Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	The “digital plant” and technologies that go along with digital transformation-such as robotics, data analytics, artificial intelligence (AI), and the industrial Internet of things (IIoT)-promise greater efficiency. Eli Lilly and Company is advancing in applying these technologies to its pharmaceutical manufacturing organization. 

spoke with Jim Weber, advisor for Manufacturing and Quality IT [Information Technology] Digital Manufacturing, and Wilfred Mascarenhas, advisor for Data and Analytics, Manufacturing, and Quality IT, both at Lilly, about some of the key issues. 

What do you see as the most significant drivers for making investments in digital manufacturing technologies?   

Our Lilly Manufacturing organization is united around a common purpose-to make medicines that make life better for people around the world, and to do that with safety first and quality always. Therefore, our biggest motivation is to achieve this purpose as best we can and to continuously strive to do even better. The digital plant can accelerate improvements. For example, we can reduce ergonomic risks through robotics lifting boxes and ensure quality through real-time analytics rather than after-the-fact testing. These technologies also drive cost efficiencies.

What do you see as the most valuable benefits of digital transformation technologies for pharma manufacturing?

For us, ‘value’ means anything that enables us to better make medicines. We start by asking our people who make the medicine: what are the problems; where is the waste; and what are the most frustrating things they have to do? Then, we think creatively about solutions. It’s at this ‘creative thinking’ step that the technology comes into play. We have to educate ourselves on emerging digital capabilities, so we can see the full set of possibilities to find a good opportunity. Before we start a project, we require a business case review and approval to keep value at the center, and not technology. Transformation will happen through time, replication and accumulated learning. We believe the most valuable benefits of digital transformation come from the new capabilities that our people develop. 

What are some examples of ‘low hanging fruit’/initial projects for digital transformation?

A tree has to be somewhat mature before it has any fruit, much less low-hanging fruit. Right now, technologies like robotics and advanced analytics tend to be a bit more mature, and thus these are the technologies of choice for our initial projects. For robotics, we’ve got projects to automate tedious material handling steps that are done manually today. Some examples include using a six-axis robotic arm to load material into packaging lines, transporting these materials to the line from the warehouse by autonomous guided vehicles (AGV), and even things as basic as picking up the trash with mobile robots. We’ve got projects that are using advanced analytics to help our people identify trends and patterns more quickly and effectively. Some examples of those include using natural language processing to find patterns in complaints, applying data models to predict process failures, and using artificial intelligence techniques to identify and fix errors in supply chain data. We’re doing these things in our existing facilities and leveraging data from current IT and automation systems.  At the same time, we’re trying to anticipate equipment and system lifecycle timelines, so that we can build digital plant capabilities into new installations from the start.

Data and analytics play a critical role in realizing the Digital Plant vision. It is recognized as one of the nine key technologies that is transforming manufacturing and industrial production (1). Not only is Big Data/analytics a critical capability in itself, but it is also foundational to many of the remaining eight technologies such as IIoT, robotics, etc. Our Digital Plant vision, also called Smart Manufacturing (whereby ‘smart machines’ and robots are inter-operating and self-adapting based on communication with one another and with humans) is largely driven by analysis of data and the communication of what adjustments need to be made based on the results of the data analysis. In many cases, this analysis will be done at the ‘edge’ (i.e., at the machine itself) and then communicated to other relevant machines/processes and humans. 

	Over the past 10 years or more, Lilly Manufacturing has been investing in building a strong data foundation. Due to this long-term investment, Lilly has a mature centralized global data store, which was recently modernized to a Big Data data lake. Data from all of the critical IT and OT systems flow into the centralized data lake, which allows the business to connect to a single data source to get all of the data required for analytics and perform a holistic end-to-end analysis. Time to find and integrate the data is minimized, which allows our people to focus on analysis of the data. The data lake is a fully validated system, allowing its use for both good manufacturing practices (GMP) and non-GMP usage. Lilly is considered one of the leaders in centralizing all manufacturing data for analytics and in having a GMP-validated data lake. 

What are the next steps for data and analytics and what are the challenges that need to be addressed? 

