Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Advanced digital ledger technology (ADLT), or “blockchain,” the system behind the digital currency, bitcoin, is being used to ensure security and establish provenance in a number of industries. Defined by its inventor, Satoshi Nakamoto, as a peer-to-peer network that timestamps transactions, blockchain “hashes transactions into an ongoing chain of hash-based proof-of-work, forming a record that cannot be changed without redoing the proof-of-work” (1). Advocates believe that use of blockchain could solve some of pharma’s thorniest supply-chain problems and broader healthcare challenges (e.g., secure transmission of sensitive patient data and clinical information). 

	As the technology becomes better known in pharma circles, a number of potential applications for it are being explored. In June 2017, a survey of 120 life-sciences executives by The Pistoia Alliance found that 83% expected the technology to be adopted within five years (2). Regulatory issues were seen as the greatest hurdle, followed by concerns over data privacy.

	Closely associated with blockchain are “smart contracts,” which feature software on a blockchain that defines agreement terms and execution and could, in theory, reduce costs, prevent fraud, and improve connectivity to the Internet of Things (IoT). The Center for Supply Chain Studies (CSCS) in Chicago is currently researching how blockchain might aid efforts to improve supply chain safety, and how it could fit in with the US Drug Supply Chain Security Act (DSCSA)(3). 

	“When you look at the realities of unit-level traceability in the supply chain, especially for a supply chain the size of that in the United States, there are challenges with data exchange, challenges around trust for sharing data across the supply chain, and challenges for ensuring the immutability of the data associated with a product and the transactions associated with it,” says Brian Daleiden, vice-president of industry marketing at TraceLink, which provides cloud-based solutions for serialization. Daleiden, a member of the CSCS blockchain committee, says that evaluation is still at a very early stage.

	“We’re still trying to figure out the possibilities for the kinds of data you should put into a blockchain node and what the tradeoffs are,” Daleiden says. In one approach, all product and traceability information could be left in the supply chain so that only trust and identity data would go into the blockchain, he says. One would query the node to find out whom to contact for product or transaction information, he explains. 

	Alternatively, in an approach seen in the earlier e-pedigree days of the early 2000s, information on product and associated transactions could go into the blockchain node itself, and a smart contract could be used to query information about it. “There can be huge tradeoffs involved with each approach,” he says.  

	The pharmaceutical industry is still a good year and a half away from understanding the space well enough to be able to articulate a cogent and well thought out model on how blockchain could work for DSCSA, and then it is going to take some field trials, he notes. The CSCS is thinking through some models and working on some testing, but whatever is developed will then require testing and implementation, says Daleiden.

	In June 2017 at Johns Hopkins University in Maryland, a conference examined blockchain and its potential in pharma and healthcare. Sponsored by the Institute of Electrical and Electronics Engineers (IEEE), the event featured speakers from one biopharmaceutical company, industry coalitions, academia, vendors, and consultants (4).  

	After the event, some speakers shared thoughts on where the technology is going with 

	Responding are Bob Celeste, former head of pharma programs for GS-1 and now director of the CSCS; Darryl Glover, chief clinical officer at iSolve; Jim Sabogal, healthcare and life-sciences leader with T-Systems; and Tim Mackey, director of the Global Health Policy Institute and associate professor at the University of California San Diego School of Medicine.

When the California pharma e-pedigree regulations were being developed during the early 2000s, some provisions were made for provenance that might have resembled blockchain. Why weren’t they retained in subsequent requirements for pharmaceutical supply chain serialization and traceability?

 The regulations provided an opportunity to consider new technologies or business practices. Although they did not envision blockchain specifically, they realized there might be additional technological advancements between 2013 and 2023, and didn’t want to tie the hands of FDA or the industry unnecessarily.

 Most likely, these requirements were extensions of the Electronic Product Code Information Services (EPCIS) standard a few years back, which is why many think that blockchain would be the best fit for serialization and traceability.

What do you see as the greatest obstacles to implementation, and how can they be overcome?

