Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	FDA established an Emerging Technologies Team (ETT) in 2014, to optimize decisions about technologies that haven’t been widely used in the industry previously. The team can help companies considering the use of a new technology, and also serves as a resource for inspectors and reviewers within the agency who may be unfamiliar with a new technology. Team chair, Sau Lee, describes the reasons for the team, and its structure.

: Which specific technologies is the team focusing on?

: The ETT does not identify technologies 

. Technologies under consideration are based on industry applications to the Emerging Technology Program. Applications to the program are evaluated to assess whether the proposed technology has the potential to improve product safety, identity, strength, quality, or purity, or whether the technology includes one or more elements subject to quality assessment for which the agency has limited review or inspection experience. 

: When would a company get in touch and how? And how does the team interact with review and inspection departments?

: The Emerging Technology Program takes a collaborative approach to engagement on the topic, both internally and externally. The ETT’s chair and members are drawn from across FDA and bring a wealth of technical expertise, regulatory insight, and institutional knowledge and experience to the group. 
	Industry participants in the program work with ETT early in the technology development process, discussing progress and challenges and addressing technical and regulatory concerns in advance of submitting a drug application for FDA’s evaluation. They benefit from the program by drawing upon FDA expertise and resolving many questions prior to submitting an application. FDA benefits by learning about a new technology in advance of its first appearance in an application for review and inspection, and the public will benefit through improved access to high-quality medications. 

	In order for the ETT to ensure consistency, continuity, and predictability in review and inspection-based science, the team engages in many facets of product development and submission of a marketing application. It starts with early engagement in the pre-submission phase. 
	A key opportunity for pre-submission engagement, in addition to face-to-face meetings, is the pre-operational visit. This provides a venue to cover technical and facility aspects in more detail and enhances shared learning and communication. During the assessment of the regulatory application, the ETT member will serve as the co-lead for the assessment, ensuring continuity from the pre-submission phase. Finally, ETT is also involved in the pre-approval inspection which is conducted by team members from FDA’s Office of Pharmaceutical Quality and Office of Regulatory Affairs.

:  What response have you seen from industry so far?

: Industry has started to be more engaged and open to FDA regarding innovative technologies under the Emerging Technology Program. We have seen an increasing number of industry proposals requesting participation in the program. 

: What is the team doing to help with reviews of post-approval changes?

: ETT is involved and helps with the review when the change involves the implementation of a new technology that meets the program’s criteria. A good example is the approval for switching from a batch to a continuous manufacturing process in April 2016 for an FDA-approved HIV drug, Prezista. The change was requested in a supplement that was reviewed and approved in less than four months.

: What are the plans for the team, both short- and long-term?

: In the short-term, ETT will continue to work with industry to implement emerging technologies, and internally, to strengthen the program management and our internal research program to support the increasing ETT workload and requests for participation. In the long-term, ETT will be engaging regulatory agencies in other countries to help promote international cooperation.


	When referring to this article, please cite it as A. Shanley, “Inside FDA’s Emerging Technologies Team with Team Chair, Sau Lee,” 

Articles

FDA’s Emerging Technologies Team (ETT) team chair Sau Lee describes the reasons for the team and its structure.


Inside FDA’s Emerging Technologies Team with Team Chair, Sau Lee

	For more than a decade, FDA’s leaders have realized that overly prescriptive regulations can inhibit innovation in the industry. Over the past few years, FDA has changed its organizational structure and processes to help encourage consistency of inspection and review, as well as a dialogue between industry and regulators. Lawrence Yu, Deputy Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research (CDER), shared insights with 

: FDA leadership has been encouraging industry to use more modern manufacturing and quality methods for years. However, some companies have sensed a disconnect between senior leadership’s position and the day-to-day actions of inspectors and reviewers. What is FDA doing to encourage trust and ensure that everyone within the agency understands and supports modern manufacturing?

: One of the hallmarks from the time that the Office of Pharmaceutical Quality (OPQ) was established has been the use of team-based integrated quality assessment, which leverages members across disciplines, including assigned investigators from the Office of Regulatory Affairs, as part of the extended review team. This approach helps ensure that reviewers and inspectors are on the same page and that there is consistency in the evaluation of modern manufacturing methods in a regulatory submission as well as during on-site inspections.

	The integrated quality assessment approach is supported by extensive training in science, technology, and communication, covering such modern manufacturing platforms as continuous manufacturing, process analytical technology (PAT) tools such as near-infrared based methods, process design tools, and process monitoring and control techniques. Guidance for industry documents, such as FDA’s PAT guidance, provide transparency regarding the agency’s current thinking and internal policies and procedures and also help ensure consistency amongst agency staff. FDA is also involved in research and development in advanced manufacturing, product analysis, data analysis, and modeling. 

	When OPQ established the Emerging Technology Program, we built on our prior experience with PAT and quality by design (QbD). The Emerging Technology Team (ETT) features members from both review and inspection programs, and is involved in FDA’s oversight of emerging technologies.  

: Many of the industry’s quality challenges are connected to legacy, rather than new, drugs. Is FDA taking any actions to help reduce the delays that can result when manufacturers submit requests for approval to improve processes for legacy products? What is your advice to managers who may have been putting off investing in more modern technologies due to fear of costs and delays?

: Managers considering implementing newer technology should consider all aspects of the business case for implementation, which can include benefits such as increased reliability and lower costs due to better process efficiency and control.  Companies concerned about implementation costs and delays are encouraged to contact the agency to have a discussion with the ETT.

: Ever since the PAT initiative, we have heard about real-time release and real-time release testing (RTRT), yet there seem to have been relatively few cases where it has been approved. What issues need to be resolved?

: There have been real-time release testing elements in approved applications. Continuous manufacturing platforms support implementation of RTRT, which can strengthen the business case for moving towards continuous manufacturing. Regarding dissolution modeling, there has been much recent work, including on FDA’s part, on physiologically-based pharmacokinetic absorption models, which could be useful to support RTRT.

: What must be done first if the industry is to be able to move to advanced process control and, eventually, advanced manufacturing, and such concepts as predictive maintenance? 

