Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Transdermal patches are used to deliver drugs through the skin for either a local or systemic effect. This route can improve patient compliance by avoiding the difficulties associated with swallowing or with injecting drugs. Transdermal patch manufacturing, however, is relatively complex because it generally has more process parameters and material attributes that can impact performance, compared to some other dosage forms, says Cormac Lyons, vice-president of R&D at Tapemark, a contract manufacturing organization specializing in transdermal patches, oral thin films, and topical drug delivery. A quality-by-design approach can help address these complexities, he says. 

 spoke with Lyons to learn more about the manufacturing parameters and quality control testing involved in transdermal patch manufacturing. 

What are the critical quality attributes (CQAs) of a transdermal patch? 

The CQAs of a transdermal patch are the attributes essential or detrimental to the product’s safety and efficacy. These may include: drug delivery, drug dissolution, patch assay, content uniformity, residual solvents, patch adhesion, patch removal from liner, adhesive shear resistance, adhesive cold flow, bioburden, crystallization, skin sensitization, and product stability in primary packaging. These CQAs will be different based on the type of patch being developed. 

 What are the critical material attributes (CMAs) or critical processing parameters (CPPs) that affect these CQAs?

There are CMAs and CPPs for each process involved in developing a transdermal patch: blending, coating, converting (i.e., making the coated film into the finished patches), and pouching (i.e., packaging individual patches). The CMAs are associated both with the raw materials and the intermediate materials made from these raw materials. 

	In blending for example, the raw materials are the adhesive, the API, and the different excipients. The viscosity of the adhesive and the purity and particle size of the API are important CMAs for these raw materials. The resulting blend is the raw material for the coating process. After blending, the intermediate blend’s CMAs are homogeneity, viscosity, and solids content. The blend CPPs that impact the final blend CMAs are blending time, speed, and equipment design.

	Another example is the coating process. In this process, the blend CMAs of homogeneity, viscosity, and solids contents are key because they will impact the drug-in-adhesive laminate (another intermediate) CMAs such as drug homogeneity, assay, and residual solvents. In addition, the CPPs that also impact the CMAs of the output drug-in-adhesive laminate are coating thickness, line speed, and drying conditions.

 What quality control tests should be performed on patches? 

There are specific quality control tests for each of the CQAs noted previously. Two main types of testing are in-process testing and finished-product testing. 

	In-process testing involves understanding how materials are affected during manufacturing. This testing can help create a more robust production process and ensure the right controls are in place. In-process testing can include methods to ensure the blending process has achieved a homogenous mix. It also can include measuring and quantifying adhesion characteristics throughout the manufacturing process.

	Finished-product testing analyzes the final product’s physical properties to help ensure the patch is produced with the desired physical characteristics and performs as expected. Adhesion and tack testing, for example, can help determine if the product will adhere to a user’s skin for a given period of time. Manufacturers must first define what levels of adhesion level and tack are required in a finished product and then implement the methods or tools to measure for those levels.


	December 2017
	Vol. 41, No. 12
	Pages: 44–45

	When referring to this article, please cite it as J. Markarian, "Critical Parameters in Transdermal Patch Manufacturing," 

	Jennifer Markarian is manufacturing editor for 

Articles

A QbD approach can address manufacturing complexities in transdermal patch manufacturing.

Critical Parameters in Transdermal Patch Manufacturing

	Medherant, a bioadhesives company formed as a spin-out from the University of Warwick (UK) in 2015, is developing its TEPI Patch technology, a higher-dosage drug-delivery patch with a constant rate of drug release. The patch is formulated by mixing the drug with an adhesive that enables high drug loading. The company’s first patch, containing ibuprofen, is being manufactured for clinical trials.

	Dr. Gabit Nurumbetov, principal scientist at Medherant, has developed an improved instrument to test the release of drugs from a transdermal patch. The device, patented by Medherant, is an improved, miniaturized, and multiplexed version of a Franz or diffusion cell, which is a device commonly used to measure the amount of drug that permeates across human skin.