 Today, there are three main obstacles to implementing blockchain in the pharmaceutical industry. The first is the wide range of blockchain technologies available. There are 17 possible blockchain platforms (5), as well as different versions of blockchain, including Hyperledger Fabric and Ethereum. Most of these will work for pharma in situations that involve a few transactions.The pharmaceutical industry, however, ships thousands of units per day. Startups are coming to the market that claim to offer scalability, which would be useful to pharma in the future.

	The other difficulty that pharma has is deciding whether to use a private or a public blockchain. Public clouds mean that your transactions could be viewed on the Internet, so private clouds are most likely to meet the typical pharmaceutical company’s data security needs. 

	But what about the distributor that provides services across multiple pharma companies? Once the scalability questions are addressed, distributors will have to decide whether they can play in multiple blockchains.
	Since regulations put the emphasis on manufacturers, small-to mid-sized distributors and contract manufacturing organizations (CMOs) are at risk because they may not have the means to work in multiple blockchains. This is why adoption is slow at the mid-to-small manufacturer and distributor level. The cost for serialization is already prohibitive for these suppliers.

	The most fundamental challenge, however, is the level of trust in the pharma supply chain, particularly between manufacturers and distributors, in terms of running a proof-of-concept (POC). Typically, these firms are at odds with each other, and often the distributor makes money from the data it collects.

  I’d expect the technology to be used first for track-and-trace purposes. Multiple, non-adjacent trading partners need to exchange data. The greatest challenges are: data confidentiality and security; flexibility in allowing data to be shared; scalability, complexity, and cost. 

	The CSCS’s study addresses all of these areas. It will take a combination of technology maturity, standard interfaces, projecting data governance rules across connected platforms, and industry agreement to use the resulting systems.

 The main obstacles are lack of awareness and education about what blockchain can do, and the fact that data shared in a blockchain can be limited on a permissions basis and can also be limited to simply verifying that a product came from the person who it was supposed to come from (not including any other proprietary data, such as pricing, shipping volumes, or underlining supplier networks). Hence, the main barrier, beyond the fact that we really don’t have much in production that showcases what blockchain can do for pharma, is the issue of data confidentiality and ensuring that proprietary information is not shared or inadvertently disclosed as part of a distributed ledger visible to more than a bilateral relationship.  

	These barriers can be partially overcome by observing good-use cases in other supply chains that focus on other regulated products, limiting initial blockchain to private and smaller blockchains, and focusing on the use of smart contracts and what they can do in the context of blockchain, instead of focusing on blockchain first.

The greatest obstacle is for the industry to identify what data they wish to collect, the format, and the level of analysis to be completed before they receive it. 

 Where might we expect to see elements of blockchain applied first in pharma and life sciences?

 Initially, we can expect to see it used between directly adjacent trading partners as a way of testing, exercising, and gaining value from the technology. It would be used mainly for product traceability and DSCSA compliance.

 There has been a clear maturation of blockchain in clinical trials and good movement in the area of sharing electronic medical record data among different hospital systems for aggregation and looking at macro trends and population health issues. I think the supply chain applications will lag behind these sectors, as inherently there are more mature business models and clear incentives for actors to participate in using the technology.

Real elements of blockchain (i.e., beyond internal proof-of-concept) may be seen in the industry early in 2018.

 Meeting the DSCSA and other regulations might prompt companies to adopt the technology, first, to meet the various global deadlines. However, there are now a number of inquiries regarding the application for clinical trials. So, one of these two applications is likely to be first.

 If the industry were to move to blockchain for product traceability, what kind of timeline would likely be required, and what changes would be needed?

 The timeline would be measured in years. Although early pilots will take place, an industry-wide agreement will take some time. Also, there are a lot of areas that need to be tested.

At T-Systems, we use IoT devices from our partner, Roambee, to provide real-time global supply chain feedback. Once companies realize that their supply chains would benefit from these devices and the data they provide, it will be easier to put these data in a blockchain.