: At this point, pharmaceutical manufacturing is still at the stage of automation, rather than advanced manufacturing. FDA has made an effort to establish staff know-how so the workforce is ready to handle applications involving multivariate data and statistics. Further, academic institutions have trained a growing number of specialists in this area, providing the necessary intelligence to support the adoption of advanced process control in the pharma industry.

	Within CDER, we have state-of-the-art research facilities in both PAT and process/product analysis. This capability provides training opportunities for reviewers on topics including various spectroscopy techniques and statistical process control. Importantly, knowledge is exchanged between researchers and reviewers to support advanced manufacturing.

	Regarding predictive maintenance, any models used for release are classified as high impact models. There is discussion of this in the International Council for Harmonization (ICH) P

oints to Consider Guide for ICH Q8/Q9/Q10 Implementation

. Facilities need detailed plans for maintenance of such models throughout the life of a product. FDA is still learning, with industry, about this evolving concept.

: What should manufacturers focus on, first and in the short term, if they are to begin to move toward Six Sigma quality? How about smaller companies making lower margin product?

: The ultimate focus should always be on benefit to the patient, and as such, firms should establish specifications based on clinical relevance--that is, potential impact on clinical performance. As companies develop a culture of quality and a focus on continuous improvement, firms should evaluate parameters that may limit process capability and conduct data analysis to understand, control, and monitor those factors. The same core values apply to companies of all sizes making all products.

	When referring to this article, please cite it as A. Shanley, “Encouraging Innovation at FDA: An Interview with CDER’s Lawrence Yu,” 

Lawrence Yu, Deputy Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research (CDER), shares insights with Pharmaceutical Technology.

Encouraging Innovation at FDA: An Interview with CDER’s Lawrence Yu

Early-stage manufacturing poses unique challenges, especially when working with outsourcing partners. Early communication, good project management, and risk management are crucial to success. In this roundtable, experts from contract research and contract development and manufacturing organizations (CROs and CDMOs) share insights on key requirements.  

	Responding are Ann Flodin, vice-president and general manager at Recipharm, which recently started up a US-based clinical manufacturing facility in Research Triangle Park, NC; Tony Street, PAREXEL’s head of global portfolio leadership for clinical trial supplies and logistics; PAREXEL’s senior director of North American depot and production services, Matthew Caponi; Marion Schrader, senior director of communications at Rentschler Biotechnologie; and Tim Roberts, director of business development for North American Clinical Services at PCI. 

 What are the biggest potential problems, and the most important points for sponsors to keep in mind, when planning to work with contract partners on early and later-stage clinical trial manufacturing? 
	
	

 Formulation development often comes quite late in the total product development chain, after the drug candidate has been selected and enough of the API has been manufactured. Even though it is possible and appropriate to work with a simple formulation in the early clinical stage, we often see that work on early stage formulation development begins too late. 

	One simple piece of advice for anyone planning a first-in-human study is to start planning for development and manufacture of the drug product at least one year before the start of the trial. This approach builds in enough time to overcome potential solubility or delivery issues, gain enough knowledge about the product, and ensure stability to cover the duration of the early studies. It is also essential to work with a regulatory expert to define a clear strategy and understand what goals must be met with the formulation development and manufacture, in order to support project timelines and study goals.  

	In later stage trials, it becomes important to develop a formulation that will ultimately be appropriate for a tech transfer and manufacturing at commercial scale. Here, it is critical to allow enough time and budget to allow quality-by-design (QbD) work to be done, and to evaluate the influence and importance of different variables in optimizing formulation. 

	At this point, the product specifications and quality target product profile must be refined, and the critical quality attributes defined and explored. Any shortcuts taken during this stage will only lead to longer timelines when the time comes to transfer the manufacturing process. During that critical point, unexpected problems can show up, resulting in a delayed launch and lost revenue. 

	It is also important to consider the final container closure system and any necessary comparisons or studies needed, depending on material or design changes along the development path.

 Fundamental to all aspects of the decision-making process is to ensure that the partners selected have a depth of experience and a strong track record.  For biopharmaceuticals, this means expertise with both upstream and downstream processes.

Roberts (PCI): As a partner for clinical trial supply, be it manufacturing of the drug product, packaging and labeling, or execution of the global logistics to the investigator sites, we provide the most value for the client when we are engaged early in the process. We consistently see requests to meet very aggressive deadlines, some of which are derived from unforeseen situations, but may also be the result of a suboptimal supply strategy. We encourage our clients to focus on development of a solid plan for execution, along with preparation of contingency plans for addressing those unforeseen surprises that can arise. 

	In a true partner role, we are engaged much earlier in the development process. With that engagement we can leverage our experience and global insights to make suggestions that take much of the stress out of the supply, as well as maximize efficiency and cost. 

  How should sponsors and contract partners manage projects associated with GMP manufacturing of clinical materials? How should responsibilities be divided?

 Communication is key. It is essential to start planning the manufacturing well ahead of when the clinical study is to take place, and to continuously update all parties involved of any changes to plans. And there will always be changes, whether they are due to sourcing problems, delays in establishing protocols and getting approvals in place, or challenges with formulation development. 

	I find it very helpful to structure the planning with a Responsible Accountable Consulted and Informed (RACI) matrix, in addition to the formal quality agreement. RACI is a project management tool that is used to clarify responsibilities and expectations. It helps ensure that no activity is overlooked, and, in a simple way, clarifies which stake holder, and what role, is responsible for what activity. 

	Using this approach also helps clarify the relation and dependence between different stakeholders and activities. If different organizations are involved, a RACI matrix also helps partners inform each other about different stages in the project, which is valuable for understanding parallel activities that are going on can help decision making and optimization of other activities. 

	The RACI approach can also help understanding, accommodating, and rescheduling due to delays or changes in the program. It may be useful to take the extra effort to ensure that an inter-disciplinary risk assessment is performed and documented, and that a risk mitigation plan is in place. 

 Establishing a steering committee with representatives from both partners is crucial to provide guidance and address key issues. For us, working in partnership means working closely together with clients, making joint decisions, and maintaining ongoing interaction. 