There are four different types of analytics typically conducted on data. These are broadly referred to as descriptive, diagnostic, predictive, and adaptive. Descriptive tells us what is happening. Diagnostic provides information on why it happened. Predictive helps predict what will happen so we can be proactive to avoid issues or optimize processes, and adaptive is where processes/machines are using analytics to self-adjust with minimal to no human intervention. 

	Due to Lilly Manufacturing's strong data foundation, Lilly Manufacturing has mature descriptive and diagnostic analytics. We have automated dashboards such as quality and maintenance, periodic reports, monthly metrics dashboards and process monitoring dashboards to help business users perform descriptive and diagnostic analytics on a daily basis. In the past two years, with the advancement of Big Data and analytics, Lilly Manufacturing has invested in predictive analytics. We have successfully completed several proof-of-concept projects that are now being piloted. A few examples of projects in advanced analytics include predictive and condition-based maintenance, natural language processing of unstructured data, and smart search. We are also evaluating Cloud services for data storage, as well as AI platforms for advanced analytics and machine learning. 

	We already have vast amounts of disparate data in our data lake, and it’s increasing on a daily basis. Some of the challenges in the data and analytics space are to adapt our information management practices to this huge scale. Data governance, data stewardship, automated data quality, data integrity, data catalog maintenance, and master data management are examples of those challenges. Lilly is proactively addressing these challenges to ensure the long-term maturity and sustainability of the data lake. These challenges require a strong partnership between business and IT for long-term success.

	1.     Boston Consulting Group, “Embracing Industry 4.0 and Rediscovering Growth,” 

www.bcg.com/en-us/capabilities/operations/embracing-industry-4.0-rediscovering-growth.aspx

Articles

Eli Lilly and Company experts share the vision and the value of the digital plant for pharmaceutical manufacturing.

Digital Transformation at Lilly Manufacturing

	The “digital plant” and the use of various modern manufacturing technologies that go along with digital transformation promise greater efficiency and quality. 

spoke with Bob Lenich, director of Global Life Sciences, and Dennis Belanger, director of Operational Certainty Consulting, both at Emerson, about digital transformation of pharmaceutical manufacturing.

What do you see as the most significant drivers for making these investments in pharma manufacturing?

Ongoing changes in the life-sciences industry are putting ever greater pressure on pharma and biotech manufacturers to make continuous changes to the way they operate. Expanding price controls industry-wide have created a strong need to optimize operating budgets and prioritize investment in the development of new products. To drive continuous innovation and profitability requires better use of the data they already have and the building of more efficient manufacturing processes. 

	Another driver for digital transformation is the shift from batch to continuous production. Continuous production allows for equivalent production volume with a much smaller capital investment and facility footprint. Manufacturing capital investment can be delayed until later in clinical trials when manufacturers have a clearer picture of a new therapy’s success. Higher capacity with a smaller footprint, all delivered with lower risk, makes a compelling argument for the transition to continuous manufacturing. Successful operation of these smaller, faster, and more flexible continuous manufacturing lines requires scalable digital transformation solutions.

	A third key driver for digital transformation is ensuring supply chain reliability and efficiency. As organizations take advantage of modular and scalable solutions for development in labs, clinical production, and commercial production, these organizations are finding that their systems are easier to integrate, operate, and audit. This translates directly into savings, with many organizations achieving 5–10% improvement in asset availability, as well as similar or even higher gains in production, safety, and quality. These gains can provide a competitive advantage and ensure that patient supply and safety requirements are realized.

What role do these technologies play in the trend to small/flexible facilities and personalized medicine?

Therapies produced for our unique genetic makeup are both tremendously exciting and uniquely complex for life-sciences organizations. Recent regulatory approval of the first CAR-T cell therapy product delivers incredible benefits to the public. For the first time in human history, patients can receive individualized treatments that change lives. As these targeted therapies become more and more prevalent, manufacturers will need to adapt to the new challenges created by new processes. 