	The Roambee IoT device (called a bee) is currently on the market today based on three use cases: 

		Theft/brand protection using global positioning systems (GPS) and global systems for mobile communications (GSM) technology 

	Many pharma companies are using this device today; while blockchain use cases are still in development, these data can be leveraged. An alternative would be to use blockchain without IoT devices. At that point, the question is about the value of using blockchain. I would suggest that companies using IoT for their pharma supply chain today reap the benefits of real-time feedback on their shipments. So, if there is a delay in blockchain technology adoption, they can still meet some of pharma’s traceability regulations.

 Assuming that an organization already has the capability to serialize data, the steps that would be required are: Conducting an assessment and identifying all of the potential trusted partners, existing systems and processes, and requirements for data transfer; designing a proof of concept with only a few business partners; developing the solution by testing a prototype; deploying the solution to production.

 How could it be used for clinical data transfer?  

 Clinical data transfer in the context of supply chains, such as applications touching patient data, or even tracing back product dispensing to end users for recalls, is a tricky issue. Once a pharmaceutical blockchain touches patient data, then disparate privacy and data sharing frameworks (such as the US Health Insurance Portability and Accountability Act [HIPAA] and EU General Data Protection Regulations [EU GDPR]) will be triggered, adding more regulatory complexity. At the start, blockchain for the pharma supply chain should be limited to traceability of product, and not attempted for full end-to-end solutions for post-market surveillance or assessing clinical care or quality outcomes.

At T-Systems, we see a key benefit in using blockchain technology from a data security perspective for clinical trial supply management. By controlling supplies from manufacturer to patient, each patient in a clinical trial could have his or her own blockchain file with relevant patient data. Alternatively, one could use blockchain for exchanging clinical data between a patient and a drug trial, but commercial electronic data collection (EDC) systems already do this (e.g., products from Medidata).

  Both clinical and DSCSA data have similar requirements, challenges, and potential solutions.

 Clinical data applications could be a strong use for blockchain technology. In this case, regulators and study sponsors would be assured that the data provided came from a specific patient and that any changes made to the data at the clinic site could be red flagged for further review. Moving data more efficiently from site to the contract research organization would facilitate data analysis and would most likely shorten clinical trials. Finally, by assigning patients digital IDs, it would become possible to ensure that the same patient does not enroll in multiple trials simultaneously or within a short period of time. 

	1. S. Nakomoto, “Bitcoin: A Peer-to-Peer Electronic Cash System,” bitcoin.org, www.bitcoin.org/bitcoin.pdf
	2. “Survey Reveals that Blockchain Will be Adopted Within Five Years,” 

, June 26, 2017.
	3. Center for Supply Chain Studies, 

. 
	4. A. Shanley, “Conference Finds Blockchain is Still Years Away from Use in Pharma,” 

, July 14, 2017.
	5. R. Nagpal, “17 Blockchain Platforms-a Brief Introduction,” 

	When referring to this article, please cite it as A. Shanley, "Could Blockchain Improve Pharmaceutical Supply Chain Security?," 

Articles

Advanced digital ledger technologies offer potential solutions, but are still several years away from practical use.

Could Blockchain Improve Pharmaceutical  Supply Chain Security?

The contract development and manufacturing organization (CDMO) Aesica Pharmaceuticals has had a serialization program in place for the past five years, and recently installed capabilities for serialization at all its packaging facilities. As operations director Catherine Kay notes, customer readiness varies widely, and working with smaller virtual pharma and small-to-mid-sized pharma companies can be challenging, especially since some have not yet formulated strategies or implementation plans.  The company recently designated a new staff position at its UK facility, expressly to help improve communications with customers and knowledge transfer.

	The company has also been installing aggregation capability at its facilities. Ms. Kay recently brought 

 What do you think of the FDA’s recent postponement of the Drug Supply Chain Safety Act’s (DSCSA) serialization enforcement?

