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PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the October 2012 edition from UFP Technologies and Mettler Toledo.

October 2012 Editor's Picks: Products from UFP Technologies and Mettler Toledo

Intelligent field devices used in manufacturing processes perform and communicate diagnostic measurements about the health of the process and process equipment. For example, intelligent control valves can detect insufficient air supply or calibration changes and intelligent analytical devices can detect electrode aging or failure (1). “Most new analog devices are intelligent, and the corresponding input/output card on the control system is capable of accessing the digital information, such as diagnostics and, in the case of control elements, feedback position,” explains Ian Verhappen, managing director of Yokogawa Canada. Suppliers note that the data generated by intelligent devices could be used to identify pending problems and thus improve maintenance and control decisions. The capability of intelligent devices, however, is underutilized in most industries that have access to these devices. More than 80% of smart-instrument data is not being used, estimates Verhappen. Verhappen is also the managing director of a new standards committee for Intelligent Device Management at the International Society of Automation (ISA), ISA108. ISA108 will define standard templates of best practices and work processes for design, development, installation, and use of diagnostic and other information provided by intelligent field devices in the process industries, ISA explained in an Aug. 15, 2012 press release.

An intelligent device management strategy is particularly important for regulated industries like pharmaceuticals. “Having an intelligent device management strategy can ease regulatory compliance and validation and improve traceability. It is also a big step towards digital record keeping. These intelligent devices leave a digital trail behind them of all the maintenance activities that are done, who did them, and when. They have the capability to store large amounts of data about themselves and the processes they control,” notes Charley Robinson, manager for Standards & Technology at ISA. 

There are various reasons that intelligent devices are underutilized in pharmaceuticals and other industries. One challenge is that many users do not know which of the many parameters are of greatest value to them, says Verhappen, who notes that a typical fieldbus transmitter has in excess of 300 parameters. “Users need a process to get the right information from the device to the right person at the right time to do something with it,” says Verhappen, “For example, operators do not need to know today that maintenance should be performed on the valve air regulator in 2 weeks, but they should know if the temperature measurement on a vessel is bad because the thermocouple has failed.”

“The main hurdle we see is not in implementation of the technology but in the access and management of the plethora of information now available from smart instruments,” agree Joe Valencia, global account manager for the pharmaceutical industry at Rockwell Automation and Ravi Shankar, industry manager for life sciences at Endress+Hauser. “A company must have bandwidth to manage, present, and analyze the data so that it is useful to operators and maintenance personnel. Once the process to present the data is defined, validation of that process will present an additional challenge.” A key to success is the interoperability between the process control system and instrumentation, note Valencia and Shankar. To this end, Endress+Hauser and Rockwell Automation both have joint integration offices and laboratories for testing Endress+Hauser devices with Rockwell’s PlantPAx process automation control system. Both Rockwell Automation and Endress+Hauser plan on active participation in ISA108. 

As in many projects, a key to successfully using this relatively new technology is having a champion who is willing to learn how to use and access the information, comments Verhappen.  He notes that technician buy-in is another crucial factor, and that technicians need to see that this information is being used to make their jobs easier rather than as a tool to monitor what they are doing. 

The ISA108 committee plans to issue a series of standards to address models and terminology, implementation guidelines, work processes, diagnostics-based maintenance, configuration management, and auditing. The committee will first start with definitions and technical reports containing recommendations, which will later, based on experience, be revised and made into full standards, says Verhappen. 

,” InTech online, Nov. 1, 2005, accessed Oct. 3, 2012.

Production Lines

Strategic management of intelligent devices is important in any processing field, and a new standards committee at the International Society of Automation aims to provide direction so that manufacturers can better utilize the devices' capabilities.

Improving Intelligent Device Management

Q. Our company needs more stability storage. What issues should we consider when deciding whether to build our own biorepository facility or outsource our storage?

A. In addition to questions of location, available facility space, and capital-equipment cost, as discussed in an 

, you should consider the time and expertise needed to maintain regulatory compliance. Any cGMP facility should incorporate chambers and rooms that are built using the most modern techniques. They must be mapped and validated for pharmaceutical stability storage and biotechnology product storage. Outsourcing companies can tailor these temperature and humidity-controlled rooms and chambers to suit individual customer requirements, as well as to accomodate shelf-life studies, intermediate testing, and accelerated testing per International Conference on Harmonization’s (ICH) Q1A (R2) (1).

The assessment of drug-substance stability is a vital and essential aspect of the development of pharmaceutical products. Stability testing is capable of providing information on how environmental factors such as temperature, humidity, and light affect a product’s quality over a period of time. Data derived from a stability study enables recommended storage conditions, retest intervals, and shelf lives to be evaluated and established.