	Because personalized medicine requires complete traceability to ensure that the right manufactured therapy gets to the right patient, extensive chain of identity management is becoming central to CAR-T success. To maintain the timeliness, pace, and traceability necessary to deliver life-saving personalized therapies to patients, manufacturers are leveraging electronic scheduling systems with material collection/tracking software and manufacturing execution systems to ensure the patient therapy is properly planned, manufactured, and delivered back to the patient in the required timeline. 

	In the small/flexible facilities delivering more traditional therapies, digital technologies such as digital twin modeling, [Industrial Internet of Things] IIoT integrated measurements, and augmented reality are driving improvements in quality and regulatory compliance. Additional focus will be put on alignment between maintenance, operations, quality, and planning so that data such as equipment maintenance records, batch manufacturing records, and out-of-spec quality results can be correlated across processes with context. This data integration/use leads to real-time release, optimized inventory management, and overall efficiency improvements.

What are some examples of ‘low hanging fruit’/initial projects for digital transformation in pharma manufacturing?

This question really gets to the heart of a common misconception about digital transformation projects-not all projects have to be complete plant overhauls. Many of the best digital transformation results come from pilot projects on operational units that underperform. Site-level teams and gap analysis can quickly highlight opportunities for improvement, and the discovered opportunities can jumpstart digital transformations. The benefit of performing pilot projects is that organizations can then scale these pilots up to achieve the full-scale benefits. Therefore, to get the most benefit from digital transformation projects, it is crucial to develop a scale-up strategy as part of pilot implementation.

	A great example is with process analytical technology (PAT) applications. Leveraging digital transformation technologies is allowing PAT solutions to go mainstream. Between wireless and IIoT architectures that bring in new measurements, integration of analytical devices digitally, and applying optimization models to unit operations using all these new data, organizations can deliver the promised efficiency benefits on existing production lines without new equipment capital investments.

	Moreover, these same systems often open opportunities for new or increased predictive analytics for advanced decision making. Not only can predictive data enable shorter time-to-market-accelerating technology transfer and driving more effective process engineering-it can also support next-gen workers with continuous access to the actionable information they need to better perform their tasks.

Are there any challenges specific to transforming existing plants/equipment systems (as compared to new facilities), and if so, what are some best practices in retrofitting systems?

One of the key issues that organizations face when implementing digital transformation pilots at existing facilities is filtering all the potential projects to discover the ones that are most likely to be successful. The increase in variety and decrease in cost of monitoring equipment has led to nearly limitless possibilities for digital transformation projects across a ‘brownfield’ plant.

	An important strategy for pursuing a highly successful digital transformation initiative is to focus on business enablers and drivers. Organizations that understand their key performance indicator (KPI) goals and use those goals to drive decisions on pilot program selection tend to create the digital transformation projects with high ROI [return on investment] impacts that they can easily quantify and demonstrate.

	These KPIs and business goals can be established with a thorough gap analysis starting with a digital maturity model assessment. By performing a digital maturity model assessment and associated gap analysis, organizations can clearly see opportunities for improvement in brownfield facilities. The results of the gap analysis can identify which assets and processes need performance improvement, and identify specific, measurable KPIs. Armed with such data, it is easier to build a business case that can be used to evaluate success. 

	One result of this assessment is identifying concerns and limitations of existing legacy systems. Many legacy control systems were not built with the ability to connect to IIoT applications and cloud analytics. As a best practice solution, these organizations typically look to integrated process control systems that allow the digital transformation team to install new automation controllers on top of existing equipment. 

	As these organizations adopt integrated solutions, they are also choosing systems that come pre-packaged with core components, such as OPC UA [unified architecture], and that support alarm management, advanced process control, mobile communications, and other technologies that improve decision making and operations efficiency. 

	Emerson has developed our Digital Jumpstart approach to help clients address the challenges noted above as well as other issues associated with approaching Digital Transformation in a logical, business-savvy manner. The approach takes users through discovery, vision, and planning through design and implementation. 

What do you see as the role of Big Data analytics for manufacturing? 

