counter to be utilized; however, liquid particle counters have been proven by many organizations to be inaccurate and not accepted to be a non-viable source of particulate counting, due to the variations in the test solution and the sensing of the particle counter, whether it be light sensing or laser sensing units.

The approved and recommended method for determination of particulate counts on clean film has always been unquestionably the microscopic inspection method.

References

1 NASA KSC-C-123H Method I, Surface Cleanliness of Fluid Systems.

2 ASTM F312-69, Standard Test Methods for Microscopical Sizing and Counting Particles from the Aerospace Fluids on Membrane Filters.

Other documents used in the development of this procedure, but not referenced in the text, include:

SAE ARP-743, Procedure for Determination of Particulate Contamination of Air in Dust Controlled Spaces by the Particulate Count Method.

Scientists Patent Corrosion-Resistant Nano-Coating for Metals

Scientists at the U.S. Department of Energy's Brookhaven National Laboratory have developed a method for coating metal surfaces with an ultrathin film containing nanoparticles which renders the metal resistant to corrosion and eliminates the use of toxic chromium for this purpose. The scientists have been awarded U.S. Patent number 7,507,480 for their method and the corrosion-resistant metals made from it. The technology is available for licensing.

"Our coating is produced right on the metal using a simple two- or three-step process to produce a thin film structure by crosslinking among the component compounds," said chemist Toshifumi Sugama, a guest researcher at Brookhaven Lab. "The result is a layer less than 10 nanometers thick that protects the metal from corrosion, even in briny conditions."

Corrosion resistance is essential for metals used in a wide range of applications, from electronics to aviation to power plants. Traditionally, compounds containing a toxic form of chromium have provided the best corrosion resistance. Scientists looking to develop chromium-free alternatives have been unable to achieve the thin layers desirable for many applications. "Ultrathin coatings reduce the amount of material needed to provide corrosion resistance, thereby reducing the cost," Sugama explained.

Sugama's approach achieves several goals-low toxicity and excellent corrosion resistance in a film measuring less than 10 nanometers that can be applied to a wide array of metals, including aluminum, steel, nickel, zinc, copper, bronze, and brass. According to Sugama, the coating should be of specific interest to industries that produce coated valves, pumps, and other components, as well as the manufacturers of aluminum fins used in air-cooled condensers at geothermal power plants, where preventing brine-induced corrosion is a high priority.

The coating can be made in a variety of ways suited to a particular application. In one embodiment, it starts as a liquid solution that can be sprayed onto the metal, or the metal can be dipped into it. The metal is then subjected to one or more treatment steps, sometimes including heating for a period of time, to trigger cross-linking reactions between the compounds, and simultaneously, to form corrosion-inhibiting metal oxide nanoparticles, such as environmentally benign cerium-based oxides.

"Among the key factors that ensure the maximum corrosion-mitigating performance of these ultrathin coating films are the great water-repellency, the deposition of metal oxide nanoparticles over the metal's surface, and their excellent adhesion to metal. The combination of these factors considerably decreased the corrosion of metals," said Sugama.

The corrosion resistance of these coatings can be comparable, and even superior, to chromium-based coatings, he said. In fact, these new coatings provide even better coverage of metal surfaces than chromium coatings. Sugama added, "This is particularly advantageous when the metal to be coated possesses fine structural detail."

Because the method deposits such a thin coating of material, it is highly economical and efficient.

Critical Cleaning For Contamination Control: Water: A Starting Point

Back in October 2007, we wrote about how significant water is to life, and how hydrogen-bonding intermolecular forces enable that. Essential as it is, however, water alone isn't sufficient for cleaning work. We have to add something to it, or take something away.

Since 1974, the U.S. has had Federal standards for drinking water which have the force of law. Generally, the Safe Drinking Water Act (SDWA, 40 CFR-141) specifies what must not be found in water at all, and the maximum permissible levels at which other impurities can be found. This is a basic level of water quality to which substantial changes are made to enable it to be used in industrial operations.

METAL CLEANING TECHNOLOGY
Typical aqueous cleaning technology starts with water which would comply with the SDWA and then adds something. There are two reasons for this: most surfaces we want to clean have significant hydrocarbon character, and hydrocarbons aren't soluble in water.

So we have to add something which is compatible with both water and the materials we want to clean. That's a surfactant — a bifunctional molecule. An example of such is shown below.

If water weren't so cheap (well, it once was so), so commonly available (also once was so), and innocuous (to humans and the environment), we could do this cleaning work with another base fluid to which we add some bi-functional molecule.

But we can't because we don't know of such an alternate fluid. The boiling point of liquid CO₂ is too low. Methanol and heptane are VOCs and flammable. HFCs are too costly. We clean metal with surfactants in water because we don't have a better fluid to which we can add something to make water attractive to what we're trying to clean.

CRITICAL CLEANING TECHNOLOGIES
It's just the opposite in critical cleaning. We start with water that would comply with the SDWA, and then remove molecules from it. We don't want added molecules contaminating what it is we are trying to do.

ELECTRONICS CLEANING TECHNOLOGY
In electronics cleaning, we seek either no ions or a measured amount of ions dissolved in the water we use for cleaning. We produce at least three levels of ion-lean (deionized or DI) water using anion and cation exchange beds.

We characterize DI water by its inability to conduct electrical current — its resistance measured in Ohm-cm. Three common levels of ion-leanness are 50,000 Ohms (50 kOHM) which is easy to produce, 1,000,000 Ohms (1 megohm) which is a fairly standard product, and 20,000,000 Ohms (20 megohm) which is so hungry for ions — it will literally cut through steel to dissolve the Iron.

PHARMACEUTICAL/MEDICAL CLEANING TECHNOLOGY
This cleaning (or processing) work demands a different kind of purity: absence of, at least, organisms and byproducts of disinfection. The U.S. Pharmacopeia lists a variety of types of pure water, all of which are produced starting with a product which would comply with the SDWA. Some of these are intended for special pharmaceutical purposes (including cleaning and processing), for hemodialysis, for injection (possibly into humans), for irrigation, purified for use in analytical testing as well as cleaning, and pure steam. In addition, each of these types is also produced in a version in which sterility is claimed.

Necessary production processes are, at least, filtration, distillation, and deionization.

WATER -- NOT REALLY A CLEANING SOLVENT
From the perspective of those doing cleaning work, much of what we ask of water is that it not get in the way. To the contrary, we ask solvents to be the cleaning process: to wash, rinse, and dry by evaporation. That's why cleaning with water is often so difficult; one has to invent the process as well.

Contamination Control In and Out of the Cleanroom: Keep Product Clean In and Out of the Cleanroom

The first step in developing an effective precision cleaning process for the product is to determine where cleaning can be avoided. Keeping the product clean, particularly during transfer and storage, is an important part of your contamination control program.