 It is imperative at the outset of any project that a full responsibility matrix be developed, assigning clear objectives and accountabilities. This approach is particularly important for the release of clinical material to the international markets.

	As regulations become increasingly complex, greater scrutiny is placed on this element of the supply chain. Although API is usually supplied by the client company, regulatory requirements exist for the outsourcing partner to better understand and approve the entire supply chain assuring total security of supply. The best way to approach this is by working closely together to establish a robust Technical Quality Agreement at the onset of any early-stage manufacturing  program. 

 Ensuring accuracy of blinded studies is essential for any clinical trial’s success. How do you approach packaging issues? What must sponsors be aware of, and how does one ensure effective collaboration?

 In today’s marketplace, where we are seeing an increase in biosimilar and injectable products, blinding an investigational medicinal product (IMP) against a marketed comparator is becoming increasingly challenging. 

Where oral solid-dose products can be routinely over-encapsulated to maintain the blinded appearance of the dose form, sterile injectables present a very different challenge. In almost all cases, it is nearly impossible to find an exact match for the vial and stopper design used on the commercially sourced comparator and the IMP for the study. This challenge can be addressed using a cover for the vials, but if a product requires re-constitution, this can lead to challenges for healthcare professionals at the study site to be able to check that the product has fully dissolved into the diluent and that no particles are present. 

	More often than not, it is good idea to employ the services of un-blinded site pharmacy staff who can prepare a patient-specific dose and provide it to the investigator for administration in a syringe or IV bag. Using an un-blinded resource at the study sites does add some cost to the site fees, but this is often offset by the reduced complexity in the packaging and labeling process, so that product can be provided to the study sites in non-patient specific ‘bulk’ kits. This is the ultimate in late-stage packaging customization and, therefore, helps to reduce, by a significant amount, the overage needed to run a study.

	Far too often, the GMP and clinical supply teams that are making decisions on kit and supply-chain design have never even visited a study site. They should have access to sites and site staff to help them better understand the processes and environment at study sites, and, ultimately, the bigger picture and the options available to deliver a successful clinical supply chain.

 The single, most important factor to ensure adequate blinding is planning. You should meet with your CRO as early as possible to discuss blinding strategy and detail dosage form.  

	It is also vital to establish the understanding that even the smallest change to any agreed-upon detail can have a major impact. Once an agreed approach is decided, no change to any part of the pack can occur at any time.

	This means that, even if you are doing a resupply three years into a long-term study, you must maintain everything as originally established. If any changes are required, plan. Anticipating a change and ensuring your strategy will address it is vital to avoid any unblinding.

	Generally, we first ensure that any packaging components must be identical. If you are making kit boxes for a four-arm study, then you would typically package all four arms using the identical lot of boxes. Not only is the efficient and practical, it also avoids even having a minor (but perceptible) difference from lot to lot create an issue. 

	After that, there is a spectrum of concerns that need to be considered around but not limited to: dosage form smell, taste, appearance, weight, and feel, as well as pack components, labels, and packaging method. Every case has its own unique concern. Sponsors need to understand that all steps of any blinding process require close consideration as early on in the supply chain as possible.  

	For example, years ago I was involved in a study that presented the product in a metered-dose inhaler (MDI) canister. The innovator’s product was manufactured well, according to GMP, but no consideration was made for its ultimate use. When it was used in a comparator study, it was difficult to find the best actuator to pair with the MDI for dispensing that would also ensure the blind. 

	This also complicated the choice of a spacer to be used as part of dosing, and resulted in a lengthy delay and considerable added expense in product development. When the innovator company launched its next large program, they came to talk about the product, their competitors’ products, and best approaches on blinding at the earliest possible point, before the active pharmaceutical ingredient was even manufactured.

 Choice of a control group is a critical decision in designing the clinical trial. The placebo is one type of control group. In order to maintain blinding during a clinical study, the placebo must be an identical-appearing treatment (i.e., it should be visually indistinguishable from the drug product during preparation and administration at the clinical site).  

	Packaging can play a crucial role in achieving a visually indistinguishable placebo. This is particularly true if it is difficult to develop a placebo formulation that exactly matches drug product. In such cases, packaging can be used to mask any differences between the placebo and the drug product. For example, if a matching placebo is developed for a yellow colored drug product, but the exact shade of yellow cannot be matched, the products can be supplied in amber containers or supplied in clear containers covered with yellow labels.  

For injectable drugs, the clinical blind must be maintained not only in the original container/closure, but also in subsequent containers used for dilution and administration (syringes, IV bags etc.). In challenging cases, blinding can be obtained by opaque packaging to cover the infusion tubing so that the patient, investigator, and study nurse cannot detect which (drug product or placebo) is being administered.  

	Protein injectable formulations can be particularly challenging because of their potential to foam. In this case, too, opaque packaging around the infusion containers can provide the necessary blinding. A small vertical slit can allow the nurse to watch the level of infusion without seeing the bubbles of the infusion.

	The decisions involved in development of a placebo require good communication between the chemistry manufacturing and control (CMC) group at the CRO or CDMO and the customer’s clinical team. These discussions should start by addressing whether a placebo is required for blinding in the clinic, or if blinding will be achieved through other means such as packaging methods or unblinded pharmacists/operators.  

	If a placebo is deemed necessary, it should be developed. If development of a sufficiently matching placebo proves challenging, packaging strategies may be used in the clinic to mask the differences between the two. There may be cases where blinding in the clinic through packaging is preferred as a first option, or simultaneous placebo development and blinding strategies are advantageous. The decision on the path forward should be made collaboratively through discussion between CMC (formulation) and clinical team members.
	If the clinical trial allows patients dosing the drug outside of clinics, it is essential that the packaging strategy addresses communication and information needs, and that the packages be marked in an unambiguous manner with regards to dosing, time points, and medication duration.  

 It is critical to ensure that we consider all of the human senses-sight, smell, taste, feel, weight, sound, etc.-to have a really well thought out plan to ensure product blinding. The same principles apply for packaging and labeling of the drug product, even down to the finest details such as variations in the shade of white in the paper stock, or perhaps ensuring that the liquid in a placebo or active vial for injection not only match at ambient temperatures, but also when the material is frozen. 