One of the value enablers for Big Data analytics that is often glossed over is how important domain knowledge is in providing context to the analysis. Data science skills are not as critical, as the tools on the market are making it easier for the average engineer to perform complex analysis. This ability allows those engineers and process and system experts to translate the findings in Big Data into actionable knowledge as we exploit the huge volumes of underused data we have been collecting in manufacturing and production operations for years. In the land of Big Data analytics, context is king!

	Digital twin simulations are moving into the mainstream because of their flexibility and scalability as a critical tool for improving operation of the plant as well as supporting upskilling of the workforce. Having an easy-to-use, accurate, and flexible digital representation of physical world assets allows life-sciences organizations to pre-test before first production, train operations personnel, and then improve plant operations by making it easier for personnel to successfully make production-improving decisions. 

	Like all the most important digital transformation technologies, digital twin simulation makes use of the data that already exists in an organization to drive improvement. The most advanced simulation packages take advantage of existing steady-state design models created by the project engineering team and integrate them into real-time dynamic simulation to simplify process engineering execution. As life-sciences organizations are being incentivized-or mandated-to start building new facilities closer to the populations they serve, digital twin technology will help them design and construct these locations faster and more cost-effectively. 

	After capital project completion, or in existing plants, digital twin technology provides even more benefits. Organizations are using their simulations to develop and deploy advanced process control schemes, seeing the impacts of proposed process improvements without any risk to operations. These same organizations can also use their digital twins to safely and securely train operators. Training on an exact, complete replica of the control system (DCS) or manufacturing execution system (MES) configuration they will experience in the real world ensures that operators are ready to face transient operations, new processes, or new equipment without any risk of process upset.

What challenges in data analytics need to be addressed? 

Although all organizations have a significant amount of collected data, not all of them agree on how to consolidate, contextualize, and analyze that data. Finding a way to get critical data from the plant floor systems and sensors to edge and cloud analytics systems with appropriate context for analysis is an essential step for most pharma manufacturers-even the ones that have already begun digital transformation. 

	Manufacturers have already begun leveraging a multitude of tools to overcome some of the most common barriers to moving data from the plant floor to the edge and the cloud. Integrated MES and DCS systems that are designed from the start to work together help eliminate the ‘islands of automation’ that inhibit the technology transfer process and limit the proper use and access of data across manufacturing units and processes.

	Integrating data flow and adding key context (time, equipment, order, etc.) are key new activities organizations are focusing on to make it easier to unlock untapped potential in production optimization and equipment reliability. Modular and scalable solutions for production are significantly accelerating the development pipeline. 

	As these changes drive optimized production and higher levels of facility reliability, the focus in pharma manufacturing will need to shift to understanding and maintaining critical quality attributes and critical quality parameters and cultivating a better understanding of how products and equipment operations affect and improve right-first-time production.

	Another common area of focus for machine learning and AI is around equipment and process reliability and availability. Due to the very predictive and prescriptive nature of these types of tools, we can get very early indications of potential production and reliability problems and take corrective actions to prevent them from occurring. Projects with industry clients have been shown to be able to reduce maintenance expenditure by 40–50%.  Machine learning and artificial intelligence can also reduce downtime; PM [predictive maintenance] workload;  calibration workload; and maintenance, repair, and operations inventory, for example.

	Big Data/analytics will play a larger and larger role in improving performance in an organization. As the bar is raised for top quartile performance due to the use of new Big Data capabilities, a new definition of top quartile performance will be established. The gap for late adopters will be greater and the pressure for the rest of the pack to get on board will be significant.

System connectivity and data analysis drive increased productivity in pharma manufacturing.


Considering Digital Transformation in Pharma Manufacturing

	Merck, known as Merck, Sharp, and Dohme outside the United States and Canada, has started construction on a new, more than $300-million facility in Rahway, NJ that features a flexible design to enable a new, more agile approach to pharmaceutical formulation and process development for both sterile and oral solid-dosage drug products. The new Merck Research Laboratories’ FLEx Center, located within the Rahway research campus and near the corporate headquarters in Kenilworth, NJ, is expected to open in 2021 and will employ approximately 130 people. 

spoke with Allen Templeton, vice-president of Pharmaceutical Sciences at Merck, about the new facility design. 