Much effort is expended in keeping the cleanroom clean, in monitoring the cleanroom. Much effort is expended in developing, validating, and monitoring cleaning processes for both so-called "high-end" products and for industrial applications. It is critical to manage three major sources of contamination for products fabricated within the cleanroom. These contamination sources are:

• People
• Equipment
• Transfer

EFFECTIVE TRANSFER
Many items such as raw materials for use in the manufacturing of the product are supplied double bagged or triple bagged depending on the manufacturing process. The outer packaging could potentially be highly contaminated so careful removal of this packaging is of utmost importance.

Sometimes pallet trucks of cardboard boxes are loaded into the transfer area. How do you remove contamination from those parts when going from the dirty side to the clean side? How do you avoid particle generation? In general, it is wise to remove all cardboard packaging outside of the controlled environment. As we explained in the previous column,¹ the material transfer room is a controlled environment that includes a 'dirty' side and a 'clean side.' However, contamination must be minimized even in the 'dirty side.' Therefore, remove the cardboard in an area outside of but proximal to the transfer area; then immediately move materials to the transfer area.

CLEANING
Set a cleaning protocol for surfaces, packaging, and product during transfer. We have observed people spraying isopropyl alcohol (IPA) on a part, then transferring it into the cleanroom. Simply anointing the material with IPA may not be adequate. Remember that effective cleaning typically involves both physical and chemical action. A more effective, but still convenient cleaning protocol is to use an alcohol spray, such as IPA, in conjunction with non-linting wipes. The IPA must be of high quality and free of residue. Large storage containers and benchtop dispensers must be made of materials that do not leach residue. While there is no perfect cleanroom wipe, the selected wipe must be optimal for the application.²

In the transfer room or area, first clean the benchtop and racking. As soon as material is transferred to the dirty side of the transfer room,¹ clean the outer bag. Very often this outer bag is removed and not cleaned down. The risk of this technique is that contamination from this outer bag can get onto the inside bag and onto the gloves of the material handler who wipes the inside bag.

STORAGE
Once cleaned, the outer bag can be removed. The inside bag should then be wiped down and left on the pre-cleaned benchtop or racking fixture for cleanroom personnel to collect. If the material is left on this racking for a long period of time, then cleanroom personnel should wipe it again as a precautionary measure, before bringing it into the cleanroom environment. The definition of "a long time," analogous to a Clean Hold Time in pharmaceutical validation, is specific to the fabrication process and facility; you should determine and document a reasonable policy.

Sometimes material is stored within the material transfer area or cleanroom environment itself until ready for use. In this case, the benchtop/racking surface and outer bag is wiped down thoroughly as described above and left on the surface for entry into the storage area. All materials stored for long periods of time within the material transfer or cleanroom should be left double bagged. It should be noted that if materials are stored within a cleanroom in totes or on racking, then these should be cleaned on a regular basis as part of the cleanroom cleaning schedule. When the material is required for use, then the outer bag should be cleaned again and removed and the inner bag cleaned before opening. Final packaging should be removed only just prior to use of the material.

CONTAMINANTS DEAD AND ALIVE
It is important to understand the source of particulate contamination, both viable and non-viable. If sterility is the only concern, then sterile materials, double or triple bagged, may not need to go through such rigorous cleaning of the packaging as each layer of packaging is sterile. However, care should be taken when removing the outer packaging to ensure it does not pose a threat to the inner packaging. Be aware that particle counts include both viable and non-viable particles.

LARGE ITEMS
Transferring bulky materials is particularly difficult. Sometimes, only parts of the assembly can be cleaned prior to transfer. In medical and pharmaceutical applications, cleanliness of large, bulky objects is typically determined by swabbing and testing for microbial contamination. Aside from the time factor in microbial analysis (perhaps three to five days), the absence of significant microbial contamination does not necessarily rule out non-viable contamination, particulate, and thin film. Sampling followed by particulate counting and/or non-volatile residue testing may be required.

Some items may have to be wheeled into the cleanroom on trolleys due to the weight or size of the material. These trolleys should be thoroughly cleaned before entering the cleanroom, in particular the wheels. Sticky mats may help to remove excess contamination from the floor area but this alone is not a good enough clean for entry into the cleanroom; the hubs and axles can also be contaminated. To minimize entry of contamination to the cleanroom, one trolley can be used to transfer the material from the warehouse to the ‘dirty' side of the material transfer room and another trolley that is dedicated for cleanroom use can be used to transfer the material into cleanroom from the ‘clean' side. This method however does involve an extra handling step. Unfortunately, more often than not, this extra desirable transfer step is judged to be consumption of valuable time. Setting up written justified policies for such activities may be helpful.

ACCOUNTABILITY
With larger assemblies there is also the issue of responsibility and accountability. The people in the warehouse may move materials into the transfer area without cleaning them, on the assumption that cleanroom technicians will take care of cleaning issues. Those in the cleanroom may assume that the parts have been pre-cleaned. Even worse, in the interest of supposed efficiency, management may tacitly support or even mandate an unwise policy of bringing materials into the cleanroom without cleaning them. If you are faced with such fallacious cost-cutting measures, and if logic does not prevail, tracking the failure rate may be the most compelling approach.

IS AUTOMATION THE ANSWER?
Not always. The assumption is made that people are the problem and that if you remove the people, there will be no contamination problems associated with materials transfer. Automation simply does things the same way each time; you may be automating a process that inherently generates particles.

The equipment itself can generate particles. We have observed transfer equipment, moving materials into a cleanroom, that had both particulate and nonparticulate contamination on the "tracks." The design and maintenance of transfer and process equipment must be considered, because equipment and fixturing can degrade. Sometimes, the same racks or trays are used in both early stages of production and in the cleanroom. It is important to separate and segregate the processes (Figure 1). People need to be involved in design, oversight, and monitoring of transfer processes.

KEY PROGRAM
The material transfer process should be a key element in the cleanroom contamination control program. Too often, the process of materials transfer is not given a huge amount of time, if any, in employees training programs. It is vital that personnel performing the material transfer process understand the responsibility and importance of their role and are fully aware of the impacts of their methods and practices. They must also understand the impact of their behaviors, particularly the negative impact of incorrect behaviours. Personnel awareness and understanding is crucial for this process to be performed effectively; for this to happen, there must be management support and understanding.

References:

1. B. Kanegsberg, E. Kanegsberg, and K. O'Donoghue, "Keeping Product Clean In and Out of the Cleanroom, Part 1: The Interface," Controlled Environments Magazine, Feb. 2009.
2. Siegerman, H., "Wiping Surfaces Clean," Vicon Publishing, 2004.

