Q: When I run a small production batch of a particular formulation with the same tablet press used to develop it, I get compressibility and disintegration issues. First I blend microcrystalline cellulose and disintegrant with the API for 10 min in a V blender. Then I add cabosil, talc, and more microcrystalline cellulose and blend the mixture for 5 min. Finally, I add magnesium stearate and blend for 3 min. In development, the turret speed was 30 rpm, and two punches were installed to generate the compaction profiles. The production run is also at 30 rpm, but with 10 punches. The paddle feeder speeds were set and the 19-mm full fill cam was used with a tablet weight of 100 mg.

A: Based on the information you provided, a production run should be successful, however the fill-cam-to-weight-cam setting could be problematic. The fill cam must provide a slightly higher volumetric fill than the weight-cam fill. Overfilling the die cavity and pushing out excess material to achieve the target weight can ensure tablet weight uniformity, but if the selected fill cam setting is much greater than the weight-cam setting, the excess material will recycle back into the paddle feeder, thus resulting in overblending, which will increase the lubricant efficiency, thus resulting in the problems you are experiencing. 

Two approaches could help. You could select the appropriate fill cam based on the weight-cam setting. You can calculate the required weight-cam depth by dividing volume by the cross-sectional area of the punch tip. The volume that the formulation will occupy in the die is the tablet weight divided by the powder bulk density. Once the weight setting is determined, the proper fill cam should be slightly higher to provide a small overfill.

Also, using less lubricant would minimize the negative effects of overblending. The right amount of lubricant can be determined from a compaction profile using your instrumented tablet press.  An external lubricant system can also help your process.

—Robert Sedlock, technical sales manager at Specialty Measurements 

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Articles

Troubleshooting

When I run a small production batch of a particular formulation with the same tablet press used to develop it, I get compressibility and disintegration issues. What am I doing wrong?

Scaling Up a Tableting Process

An FDA review of data indicated that, since 2003, the majority of injectable-product recalls related to particulate contamination have involved glass, metal, and the formation of crystals, according to an agency spokesperson. These recalls have contributed to the pharmaceutical industry’s heightened awareness of glass delamination (i.e., the formation of glass flakes in a vial), which could affect drug quality and patient safety. To confront this growing problem effectively, drugmakers must understand its causes.

Glass delamination results from the interaction between the product formulation and the glass container. Formulations with a high pH, and those that include phosphate and citrate buffers increase the risk of glass delamination, according to John Shabushnig, senior manager at Pfizer, leader of the Parenteral Drug Association’s (PDA’s) Visual Inspection Interest Group, and member of the US Pharmacopeia’s Visual Inspection Expert Panel. 

Changing a product’s formulation to prevent glass delamination is not a straightforward proposition, however. Many drugs, particularly biopharmaceuticals, require certain formulation components to remain stable. Although phosphate and citrate buffers can corrode glass, for example, the active molecule may require the attributes of those ingredients. “Any change to the formulation may affect the safety and efficacy of the product. Therefore, changes must be considered carefully out of concern for patient safety,” says Ronald Iacocca, senior research advisor for physical and structural characterization at Eli Lilly and Company. 

Characteristics of the glass vial itself also can heighten the risk of delamination, and changing the vial that holds a formulation could be easier than changing the formulation itself. High alkali content in glass could accelerate erosion, so manufacturers should choose vials with low alkali content if possible, says Iacocca. 

In addition, evidence suggests that high temperatures during the vial-forming process increase the risk of glass delamination, says Shabushnig. Appropriate control of temperatures during the glass-forming process is especially important when the containers will store corrosive product formulations. Drug manufacturers should ask vial vendors about their process control, and also test vials to ensure their suitability for the product in question.

Drugmakers could adapt their manufacturing processes in certain ways to reduce the risk of glass delamination. For example, treating the surface of the glass vials with materials, such as ammonium sulfate, can reduce the rate of glass erosion, says Shabushnig. Terminal sterilization also is a risk factor that, together with specific products, could cause delamination. But drugmakers would consider alternative sterilization methods only in rare cases.

Storage conditions also should be evaluated. High product-storage temperatures and long exposure times can increase the rate and severity of glass delamination. Firms should examine both factors during stability testing to determine the appropriate expiration date for a given formulation. 

Plastic primary container–closure systems are an option, but they may interact with the drug product like glass does, thus creating an undesirable extractables and leachables profile. In addition, polymers may not afford the necessary protection against oxygen or moisture that glass does.

It typically takes months or years for glass delamination to occur, so the phenomenon cannot be detected as part of routine 100% inspection during manufacturing. Ideally, drugmakers should identify and address this form of particulate contamination during product development, says Shabushnig.

“The phenomenon is best investigated as a systems-based approach by looking at the interaction between the drug product and the glass together,” says Iacocca. Drug-specific compatibility tests are the most important way of mitigating delamination in marketed products, he adds. These tests could be the first step toward deciding how to prevent this potential source of particulate contamination.

For more information about glass delamination, see Ron Iacocca’s article in the November “Analytical Technology” supplement to 

Production Lines

Recent recalls have contributed to the pharmaceutical industry?s heightened awareness of glass delamination (i.e., the formation of glass flakes in a vial), which could affect drug quality and patient safety. To confront this growing problem effectively, drugmakers must understand its causes.

Steps for Reducing Glass Delamination

Edwards
 Dry pump includes tapered, variable-pitch screw technology


 The CXS dry vacuum pumps from Edwards incorporate tapered, variable-pitch screw technology that enables gradual compression along the length of the rotor. As a result, users can control the temperature better than they can with other dry-pump technology.