	There are many factors to consider, and a critical part of our development is utilizing experts, but also fresh sets of eyes and various phases of project planning. Documentation and communication with interactive response technology (IRT) systems also have the potential to inadvertently unblind a study. Avoiding this problem requires rigorous training and constant review of procedures, to maintain the level of diligence required.

	Communication and early planning are paramount for success, with all stakeholders including the sponsor company, the CROs, ourselves, as well as the supporting vendors, and certainly the investigator sites.

	Factoring logistics requirements into development

Logistics concerns are becoming more important for development of products. To what extent do you see them being factored into drug development?

 Considerations of logistics and the challenges they bring are an essential factor for drug development, especially for development of the drug formulation. 

Often in the current manufacturing process, formulation development is suboptimal, and standard commercial formulation development often starts late in Phase III clinical trials. In order to capitalize on the full product potential and to improve market implementation logistics, advanced formulation development of the drug should be considered at every step of the manufacturing process. 

 Given the need to do more with less, and in less time, we are seeing increasing pressure on chemistry manufacturing and control (CMC) teams to press ahead with clinical studies with limited stability data. This trend is driving an increase in the use of cold chain conditions for IMP during the clinical phase of a product lifecycle. 

	With this in mind, the ability to actively monitor product temperature to avoid excursions and wastage is becoming increasingly important. 

 Logistic concerns have always been part of drug development. It is logically much easier to supply and ensure the safety and efficacy of a product if it can be stored at 2 °C to 30 °C with no real concern for minor temperature excursions, relative humidity, or the actual packaging type. 

	Ideally, any formulator is going to look to develop a more robust dosage form. However, not all products can be supplied this way, which is where CROs and CDMOs come in, to handle all aspects of drug production, and ensure that the product and processes supporting it are as robust as possible. This is accomplished by a challenging development program supported by rigorous stability testing to ensure that the properties of any given drug will withstand a range of environments--from ultra-low frozen temperatures to very hot and humid ranges, in a variety of packages. Then they also ensure that all points of the supply chain that have custody of this material can ensure it is stored and handled as directed, ensuring the conditions are maintained such that no negative impact to the product occurs.  

	Now, with the rise of biopharmaceuticals that are more fragile than small-molecule drug formulations, there is a requirement for more stringent and challenging approaches required to deliver these products.  While this is a challenge, we see it as a good thing. In the past, some of these products would not have existed. Now we can supply vaccines around the world consistently that might require ultra-low freezing throughout the supply chain-this would have been impossible or at least an extreme challenge not too many years ago.

 Shelf life and storage conditions have an impact on the profitability of any pharmaceutical. For most new commercial products, at least 36 months’ shelf life at room temperature is needed in order to be competitive. This is a property that has to be built into the product from the start.  A clinical trial material of course only has to be stable long enough to complete the trial. 

	However, many studies run for a longer time than intended, as inclusion rates are lower than expected. Additional clinical trial material can be manufactured but this will be costly and may in worst case cause further delays. A long shelf life is achieved by optimizing the formulation and choosing an appropriate container closure system.  This work is important, not only for commercial products, but also for products to be used in clinical trials

We see two significant trends in clinical trial supply in the area of logistics. One is the growth of biologics and emergence of cell and gene therapies, both with critical cold chain demands to ensure product safety and effectiveness. Biologic products traditionally need to be maintained at 2-8 °C in an end-to-end supply chain. That model includes transport from the sterile fill/finish manufacturer to the site where packaging and labeling happens, to the storage depot and ultimately the distribution to the investigator site, and even potentially to the home if it is for a direct to patient study.   There are so many opportunities for risk in the supply chain and therefore sponsor companies need to select a partner that can assure with 100% confidence that every touch point and every transfer is done with compliance to the temperature range. We see emerging technologies such as TrakCel that can provide that real-time, end-to-end supply chain temperature monitoring, vitally important in a robust supply chain. A critical aspect for successful execution is the preparation of a global supply plan. This is a collaborative effort to identify best practices and standards, as well a systematic approach to addressing risk at various points in the supply chain. 

	Often in clinical development these therapies may not even have established data for long term storage in a 2 -8 °C refrigerated environment, so they may opt to utilize frozen temperature points such as -20 °C, -40 °C, or -80 °C, and potentially even a custom temperature such as -30 °C.  This creates additional concerns for sponsor companies to select that expert solution with infrastructure and practices to support.

	Emergence of global clinical studies has led to investigator sites being utilized in emerging market economies, both with financial benefit as well as access to treatment naïve patient populations. These countries may lack the infrastructure found in the developed markets, and challenges may be compounded by concerns about extreme temperature and humidity levels.  

	With the development of personalized medicines, including cell and gene therapy, another level of complexity is added. Each vial is a unique and invaluable specimen, with a potentially circular supply chain and a very short time window, and often needs to be kept at cryogenic temperatures such as -140 °C or -196 °C. The considerations for risk in this supply chain are infinitely more intense given the nature of the product. 

  How are you collaborating with logistics firms and do you see ‘direct-to-patient’ clinical trials, e-trials, and other alternative clinical trial formats having an impact on how you work with sponsors and manage projects? 

Many late-stage clinical trials today are performed at different sites on several continents at the same time. Relatively small trials may be also performed at multiple sites, especially if they are for a drug that is being developed to treat a rare disease. Because it is extremely difficult to predict inclusion rates at different trial sites, it may be advantageous to be able to ship product rapidly to different locations around the globe, as need for the material arises. 

In order to ensure the quality of the product, it is important to be able to monitor the shipment, for example, if cold chain supply is required. For this reason, working together with companies specialized in the shipment of clinical trial material may be crucial to success. By ensuring that there will always be clinical trial material available as new patients are included without storing a huge excess at each site, time and money can be saved. Collaboration between the logistics company and the manufacturer is extremely important. 

 Direct-to-patient studies present a number of new challenges and considerations, such as kit design. In order to ensure patient confidentiality, the process must be designed to ensure that patients’ addresses and personal details are kept remote from study sponsors. 