Understanding Cleanroom Wiper Test Data and The Role of Product Data/Information Sheets

Just as the materials and performance requirements have changed since the first cleanroom wipers were introduced in the 1960s, so too have the data reporting requirements and test methods utilized to support those requirements. Early testing was primarily based on TAPPI (Technical Association of the Pulp and Paper Industry) and ASTM (American Society for Testing and Materials) methods created for other materials. As contamination cause and control knowledge have evolved, new test methods and measurement equipment have evolved. Today, most cleanroom wiper testing is performed in accordance with the recommended practices developed by the Contamination Control Division of IEST (Institute for Environmental Sciences and Technology) in conjunction with cleanroom wiper manufacturers and end-users. The cleanroom wiper manufacturer's data is gathered internally and then presented along with pertinent narrative information in the form a product data/information sheet for use by customers as an aid in cleanroom wiper selection. However, variations do exist within some of the test methods dependent on the section of the method applied; this is particularly true for the methods measuring particles, fibers, and extractions. Furthermore, some cleanroom wiper manufacturers still use the older methodologies for testing and reporting purposes. This combination of factors combined with slight differences in the analytical equipment utilized by the labs performing the testing will cause differences in the data reported on supplier's product data/information sheets. And finally, cleanroom wiper manufacturers often present the information and data in different formats.

How then does the customer understand the cleanroom wiper data presented and the degree of comparability between data presented by cleanroom wiper manufacturers?
Let's begin with a basic primer on the critical wiper data reported by most cleanroom wiper manufacturers in product data/information sheets:

Basis Weight is the actual material weight of the product and is generally reported in the format of g/m². The determination of basis weight is a simple technique and therefore should be comparable among different product data/information sheets.

Sorbency, sometimes referred to as absorbency, is related to the amount of solution a wiping material can take up either through absorption or adsorption. Absorption is typically related to naturally hydrophilic materials, such as cellulose non-wovens, while adsorption typically relates to synthetic materials, such as polyester knits, which without treatment are hydrophobic. Sorbency is measured in terms of capacity, efficiency, and rate with fairly straightforward calculations which should be comparable among different product data/information sheets:

Capacity is the term typically used to express the total volume of liquid that can be held by a wiper and is expressed as cc/m² or mL/m². Other terms used include absorbency and extrinsic sorbency.

Efficiency is related to how effective the material is at absorbing or adsorbing a liquid and is expressed as cc/g or mL/g. Other terms used are specific absorbency or intrinsic sorbency.

Rate is related to how fast a water drop's specular reflection can disappear after dropped onto a wiper surface and is expressed in seconds. Other terms used are time to ½ and time to sorption.

Non-Volatile Residues are the unspecified extractable matter that can be extracted from a wiper under a certain set of circumstances related to time, temperature, and solution and is generally reported as % by weight or g/m². Other commonly used terms are NVRs and extractables. Typically non-volatile residues are extracted in DI water and in IPA. Other solutions, such as Acetone, may be used based on customer requirements or process. There are two basic methods for performing the extractions:

1. The first method exhaustively extracts all non-volatile matter using boiling solvent.
2. The second method is a short-term or ambient temperature extraction that more closely relates to how actual wipers are used in most processes.

Most wiper manufacturers typically report short term or ambient temperature extraction data; however, some do report using the full exhaustion method.

Ions are the quantified species of matter that can be extracted from a wiper and are generally expressed as ppm or ppb. While the extraction method could use elevated temperature most, if not all, wiper manufacturers use an ambient temperature soak for the extraction. Most, if not all, wiper manufacturers also utilize Ion Chromatography (IC) to measure the extracted ion content. Due to the consistency in technique and measurement equipment, ionic content is typically comparable among competitor product data/information sheets.

Fibers and Particles state the amount of burden released from a wiper under a given set of conditions and are composed of releasable particles, those present on a wipers surface, and generated particles, those that are created by exposing the wiper to mechanical energy. The typical data reported is for fibers and particles released under mechanical energy and generally expressed as fibers and particles/cm² or fibers and particles/ m². Fibers and particles can also be reported in different size ranges. Typically fibers are reported in the 100 µm size. Particles are typically reported in the 0.5 µm size; however, other sizes such as 0.3 µm and 5.0 µm may also be reported.

There are three main methods that can be used in fiber and particle testing: zero stress, orbital shake, and biaxial shake. Zero stress measures readily releasable fibers and particles with no mechanical energy applied. Orbital shake is used to impart moderate mechanical energy to the surface of the wiper at 150 rpm (rotations per minute). Biaxial shake is used to impart vigorous mechanical energy to the surface of the wiper at approximately 280 opm (oscillations per minute). Both the orbital and biaxial shake methods produce a combination of readily releasable and generated fibers and particles. As part of the testing methodology, wipers are immersed in either a 100% DI water solution or a surfactant/ DI water solution. Fibers and particles are typically measured by LPC (Liquid Particles Counter) with SEM (Scanning Electron Microscopy) used as an alternate method. Due to the multiple combinations allowed within the particle and fiber testing methodologies for shake equipment, immersion solutions, and analytical measurement devices, trying to compare fiber and particle data presented on product data/information sheets is most often not an apples to apples comparison and should only be used with caution and a complete understanding of the exact differences in the product test methods.

What role does the product data/information sheet play in wiper selection?
Now that you have a basic understanding of wiper test methods, data, and terminology, let's focus on how to properly use the product data/information sheets provided by cleanroom wiper manufacturers in the wiper selection process.

The product data/information sheet is generally formatted to include sections that provide general information about the product including composition, attributes, benefits, and applications in addition to the specific test data about the particular product. Generally, standard product offerings will be listed with alternative versions, such as pre-wetted and sterile, sometimes referenced. The role of the product data/information sheet is to provide the customer with a basic understanding of the wiper material and product format and data related to that product for a first cut general comparison to a current or competitive product used for a similar application. In using the product data/information sheet as a tool, the following basic guideline steps should be used:

Step 1: Compare the composition, attributes, and benefits presented in the narrative section to the composition, attributes, and benefits of the current or competitive product. If the wipers are similar in the above factors, then they may be comparable. For example:

• Are the products all sealed edge, cleanroom laundered, 100% polyester knits?
• Are the products all compatible with all solutions used in the process?
• Are the products all abrasion resistant?
• Is the packaging of the products comparable?
• Are the products all validated sterile?

Step 2: Compare the types of applications that the wipers are recommended for in the narrative. If the wipers are similar in recommended applications or used for higher end applications, then they may be comparable. For example:

• Are the recommended ISO classification uses the same?
• Are they recommended for aseptic applications?
• Are they recommended for semiconductor applications?
• Are they recommended for sensitive or optical applications?