	“In essence, the cell is a vial with a modified top part where you can place human skin and your formulation (gel, cream, or patch). The volume below the skin is filled with a biological fluid, which is taken out for analysis through a sampling port,” explains Nurumbetov. “The amount of drug permeated across the skin is then measured by means of chromatographic and/or spectroscopic methods allowing estimation of parameters such as API flux, patch area efficacy, and others.”

	The improved diffusion cell, which is patented by Medherant, can test more than 100 formulations per day, compared to approximately 12 in the same period with traditional Franz cells, reports the company.

	Drug release in a transdermal formulation is complex. “It is affected by physico-chemical properties of the adhesive and drug and the presence or absence of additional excipients in a formulation,” says Nurumbetov. “Some adhesives can chemically ‘hold’ drug molecules leading to a lesser amount of drug delivered. Also, if the molar mass of a drug is higher than 500 Daltons, it is likely to be not suitable for transdermal applications. Additional chemicals (permeation enhancers) in the formulation can also affect the drug-delivery performance.” The new instrument will allow high-throughput testing for faster development. 


	December 2017
	Vol. 41, No. 12
	Pages: 45

	When referring to this article, please cite it as J. Markarian, "Advances in Transdermal Patch Drug Delivery and Measurement," 

Medherant has developed an improved instrument for testing drug release from transdermal patches.

Advances in Transdermal Patch Drug Delivery and Measurement

An enhanced instrument for testing drug release from transdermal patches has been developed by Medherant.

Transdermal Patch Drug Delivery and Measurement Innovations

	Environmental sustainability is a growing concern in many manufacturing industries, and the pharma industry is no exception. Facilities and operations that are designed to conserve resources, such as energy and water, can improve a company’s “green” image as well as reduce its manufacturing costs. Although there are some instances where GMP requirements may not be the most energy or water-conserving mode of operation, it is possible to attain both GMP compliance and efficiency, say experts (1, 2). Big Pharma companies have already made progress toward reducing water, energy, and waste, thus improving carbon footprint (3, 4).

	Drinking water, a crucial input to pharma manufacturing, is expected to become an increasingly limited resource, which means its cost will rise (2). Careful use, including repurposing discharge water from pharma processes for other uses (e.g., cooling towers or building sanitation systems) would help address this problem (2). Discharge of polluted water from some API manufacturing facilities, particularly effluents that could cause antimicrobial resistance, is also a growing concern that is beginning to be addressed (5).

	Although different types of pharmaceutical manufacturing processes use energy in different amounts, HVAC (heating, ventilation, and air conditioning) systems, used to control the air quality of the process environment, consume more energy than any other system across all types of manufacturing. In API manufacturing, for example, HVAC may account for 35–40% of manufacturing site energy use, and in drug product manufacturing, HVAC may account for 60–75%, says Keith Beattie, Life Science lead at EECO2, a UK-based energy efficiency consultancy. “Optimizing other utilities, such as installing a more energy-efficient chiller or implementing control strategies, can improve efficiency by a few percent, but improving HVAC is the quickest return on investment,” he adds.

	There are some straightforward methods for reducing HVAC energy use, often using existing systems and reengineering or optimizing them. “The first step is to minimize the quantity of air used,” suggests Beattie. “Cleanrooms often use higher air change rates than required to meet their classification, and reducing air flow by even a small amount can result in significant savings.” A second step is to minimize the energy going into conditioning of the air. Systems can be set back or even switched off when not needed, and widening the set points for temperature and humidity can allow the system to run more efficiently. Conditioning more efficiently-using high-efficiency motors and fans, for example-also creates energy savings. Finally, says Beattie, companies should maintain their systems by monitoring, optimizing, and not neglecting mechanical maintenance.