 In some ways, the news came as a bit of a surprise. Serialization efforts have been going on for quite a few years, and, at many industry events, the message was repeated that the date had been set. But I guess that regulators realized that many smaller and virtual companies aren’t ready yet.

 As a CDMO, what have you seen as the greatest challenges in setting up a serialization program for clients that is flexible enough to handle diverse client needs, yet rigorous and deep enough to work for different national requirements?

 Our large pharma clients have been very organized in specifying the scope of their serialization projects, defining what they want, and how they want to provide numbers and receive data, as well as what the trigger points should be for receiving data. When we began our serialization journey five years ago, we found that this group of customers was ahead of the regulations. 

	It has been challenging, however, to gain engagement from some of our smaller to medium, and virtual pharma clients, for products that we already package for them for the EU market, and to understand the scope of their requirements. Some clients have not fully mapped out their processes and requirements, for example, the optimal format for transmitting and receiving data. To push those thought processes, we have developed standard templates and share with them what we can provide so that we can then work with them to arrive at that detailed scope of supply.

	The other challenge is determining the trigger points for when the data need to be transmitted.  Some smaller clients want to receive serial numbers at the point of shipping and others at the point of QC and product release. It’s the marketing authorization holder’s responsibility to ensure that those numbers are transmitted to the regulatory authority, but we are doing all we can to support them so that they meet these requirements.

  Have you launched any new initiatives within the past year?

  We have been working on serialization for a number of years. Most recently, we made a conscious decision to make sure that all of our sites are serialization ready. We felt that we needed to be prepared for where the market is going. Our lines can also aggregate to the shipper and the pallet level. Some of that has been driven by our larger pharma companies, and aggregation is now seen as a key enabler to the future of track and trace.

 Do you find yourself educating clients on best practices?

 Experts at the site level are sharing knowledge, especially with smaller pharma clients. At our UK facility in Queensborough, for example, we created a new position: client implementation manager for serialization, to work with clients, aid with engagement, and share information proactively. We see client education as a key part of our role.

 Do you offer clients a ‘quick compliance’ option?

 We don’t have an accelerated program but we can offer some quick solutions such as printing cartons and labels off line and verifying them during the packaging process. What we can achieve when we take this approach depends on the scale of customer requirements and whether changes are needed to the artwork, which, depending on the market, could need approval. Timelines can be challenging, but delivering rapid solutions can be achieved by working in true partnership, in which both parties have clarity on requirements and activities. 

  What will happen to firms that continue to put off serialization?  

 I find it difficult to believe that some people still aren’t taking this seriously, certainly within the EU, where regulators have made it quite clear that you won’t be able to sell a product without a product identifier after the 2019 deadline. This requirement has been out there for such a long time that I can’t see the deadline being extended. People have to look at investing, and examining the options available to meet that need. Whether pharmacies will be ready at the point of dispensing remains an open question, but manufacturers will have to do this or they won’t be able to sell products, and CDMOs won’t be able to offer services if they don’t support compliance. 

 What types of IT solutions are you working with? 

 We use different solutions, depending on the site. In the UK, for example, we partner with TraceLink, using its cloud-based solution. In Germany we have a partnership with Avarto, to use a data management system that links into the SAP system and then, through an interface, into our customers’ IT systems, so we have experience with different systems.

	When referring to this article, please cite it as A. Shanley, "Serialization at Aesica: An Interview with Catherine Kay, Operations Director," 

The contract development and manufacturing organization (CDMO) Aesica Pharmaceuticals has had a serialization program in place for the past five years, and recently installed capabilities for serialization at all its packaging facilities.

Serialization at Aesica: An Interview with Catherine Kay, Operations Director

	Digital ledger technology (DLT), or “blockchain,” the digital ledger system behind the digital currency, bitcoin, is being applied in a number of industries, including finance and insurance, to ensure security and establish provenance.  Advocates believe that it could solve a number of pharma’s supply chain problems, as well as broader healthcare issues (e.g. secure transmission of sensitive patient data and clinical information).