Step 3: Compare the technical data using the information provided in the above primer on test methods, data, and terminology remembering the following key facts:

• Basis weight data is generally comparable.
• Absorbency data is generally comparable.
• Ionic data is generally comparable.
• NVR data is generally comparable by method: Short term or ambient extractions are comparable to each other and exhaustive extractions are comparable to each other; however, the two different methods are not comparable.
• Fiber and particle data are the most complicated and contain the most variation. If the test methods are fully explained and the same, are the numbers in the same general range? If so, then they may be comparable. If the test methods are different, then the results are not comparable. Fiber and particle data is at best a general indicator and not an absolute determinant.
• Is the data presented an average of all data tested or is the data presented "typical." "Typical" data may or may not be a statistical average and should be defined by the manufacturer as to how the data is derived.
• Valid technical data comparisons can only be gained through side-by-side testing of multiple samples in the same facility utilizing the same methods and the same equipment under the same conditions.

SUMMARY
Cleanroom wiper testing is based on recommended practices, methods, and analytical equipment that have been developed over many years by cleanroom wiper manufacturers, end-users, and testing organizations. While standardization has been the goal, variations do exist in the practices, equipment, and reporting formats between cleanroom wiper manufacturers. For this reason, product data/information sheets should only be used as an aid in cleanroom wiper selection and not as an absolute measure of the true performance comparability. Valid comparisons can only be accomplished through side-by-side testing performed in the same test facility utilizing the same method and the same equipment under the same conditions with the ultimate indicator being actual internal process validation.

CONCLUSION
Selecting the correct cleanroom wiping product is critical for the most effective operation of the customer's process. While knowledge can be gained from Cleanroom Wiper Product Data/Information Sheets, applying that knowledge effectively to make the best choice can be difficult at best. For these reasons, it can be extremely beneficial to consult the cleanroom wiper manufacturer and draw on their expertise directly. With extensive knowledge of cleanroom wiping materials and applications, the cleanroom wiper manufacturer can enhance the selection process by fully evaluating the application and presenting a total value package with technical comparisons, insights, and options that may not otherwise be gained prior to final selection and process validation.

Magnesium Stearate and Tableting Lubrication

Nutraceutical manufacturers have had many issues to consider since FDA released the GMP (good manufacturing practice) guidelines for the dietary supplement industry last summer. Among these concerns is the definition or application of a “scientifically valid argument,” a concept presented in the GMPs.

The intent of the phrase is to establish, as a minimum requirement, a documented explanation of well-grounded logic which justifies how and why one conducts a key manufacturing process, material qualification or analytical test using science. The scientific portion of the explanation should be a combination of theory, experimentation and test results. An example of applying this concept is given below for the addition of magnesium stearate (as a lubricant) to a homogenous nutraceutical powder blend.

Magnesium stearate is the most common ingredient used in tablet formulations. For nutraceutical tablet manufacturing, it is the lubricant of choice. It is common manufacturing behavior to add a minimum amount after first achieving a homogenous powder blend of all other ingredients and additionally mixing-in the lubricant for a brief period of time. This enables the powder blend particle surface to be sufficiently coated while limiting penetration of the lubricant within the particle matrix. Within the FDA concept, this is part of the theoretical explanation.

There are several problems associated with incorrect lubrication in tablet compression. Under-lubricating a powder blend leads to adherence of material on the metal surfaces of the punches and die walls of the tablet press. Over-lubrication leads to soft tablets and poor disintegration and/or dissolution. These are some of the experimental outcomes to be used in determining an optimal level of magnesium stearate in a formulation.

Other variables to address when determining magnesium stearate concentration and blend time experiments include:

• Powder blend particle size distribution,
• Powder blend bulk and tapped density,
• Powder blend moisture content,
• Powder blend chemical nature,
• Powder blend filler/component solubility,
• Powder blend filler/component cohesive nature,
• Blender type, and
• Powder blend fill percentage vs. blender capacity.

These variables have different impacts on this experimental model, and can become part of analytical tests. For example, powder blend particle size distribution provides powder flow insight, as poor powder flow characteristics can reduce formation of a lubricant film. Powder blend bulk and tapped density will affect powder flow and blender capacity, and the addition of magnesium stearate will densify the blend. As far as moisture content, the amount of moisture can affect lubricant concentration due to hydrophobic nature. The chemical nature of the powder blend can be defined as the sum of the chemical tendencies of the powder blend ingredients toward being hydrophobic, hydrophilic or a mixture of the two.

The solubility and cohesive nature of the filler and components in the powder blend are related concerns. Solubility addresses the tendencies of the powder blend ingredients to interact with either water-soluble or fat-soluble solvents, while the cohesive nature refers to the chemical and/or physical attributes of certain molecules (such as MCC, DCP, lactose, etc.) in which the material cohesion properties vary (plastic or brittle deformation, etc.).

Regarding blender issues, looking at blender type means examining the mixing profile relative to the amount of horizontal vs. vertical mixing capabilities. Consider how as the fill percentage increases, the mixing efficiency decreases and extends mixing time. The concept of blender validation should also be considered in study design.

To complete the “argument,” consider the collection, comparison and analysis of the variables listed above to characterize the formulation. Make determinations from this to set a target amount of lubricant with statistically significant variations of concentration. Set a minimum mixing time, pull blender samples and analyze for magnesium stearate concentration. An FT-NIR can be used for this measurement. More than one source of magnesium stearate should be used. Positive performance results can be used to qualify a source. Negative performance results can disqualify a source. Evaluation of performance can be determined several ways: by using an instrumented tablet press to evaluate ejection and compression forces, tablet hardness measurements and by conducting disintegration/dissolution tests. Powder blend without lubrication should be included within the testing matrix and compared to samples with multiple levels of lubricant. The totality of the work should be organized in a style similar to a laboratory experiment while having a documented format with change control similar to an SOP. This report should be filed with the master file for audit purposes.

A simple style such as the following would suffice:

• Header with the title and any applicable experiment numbering references with date.
• Introduction that incorporates the purpose, scope and background.
• Study design.
• Experimental details, including materials and methods.
• Results with discussion.
• Summary and conclusions.
• Footer and ending approval, which should contain the signatures of the author and reviewer for quality purposes.

Development of “scientifically valid process steps” enables a company to be compliant with GMP guidelines. Performing this process optimizes tableting blends and minimizes associated processing problems. As this methodology is required for compliance, it should become routine in the future.

Determination ofMagnesium Stearate in Capsule- or Tablet-Type Supplements

A simple method for the determination of magnesium stearate in capsule- or tablet-type supplements was developed. Free stearic acid in the sample was removed by extraction with tetrahydrofuran. The remaining stearate was converted to stearic acid by reaction with a cation-exchange resin. The resulting stearic acid was determined by gas chromatography with a polar column. Esters of stearic acid were not converted to stearic acid and would not cause a positive error in the amount of stearate. The amount of magnesium stearate was calculated based on the stearic acid concentration thus obtained. Magnesium stearate levels in 5 out of 25 supplements exceeded 2500 μg/g, which indicated the possible admixture of magnesium stearate.