	EECO2 has developed an innovative approach to make cleanroom operations even more efficient using a control system that maintains a fixed air quality level (i.e., particulate count) by varying air flow rates, rather than the traditional method of fixed air change rate. The company has been able to reduce energy consumption by nearly 70% using this method of model predictive control in the company’s test facility, which is representative of a commercial cleanroom, says Beattie. He reports that this energy savings using the adaptive, demand-based system is measured from an already energy-efficient baseline traditional system. “Our adaptive system analyzes the data from particle counters in real time and uses these data to control the air change rate. From a compliance point of view, we are controlling the contamination level and we have data on the real performance of the cleanroom. This control system can thus assure quality and improve efficiency.” How to validate such a system is a question that needs to be answered, because the current validation methods were based on traditional methods, notes Beattie.

Single-use systems impact in biopharma manufacturing

	In biopharma manufacturing, single-use systems are considered beneficial for various reasons, including significantly reducing the water use required for cleaning of traditional stainless-steel systems. Another benefit is that, because they are closed systems, single-use systems can operate in a cleanroom with a lower grade classification, which corresponds to operational savings (6).

	To better understand the factors affecting the sustainability of a biopharmaceutical facility, the M+W engineering construction company conducted a lifecycle assessment (LCA) on a facility model. LCA is standard methodology used to evaluate environmental impact of a product, process, or service (or in this case, a facility), explains David Estapé, technology manager for Life Sciences in the Global Business Unit, Life Sciences & Chemicals, of M+W Group. An LCA can look at different environmental impact categories; this study considered climate change impact (i.e., carbon footprint in carbon dioxide equivalents). An LCA from “cradle to grave” takes into account not just the facility operation, but all materials and resources from construction to demolition of a facility. Facility operation, however, is the largest contribution to carbon footprint, the study confirmed (7). 

	Using a software program designed to evaluate LCA via mass and energy balances, M+W looked at process, building, and utility systems for a generic monoclonal antibody production process using single-use systems and modular construction for a manufacturing facility located in China.

	The study concluded (7) that transportation of the building modules (by ship) had a small percent of the total environmental impact of the facility (only 1%). The building systems (particularly HVAC) had a significant impact that varied by facility output (28–38%). Surprisingly, the production and disposal of single-use components accounted for only 9–11% of the total impact, while transportation of the consumables to the facility site accounted for 25–30% of the total. “The waste generated by consumables has been raised as a possible concern for single-use systems, but we found that waste was, in reality, a relatively small component. For a facility located at a long distance from the single-use system source, air transportation of the consumables was the biggest impact,” reports Estapé. Optimizing the supply chain for consumables is thus important. “Facility location is significant for transportation as well as for the ‘greenness’ of the energy source used in the LCA,” he adds.

	“Sustainability of facility design is increasingly important, and programs like LEED [the United States Green Building Council’s Leadership in Energy and Environmental Design] certification are desired,” notes Estapé. “It is necessary, however, to understand what exactly contributes to the environmental impact for a particular facility, given its location and all aspects of its operation, not only factors such as energy-efficient lighting and HVAC. We can design the best facility but not truly solve the problem, if the majority of the impact is outside the facility, in transportation, for example. Looking at the LCA is crucial to addressing the real impacts.”

	1.     PharmTech, “Energy Management in Bio/pharmaceutical Facilities,” (Feb. 20, 2013), 

www.pharmtech.com/energy-management-biopharmaceutical-facilities

	2.     J. Markarian, “Considering Water Use in Pharma Manufacturing,” (Oct. 18, 2017), 

www.pharmtech.com/considering-water-use-pharma-manufacturing

	7.     D. Estape, “Sustainable Facilities: Global Environment Impact of a Biopharmaceutical Facility,” presentation at 2017 ISPE Annual Meeting & Expo (San Diego, Oct. 30, 2017). 

Optimizing water and HVAC systems can reduce resource use in all pharma facilities, and, for biopharma manufacturing, the supply chain of consumables should be evaluated.  