	Supporting technology to manage the patient data segregation and supply process is critical to success. In the EU, the regulatory environment makes direct-from-depot-to-patient delivery almost impossible, so a depot-to-site-to-patient model is needed. 

	Wearable patient technologies have the potential to address several challenges related to remote or e-clinical trials and to improve execution by increasing patients’ ability to participate, driving patient engagement, and creating more opportunities for decentralized trial sites. PAREXEL recently announced a collaboration with Sanofi to advance the use of wearable devices to transform the collection of data in clinical trials. 

	Currently, PAREXEL and Sanofi are collaborating on a pilot study. Using PAREXEL’s sensor solution based on the Perceptive MyTrials platform, the study aims to facilitate the remote collection of clinical trial subject data. 
	In an ongoing single-site study, patient data are being collected remotely and simultaneously via multiple wearable devices. Publication of results is expected in the near future.

 Traditional models that consider supplies maintained at central hubs of key depots around the world now require analysis because every country has a different regulation. Many countries will not permit the supply of material direct to patient, so, an exhaustive study of all the countries that permit this practice helps ensure compliance. In turn, the larger supply strategy now requires a hybrid approach considering countries that must be supplied using current models as well as those that permit direct to patient. This can be quite complicated, and requires early planning and frequent communication with partners.

 Yes we see impact from the changes in clinical trial administration as well as changes in clinical supply models. Direct To Patient is one such approach, and impacts the overall planning and execution for clinical trial supply. Likewise, companies are looking at global studies, and assessing what makes the most sense for multi-country studies. One approach is to pool supplies (for supplies that can be used across multiple studies a protocol label is applied to the supplies at the time of dispatch) and include as many languages as possible. This can sometimes involve up to 16 or 20 distinct languages, which allow for redirecting of supplies but also many create lead time challenges for developing translations and integrating them into one singular booklet label. The alternative approach would be a supply model of late-stage customization or just-in-time supply, whereby product is dressed with language or site-specific labeling in an on-demand approach. This model relies heavily on a robust IRT solution and a reactive supply chain.  


	Supplement: Outsourcing Resources
	Vol. 41
	August 2017
	Pages: s16-s23

	When referring to this article, please cite it as A. Shanley, "What to Watch Out for in Clinical Trials Manufacturing," 

Requirements for early- and late-stage trial manufacturing may differ, but complying with good practices, maintaining blind studies, and considering logistics remain crucial at all times.

What to Watch Out for in Clinical Trials Manufacturing

This year, Patheon has officially launched a continuous manufacturing initiative. Its new continuous processing facility in Greenville, NC was completed in September of 2016, and the company’s director of continuous manufacturing, Eric Jayjock, is bringing newer approaches into the company’s toolkit and culture.

	Although oral solid dosage (OSD) forms are now the focus, the company’s division in Linz, Austria, offers expertise in continuous API flow reactor chemistry that might be used in the future. Dr. Jayjock discussed plans and thoughts about continuous manufacturing with 

	Experience developed at Janssen and Rutgers

 How did you get into continuous manufacturing?

 I was a PhD candidate at Rutgers working for Fernando Muzzio, and my thesis was on a completely different subject involving inhalable drugs. However, during this time, I had developed the ability to combine a chemical engineer’s process knowledge with the building aptitude of a mechanical engineer. 

	These two skills came into play when Johnson & Johnson asked Rutgers to help them build a prototype continuous, direct compression line to evaluate the technology for their facilities. This became my post doctorial project and eventually led to Janssen offering me a position. My family and I moved to Puerto Rico in 2013, where I supported the development of a continuous direct compression line for the production of Prezista.  

 A lot is being written about continuous processing, but what makes it different from earlier movements such as process analytical technology (PAT) and pharmaceutical quality by design (QbD), which, initially, were embraced by an elite and only slowly gained traction throughout pharma?

 PAT and QbD are highly scientific pursuits, allowing organizations to develop the depth of knowledge that will help them run product more efficiently. At first, companies may have assumed using these approaches would bring some regulatory relief, but that didn’t necessarily play out as some people had anticipated. 
	In the end, however, you still make the product the same way with PAT and QbD, so there was no real sea change. From a high-level business perspective, the question became: Where do I save money if I use PAT or QbD? Of course, these methodologies allow you to save money because they will enable you to develop more robust products. Pharma, however, is driven by new products and that’s where most of the industry’s investment goes. There are significant financial benefits to producing products continuously. 

	Continuous manufacturing reduces plant footprint and labor, and permits higher capacity utilization. Today, 30% capacity utilization is still typical for many batch pharma facilities, but with continuous pharma, plants will be able to run closer to chemical plant levels, i.e., with 80-90% capacity utilization. That way, every dollar spent on equipment can potentially yield two or three times more bang for the buck.

 Is Patheon’s continuous manufacturing line now up and running?

 We’re close. We started building the new facility in Greenville, NC in March 2016, and finished it by September 2016, then we had to install equipment and start commissioning various aspects of the system. 
	We begin detailed process development in early 2017, adding a supervisory process control system that will integrate all the pieces of equipment into a flexible framework of units. This framework will allow Patheon to use a common suite to manufacture products with different processing needs. So 2017 marks the start of our continuous processing initiative, and our facility is almost ready to begin manufacturing. 

 Will Patheon offer continuous for OSD forms, APIs, or both?

 Long term, we’re looking at being able to provide continuous manufacturing wherever it makes sense from a business and quality perspective. Right now, my focus is on OSD, but we might want to branch out into other areas at some point in the future.

As you go farther back along the pharmaceutical value chain to the drug substance, it becomes more like a chemical process and less like a traditional pharma stream, and we already have continuous chemistry capability in Linz, Austria, for API manufacturing. Patheon’s group in Linz has scaled up several different reaction pathways using a continuous flow reactor. This approach allows development trials to be run on ,a very small scale, using very low flow rates, and then scaled up via large manifolds. Our colleagues in Austria have been doing this type of work for 10 years now.

 From what you’ve seen, are people in pharma skeptical, fearful, or interested in continuous processing?