Lubrication Potential of Magnesium Stearate Studied on Instrumented Rotary Tablet Press

The aim of this study was to investigate the lubrication potential of 2 grades of magnesium stearate (MS) blended with a mix of dicalcium phosphate dihydrate and microcrystalline cellulose. Force-displacement, force-time, and ejection profiles were generated using an instrumented rotary tablet press, and the effect of MS mixing time (10, 20, and 30 minutes) and tableting speed (10.7, 13.8, and 17.5 rpm) was investigated. The packing index (PI), frictional index (FI), and packing energy (PE) derived from the force-displacement profiles showed that MS sample I performed better than sample II. At higher lubricant mixing times, the values of PI were observed to increase, and values of FI and PE were observed to decrease for both MS samples. Lower values of area under the curve (AUC) calculated from force-time compression profiles also showed sample I to be superior to sample II in lubrication potential. For both the samples, the values of AUC were observed to decrease with higher lubricant mixing times. Tapping volumetry that simulates the initial particle rearrangement gave values of parameter a and C_max that were higher for sample I than sample II and also increased with lubricant mixing time. The superior lubrication potential of sample I was also established by the lower values of peak ejection force encountered in the ejection profile. Lower ejection forces were also found to result from higher tableting speeds and longer lubricant mixing times. The difference in lubrication efficacy of the 2 samples could be attributed to differences in their solid-state properties, such as particle size, specific surface area, and d-spacing.

Keywords: Magnesium stearate, lubrication efficiency, force-displacement profile, force-time profile, particle rearrangement, ejection profile

Introduction

Tablet dosage forms have been the first choice in the development of new drug entities and account for some 70% to 80% of all pharmaceutical preparations.^1,2 As with other classes of pharmaceutical excipients, lubricating agents aid in the manufacture of tablets and ensure that the finished products are of appropriate quality. Lubricants with low shear strength but cohesive tendencies perpendicular to shear plane serve this purpose optimally.³ Magnesium stearate (MS), with its low friction coefficient and large “covering potential,” is an ideal lubricant widely used in tablet manufacturing.⁴ The increased use of high-speed tableting and capsule machines has placed greater demands on lubricants, which are expected to help speed up the manufacturing process. This often requires the use of higher concentrations of MS, but because of MS’s hydrophobic nature, increasing the concentration can adversely affect the tensile strength, flow properties, and dissolution rate.^5,6 Hence, there exists a need to control and optimize the level of MS in formulations to balance the lubrication potential against the effect on content uniformity, tablet hardness, compaction, and dissolution.

In a previous study, the lubrication efficacy of 6 samples of MS was investigated using a texture analyzer, and the results were correlated to the solid-state properties of MS samples.⁷ The “net work done” method using a texture analyzer (with a load cell of 50 kg, equivalent of 500 N) was employed to simulate the lubrication efficacy of MS for use in a tamping capsule-filling machine, where forces in the range of 100 to 200 N are involved.⁸ The study had identified the best and the worst performers and related their performance to solid-state properties. Tableting, which requires application of much higher forces (in the range of 5-15 kN), can be divided into 2 distinct stages: initial compression (reduction in bulk volume because of displacement of gaseous phase) and consolidation (increase in mechanical strength because of cold welding and fusion bonding between the particles).⁹ An ideal lubricant needs to perform during both the stages. A texture analyzer–based method can only mimic slug formation in dosators and tamping capsule-filling machines. From a tableting point of view, the texture analyzer–based method only measures the particle rearrangement and slippage and is of limited value because it cannot simulate the higher forces used in tablet compression. In a real tableting condition on a rotary tablet machine, a lubricant not only plays a role during particle rearrangement but, more critically, minimizes stress during ejection. An instrumented rotary tableting machine provides an attractive alternative for the study of basic compaction phenomena and gives a parametric view with respect to the actual tableting condition.¹⁰

The present study attempted to evaluate the lubrication potential of 2 MS samples (the best and worst performers as identified in the previous study) on an instrumented rotary tablet press using force-displacement and force-time compression profiles to quantify the packing and frictional behavior during initial particle rearrangement, and the ejection profile as a measure of tablet ejection. In addition, the effect of MS mixing time and tableting speed on the lubrication efficacy of MS was studied for both samples.

Materials and Methods

Materials

Two samples of MS from different manufacturers, designated as sample I (Lot no RMK01248, Famy Care, Mumbai, India; British Pharmacopoeia grade) and sample II (Lot no BR41, Global Medicine, India; Indian Pharmacopoeia grade), were procured. Dicalcium phosphate dihydrate (DCP) of granular grade (Engranule, Enar Chemie Private Limited, Gujarat, India) and microcrystalline cellulose (MCC) (Avicel PH102, FMC Biopolymer, Philadelphia, PA) were used as excipients.

Methods

Characterization of Excipients

The moisture content of the excipients was determined by Karl Fisher titration (Metrohm 794 Basic Titrino, Herisau, Switzerland). The instrument was calibrated with disodium tartrate dihydrate for the accuracy of moisture determination. A sample size of 100 to 120 mg was used for the determination of moisture content. The particle size of excipients was determined by optical microscopy by measuring the diameter along the longest axis for at least 300 particles (DMLP microscope, Leica Microsystems, Wetzlar, Germany). The melting point of MS samples was determined by a differential scanning calorimeter (821^e Mettler Toledo, Greifensee, Switzerland, operating with STAR system, version 5.1) with a temperature range of –10°C to 210°C at a heating rate of 5°C/min and nitrogen purge of 100 mL/min.

Preparation of the Excipient Blend

The selection of excipients for lubricant performance evaluation was based on the consolidation behavior of the excipients. A blend containing 92% DCP (brittle material) and 8% MCC (plastic material) was selected. The required amounts of DCP and MCC were weighed and mixed, and then MS was sieved through British Standard Sieve #60 and added in a geometric progression. The total blend was mixed in a Kalweka blender (VDM 4SP, Kalweka, Ahmedabad, India) at 20 rpm for 10 minutes. To differentiate the lubrication potential of the MS samples, blends were mixed for 10, 20, and 30 minutes at 20 rpm. Except otherwise indicated, a concentration of 0.2% wt/wt of MS was used throughout this study.