	Not only could the use of blockchain establish that a given pharmaceutical is authentic, it could provide assurance that the patient whose physician prescribed that medicine, actually took the prescribed dose. This would be important in assessing patient outcomes, which, in turn, would help determine physician reimbursement, and, in value-based contracts, pharmaceutical company payments.

	As the technology becomes better known in pharma circles, a number of potential applications for it are being explored, as 

of 120 life sciences executives found that 83% expect the technology to be adopted within five years. 

	On June 6, 2017 at Johns Hopkins University in Maryland, a conference focused exclusively on blockchain and its potential in pharma and healthcare.  Sponsored by the Institute of Electrical and Electronics Engineers (IEEE), the event featured speakers from one biopharmaceutical company, industry coalitions, academia, vendors and consultants.  This serves as a brief summary of the program.

	Amgen’s senior manager of supply chain, Ashish Srivastava and David Mahlum, director of new innovation and technology at the company opened the program with the question:  Is blockchain a pipe dream or the right fit for pharm?  The consensus is that the technology is definitely promising, but likely a decade away from taking any real shape in pharma and life sciences.

	They pointed out the technology’s ability to build trust, based on the fact that it has been designed to prevent hacking, and the fact that it allows transactions to be audited and traced.  They also noted its potential to improve collaboration with business partners and suppliers, and to increase inventory visibility. They see it as being a “foundational technology,” but, like other such technologies (notably, the Internet, which took 20 years to become the pervasive medium it is today), it will take time to be established and is still in the very early stages.  Using 

, they see blockchain in pharma getting closer to the peak of “inflated expectations,” and, thus, is probably five to ten years away from becoming a force to reckon with.  As they noted, comparing its evolution with that of the Internet, “the TCP/IP moment for blockchain has not arrived yet.”

	Ken Cottrill, cofounder of Chain Business Insights, discussed “smart contracts,” invented in the 1990s, which feature software on a blockchain that defines agreement terms and execution clearly and could lower costs, help protect both parties against fraud, and offer enhanced connectivity to the Internet of Things.

	IBM and a partner in China have already launched 

a blockchain-based platform involving hospitals and pharmaceutical retainers, to provide financial services for pharmaceutical procurement.

 This solution was designed to speed up payments. Companies in China can otherwise wait for payment after shipping their product, or buyers can be prevented from acquiring products due to credit issues.  

	At the conference, Cottrill discussed a case study in which two banks and a shipper handled cotton shipments to China, in which blockchain and smart contracts were used. The setup involved blockchain, smart contracts, and an Internet of Things sensor, and validated the concept for other transactions, he said.

	Other speakers discussed specific applications being discussed in healthcare, and in pharma supply chain management, 

	Speakers suggested that industry professionals learn more about the technology, and connect with blockchain industry focus groups to learn more about whether, or how, it might benefit day to day operations.  The Center for Supply Chain Studies in Chicago is currently doing 

, focusing on how blockchain might fit in with pharmaceutical supply chain management and with traceability and compliance with the US Drug Supply Chain Security Act. 

A June conference at Johns Hopkins examined the potential for digital ledgers and smart contracts in pharma and healthcare

Conference Finds That Blockchain Is Still Years Away From Use in Pharma

	In June, some who have been working (or even simply observing) the pharma industry for a while had to feel a sense of 

Lawrence Yu and Michael Kopcha’s “The Future of Pharmaceutical Quality and the Path to Get There” 

	The spirit of the paper resembled that of publications from the early 2000s, when FDA’s Office of Pharmaceutical Sciences, led by Ajaz Hussain, brought the work of Deming, and concepts like process analytical technology, into mainstream pharma’s vocabulary. FDA openly invited experts from other industries to present best practices at science board meetings, discussed at industry meetings how pharma could develop supplier quality management systems like the automotive industry's, and often asked why manufacturing had to be the industry’s “stepchild” function. 