 Branded drug companies with new drug entities are either already on board with continuous or coming on board rapidly, while others are still studying the best way to get into this area. Small- and medium-sized branded pharma companies, for whom CDMOs are the hands of their operations, are very interested.
	The work on continuous that has been done by Vertex and Janssen has shown that continuous processing can save a great deal of material because it eliminates the need for scale-up. For high priority, rapid designation product, continuous processing can allow a great deal of drug development time to be saved. In general, there’s been a lot of interest.

 How do you educate clients and would-be clients about what will be required?

 I’m spending a quarter to 30% of my time doing some educational work, both internally and externally with clients. This type of approach is necessary because continuous manufacturing is so data driven. You can study much more about a process than you could in the batch world, so you can determine what poses the greatest risk to each product. By combining a risk-based program with the data rich nature of continuous manufacturing, we drive a much deeper understanding of our products and processes.

	It would be a real disservice to treat this like a traditional, cut and dried batch manufacturing project, as in ‘We’re going to produce X batches of Y size’.  

	With continuous processing, we bring our customers’ scientists on board to talk about problems and custom tailor programs to the unique attributes of each product. 

What I advise companies of all sizes, whether they want to go into continuous manufacturing themselves or are looking to work with a partner, is that it’s not just about equipment, or even technology, but about people. You need to change mindsets throughout the organization and that’s often the most difficult issue.
	For example, we tell people they will have to work with their quality teams to show them how continuous -processing is different from batch to help them understand. Typically, people think about the process and technology first. Then, when they become more comfortable with those aspects, they worry about integrating a different approach into the mindset of their organizations.

 Are quality departments afraid of continuous, and potential loss of employment?

 I would not say afraid, but rather unsure. Continuous manufacturing quality assurance requires a different skill set from that used for batch. Quality for batch manufacturing is set up so that you simply run quality tests, run metrics on the batch and then have a conversation about whether you pass or fail the batch.  
	With continuous manufacturing, you see an issue in production that may lead to an automated response by the control system. This is something quality needs to be a part of developing up front during validation. Once you implement control loops to keep your process within specifications. Then a deeper level of quality conversation can take place. 

Let’s say you are producing products which are on spec, but the combination of processing conditions needed to get the product there is different from typical batches. Is this a quality issue? The answer is it is, of course, very product dependent.  So the quality organization needs to be a partner in the development process to determine what is critical for each product. The quality conversations come much up earlier and quality has to be involved from the beginning.

	It’s like learning a new language. We see there is hesitancy and concern at some companies, because it is different from what everyone is used to, and they are not sure how to train the new organization.

  How would the way you start a continuous project with a client differ from the approach that you’d take with batch?

 The financials are very different. In the batch world, for example, it doesn’t make a big difference whether you have four or eight components in a blend. With continuous manufacturing, it makes a very big difference, because you’ll either need four or eight individual blenders, so there will be a significant engineering difference between the two approaches.

	As far as transferring information is concerned, the biggest difference is the traditional batch approach is pretty well scripted. We know from the outset, for instance, that we’re going to make X batches of Y size, and scale to Z, so we can easily predict how much material and time will be needed, and what type of work must be done.
	Continuous manufacturing is more iterative, as in ‘We’re going to do this bundle of work, these small scale experiments, to establish whether or not these risk factors are critical to the process. We’re going to study these factors, then we can remove some from the list or prioritize other factors for the next round of study … maybe additional factors will be needed, so there will be a little more work required than we originally anticipated.’  
	With continuous processing, there’s a stage gate approach where the scope of work is always changing. The idea is that we’re always looking at risk to the product and making sure we’re putting resources toward the most valuable studies we can run. 

	From the business side, it’s a challenge because we can’t quote with the same type of regularity seen with batch manufacturing, so there is no cookie cutter approach. More conversations have to happen in order to determine the scope of work.

 How many of your clients are embarking on continuous?

 We currently have two projects signed on to the continuous manufacturing train. 

 How well do most clients understand the foundational concepts, PAT, QbD, and process control, behind continuous manufacturing? 

 Companies who are looking for continuous solutions tend to have people working for them, each of whom has one or another piece of the puzzle in place, given the data-driven nature of continuous. For instance, companies may have people with statistics, PAT, or Six Sigma backgrounds.

	Our goal is to take something that is, on the surface, highly complicated-a process where there may be 10-15 different parameters we can adjust to keep it in control, with 5-10 material properties that can have an impact on the product-and boil it down to its simplest, easiest to understand, form: ‘These are the two things that matter most to our product, and these are the two things that can control them.’ In pharmaceutical development, we need to have a clear control strategy that outlines risks to the product, and how we can best handle them.

	The secret to manufacturing is that only a handful of factors really drive quality. A process engineer’s job is to sort out the bad from the good and determine which ones are most important to the final product’s quality.

 What is being done to develop real time release testing (RTRT) for continuous? Janssen has filed for this, but PAT guidance had promised that this would be possible.  What is needed, since dosage forms today are becoming more complex?

 Often continuous manufacturing and RTR are put in one category, with the oversimplified idea that you make product continuously and it just goes out the door. There can be certain advantages to doing RTRT for continuous manufacturing in some cases, but not always. There are many more tests we run on batch products for which we have superior surrogates, but you’re not always going to do RTRT on continuous processes.

	For more complex formulations, continuous processing gives us a test point. Right now, we have variability in materials, put them into a fixed process and get variable product, so we test it to determine quality.  

	With the continuous development cycle, you can vary the process and see the effect on the product in near real time within a few minutes so we can tie that knowledge together. The most valuable thing we’ll have for RTRT is process data. If a product is being produced, with attributes tightly controlled using a combination of process conditions which are statistically comparable from traditional production, you have a lot of data to support the quality of your product. In general, continuous is a great enabler, but not necessary for RTRT.

	My personal point of view (not that of my employer) is that we’ve set up this culture of testing for quality, but some tests may have questionable utility, for example, dissolution, which shows little in vivo in vitro correlation. It’s not clear what the test is supposed to be doing, except to measure variation in quality for a particular tablet. Statistically, however, it is not that good at determining variability in quality. Yet we keep using it, despite the fact there are better methods for doing this. The largest barrier for RTRT is that we’re being held to this test, which doesn’t have a lot of statistical meaning.