Tableting and Data Acquisition

The rotary tablet press (Mini II, Rimek, Ahmedabad) was equipped at 1 of the 8 stations with an 8-mm D-tooling with a flat punch tip. A feed frame was used for uniform die filling, and blind dies were used at all other positions. Precompression rollers were set out of function. The tablet weight was kept constant at 300 ± 4 mg, and the applied force was leveled by moving the pressure roller with a hand wheel. Humidity (40 ± 5% relative humidity) and temperature (25°C ± 5°C) conditions were controlled throughout the study. All blends were subjected to a constant main compression force (13.8 ± 0.2 kN) to minimize the effect of other experimental variables. Routine experiments were performed at 13.8 rpm (round time of 4358 msec). However, for the study of tableting speed, an additional 2 speeds of 10.7 and 17.5 rpm were selected (round time of 5604 and 3419 msec, respectively).

Data was acquired by Portable Press Analyzer (PPA) version 1.2, revision D (Data Acquisition and Analyzing System, PuuMan Oy, Kuopio, Finland), through an infrared (IR) telemetric device with 16-bit analog-to-digital converter (6 kHz). Force was measured by strain gauges at upper and lower punches (350 Ω, full Wheatstone bridge; I. Holland Tableting Science, Nottingham, UK), which were coupled with displacement transducers (linear potentiometer, 1000 Ω). Upper and lower punch data were recorded and transmitted on separate channels by individual amplifiers (“Boomerangs”). The amplifiers truncated the raw data from 16 bit to 12 bit after measuring to check IR transmission (data transmission rate: 50 kbaud; internal data buffer: 1024 measurement points). Analysis of compaction data was performed by the PPA software. The accuracy of force and displacement transducers was 1% and 0.02%, respectively. The suitability of the data acquisition system has previously been reported.¹⁰

Tapping Volumetry

Tapping experiments were performed in triplicate on a tap density apparatus (ETD-1020, Electrolab, Mumbai, India) equipped with a 10-mL graduated glass cylinder. Blends containing MS were gently poured through a funnel into a graduated cylinder, and the tapped volume was read to the nearest millimeter at 0, 50, 100, 200, 300, 500, 700, 1000, 1300, 1700, and 2000 tap numbers.

Statistical Analysis

SigmaStat version 2.03 (Systat Software Inc, SPSS Ltd, San Rafael, CA) was employed for all regression and statistical analysis. Data are expressed as mean ± SEM. To check whether there was any significant difference in the mean of the treated groups, and hence the lubrication efficacy of different blends, comparison of the mean values of various groups was performed by 1-way analysis of variance followed by multiple comparisons using the Tukey test. The data was analyzed and it showed a normal distribution at 99% confidence limits. Differences between groups were considered significant when P < .01.

Results and Discussion

Characterization of Excipients

The moisture content of DCP and MCC was found to be 0.32% and 4%, respectively. The median particle size for DCP and MCC was found to be 110 to 140 μm and 80 to 100 μm, respectively. The moisture content and the particle size distribution of both the samples have been reported previously.⁷ The values of the stoichiometric ratio of water molecules per molecule of magnesium stearate present in the crystal structure for sample I and sample II were found to be ~1.8 and 1.86, respectively. The results indicated that both the samples were dihydrate. The percentage distribution of particle size (d_%) was calculated for both the samples of MS. The d_1%, d_50%, and d_95% for sample I were >24.12 μm, >6.12 μm, and >1.12 μm, respectively; and for sample II were >84.63 μm, >24.42 μm, and >1.38 μm, respectively.⁷ The melting point of samples I and II was found to be 108°C to 120°C and 112°C to 125°C, respectively.

Selection of Excipients and MS Concentration

DCP is a brittle material. The fragmentation under confined loading generates new surfaces, which increases the surface area of the particles over which the lubricant particles can distribute. DCP’s brittle nature and high propensity toward fragmentation make it lubricant-insensitive. On the contrary, MCC, which consolidates by plastic deformation, remains lubricant-sensitive. Therefore, the blend containing a higher proportion of DCP was used in the study. The lead was also indicated in a previous study on the lubrication potential of MS.⁷ The use of MS at 1% and 2% wt/wt in the selected excipient blend gave a very low ejection force that was not quantifiable. The aim of the investigation was to differentiate the lubrication potential of MS using different compaction profiles generated during tableting of the blend and to identify the relationship between lubrication potential and the solid-state properties of MS during a real tableting condition. Hence, lower concentrations were screened and a concentration of 0.2% wt/wt was selected for further experimentation.

Force-Displacement Compression Profile

The tendency of a material to undergo rearrangement, fragmentation, plastic deformation, and/or elastic recovery can be expressed and quantified as numerical values from a force-displacement curve.^11-13Figure 1 illustrates the different energies involved during the complete compression cycle and the stage-specific energy allocations of different stages from the force-displacement compression profile. Triangle ACD describes the mechanical energy (energy of compaction); triangle BCD is the theoretical energy (energy of compaction, excluding initial packing phase, AB); curve BCD is the total energy (energy involved during compaction, excluding initial packing and interparticulate friction); curve BCB is the frictional energy (friction arising due to particle-particle and particle-die wall friction, ie, difference between theoretical energy and total energy); curve CDE is the elastic energy (energy released as a result of elastic deformation during compression unloading); and curve BCE is the net energy (energy required to yield a particle under force).

Figure 1. A theoretical force-displacement compression profile showing the different areas of the compression event.

Under a low applied force (at the start of the compression cycle), the initial portion of the force-displacement profile gives information about particle rearrangement. The particle sliding and rearrangement in this phase does not contribute significantly to the densification.^14,15 The phenomenon of initial particle rearrangement can be expressed as packing index (PI) and frictional index (FI), each of which involves 2 different energies that are related by linear law over the entire force profile. PI relates the transformation of mechanical energy (ME) into theoretical energy (ThE), while FI characterizes the transformation of theoretical energy into total energy (TE). They can be presented as follows:

P I = 1 − ( T h E / M E )

(1)

F I = 1 − ( T E / T h E )

(2)

Lubricants play a significant role in facilitating the packing of particles,¹⁶ which is reflected as a change in the value of PI, FI, and packing energy (PE). Table 1 shows the values of PI, FI, and PE obtained from the force-displacement compression profile for blends prepared using samples I and II, each mixed at 3 different mixing times (10, 20, and 30 minutes), along with the control (no MS added). Values of PI increased with an increase in mixing time for both sample I and sample II, and values for sample I were greater than those for sample II for any given mixing time. PI is a measure of a material’s ability to pack under the influence of interparticulate and die-wall frictions at a very low applied force. The mixing time of MS significantly altered the PI parameter for sample I (P < .01) but not for sample II. When samples I and II were compared, a significant difference in the value of PI was apparent at a mixing time of 20 and 30 minutes, although the difference was not significant at 10 minutes.