Unlike other marketed pumps that use screw technology, the CXS pumps do not have a cantilever rotor design, and they do not have an end compression plate. The pumps thus do not compact any material when they cool down and have excellent solids handling. These characteristics help to prevent cold seizures and make it easy to restart with solids still in the pump.

The pump’s rotors are designed to not match each other exactly. When one rotor is damaged, a user thus can replace it without having to replace both. The CXS pump also monitors its own temperature and does not begin processing until it is ready. When the pump is not needed, it runs at a lower speed and power level to save energy. The pump is designed to require an exceptionally low level of energy for operation.

Moyno 
 Positive-displacement pump facilitates maintenance


Moyno’s Moyno 1000 close-coupled positive-displacement pump is designed to provide more versatility and performance advantages than other types of positive-displacement pumps. The pump’s two-piece drive shaft facilitates assembly, maintenance, and access to the mechanical seal. The drive-shaft configuration eliminates the need to disassemble the pump completely when servicing the mechanical seal. In addition, the machine’s pin-type universal joint is sealed and lubricated, which lengthens the device’s service life and reduces maintenance requirements.

The Moyno 1000 pump provides smooth, nonpulsating flow at rates from 0.38 to 320 gpm. The unit is also designed for low-shear pumping action and provides pressures as high as 350 psi. The pump can handle viscosities as great as 1,000,000 cps and fluid temperatures as high as 350 °F. The unit’s compact configuration is appropriate for areas with limited space. The pump can perform applications that involve shear-sensitive chemicals, pharmaceutical pastes, and lotions.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the October 2011 edition from Edwards and Moyno.

October 2011 Editor's Picks: Products from Edwards and Moyno

The United States Air Force has invested in robotic aircraft because manned aircraft are complex and expensive to build and operate, and because robots spare humans from potential hazards and reduce failure rates. These same considerations are relevant in the modern aseptic pharmaceutical plant that produces life-saving drugs. Complex, multistep processes performed at these sites with expensive materials result in fragile and valuable products. Building facilities that rely on manned operation requires large volumes of highly filtered air and space sufficient for human motion and intervention into processes. Manned operation also limits the ambient conditions possible for processing. Sites intended for human operators can be expensive, complex, and prone to failure.

With a history of more than 40 years in the manufacturing industries, robotic manufacturing is not a novel approach to producing goods. Indeed, many industries consider robotics as their first choice for sensitive or hazardous processing. It has taken until today, however, for robotics to enter the modern aseptic pharmaceutical facility and, most importantly, isolator systems. This delayed entrance has resulted from traditional cleanroom robots’ failure to accomplish the following things:

Limit particle generation to levels acceptable within an ISO 5 space

Seal sufficiently, with respect to the ingress of clean-in-place water and the egress of toxic material from the isolated space

Withstand sterilizing agents, such as hydrogen peroxide and chlorine dioxide 

Be effectively and reliably sterilizable with these same surface-sterilization agents.

Almost no other industry has required these conditions, and, consequently, the robotics industry showed little interest in fulfilling them. But all of these conditions are crucial for the successful and efficient deployment of robotics within modern isolator systems. Recent developments in the field, however, have advanced robotic technologies to a state of readiness for GMP deployment. Yet these strategies must not be applied as an added level of complexity to existing filling or processing systems. 

The development of cleanroom-grade, 316L stainless-steel robotics with sealed structures has enabled engineers and architects to look at design strategies without the limitations present previously in manned operations. The required clean space necessary for isolated robotics is often less than one quarter of that required for manned operation. Isolated robotics also have the potential to operate under inert gas, thus providing the ability to limit products’ exposure to oxygen. 

Furthermore, isolators designed for robotic operations have the potential to be much simpler in shape and layout because they do not have the limitations of gloved access imposed by manned operation. Contrasting traditional isolator designs with a multitude of gloves and complex shapes often require peroxide aeration times of greater than 20 h. This requirement massively reduces facility uptime and makes product changeover difficult and time-consuming. Indeed, the cost and complexity of such systems have prompted some companies to back away from isolator technology in favor of restricted-access barrier systems (RABS). This change is a step backwards, however, because the procurement and implementation costs of RABS are greater than those of isolators. Operating costs for RABS are roughly double those of isolators.

Regulatory factors are also encouraging the advancement of unmanned aseptic production. FDA and EMA have asserted the need to eliminate human interventions in aseptic operations (1, 2). These interventions are viewed as the largest source of contamination risk, and pharmaceutical companies are increasingly experiencing difficulties in justifying previously acceptable facility designs and practices. Removing gloves and personnel from direct interaction with the process yields a more predictable and reliable product.

Large pharmaceutical companies are now undertaking efforts to define their factory of the future. In many ways, they are coming to the same conclusions as many industries engaged in complex, expensive operations that carry significant risk to humans have.

The future, and increasingly the present, for aseptic operations is isolated robotics. Companies that wish to gain competitive advantages in their operations are stepping up and taking notice. The result will be cheaper, safer medicines when and where they are needed. 


 1. Rick Friedman, presentation at the ISPE Conference (Washington, DC, 2009).
 2. Ian Thrussell, presentation at the ISPE Conference (Strasbourg, France, 2009).

Christopher Procyshyn is chief executive officer of VanRX, #200 - 3731 N. Fraser Way, Burnaby, BC, Canada, tel. 604.453.8660. 

In the Mixer

The future, and increasingly the present, for aseptic operations is isolated robotics. Companies that wish to gain competitive advantages in their operations are stepping up and taking notice.

Equipment and Processing Report-10-19-2011

Scaling Up a Tableting Process

Steps for Reducing Glass Delamination

October 2011 Editor's Picks: Products from Edwards and Moyno

Isolated Robotics: The Future of Aseptic Operations