	For many reasons-from ease of administration to dosing accuracy to manufacturing efficiency-pharmaceutical manufacturers prefer to formulate their APIs as solid dosage drugs, and particularly tablets. There is significant room, however, for improvement of tableting processes.


	Lubricants (commonly magnesium stearate) affect the tableting process and the finished tablet. They not only reduce the compression force during tableting, but also prevent product buildup on tablet press tools and give the tablet a smooth surface. Too much lubricant can, however, reduce the hardness of the tablet to an undesired level, according to Sharon Nowak, business development manager with Coperion K-Tron Food & Pharmaceutical Industries. Traditionally, lubricants have been mixed with the solids used to form tablets, but this approach often leads to non-uniform distribution of the lubricant. To compensate, excess lubricant is used, which can negatively affect tablet properties.
	
	Recently, equipment has been developed that allows for spraying of the lubricant onto the tablet press tooling, allowing for significant reduction in the quantity of lubricant required. Original systems sprayed powdered lubricants on to the tablet press tooling to prevent sticking of the powder to the tool and die of the tablet press, according to Nowak. Importantly, these applications were done primarily volumetrically, with no measurement of the actual weight of the lubricant delivered. Magnesium stearate does not flow well, which can cause high variations in the feed rate with volumetric feeders because of inconsistent filling of the twin screws. As a result, there has been an increased demand for automated tablet press lubrication systems with highly accurate gravimetric feed designs, according to Nowak.

	“High accuracy twin-screw gravimetric feeders quantitatively deliver a specific amount of lubricant to the tablet. They also allow accurate determination of the amount of lubricant delivered to each tablet, even though the quantity of lubricant that ends up in the tablet granulation formulation is significantly decreased,” she observes. As a result, not only are the material handling properties of the granulation process improved, the overall dissolution rates of tablets can be increased. The lower quantities of lubricants required for tableting have also led to a need for lower and lower feed rate deliveries, according to Nowak. “For this reason, automated lubricant feeding systems today require highly accurate, specialized low-rate feeding,” she says.

	Coperion K-Tron’s solution uses patented load cell technology that continuously measures the weight of the lubricant and maintains a constant mass flow (weight per unit of time) by adjusting the speed of the twin-screw feeder. As a result, according to Nowak, the unit can be validated for a steady and uniform feed of lubricant to the tablet press. In addition, because the lubricant is delivered to the tools in a fraction of a second, the short-term accuracy is high. “With a nearly constant feed rate, it is possible to achieve uniform coating of the tablet tools and eliminate sticking problems, all with reduced stearate consumption and lower overall operating costs,” Nowak states.
	
	

Multi-tipped tooling and advanced coatings


	The key drivers in tablet manufacturing are the need to increase yield and capacity while reducing manufacturing costs and minimizing the space used and the time spent setting up each press, and increasing productivity has always been a challenge in modern tablet production, according to Steve Deakin, owner director of I Holland. That is why he believes the widespread use of multi-tipped tooling and the continued development of punch-and-die treatments and coatings have been great advances in the pharmaceutical industry.
	
	“Our ongoing development of multi-tip tooling is specifically driven by the desire to assist our customers in increasing productivity and capacity,” he says. Multi-tip punches allow the number of tablets per turret rotation to be multiplied by the number of tips on the punch. They also require less floor space, because more tablets can be produced with fewer tablet presses, leading to a reduction in overall plant running costs. “The development of a technology like multi-tip tooling is beneficial to many end users,” says Deakin.

	With respect to treatment and coating technologies, I Holland categorizes them based on their function: improving wear resistance, improving corrosion resistance, and improving anti-stick properties. “Treatments and coatings with these properties can help preserve the life of our punches and increase productivity for our customers,” Deakin comments. “The overall result is reduced press downtime and increased productivity, which is what every company wants,” he adds.


	Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology. Read the complete article by Cynthia Challener, with additional discussion of continuous manufacturing, systems integration, and modeling, in the 

Learn More from Sharon Nowak and Others at Interphex

 will host solid dosage manufacturing experts on the Innovation Stage. Come hear Sharon Nowak, Business Development Manager, Coperion K-Tron Food & Pharmaceutical Industries, speak about 

Optimization of Feeding and Conveying Technologies for Difficult Flowing Pharmaceutical Powders; 

Martin Hack, vice-president and general manager, L.B. Bohle, speak about 

Fluid Bed Technologies for Improved Processing; 

and Fred Murray, president, Korsch America, speak about 

Articles

Production Trends

Innovations for tablet tooling and presses improve quality and productivity.