Improving Sustainability in Pharma Manufacturing

 of the Center for Structured Particulate Systems (C-SOPS) held at Rutgers University on Oct. 16, 2017, presenters detailed work that had been done and future plans to educate regulators and industry members about advances in and best practices for practical implementation of continuous manufacturing for solid-dosage drug products. Presenters from Rutgers University and the New Jersey Institute of Technology (NJIT), which are two of C-SOPS academic member institutions (along with Purdue University and the University of Puerto Rico at Mayaguez), shared recent research project results, and a speaker from FDA shared some of the work his group is doing in continuous manufacturing. In 

, on the second day of the conference, the New Jersey Innovation Institute (an NJIT Corporation) and Rutgers announced plans to form the New Jersey Continuous Manufacturing Institute, which will be a center of excellence to advance continuous manufacturing for both solid-dosage drugs and for biopharmaceuticals.

	This year’s annual meeting was the first to be open to the industry and community (in addition to the consortium’s members), with the goal of reaching a broader audience. In addition to research activities, C-SOPS had convened a working group to submit a document to FDA that could potentially form the basis of a guidance on continuous manufacturing. The group submitted their document in June 2016, and in June 2017 it was posted in an 

. The public comment period closed Sept. 21, 2017. The working group hopes to be able to reconvene and update the document with advances in technology that have occurred in the past two years. Another highlight from 2017 was the first meeting of an expert panel on continuous manufacturing established by the US Pharmacopoeial Convention (USP), which was launched following the 2016 partnership of USP and C-SOPS to bring together experts to begin addressing the development of standards in continuous pharmaceutical manufacturing.

	Another key role for C-SOPS is education in continuous manufacturing. Since 2007, the group has trained nearly 100 doctoral and post-doctoral students who have moved on to positions in industry and FDA. The International Institute for Advanced Pharmaceutical Manufacturing (I2APM)-a partnership between C-SOPS, the EPSRC Future Continuous Manufacturing and Advanced Crystallisation (CMAC) Hub in the UK, and the Research Center Pharmaceutical Engineering in Austria-is also focusing on education efforts, noted presenters at the conference. The group is working on organizing existing educational material in order to make it more accessible and hopes to develop online training. I2APM plans to expand its educational efforts to Asia, including reaching regulators from India, China, and Japan.   

	Industry has been making progress in the implementation of continuous manufacturing. Several research projects presented at the conference described advances in modeling and control for solid-dosage continuous manufacturing processes. Xiaochuan “Ben” Yang, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, noted in a conference presentation that companies who want to implement continuous manufacturing can apply to the Emerging Technology Team as described in the 

 involving the submission of chemistry, manufacturing, and controls information containing emerging technology that was finalized in September 2017. In addition, FDA is supporting continuous manufacturing through grants for science activities outside of FDA and internal FDA projects, which are looking at issues such as how to use process analytical technology (PAT) to monitor continuous manufacturing for either identifying a state of control or for real-time release testing. 

Rutgers University-based C-SOPS annual meeting described advances in continuous manufacturing understanding and future plans for broader education efforts.  

Organizations Seek to Advance Industry Knowledge of Continuous Manufacturing

	Pure water is essential for pharmaceutical manufacturing. The 

) and other global pharmacopeias require pharma manufacturers to begin with drinking water and purify it further to standards depending on the use, such as purified water or water for injection (WFI).

	Modern purified water systems are well designed and generally do not have any problems meeting pharmacopeial requirements, says Nissan Cohen, principal scientist for High Purity Water Systems at Commissioning Agents, Inc., a US consultancy. Systems typically include pretreatment followed by purification, which can include reverse osmosis, deionization, distillation, ozone, and ultraviolet sterilization. Cohen sees two major issues, however, that pharma manufacturers must deal with soon or be faced with increased operational costs: drinking water shortages and inefficient legacy laboratory-based testing.

	Drinking water-the source for purified water for pharma-is a limited resource. The World Health Organization (WHO) predicts that by 2025, half of the world’s population will “be living in water-stressed areas.” (1). Although numbers vary regarding the severity of this complex problem, the Water Resources Group predicts that, if nothing is done to improve efficiency, global water demand would be 40% more than accessible, reliable supply by 2030 (2).