The need for flexibility in product development and manufacturing to support drugs for smaller patient populations seems to be increasing. Can you comment on this trend and its role in Merck’s decision to build a lab with flexible capabilities?

Merck believes that flexibility is a true enabler of pharmaceutical product development and manufacturing of the future. We are enabling a ‘scale-out’ approach to address the increasing demands to treat diverse patient populations. We have leveraged this flexibility using a combination of ‘modular’ (ability to reconfigure a defined space) and ‘podular’ (fixed space that can be transported intra- and inter- facilities globally) configurations within our new FLEx Center cGMP manufacturing suites. Additionally, we have scoped multiple modalities (small and large molecule, sterile and oral) into the facility to allow for greater modality agnosticism for new chemical entities in our pipeline while integrating both human and animal health capabilities into the facility.

What are some of the flexible technologies used for formulation development?

The laboratory design delivers flexibility through the implementation of an open floor plan layout with mobile case work and ceiling drop utilities. This design will enable easy laboratory reconfiguration to transition the space and technical capabilities to meet new analytical demands of an evolving pipeline. In the new Formulation Center, formulation flexibility will be achieved through a facility design that will enable the cGMP space to be manipulated (expandable, transportable etc.) as required by our pipeline demands. Similarly, designs and user requirements are targeting small scale, portable equipment enabling rapid changeover and movement between products and formulation areas.

What are some of the technologies that allow rapid reconfiguration for manufacturing?  

Our facility design will include both modular and podular construction approaches for the cGMP space within a shell building structure. Modularly built and installed cleanrooms will enable reconfiguration of existing space or creation of new space in expansion areas. Podular built and installed cleanrooms will enable elements within the facility to be portable within the facility or transportable outside of the facility. The application of both concepts will enable the new Formulation Center to have the ability to adapt over time to meet the evolving needs of the business. We will also use the FLEx center to explore a variety of flexible manufacturing approaches, such as continuous manufacturing, as well as install first-in-industry capabilities.

What features will ease scaleup/tech transfer from R&D to manufacturing?

In addition to supporting product development, the vision for the facility is to simultaneously support the development of new manufacturing approaches for future products. The FLEx Center design includes podular manufacturing space that will enable products to be developed and supplied from the Formulation Center and, when necessary, the equipment and space can be moved to a commercial site to support product launch and commercial supply. Benefits of this approach include reduced cost, time, effort, and risk associated with the technology transfer as the same equipment used through product development will be used for commercial supply. We see this approach as being most applicable to small-volume products requiring complex, niche drug-delivery solutions.

What do you see as trends in requirements in the area of containment for worker/product safety?

At Merck, we have seen a significant increase in the number of potent compounds in the pipeline that require increased control and containment for facilities and equipment. Given this, the facility is being designed to support activities associated with highly potent compounds. This capability was included in the project scope as it was deemed critical for the facility to deliver on the future pipeline. Our philosophy and guiding principle for worker safety is containment at source. From an operations perspective, we are evaluating a variety of technologies to deliver on this principle, ranging from the use of contained charging/discharging solutions up to and including the implementation of hard-wall isolators where the highest levels of containment are required. For cleaning, equipment with wet and/or wash-in-place capabilities are being implemented where possible to ensure the necessary containment control is established for those activities.

Digitalization and designing a ‘digital factory’ is another growing trend. Can you comment on what digital approaches you are employing in the new lab and the advantages you think they will bring?

The desire is to adopt Industry 4.0 concepts into the design. The intent is to enable IT [information technology] infrastructure platforms that will adapt to the evolving technologies. The new facility will create a data-rich ecosystem, encompassing integration of all people, product, equipment, and facility data, with simple human interfaces for both use and visualization. Current exploration activities are leveraging video, voice, barcodes, RFID [radio frequency identification], and integrated workflows. Use of AI [artificial intelligence] or VR [virtual reality] technologies for virtual reality standard operating procedure instruction, knowledge management, and job aid/standard work tools are also being explored, so as to create a digitally enhanced work environment.

Will 3D printing be part of your new facility?