Specialized Equipment Improves Tableting

	
	Cytotoxic drugs are widely used in the healthcare industry. However, whilst effective in treating diseases, the toxicity of these drugs can present a significant health risk to the manufacturers, pharmacists, and other healthcare professionals who handle them. Occupational exposure can occur in many ways; staff are at most risk when preparing the cytotoxic drugs. The greatest hazards arise through the formation of dusts (e.g., in the event of defective injection vials containing dry solids), liquids (e.g., on transfer and dispensing of the dissolved substance), aerosol formation (e.g., when dissolving the dry solids), or when containers containing cytostatics are inadvertently dropped. Once exposed, a wide range of potential side effects could occur, including abdominal pain, vomiting, and allergic reactions. To mitigate the risk of exposure, it is vital that companies involved in the manufacturing and handling of cytotoxic drugs ensure that staff are given the highest possible levels of protection.

It is important that all possibilities of removing the hazard altogether are exhausted before considering ways of limiting staff exposure. The following hazard-control hierarchy can be used as a guide to good practice:

-find a safer substitute (e.g., a less toxic material or a different working method).

-put technical solutions in place that protect the worker (e.g., mechanical ventilation, machinery guards, and remote controls).

-implement worker training and install suitable alarm and warning systems.

	It is the responsibility of management to implement safe working methods and to reassess procedures in response to changing conditions such as the emergence of new hazards. However, employees must also be trained and educated to accept responsibility for identifying risk situations and for taking the necessary safety precautions. This includes a responsibility for using the personal protective equipment (PPE) provided in the correct manner and being aware of its use, its limitations, and its correct disposal.


	PPE is the final line of defense when it comes to protecting personnel from toxic substances. PPE, whilst primarily intended to prevent the body from coming into contact with hazardous chemicals and dusts, also plays a vital part in protecting the manufacturing process from human contamination, including hair, shedding skin, and clothing fibers. As such, it is a crucial safety measure that cannot be compromised. The following factors should be considered when choosing coveralls and protective garments.

Barrier efficiency against migrating particles, such as those from clothing or human skin, is a crucial performance feature when working with cytostatics. When determining the level of protection from particle intrusion, it is important to look at the Type 5 test results. The Type 5 test specifies the minimum requirements for chemical protective clothing resistant to penetration by airborne solid particles. To test particle intrusion, the Type 5 test method uses sodium chloride particles at 0.6 micron sizes suspended in a fine spray in a test chamber. The 9-minute test (3 minutes standing, 3 minutes walking, and 3 minutes squatting) is repeated on 10 suits. To pass the test, eight out of the 10 suits tested must have on average less than 15% inward leakage into the suits. This means that coveralls that have passed the Type 5 test offer a certain level of protection against fine particulates. It is important to choose a coverall that offers the lowest level of inward leakage for the best possible protection when working with cytostatic drugs.

. While most coveralls look similar, the material used makes a difference in determining the end protection level. There are three common types of material: microporous film (MPF), spun bond–melt blown–spun bond (SMS) and Tyvek (DuPont), which is a synthetic material made out of flashspun high-density polyethylene fibres. When tested against BS 6909, these materials perform differently. MPF (sometimes known as LMPF) is made using a spunbond polypropylene and a film of polyethylene. Due to the structure of the material, it is not breathable and has a high particle shed count. SMS is a breathable material but has poor liquid repellency. Due to the short fibres in the material, it sheds fibres quickly and is, therefore, unsuitable for cleanroom environments. Tyvek, manufactured only by DuPont, is made up of ultrafine endless high-density polyethylene fibres using specific spinning and bonding technology. Because of the endless fibres, it has a low particle shed count.

Whilst protecting both the worker and the process is crucial, a further, important issue is having coveralls that are comfortable. If workers are comfortable, they are more willing to wear the protective garments and protection is, therefore, heightened. The garments should ideally be designed to be durable enough to allow for a range of movement and flexibility, without compromising safety through ripped seams. At the same time, the fabric should offer sufficiently high levels of permeability to both air and water vapour to allow it to “breathe.”