	Industrial use represents a significant part of this demand, says Nik Krpan, president of Cheme Engineering, a Canadian consultancy focused on water systems for the bio/pharma industry. “The pharma industry needs to think about how to use water more efficiently, because the cost is going up,” says Krpan.

	Zero liquid discharge, a concept that is new to the pharma industry, is a potential solution to the water-shortage problem that involves recycling or reusing process water.  

	“There are many uses for water; the key is how to reuse what is being sent to the drain-maybe in the process itself, or in cooling towers or building sanitation systems,” says Cohen. “For example, you could take water draining from the clean-in-place system and retreat it or use it for tertiary systems in the building. As another example, water from flushing studies (in which water is run for 30 seconds before microbial sampling) could be reused.” 

	“Water reuse must be carefully implemented so that you don’t affect quality, but it can be done,” notes Krpan.

	At the International Society for Pharmaceutical Engineering (ISPE) annual meeting, on Oct. 30, 2017, Krpan, Cohen, and others will discuss these concepts and the technologies used in zero liquid discharge in more detail.

	Compendial tests required for water for pharma manufacturing are total organic carbon (TOC), conductivity, bioburden (i.e., microbial content), and, for WFI, endotoxin. It is common practice for manufacturers to use online process analytical technology (PAT) for testing TOC and conductivity for process control.

	“More companies are relying on the integrity of data from online PAT instruments to increase their process understanding,” says Luke Swanson, Life Science applications engineer for GE’s Analytical Instruments, now part of Suez, which acquired GE Water & Process Technologies on Oct. 2, 2017. “A best practice is to have at least one online instrument at the end of the high purity water loop. Some companies also have one at the front end of the loop and do occasional grab samples, tested in the laboratory, in the middle of the loop as checks.”

	There is a trend toward real-time release (RTR) of process water using PAT. “RTR requires the manufacturer to do instrument qualification, method validation, and process validation,” Swanson explains. “The principle behind RTR is driving cost efficiency while not compromising product integrity or traceability of release testing.”

	Laboratory TOC testing, however, is still widely used for release of process water, and one of the challenges is that laboratory and online tests can have different TOC results because “carbon is everywhere, and intermediate handling steps can contaminate the sample,” explains Swanson.

	Online rapid microbial testing is available, but at this point typically needs discrete sampling to verify results, says Cohen, who notes that endotoxin testing is also not yet automated.

	Treating manufacturing effluents, particularly from API manufacturing, is also a concern that is increasingly being recognized by manufacturers.  

	“In Europe, this [need for improved effluent treatment] very much depends on the Integrated Pollution Prevention and Control (IPPC) Directive, which is now part of the Industrial Emission Directive,” notes Bjarne Sandberg, Managing Director, Cambrex Karlskoga. The company is currently constructing a new wastewater treatment plant at its facility in Karlskoga, Sweden to support the expansion of cGMP capacity for small-molecule APIs, the company announced on Sept. 26, 2017. When completed, the wastewater facility will reduce the emission of nitrogen, total organic compounds, and suspended material, improving the site’s environmental footprint (3).

	“The original wastewater treatment plant at our facility in Karlskoga, Sweden was built in 2000, and this recent investment is to increase the capacity of the plant for both existing and future needs. The investment will also help improve our environmental footprint at the Karlskoga site,” explains Sandberg. Cambrex also recently completed an upgrade of wastewater handling capabilities at its Milan, Italy manufacturing facility, he reports.

	1. WHO, “Drinking-Water: Fact Sheet updated July 2017,” 

www.who.int/mediacentre/factsheets/fs391/en/

	2. 2030 Water Resources Group, “Charting Our Water Future” (2009).

	3. Cambrex, “Cambrex Opens API manufacturing Facility and Invests in Supporting Waste Water Treatment Plant at its Karlskoga, Sweden Site,” Press Release, Sept. 26, 2017.

Water shortages, testing expenses, and effluent treatment are important issues for pharma manufacturers.