3D printing (3DP) is an active research and development area at Merck. We are currently developing 3DP technology for use as an early clinical platform for oral products and have several peer-reviewed publications that detail our technology and approach. There is no immediate plan for inclusion of drug product 3D printing in our new facility, but as we and others develop 3DP and new manufacturing technologies, we will continue to re-evaluate our approaches and integration into our FLEx facility. It is worth noting that we do have an established, state-of-the-art, 3D-printing facility in Rahway, adjacent to the FLEx Center, that we will leverage for prototyping new process engineering concepts.

Modular and podular laboratory and manufacturing allow rapid reconfiguration to support development of drugs for diverse patient populations.

Merck’s Flexible Facility Design Reinvents Pharma Formulation and Process Development

In August 2018, Boehringer Ingelheim broke ground on the Solids Launch facility at its production site in Ingelheim, Germany. The facility, which will open in 2020, will develop manufacturing processes for drugs in tablet form. 

spoke with Peter Comes, head of the Factory Solids Launch at Boehringer Ingelheim, about plans for the new facility and what the company views as best practices in scaling up new products and manufacturing processes. 

What is the mission and purpose of the new Solids Launch facility? How does it fit into the overall structure of Boehringer Ingelheim’s development and production for solid- dosage drugs?

The new Solids Launch facility in Ingelheim will focus on launch and industrialization activities for drugs in tablet form. Starting in 2020, 75 employees will start operations, including new production methods for tablet preparations, and manufacture these centrally for all global market launches. Therefore, the deeper mission and purpose of the facility is to industrialize and launch Boehringer Ingelheim´s new chemical entities (NCEs). It allows an early transfer of NCEs from development, approximately four years before launch, industrialization, and early transfer into a routine production network.

	Moreover, the Solids Launch facility will be Boehringer Ingelheim´s technology competence center for current and future production technologies for small molecules. It will be the lead site to develop and industrialize modern pharmaceutical manufacturing, for example, in development, test, and implementation of Industry 4.0 tools for the production network.

	The facility is an important piece of the puzzle, allowing Boehringer Ingelheim to manage the entire value chain over the long term, from research and development through launch site to routine production.

What are some of the technologies planned for the new facility?

Fluid-bed granulation, dry granulation, roller compaction, tableting, and film coating are technologies to be implemented. Planned technologies for the future, which are not going to be installed initially, are, for example, twin-screw extrusion and continuous granulation. In addition, we have one train designed as contained equipment to handle higher potent compounds. Production activities will be controlled using process analytical technology.

	The new facility will be used to test and to initially implement technology standards for pharmaceutical production. One example is a fully contained production train that will be implemented to handle higher potency compounds.

	Beyond pharmaceutical production, the site serves as the lead site to develop and industrialize modern production processes, such as the usage of smart glasses in pharmaceutical production for changeover or remote maintenance. The Solids Launch facility will be used to implement the next generation of electronic batch records, integrating currently independent information technology systems.

What are some of the best practices for connecting early development to future manufacturing scale-up? 

 The former philosophy was to adapt production processes to existing manufacturing equipment. This procedure was unfavorable as it led to significant efforts concerning the ‘re-development’ of production processes and validation activities. Boehringer Ingelheim is currently implementing its ‘Supply Network Strategy,’ which describes technology standards from development to the launch side and again to routine production with regard to technology and equipment. Preferably during transfer, the manufacturing scale will be maintained. If necessary, scale-up will be performed at routine sites, including internal and external sites.

Can you describe some best practices for analytical testing/quality control testing in a scale-up project?

With regard to best practices, it is important to mention the use of standardized quality control equipment, which is currently being rolled out at the relevant locations. In addition, we have a dedicated organization for transfer activities and a global team that coordinates the respective transfer activities. This [coordination] helps enormously to make processes smoother.

In 2016 and 2017, the company constructed the “Diabetes Factory” in Ingelheim, which will develop and launch innovative antidiabetic agents. How will what was learned from that project be applied to the Solids Launch facility?