Table 1. PI, FI, PE, and AUC for Blends Mixed for Varying Time Periods (n = 6)*

Mixing Time 10 Minutes 20 Minutes 30 Minutes Sample PI FI PE (J) AUC (Nsec) PI FI PE (J) AUC (Nsec) PI FI PE (J) AUC (Nsec) I 0.4485 (0.006) †abc 0.6157 (0.006) †abc 8.73 (0.08) †abc 53.58 (0.97) †abc 0.4634 (0.003) †a, ‡c 0.6006 (0.002) †a, ‡c 7.99 (0.13) †ac 49.39 (0.08) †a, ‡c 0.4989 (0.005) †a 0.5749 (0.003) †a 7.33 (0.11) †a 47.17 (0.15) †a II 0.4409 (0.003) †abc 0.6206 (0.005) †a, ‡bc 9.10 (0.17) †abc 54.97 (0.75) †a, ‡bc 0.4491 (0.003) †a, ‡z 0.6118 (0.003) †a, ‡cz 8.68 (0.03) †acz 53.51 (0.34) †az, ‡c 0.4528 (0.005) †az 0.6014 (0.002) †az 8.18 (0.09) †az 50.49 (0.97) †az 0% MS (control) 0.3195 (0.016) 0.6563 (0.009) 10.78 (0.39) 58.66 (1.14) — — — — — — — — *PI indicates packing index; FI, frictional index; PE, packing energy; AUC, area under the force-time curve; MS, magnesium stearate. †P < .001. ‡P < .01. avs control. bvs 20 minutes. cvs 30 minutes. zvs sample I.

FI represents the sum total of interparticulate and die-wall frictions encountered during this phase. The energy required for initial packing under particle rearrangement was also calculated by considering the area corresponding to PE (triangular area ABC, Figure 1) from the force-displacement compression profile. Values of FI and PE were observed to decrease with higher mixing time of MS and were lower for sample I than for sample II at any mixing time. The mixing time of MS significantly altered the FI and PE parameters for both sample I and sample II (P < .01). A significant difference in the value of FI and PE was apparent when samples I and II were compared at a mixing time of 20 and 30 minutes but not at 10 minutes (Table 1). These results indicate that mixing time has an influence on the surface distribution of MS particles and a longer mixing time imparts greater surface distribution, which affects the frictional forces arising from the interparticulate and die-wall frictions.

Force-Time Compression Profile

A force-time compression profile (Figure 2) can also be used to distinguish the various stages of compression.¹⁷ The area under the curve (AUC) of the initial phase of the force-time compression profile (area a, below 2.8 kN, Figure 2) was used as a quantitative measure of the material’s ability to rearrange under the influence of frictional forces resulting from the sliding of the particle planes with respect to each other and the die-wall frictional forces.^18,19

Figure 2. A representative force-time compression profile obtained from powder bed compression.

Table 1 lists the values of AUC calculated from the initial region of the force-time compression profile. Sample I yielded a lower value of AUC than did sample II, which was attributed to the lower force required to rearrange particles in sample I. As the mixing time was increased, the force required to rearrange particles up to a certain densification was reduced. This observation also confirmed the effect of lubricant distribution on the performance. Values of AUC were significantly affected by the mixing time of MS for both sample I and sample II (P < .01). A significant difference in the value of AUC was noticeable when samples I and II were compared at a mixing time of 20 and 30 minutes but not at 10 minutes. The results from the force-time profile were parallel to those obtained from the force-displacement profile. This confirmed the ability of parameters obtained from force-displacement and force-time profiles to represent the phenomenon of initial particle rearrangement under the influence of MS.

Tapping Volumetry

Tapping volumetry gives an approximation of volume reduction under the influence of lubricant and can be modeled using the Kawakita equation, which relates the state of volume reduction as a function of applied stress.²⁰ It is generally accepted that the Kawakita equation is best used for low pressures and high porosities and can be applied to data obtained from tapping volumetry.²¹ For tapping experiments, the Kawakita equation can be expressed as follows:

n / C = [ n / a   + 1 / a b ]

(3)

C = [ V O   − V n ] V O

(4)

where n is the tap number and a is the value of initial porosity that corresponds to the total portion of reducible volume. V_n and V₀ are the powder volume at the initial and nth tapped state, respectively. C describes the relative volume reduction, and b is a constant.

Results of tapping volumetry describing the Kawakita parameter (a) and maximum reducible volume (C_max) for blends containing 0.2% wt/wt of MS samples I and II, each mixed for 10, 20, and 30 minutes, and the values for control are presented in Table 2. The values of both a and C_max (maximum relative volume reduction) obtained from Kawakita analysis increased with higher mixing times for sample I and sample II. However, greater volume reduction was observed for sample I than for sample II. Lubricant mixing time influenced the total volume reduction because the lubricant distribution at the particle level assists the particle rearrangement under tapping by reducing the interparticulate friction. From a mathematical point of view, the a term describes the total amount of reducible volume while considering the packing efficiency of the powder under applied stress. The mixing time of MS significantly altered the volume reduction parameters a and C_max for samples I and II (P < .01). A significant difference in the values of a and C_max was evident at all mixing times when samples I and II were compared.

Table 2. Kawakita Parameter (a) and Maximum Reducible Volume (Cmax) for Blends Mixed for Varying Time Periods Along With the Values of Control Sample (n = 3)*

Mixing Time 10 Minutes 20 Minutes 30 Minutes Sample a Cmax a Cmax a Cmax I 0.2374 (0.0002) †abc 0.2317 (0.0017) †a, ‡bc 0.2494 (0.0003) †ac 0.2433 (0.0017) †a, ‡c 0.2665 (0.0018) †a 0.2567 (0.0017) †a II 0.2249 (0.0004) †abz 0.2183 (0.0017) †az, ‡b 0.2409 (0.0007) †a, ‡z 0.2317 (0.0017) †a, ‡z 0.2476 (0.001) †a, ‡z 0.2367 (0.0017) †a, ‡z 0% MS (control) 0.2026 (0.005) 0.1950 (0.0029) — — — — *MS indicates magnesium stearate. †P < .001. ‡P < .01. avs control. bvs 20 minutes. cvs 30 minutes. zvs sample I.

Ejection Profile

The force necessary to eject a tablet involves the distinctive peak force required to initiate ejection by breaking the die-wall tablet adhesion.²² The second stage involves the force required to push the tablet up the die wall, and the last force is required for ejection of a tablet from the die.²³ The distance traveled by the lower punch to push the tablet up to die level is the ejection displacement (Figure 3a). The integration of the areas under the force and displacement is the ejection work—that is, energy utilization during ejection (Figure 3b). Ejection displacement and ejection work at each lubricant mixing time are reported in Table 3. The peak ejection force (Figure 3c) recorded during tableting was used as a measure of the ejection. Each compression was performed under a similar main compression force so the possibility of a change in the ejection force being caused by a change in the main compression force could be ruled out.