	Over ten years later, some might argue, little has changed.  The industry remains at 2 to 3 sigma quality levels (308,537 defects per million opportunities for 2 sigma, compared with 3.4 defects per million for 6 sigma, as defined in the paper).  While the quality of new drugs has improved, shortages and recalls continue to be seen, particularly for legacy products, and, for many drug companies, manufacturing is far less important than clinical goals, evidenced by the number of complete response letters, 483s and Warning Letters that FDA presents manufacturers with each year.

	However, pharma’s future will be Six Sigma, the authors state, as the industry moves from management- to performance-based regulation, and toward specifications that are based on clinically relevant goals. Currently, it relies on a combination of the two approaches, with management-based approaches still required for more complex products.

	The paper reaffirms the mission statements articulated over 10 years by CDER Director Janet Woodcock, and touches on all the programs and concepts that the agency has advanced over the years to help modernize manufacturing and quality:  PAT, quality by design (QbD) and its core concepts, emerging technologies (including continuous manufacturing as well as automated processes), the need to reduce variability, and the idea of continuous improvement and operational excellence.

	It also brings up the need for companies to establish a “culture of quality,” and all that it entails, from senior management commitment to operator engagement.

	These changes still seem extremely ambitious, especially since product complexity and production targets have increased so dramatically for most pharmaceutical manufacturers over the past 10 years, but some progress is being made.  One area where more active exploration is occurring is in continuous manufacturing.  Once considered only for new products, continuous is also being adopted for legacy products, for APIs, and in biopharma. At the very least, more unit operations are being run continuously, and a growing number of generics companies are being sold on its ability to reduce the cost of goods sold. FDA has been collaborating on pilot projects to study continuous processing and the challenges it presents.

	On a broader level, the Agency has also instituted some important changes, with relatively little fanfare.  In May 2017, for example, with its 

 FDA’s Office of Regulatory Affairs realigned staff so that inspectors specialize in one area, e.g. food, pharmaceuticals, biologics, devices, instead of trying to do everything. This simple change promises to bring specialized skills to individuals within each group, to improve communication and coordination of efforts, and, in the future, should result in faster and more systematic and objective inspections, and, to throw the term back at the regulators, less variability.

	In 2014, the Agency also established an 

to advise companies and colleagues within FDA. Senior science policy advisor Tara Gooen Bizjack

 as a small cross functional group with representation from all relevant CDER review and inspection programs.  It aims to support adoption of innovative technology to modernize drug development and manufacturing in cases where the FDA has limited review or inspection experience in that field.

	In addition, FDA has been steadily increasing its recruitment of chemical engineers, an important minority in the industry workforce that will be crucial to getting more drug manufacturers to embrace different methodologies.  Yu, who has a chemical engineering degree and studied with Hussain, is one example of a new FDA leader, with chemical engineering background rather than the traditional MD degree.  Like his mentor, he brings an academic (rather than a hard-boiled industrial) background, and some of the idealism that presents, to FDA.

	Yu's and Kopcha's paper presents a look back and acknowledgement of the foundations set in the past, while outlining the challenges to come in redefining quality in more modern terms. Pharma’s journey to the long-awaited “desired state” may not prove easy or fast, but at least it is under way.

 will look at some of the obstacles to modernizing and improving drug manufacturing and how they are being overcome, both by drug manufacturers and the regulatory community.

A recent paper coauthored by FDA’s Lawrence Yu and Michael Kopcha describes how the industry might modernize drug manufacturing.

Will the Pharmaceutical Industry Ever Get to Six Sigma?

	A growing number of companies around the world are using continuous processes to make small-molecule APIs. “There’s more potential for continuous with APIs, just from a cost standpoint, than for drug product,” says Kevin Nepveux, vice-president of global technology services at Pfizer, which is taking a hybrid, or case-by-case approach to continuous API and oral solid dosage (OSD) form manufacturing.