The Diabetes Facility was built to [meet] additional market demands. The highest priority for the facility was time. Only 18 months passed from the starting point of the planning phase until the first products were produced. The pure construction time was 12 months. A key element to realize the tight construction timelines of the facility was the stringent usage of BIM [building information modeling]. BIM technology will also be used to plan and build the Solids Launch facility. 

	Layout wise, the new Solids Launch facility consists of two trains allocated in separated compartments, which reflect the Diabetes facility’s production train with a central compartment for dispensing, cleaning, and storage. The design philosophy of the Solids Launch facility is similar to that of the Diabetes facility. The outer shell provides maximum flexibility in the allocation of production facilities. The shell-in-shell design and a technical area accessible from the outside allow individual production rooms to be modified without affecting the rest of the plant.

	The schedules of the Diabetes facility could be optimized by mapping existing production facilities on site to avoid lengthy validation and stability activities. The same philosophy is applied at the Solids Launch facility, with the use of standardized manufacturing facilities from development through commissioning, to routine production facilities.


	Vol. 42, No. 12
	December 2018
	Pages: 43,48

	When referring to this article, please cite it as J. Markarian, "Scaling Up and Launching Solid-Dosage Drugs," 

Boehringer Ingelheim plans to develop and test new strategies at its Solids Launch facility.

Scaling Up and Launching Solid-Dosage Drugs

	Transdermal patches deliver drug through the skin and can be designed for extended release from hours to several days. 

spoke with Gene McNamara, Research Specialist at 3M Drug Delivery Systems, about some of the considerations for developing and manufacturing transdermal patches. 

What are some of the primary considerations for developing and manufacturing patches?

Transdermal patches are a non-invasive way of self-administering medication. Because the drug is delivered through the skin, it avoids the gastrointestinal tract, so there are potentially fewer side-effects. Patches offer the ability to maintain a constant therapeutic effect for up to seven days. Transdermal patches also allow for removal of a drug in the event of an adverse reaction.

	Not all medications are the right fit [for delivery using a patch]. In order to achieve proper skin absorption and penetration, the API should be non-ionic  and be relatively lipophilic to enable partitioning into the lipophilic skin barrier. The molecular weight should be under 500 Dalton, as larger molecules cannot pass through the stratum corneum. The therapeutic dose of the drug should also be less than about 10 mg per day. Finally, FDA has strict standards on elemental impurities in drug substances and delivery methods that must be considered.

	When it comes to pairing a drug with a patch, there are many things to consider. What is the release rate of the drug? Does it need to be administered over the course of a few hours, a day, or a week? When the API and adhesive are mixed together, it can speed up the rate at which the drug passes through the skin (because the drug is closer in proximity to the skin), but it can lessen the effectiveness of the adhesive itself. In some cases, the API and adhesive cannot be mixed together, because their material components are simply not compatible, thus requiring an alternative layering structure within the patch.   

	When it comes to manufacturing controlled substances, there are significant challenges to consider, including regulatory hurdles, supply chain issues, and safety and security concerns. It is important to maintain strict checks and balances in order to properly follow policies and procedures. 

	We have developed four options for the construction of a patch to ensure the optimized delivery of any given drug based on varying factors, such as the prescribed release rate of the drug and how long the patch must stick to the skin. The differences between these options boil down to how the liners, membranes, backings, and overlay tapes are all layered together. In two of those layering options, the drug is mixed with the adhesive (known as drug-in adhesive), and in the other two layering options, the drug is in a separate layer of its own. 

What variables affect adhesion of the patch to the skin?

Patient skin is the single biggest variable. Everyone has different levels of tolerance and sensitivity to adhesive materials. We run tests to the extent that we can, but until someone tries a patch for the first time, there is no way to know how his/her skin will react to it. 

	Beyond that, anything that you put into an adhesive can have an adverse effect on adhesion. If the drug and the adhesive are mixed together, the strength of adhesive may be diminished. Conversely, if the drug is not combined with the adhesive, and instead placed into a different layer of the patch, the adhesive will stick to the skin for a longer period of time.

	On the manufacturing side, there are a number of things that can affect adhesion. For instance, to maintain high adhesion, the material can’t be too thick or too thin. The processes for laminating and drying the product also play a role. 