Table 3. Values of Ejection Displacement and Ejection Work Obtained for Blends Mixed for Varying Time Periods and Compressed at Different Tableting Speeds (n = 3)*

Sample Ejection Parameter Mixing Time (min) Tableting Speed (rpm) 10 20 30 10.7 13.8 17.5 I Displacement (mm) 4.69 (0.02) 4.80 (0.03) 4.71 (0.01) 4.60 (0.04) 4.85 (0.06) 4.76 (0.04) Work (J) 1.17 (0.08) 0.92 (0.05) 0.79 (0.03) 1.60 (0.08) 1.01 (0.06) 0.94 (0.05) II Displacement (mm) 4.81 (0.08) 4.78 (0.01) 4.64 (0.07) 4.70 (0.03) 4.77 (0.02) 4.83 (0.03) Work (J) 1.50 (0.10) 1.14 (0.07) 1.02 (0.04) 1.91 (0.3) 1.18 (0.02) 1.09 (0.04) *Values of control blend (no magnesium stearate added) for ejection work and ejection displacement were 2.92 (0.1) kN and 4.95 (0.06) mm, respectively.

Figure 3. Ejection profiles: (A) displacement-time, (B) force-displacement, and (C) force-time; profiles obtained at 13.8 rpm.

The ejection force results obtained for sample I and sample II, each at 10, 20, and 30 minutes of mixing, are presented in Figure 4a. The observed corresponding value of the ejection force for the control blend (no MS added) was 1736 ± 12.1 kN. A significant difference in ejection force was evident at all mixing times when samples I and II were compared. The ejection force values were significantly different at all mixing times for sample I (P < .01). However, for sample II, the difference was significant between the blends prepared at mixing times of 10 and 20 minutes, but not significant between the blends prepared at mixing times of 20 and 30 minutes. This indicated optimal distribution of MS over particles of DCP and MCC, occurring in 20 minutes, with no further improvement thereafter. The latter is reflected as no futher reduction in ejection force. The values of ejection displacement and work (Table 3) calculated for the above experimental sets supplement the data obtained for ejection force.

Figure 4. Average ejection force values for 24 tablets for blends (A) mixed for varying time periods, and (B) compressed at different tableting speeds. †P < .001; ‡P < .01; avs control; bvs 20 minutes; cvs 30 minutes; dvs 13.8 rpm; evs 17.5 rpm; zvs sample I.

To investigate the effect of tableting speed on the lubrication performance of MS samples, tableting was done at 3 speeds: 10.7, 13.8, and 17.5 rpm. Results showed that as the tableting speed was increased, the values of the ejection force for both the MS samples decreased (Figure 4b). The tableting speed significantly altered the ejection force for both sample I and sample II (P < .01). A significant difference in the ejection force was also observed at all 3 tableting speeds when samples I and II were compared. The plastic deformation and fragmentation tendency of materials are time-dependent and occur at different rates during the compaction sequence, so the tablet mass is never in a state/strain equilibrium during the actual tableting event.²⁴ This means that the rate at which load is applied and removed may be a critical factor in elastic recovery and radial transmission force. The ejection force depends on the main compression force; hence, while the effect of dwell time was studied, the main compression force was kept constant. An increase in dwell time resulted in an increase in the main compression contact time of the upper and lower punch with the compact, which resulted in an increase in the radial force transmission to the die wall and a greater fragmentation propensity of brittle materials. The radial force acts as an indicator of friction forces between the compact and the die wall. Hence, increasing the dwell time is expected to increase the ejection force.²⁵ The extent of fragmentation of DCP (a major component in the blend) is also affected by the dwell time of the material, since at a higher dwell time, DCP particles undergo more fragmentation than they do at a lower dwell time. The lubricant surface distribution during the actual tableting event is affected by the extent of new surface created. Hence, higher tableting speed (reduced dwell time) reduces the chance for the formation of new surfaces. The reduction in ejection force at increased speed can therefore be attributed to the lower fragmentation propensity. The values of ejection force were also substantiated by the results of ejection work (Table 3).

Solid-State Properties and Lubrication Potential

The solid-state properties of MS samples and the lubrication potential using a texture analyzer were reported.⁷ Molecular-level (d-spacing) and particle-level (habit, particle size, surface area) properties of the 2 MS samples used in this study are reproduced in Table 4. It can be seen that the 2 samples differ substantially in their crystal habit (plate vs irregular), particle size (1.12 μm vs 1.38 μm), specific surface area (6.63 m²/g vs 1.66 m²/g), and d-spacing (11.7 Å vs 9.9 Å). These differences may contribute critically to the lubrication potential of MS. Compared with sample II, sample I exhibited a smaller particle size and a higher surface area, which helped the MS particles to distribute themselves well on the excipient surface. Sample I had flat, platelike crystals, whereas agglomerates were present in sample II, which again would affect the distribution over the particles. An increase in mixing time with MS led to increased surface distribution, which resulted in favorable particle rearrangement and a reduction in ejection force. Hence, the better performance of sample I can be attributed to its superior solid-state properties. A difference in the d-spacing values for samples I and II was also apparent from powder X-ray analysis. Shearability of a lubricant is a desired attribute and is related to elongation of lattice spaces of the crystal.⁶ A crystal with a longer lattice space would be expected to be a better performer (here, sample I over sample II).

Table 4. Molecular Level (d-Spacing) and Particle Level (Habit, Particle Size, Surface Area) Properties of Magnesium Stearate Samples7*

Solid-State Property Sample I Sample II Particle size (μm) d1% > 24.12 d50% > 6.12 d95% > 1.12 d1% > 84.63 d50% > 24.42 d95% > 1.38 BET specific surface area (m2/g) 6.63 1.66 Monolayer volume,† Vm at STP (cc/g) 1.5224 0.3814 Crystal habit Plate Irregular d-spacing (Å) 11.7 9.9 *BET indicates Brunauer-Emmett-Teller; STP, standard temperature and pressure. d1%, d50%, and d95% represent the 1%, 50%, and 95% distribution of particle size (μm), respectively. †The larger the surface area, the greater the volume of gas adsorbed.

Conclusions

An instrumented rotary tablet press can be used to study the role of MS in initial particle rearrangement and ejection phases. PI, FI, PE, AUC of the force-time compression profile, and ejection force can be used to differentiate the lubrication potential of different MS samples as well as the effect of lubricant mixing time and tableting compression speed. Solid-state properties of the MS samples—crystal d-spacing, particle size, and specific surface area—have an influence on the lubrication performance.

Acknowledgments

Aditya M. Kaushal would like to acknowledge CSIR, India for providing a senior research fellowship. The authors also wish to thank Mr Bhoomi Viswanad for help with the statistical analyses.

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