	“There is a lot of value to using continuous to telescope API steps and replace traditional steps that are bottlenecks or safety risks,” he says. “And you can do a lot of chemistry in flow cells that you wouldn’t want to do in a batch environment, just for safety and process control reasons.” One application would be flow hydrogenation for catalytic hydrogenations, while opportunities also exist in continuous crystallization and drying, he says. 

	The need for safer API production is driving demand for industrial-scale continuous chemical reactors, says Yi Jiang, global business director, Corning Reactor Technologies, which has developed continuous Advanced Flow Reactor (AFR) products for use in API and fine-chemical manufacturing. 

	Corning began developing the technology in 2002 and has improved it, Jiang says, to the point where, compared with traditional batch reactors, AFR reactors can enable at least 100 times enhancement in mixing and 1000 times improvement in heat transfer performance, allowing operating cost reductions of 30-40%. “Continuous flow technology has redefined reactor productivity,” says Jiang, “so that it is no longer based on volume of output, but on how effectively the chemical is processed.” Continuous also speeds up and simplifies API scale up, just as it does for OSD.

Corning’s AFR has been recognized as an inherently safer technology (IST), says Jiang, and Corning has been seeing increased demand for the technology, particularly in China. The Chinese government has mandated increased chemical reactor safety since 2016, when a major explosion at one facility in Tianjin killed more than 160 people.

	Recent years have seen growing worldwide demand for industrial-scale APR equipment, says Jiang. In October 2016, the API manufacturer Angelini Pharma, installed an industrial-scale AFR reactor at its facility in Aprilia, Italy (1). Demand is particularly strong in India and China, which are producing more of the world’s APIs. AFR is installed at the top 10 API manufacturers’ facilities in India, says Jiang. “There is a clear need for inherently safer technology which will continue to drive growth, but in a greener way that reduces environmental impact,” Jiang says.

	Could end-to-end take off in developing markets?

	Where integrated facilities might not always make economic sense in the United States and Western Europe, there are questions about whether end-to-end continuous processing facilities might take off in developing markets. A number of countries are requiring that more drug substance be developed onshore and integrated with drug product manufacturing.

	Dave Di Prospero, director of pharmaceutical process technology at CRB USA and cofounder of the International Society of Pharmaceutical Engineers (ISPE)’s OSD Community of Practice, recalls Kalbio Medika, an Indonesian company that won honorable mention at ISPE’s 2017 Facility of the Year awards program for its new biopharma API facility (1). Even though the facility manufactures biopharmaceuticals and is not completely continuous, the reasons for its design reflect Indonesia’s goals to have more of its pharmaceutical supply chain located on shore. Indonesia manufactures 70% of its fiinished drugs, but still imports 90% of raw materials, and the government wants its drug manufacturers to make more ingredients onshore, says Di Prospero. 

	When referring to this article, please cite it as A. Shanley, “Continuous API Manufacturing,” 

Industrial-scale continuous API manufacturing may offer cost and safety benefits.

Continuous API Manufacturing

	One challenge that continuous processing faces is the difficulties of developing real-time alternatives to dissolution that would allow real-time release testing (RTRT), promised years ago by FDA’s process analytical technology (PAT) initiative, to be used with continuous manufacturing.

	Progress has been made for more straightforward products, and Janssen Pharma is expected to file a post-approval change including RTRT for its continuous facility in Puerto Rico, according to Doug Hausner, associate director of the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), which helped Janssen develop the approach.

	“The industry has made progress in developing process models, establishing a foundation for inputs and outputs to the system, understanding what needs to be controlled and modeling that,” says Hausner. “Manufacturers have also gained an understanding of how PAT fits into that picture, how much time you have to make a certain measurement and where that information needs to go.” Without a model for dissolution, however, you may be doing quality assurance (QA) online, but you aren’t truly releasing product in the regulatory sense, he says.

	Currently, the only method widely applied in dissolution testing is the offline laboratory-based method of dissolving samples in heated, agitated liquid baths and drawing samples for spectral transmission analysis, says Chris O’Callaghan, senior product manager at Innopharma Technology, which develops near infra-red (NIR) PAT and visualization systems.