	The German Apothekenbetriebsordnung (ApBetrO, regulation on the operation of pharmacies), which has been in force since June 2012, has also set out specific hygiene conditions for working with cytostatics. According to the regulation, protective clothing must also comply with the following requirements:

	·        Liquid-tight at arms and front
	·        Long sleeves
	·        Closed at the front                
	·        Tight seal at cuffs            
	·        Low-linting
	·        Barrier against pure and dilute cytostatics as well as fine particles
	·        Smooth surface (prevents particles from adhering to the surface)
	·        Optional: comfortable to wear, antistatic treatment, sterilizable.

	Ian Samson is a DuPont consultant for the EMEA and Russia regions, 

Troubleshooting

Companies manufacturing cytotoxic drugs must ensure that staff are given the highest possible levels of protection.

Choosing Personal Protective Equipment for Handling Cytotoxic Drugs

 General Chapter <1207>, Sterile Product Package-Integrity Evaluation calls for a shift to more quantitative, validated test methods. Although there is no set timetable, industry observers expect the chapter to be effective at the end of 2016.
	
	“The first round of proposed revisions were included in the 

 in September 2014,” says Justine Young, project manager, container closure integrity testing (CCIT) at Whitehouse Laboratories. “The comment period has elapsed, and feedback has been received,” adds Brandon Zurawlow, who also serves as a project manager, CCIT at Whitehouse Laboratories. “The expert committee is now in the process of preparing a second revision to be released to PF. If sufficient comments are received, the chapter will need to undergo an additional revision process,” he explains.

	According to Oliver Stauffer, chief operating officer at PTI-Packaging Technologies & Inspection, the revised chapter “clearly outlines the various container closure integrity (CCI) test methods fit for use in the pharmaceutical industry. It identifies deterministic methods that are quantitative and definitive in measuring the integrity of a package. It also identifies probabilistic methods that use qualitative information or attribute results derived from human judgment. The document strongly advises use of deterministic methodology to assure CCI.”

	“Many of the technologies included in the revisions have been available for decades,” notes Young. “Despite this,” she says, “industry has continued to rely on probabilistic test methods to evaluate the integrity of parenteral packages.” Once the chapter is effective, she predicts, “FDA will become more stringent in its review process of package integrity data.”

	Zurawlow adds, “From discussions with others in industry, FDA is already beginning this shift, and companies are beginning to receive pushback when submitting data obtained by the dye ingress method.” Whitehouse Laboratories already employs deterministic leak-test technologies and currently relies on vacuum decay, mass extraction, helium mass spectrometry, high-voltage leak detection, and laser-based headspace analysis systems.

 <1207> does not necessarily change methods or technologies. It changes the way that organizations relate to those methods and the information they offer [and]… encourages organizations to adopt test methods that provide the highest level of quality assurance. The chapter removes gray areas within CCI, highlighting some methods that have industry-proven capability, and drives industry to deploy solutions that have a higher detection capability.”

	Regardless of the CCIT methodology chosen, testing should be quantitative, repeatable, reliable, and validated for each product-package system. Ideally, any test also should be nondestructive to prevent waste and loss of costly product.

	As a result, it seems inevitable there will be a shift from probabilistic testing such as dye ingress to more deterministic methodologies. However, Louis Brasten, supervisor, routine and functional analysis/filling services at West Pharmaceutical Services, notes, “Chapter <1207> has become more of a guideline… No ‘one test’ is the key to defining a client’s closure integrity. It is the right combination of testing that shows the complete picture over the lifecycle of the product.” West relies on state-of-the-art equipment and CCIT techniques to paint a complete picture of CCI for the lifecycle of its customer’s products.

	Whitehouse Laboratories provides CCI method development and validation services for client-specific product-package systems in a cGMP, FDA-regulated laboratory environment. “We will work with clients to understand their product-package systems and to determine the most applicable CCI technology to employ for integrity evaluation, offering our knowledge and years of experience to optimize the use of these technologies,” says Young.

Packaging

Revisions to USP General Chapter  may impact evaluation of sterile product package integrity.

Equipment and Processing Report-04-08-2015

Specialized Equipment Improves Tableting

Choosing Personal Protective Equipment for Handling Cytotoxic Drugs

Pending Guideline Revisions Call For Updated Package Integrity Testing