	For some time, the conversation in industry has been: ‘Can we predict what happens in a dissolution test?’ That would make sense if the dissolution test itself were a statistically better predictive measure. We’re spending a lot of energy on dissolution when we could use other measures, such as the physical properties of tablets, that are greater indicators of  product quality.

What are your goals, short and long term?

 In the short term (i.e., next six months to year), we’ll be getting the first suite up, and bringing the whole organization along into the technology. We want to bring the company’s culture to the point where we understand and can execute continuous projects as an organization.

	Medium term, we want to focus on ensuring suites are multifunctional and batches can be turned over very quickly. The engineering challenges involved are very real, and we have a plan so that we can make continuous better, not just from quality, but from business perspective.

	Long term, we want to build a manufacturing framework within which we can roll continuous manufacturing projects out anywhere in the world, and where we have the utilities in place to support them (e.g., to build modular unit operations, ship them and be able to run the process six weeks later after we have them on hand).

 Do you have a dedicated staff for continuous?

 Currently, three senior level scientists (including myself) on the development team, and we are developing an operations team. 

	We staffed the development team this way because the three interaction points are:

		Understanding material properties and variability

		Understanding what’s happening in real time (that’s where the chemometrician comes in) so we can sense changes in the line. 

 Which equipment vendors you are working with?

 My personal belief is flexibility should be the focus, so which equipment we use is secondary to how we bring it all together (e.g., the piping), which can work for one product but not another. We also need deep process understanding, and a feel for what works well and what doesn’t.

	The concept behind our design is we can integrate any equipment into our suite in which the vendor will work with us. For the first wave of work on the new facility we selected equipment we thought would be a good fit for our system: Gericke for continuous feeders; Korsch for compression; Lodige for wet compression and automation, and a Gerteis minipactor for dry compaction. We’re considering adding a new continuous coating system for future expansion. 

 How does turnaround time differ for a batch vs. a continuous product?

 It is difficult to generalize, but the time required to turn a continuous line around and switch product is not a problem for manufacturing. Where it can be challenging is in drug development, however, when you are running many, short product runs. 

	When referring to this article, please cite it as A. Shanley, "Building a Continuous Processing Culture," 

Eric Jayjock, Patheon’s director of continuous manufacturing, discusses the CDMO’s plans for its new continuous manufacturing business. 

Building a Continuous Processing Culture

Inhalation therapies are notoriously difficult to develop, and history is full of failures, whether Pfizer’s Exubera, or generic versions of GlaxoSmithKline’s (GSK’s) blockbuster, Advair dry powder inhaler. This year, both Hikma and Mylan presented FDA with abbreviated new drug applications for generic versions of Advair, and both were sent back to the drawing board. 

	“This shows the regulatory and clinical complexity of developing new inhalation devices that regulators will see as equivalent to the name-brand device,” says Steve Ellul, commercial director of Bespak, a contract development and manufacturing organization (CDMO) based in the United Kingdom. Working for both name brand and generic-drug sponsors, the company manufactures a number of different devices and components for different therapy areas, including about one third of the current 600 million/yr global output of metered dose inhalers (MDIs).

	Modern manufacturing design technologies promote rapid proof of concept. “Combined with established design for manufacture tools and techniques, we can increase the probability of a successful outcome for our clients,” says Bespak’s head of product engineering, Mark Knowles. He points to MDI technology,  where significant gains have been made using these tools, along with modeling and prototyping, to improve product design.  

	But if inhalation therapies are hard to manufacture, they are often difficult for patients to take, particularly children and adolescents, who need to synchronize inhalation and device actuation in order to ensure that they receive the proper dose. Currently, significant resources go into instructing patients and their families on how to use inhalers properly. Cylindrical spacers offer a solution, but they are large and require maintenance.

	As a result, between 76% and 94% of inhaler users are using their devices incorrectly (1), while 60% do not always take their medication (2). According to the Global Asthma Network’s 2014 Global Asthma Report, a significant number of deaths from asthma, particularly in the UK, might have been prevented by a combination of more, and more effective, treatment (3). 

	A number of manufacturers are looking into alternative devices, including 3M, which is close to introducing the Intelligent Control Inhaler to the clinic for trials. The company expects to start clinical trials of the technology early in 2018, says Stewart Griffiths, head of product development at 3M. 

	The device uses an electronic rather than mechanical actuator. As Griffiths explains, both powder MDIs and dry powder inhalers (DPI) pose challenges. With MDIs, the user must press the canister’s actuator at exactly the right time to get the right amount of drug deposited in the lungs. 

	DPIs, meanwhile, are higher resistance devices that require higher inspiratory flow to break up the formulation and deliver the drug to the optimal part of the lung. “We’re working to eliminate the need for coordination and have the device manage that, so that the patient need only place his or her mouth around the mouthpiece and inhale to trigger the release of medicine,” says Griffiths. 

	Ellul, Griffiths, and Knowles discussed best practices for working with contract manufacturers, operational excellence, industry trends, and the move to connected devices with 

 What trends are you seeing in the market?

 There’s an increasing emphasis on smart inhalers, which brings the question: How do we try and apply modern technology to relatively established products? Factors such as health economics and reducing total healthcare system costs are a key driver of smart inhalers. 

	We need to examine how we can reduce overall healthcare costs by introducing technology to track patient activity and determine whether people are taking the right amount of medicines at the right time and adhering to prescriptions. There’s technology out there now that allows us to try and monitor these things, providing better insight into real-world situations than we’ve ever had before.

 One of the trends we’re seeing is the rise of generic therapies, although, so far, generic-drug companies have not been able to succeed in developing versions of Advair. Over the next few years, we’re expecting to see new generic versions of branded Albuterol products in the United States, such as Proair, Proventil, and Ventolin. 

	Another trend is the move to connected and smart devices.  It’s not clear how that will play out. There aren’t any imminent launches yet, but clearly, things are happening.

 What are the greatest challenges to developing and manufacturing these treatments?