	There are ways to assist adhesion. If a patch itself is not strong enough to stick for the prescribed length of time, overlay tape can be used to help keep it in place. Medical tape can provide for a longer wear period, without affecting the drug delivery. So, when a longer lasting patch is necessary, we incorporate overlay tape into the design of a patch.

What trends do you see in use or manufacturing of transdermal patches?

The switch from new patch formulations to generics continues to be a trend that is impacting many aspects of our industry. Most of the major categories of transdermal drugs in the United States have generic forms, and there are now also over-the-counter options competing for consumer dollars. With that trend comes the growing need for increased speed and flexibility in order to compete in a fiercely competitive space. 

	In the generics world, a successful business model is dictated by three main factors:  being the first to arrive on the market, offering the lowest cost option for consumers, and maintaining the quality expected from the brand-name product. Manufacturers of transdermal patches are facing significant price pressure. They must produce a high-value product at a low cost.

	We know this reality creates major pain points for everyone in this industry. At 3M Drug Delivery Systems, we’ve recently made significant investments in new high-efficiency transdermal manufacturing equipment to make the process more efficient. Under current market pressures and time constraints, it is more important than ever to prevent malfunctions of equipment and materials, so quality is key. Using lower-cost/lower-quality materials may seem like a smart move, but in fact, it poses a substantial risk.


	Vol. 42, No. 12
	December 2018
	Page: 41

	When referring to this article, please cite it as J. Markarian, "Developing and Manufacturing Transdermal Patches," 

Transdermal patch design, materials, and manufacturing variables, as well as drug formulation and interactions between the API and the adhesive, can affect adhesion and drug delivery. 

Developing and Manufacturing Transdermal Patches

	Virpax Pharmaceuticals is developing a Patch-in-a-Can metered-dose spray film technology for topical drugs that it says will solve many of the drawbacks associated with other topical and transdermal drug delivery technologies. The technology uses a prefilled canister in a metered-dose aerosol spray device, similar to inhalation drug-delivery devices. Sprayed onto the skin, the API and a translucent polymer coating dry in approximately 1.5 minutes. The dose is clear, so it is more discrete than a patch, avoids the problem of patches that don’t stay in place, and is less messy than other topical forms, such as creams or gels, says the company. 

	“The metered dosing of this technology allows timed release from 12 hours up to four days, which can match some of the existing timed-release patches,” comments Anthony P. Mack, CEO of Virpax. In addition, the spray form is economically more efficient compared to some patches that are overloaded and have some of the drug remaining in the discarded patch, says Mack.

	The company plans to use the technology to deliver nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief, but it could also be used for other active ingredients, such as central nervous system drugs, notes Mack. 

	In September 2018, Virpax Pharmaceuticals received guidance from FDA regarding its pre-investigational new drug (IND) application for its non-opioid therapy, DSF100 (1.3% diclofenac epolamine) spray, for acute pain due to minor strains, sprains, and contusions (1). FDA agreed that it is reasonable for Virpax to pursue a pursue a 505(b)(2) new drug application (NDA), which is an abbreviated approval pathway allowing Virpax to reference safety and efficacy data of a listed drug. Given this feedback, Virpax plans to finalize its IND application and prepare for a Phase I study of DSF100 in humans. Additionally, Virpax intends to submit a Canadian Clinical Trial Application. 

	“We believe the advanced delivery system of DSF100 could provide an important tool in the management of acute pain without the use of opioid analgesics, which is a priority in today’s healthcare environment,” said Mack in the press release. “We are looking forward to moving ahead with our planned studies and executing on our clinical milestones in an accelerated manner through this regulatory pathway.”

	1. Virpax, “Virpax Pharmaceuticals Reports Pre-IND Guidance From FDA for DSF100,” Press Release, Sept. 12, 2018.


	Vol. 42, No. 12
	December 2018
	Page: 42

	When referring to this article, please cite it as J. Markarian, "Spray Film Provides Alternative to Patches," 

Virpax’s Patch-in-a-Can technology delivers pain medication using a metered-dose spray film.