It is the norm for controlled environment rooms to be built and validated to provide climatic conditions specified in ICH guidelines. Rooms should include equipment to allow for simulating conditions in all four climatic zones for long-term, intermediate, and accelerated testing. An outsourcing facility should have a comprehensive range of conditions including ICH Photostability Option 1 and Option 2 studies, as well as the capacity for customization. All staff should be fully accountable and provide a service that complies with regulatory requirements.

Stability Testing of New Drug Substances and Products

—Patrick Jackson is business development director at Vindon Scientific.

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

Consider the time and expertise needed to maintain regulatory compliance and perform stability testing.

Considerations for Outsourcing Stability Storage

An ideal topical formulation can be produced using a simple, flexible process. Most topical formulations developed today, however, are complex and therefore require tightly controlled processing parameters. September’s 

 that described five critical process parameters: temperature, rates of heating and cooling, mixing methods and speeds, mixing times, and flow rates. Following are additional strategies to optimize the manufacturing process for topical dosage forms.

Although preserved topical products do not require the strict process controls involved in sterile manufacturing, a well understood and controlled process is crucial.  Emulsions, for example, can be difficult to process because they are inherently thermodynamically unstable.  The use of manufacturing vessels with programmable logic controllers (PLCs) is one tool that can provide more reliable and accurate control of the pressure/temperature and mixing speed and times.

Add ingredients in the optimal phase and order

Generally, topical formulations comprise one or more phases.  Emulsions, for example, primarily comprise an aqueous phase and a hydrophobic phase. Adding ingredients in the correct phase contributes to overall stability. For example, some polymers, such as microcrycrystalline cellulose/sodium carboymethylcellulose, must be dispersed and hydrated prior to adding other ingredients.

Most ingredients have an optimal method of incorporation into a formulation. Preservatives, such as parabens, should be added just prior to emulsification to reduce time in contact with water-soluble surfactants at elevated temperatures. Polymers (e.g., carbomer) and gums (e.g., xanthan) must be added slowly to avoid formation of fish eyes and other partially hydrated, undispersed material.  These problems can be avoided by using eductors (e.g., Tri-Blender and Quadro Ytron dispersers) or by preparing a slurry of polymer or gum in a medium of low or no solubility (e.g., glycerin or glycols for certain gums or oils for carbomers). These thickeners act as emulsion stabilizers to keep oils or creams suspended in water and prevent separation.  Such thickeners can be shear sensitive, however, so they must be processed with care.

As an example, DPT Labs was tasked with manufacturing a formulation that was a fatty-acid-based emulsion neutralized using an amine. With the amine in the water phase upon emulsification, the product immediately gained viscosity, requiring a higher mixing speed. As the product cooled, the formulation hit a critical temperature in which it rapidly thinned out and began splashing out of the mixing tank. DPT resequenced the product and added the amine post-emulsification. This change maintained the quality of the product and eliminated negative effects on the formulation and potential danger to staff.

The manufacturing process must be designed to protect APIs from physical degradation.  Some APIs, such as retinoic acid compounds, are sensitive to both UV light and oxygen.  These APIs can be protected by using yellow or amber light that is free from harmful low-wavelength UV rays and by using nitrogen, argon, or another inert gas to purge the product of oxygen.

The manufacturer must be able to perform all processes using its current equipment capabilities. The scale-up path for a 1:10 batch size from the pilot or clinical size to commercial level must exist with similar equipment. Guidance from FDA’s Scale-Up and Postapproval Changes Semisolids (SUPAC-SS) Working Group provides the basis of comparison for the design and operating principles of equipment (1).

Satisfying regulatory requirements for the scale-up or transfer of a process can be challenging. To scale up a process used for clinical batch manufacturing or transfer a commercial process to a new manufacturing site, the equipment must at least be of the same materials of construction and employ the same type of mixing, as defined in the SUPAC-SS guidance (1).

The manufacturing process can influence a topical product’s stability and performance.  If a formulation is transferred to a contract manufacturer, changes in mixing speeds, temperature controls, and order of ingredient addition may be needed.  Outsourcing formulation development and manufacturing to a contract development and manufacturing organization (CDMO) allows technology transfer, scale-up, and manufacturing to take place at one location, which ensures project continuity.

Guidance for Industry, Nonsterile Semisolid Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation 

Michael Lowenborg is research and development manager at DPT Laboratories, 3300 Research Plaza, San Antonio, TX 78235, tel. 210.531.7125, 

In the Mixer

Consider these tools and strategies for optimizing the manufacturing process.

Equipment and Processing Report-10-17-2012

October 2012 Editor's Picks: Products from UFP Technologies and Mettler Toledo

Improving Intelligent Device Management

Considerations for Outsourcing Stability Storage

Challenges in Topical Drug Manufacturing