	Innopharma has been collaborating with Glatt and other technology vendors who work in the continuous processing space to develop models that would enable real-time prediction of the release profile of a coated multiparticulate material in controlled-release formulas (1). The company is now working to improve and expand its predictive model, says O’Callaghan (

	“As a method, dissolution is right up there with reading the entrails of goats,” says NIR spectroscopist Emil Ciurczak, principal of Doramax Consulting. “We want to know whether a tablet or capsule will break if moisture changes and whether it will extract and be available to the body. There’s a very tenuous dotted line between releasing in a 900-mL flask and blood levels. The testing is clinically done once, but they don’t really know, if after six months or a year if it changes, short of doing clinical studies on older batches,” he says.

While a clear need exists for an in-line real-time alternative to this method, development in the field has been limited, says O’Callaghan. The physical and chemical interactions governing the in-vitro dissolution process are highly complex and cannot be easily modeled from first principles based on the product data that are available inline, or accelerated in a way to make the testing applicable in-line, he says.

	This leaves model-based prediction of dissolution performance based on measurable process parameters and critical quality attributes (CQAs) as the only possible real-time method available. Approaches using spectrometry or particle size have been discussed, but haven’t yet been widely adopted, due in part to the difficulty of modeling.

	“The effects of multiple key processing parameters on the relationship between coating thickness and release profile are being studied in order to develop a more comprehensive dissolution prediction mechanism,” he says, noting that this would be a key control element for a new self-guided coating control system that the company is now developing. “The coating’s aim is to reduce waste and improve the speed in manufacturing of modified release products by aiding to maintain an optimal coating trajectory and rapid determination of the process end-point, with the ultimate goal of enabling true real-time release,” says O’ Callahan.

	The next stage of evolution will see pharma adopting advanced manufacturing techniques, for both batch and continuous, says Ian Jones, Innopharma’s CEO. “When we talk about advanced manufacturing, we think of the Industrial Internet of Things (IoT), Industry 4.0, machine-to-machine connectivity, and the adoption of artificial intelligence philosophies. All of these components can be used to develop and manufacture formulations in a more rapid, lean, and safe manner,” he says.

	“In order for there to be a real opportunity for real-time release to be realized, these PAT techniques need to be combined with control models thereby enabling predictive control of these dynamic batch and continuous processes,” Jones says.

	The company is now working to develop self-guided granulation and coating, and demonstrating their potential use in ‘hands off’ manufacturing at the company’s pilot plant in Dublin. “We can track CQAs of the process using our PAT tools, track and control the process in accordance with a model and activate the phase changes and endpoint based on our tools and models, monitoring progress from a mobile phone in real time,” says Jones.

	On a more basic level, for RTRT to take shape throughout pharma, the industry will have to change the way it views control. “Manufacturers have to understand that the process signature is key, and not the measurements and numbers you got out of the operation. Process signature shows that process is where it belongs, and that’s where RTRT comes in,” says Russ Somma, principal of Sommatech Consulting, noting that some companies are already at this point. “When they aren’t, it’s often because quality organizations are not comfortable with that approach,” he says.

	Where dissolution testing is concerned, Somma worries about whether it will be used for process control, or for the patient. “In the end, the therapeutic window on a particular compound could be a lot wider, based on pharmacokinetics, than dissolution allows, and dissolution may have no direct relevance on effect, if, for example, the drug is very soluble,” Somma says.

	With a poorly absorbed compound, however, the problem becomes more complex. “Until we get in-vitro in-vivo correlation really working well, we still have a lot of work to do,” he says.

Predicting Multiparticulate Dissolution in Real Time for Modified and Extended Release Formulations

, 2017 Solid Dosage Supplement, April 2017.

	When referring to this article, please cite it as A. Shanley, “Moving Toward Real-Time Release Testing,” 

Real-time alternatives to dissolution testing are required for continuous manufacturing to reach mainstream use.