  The challenges comes from developing precision components and assembly that deliver to high volume and maintain the high levels of quality. We have been very successful with our customers as we customize our MDI designs to meet their needs. However, this results in many variants which creates a range of manufacturing tools and assemblies to manage and maintain. We manufacture over four million MDI’s per week, to six sigma quality levels (i.e., 3.4 failures per million devices).

	By adopting robust design techniques and adhering to rigorous change-control management, we ensure that any variance in manufacturing product and process remain within specification. Any deviation is detected and we can act immediately, invoking our corrective and preventative  action (CAPA) processes. Some aspects of change are not in our control (e.g., raw material quality), so we install quality-control measures (e.g., quality inspections, quarantines, off line sampling) that provide safe guards. Continual risk assessment and impact analysis ensure these safeguards are regularly reviewed and updated.

 When a pharmaceutical manufacturer starts an inhalation therapy development project with a contract partner, what are the key issues that have to be addressed when the project starts?

From the CDMO’s perspective, one of the fundamentals when working as a service organization in drug delivery systems is that you really have to ensure that you’ve got a good product definition, that you’ve got quality, and a good process for gathering requirements from a partner. Both sponsor and partner must be aligned to start with, with the target product profile, for instance, and establishing the dosage form, whether MDI, solution, suspension, DPI, reservoir device, or capsule. 

	Other crucial questions include: What shelf life do you need?  What cost of goods do you need? Commercial intent is needed from the start, as well. If you are looking more around the device, you must ensure that you understand the target patient population and that human factors are going to work with what you’re designing. 
	Assuming that both sponsor and contract partner can get to that same starting point, the work can move into product optimization and compatibility experiments, considering long-term storage, and determining the project’s likelihood of succeeding with the right long-term stability profile.

 By definition, a project has a beginning, a middle and an end. These types of projects typically follow a gated process. Each gate provides a check point to assess whether the project is still on track to meet the three key dimensions; commercial business case, technical feasibility and project costs  and timelines. A disciplined approach and adherence to these check points is key to a successful project.

	Continual risk management flows through the life of the project. If done well, risks are driven down to levels that are acceptable, while knowledge and confidence are increased surrounding the likely project outcome.

 From a technical point of view, it requires establishing clear customer and clinical needs and a corresponding concept with a performance window, or design space, that will meet this need. The design space must be capable of meeting the agreed-upon level of cost and quality. Our projects are mainly high volume (i.e., over five million per year) drug delivery devices; for example, dry powder inhalers, auto injectors, and inhaler systems (valves, actuators, dose counters), but we also manufacture diagnostic devices. For these types of device, it is important to consider closely the clinical needs of the device (i.e., what capabilities will be critical to function) and prove that the technology can perform this need (critical to quality) to an agreed-upon level of confidence or sigma level. 

One example would be mapping the dose delivered performance required to the device functions that contribute to this critical need. Then, the assemblies and componentry technical requirements (e.g., dimensions, materials, tensile properties, surface finish) must be mapped or related to these functions. As a simple example, MDI dose (or shot weight) can be correlated to the chamber component volume in the valve mechanism. The volume variance of this component must produce a shot weight variance within an acceptable clinical tolerance. The design challenge is to ensure that the material and manufacturing processes are capable and, through normative use, meet this need. 

What modern design concepts are you using in development? 

 A lot of what we do comes back to project management. At 3M, we apply quality by design (QbD) and design controls for development of combination products and devices. A risk management process must underpin component development, where you’re looking for critical quality attributes. 

	Then you must consider the manufacturing process, where you’re looking for critical process parameters. You apply risk assessment to all these factors in the product definition, to assess the likelihood that they could affect product quality. Risk management highlights the attributes that need to be explored further through product and process understanding work. Expectations are managed against the original project profile.

There are a number of design tools and techniques. The key issue is not to lose sight of the key goal in any design approach: to ensure the alignment of user need to design intent, and the level of capability, cost and quality you are trying to achieve. 

	We use analytical (e.g. modeling) and experimental (e.g design of experiments through rapid prototyping) techniques to assess rapidly if a design concept will meet the design intent. We’ve been using 3-D printing since it came on board three years ago, and it has become an invaluable tool. It allows us to reproduce representative manufacturing parts very quickly within the lab.  

	These tools promote robust designs through a marriage of analytical (e.g. modelling, 3D CAD), empirical (e.g. design of experiments) approaches, underpinned by SMART success criteria (Specific Measureable Achievable Reliable Testable) design documentation and evidence (verification and validation). Best practices for the industry include Lean Six Sigma and QbD tools. We regularly use design and process failure mode effects and analysis, which aim to design out product and manufacturing process errors.

 Are clients using these approaches and providing you with the right information, or have you had to educate them in order to get what you need to start the work?

 It varies considerably, as we work with many different types of clients. The more experienced companies have generally learned from past mistakes and have adopted/tuned their practices. For example, we are seeing evidence of companies designing the drug and device together, using the systems engineering or QbD approach. Convention has been to formulate the drug, and then find a device for it. If all components of a system are designed at the same time, however, the overall system can be optimized to meet the user needs; this leads to a more efficient and cost effective product.

	Ideally, we are approached at the early design phase of projects, so that design for manufacturing can be done more easily and more cost effectively.  This happens with our own Innovations group in Cambridge, UK; we work with clients on their early concepts and prepare them, by design, for manufacturing.

Are you using analytics and process analytical technology?

 New drugs promote new device design challenges; constant differences and changes in particle size, viscosity, density, and coagulation properties. For plume, droplet size and lung yield, our clients tend to use the electronic lung or Anderson cascade to optimize their formulation. We then use corresponding lab instrumentation, such as spray plume and particle size analysis to prove the active ingredient performance with the device design.

	Several strands of physics are involved in drug delivery device design (e.g., chemistry, thermodynamics, friction, force). Knowing the relationship of these to the required system pharmaceutical performance is key. Where it is cost effective, we buy in house laboratory equipment (e.g. MDI leakage test equipment used for every release test). 

Successful development requires coordinating and aligning drug and device design, focusing on a complete drug delivery system that meets patients’ needs.