Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

The past five years have been troubled ones for sterile injectables manufacturing, with key players and contract manufacturers jumping ship, facilities being shut down, and shortages of critical drugs and cancer therapies ensuing.

	During this period, companies including Teva, Ben Venue, Hospira, SCM Pharma, and Aesica Pharma have either shut down major facilities or left the market entirely, citing high costs and inadequate funding. BenVenue, which went out of business in 2014, spent more than $350 million to improve its facility in Ohio after receiving an FDA warning letter, but still expected financial losses of $700 million through 2020 had it stayed in business. Hospira spent $375 million in improvements after its Clayton and Rocky Mount, NC plants were cited by FDA, but still decided to close Clayton. Now the company is being acquired by Pfizer.

	New companies, including BioTechnique and Symbiosis, are entering niche parts of the business, and AMRI bought OsoBio’s business in 2014. Mistakes and compliance slips have brought new attention to what is needed for compliance. In addition, equipment is now available to automate more of the processes and offer features such as process analytical technology (PAT) to improve quality. What will be needed to invigorate sterile manufacturing? Industry associations, particularly Parenteral Drug Assocation (PDA) and International Society of Pharmaceutical Engineers (ISPE), are examining these issues as they connect to infrastructure and product scarcity.

	Experts in the field-James Agalloco, principal consultant, Agalloco and Associates, Inc.; Jacques Navellou, co-founder of Axys Network; and Victor Lee, vice-president of business development at BioTechnique-shared insights and views with Pharmaceutical Technology on the status of the market and needed steps to make corrections in business operations.

: What has the industry learned from all these issues with sterile injectables? Are conditions improving?

: Employees are aging and people are retiring, so there is less mentoring going on, and less talent available. We had a headcount cut 20 years ago and we’re finally feeling the effects of it, because there is nobody left around to keep things going. Companies are running without sufficient technical knowledge.

: The problem with outsourcing is that, when you outsource, you need two people who know what they’re doing: one on the inside, and one on the outside.

: Have companies gotten better at contract manufacturing organization (CMO) oversight in this area?

: I think that the problem again is headcount. CMOs want to operate lean. They are not overstaffed, and the processes have not gotten any simpler in the past 20 years. They’ve gotten harder, and we don’t have the knowledge on the CMO side or even the sponsor side to really cover this. We’re doing a good job on the development side, to develop products, but when you bring any new product into a commercial setting, there are all kinds of perturbations that can happen, for instance, changes in materials, in scale of equipment, analytical methods. It’s not as simple as it was years ago. It now requires more, and we don’t have the people.

: Has there been improvement in spite of these challenges?

: Very few CMOs have really invested in top-of-the art technology. There are a couple that are trying to get there, but it’s difficult for them. Many of the CMO facilities that we see are older. They’re the original innovator plants that were sold off or declared excess. If you’re a major pharma company, you don’t sell your best plants, you sell your oldest ones. So the buyers end up with less satisfactory operations, weaker utilities, less infrastructure, older equipment. It all contributes to the trouble.

: What types of investments did the industry make in equipment and training after so many FDA warning letters were issued?

: Basically, a lot of bandaging was done, and fixing what is here because it is much harder to anticipate and build new and start fresh, which is what should have been done. Today, so many CMOs and generics companies are using older plants. There is a need to invest, but the economic incentive is gone.

	I’m very worried. Think about biosimilars. It’s great that all these sophisticated products will now be less expensive, but it will effectively start another race to the bottom, as we saw with generics. It may take another 10 to 15 years to get there, but, again, we will be chasing lower and lower cost without the knowledge and ability to deliver the consistent quality that we should have.

	The answer to quality is simple, to me: Having enough qualified people, having the ability and willingness to invest in technology. Consider the smart phone. Electronics manufacturers invested in that. Where is the comparable investment in pharma? Who is challenging the system and saying, ‘We should have better equipment and more reliable controls and instant feedback from our systems.’ Instead we are satisfied with quality that is, at best, mediocre.

	We need to rethink our whole philosophy. Is quality about meeting the spec or the test or eliminating defects and reducing variance so we can reduce the testing and improve the reliability of the output? We give lip service to quality, but it’s all about bandaging and fixing and documenting, not about really making the process more reliable and more robust so that the output is better and always meets the needs of patients.

: Regulatory agencies help in pointing out problems. They make it clear there’s something wrong. But they are not helping with reviews and institutionalized checks and balances. The time required to get an abbreviated new drug application (ANDA) approved is abysmal.

	But if I say that I have a great way to improve the way I make a product, which will need new equipment, or a new test method, another submission will be needed, and it will take months or years to get an answer. No wonder people just say ‘why bother?’

: Is regulation in sterile processing excessive, and is it really based on science?

: Today, some folks yell about objectionable microorganisms. In the past two to three years, the National Institutes of Health (NIH) funded the Human Microbiome project, sending researchers to do studies, and found that 30% of humans on the planet have staph in their nose. Now I’m going to tell you that you can’t make a tablet that contains trace levels of staph even though 30% of the patients already have it. Who are we protecting and what are we protecting them from?

	Maybe FDA’s expectations are too stringent. In some cases, they may be pushing for things that don’t add value to patients.

: Where are you seeing innovation in sterile processing equipment?

: The equipment side is the only place we’re seeing innovation. Vendors have come up with equipment that provides more feedback, that compresses and contains at the same time, that features PAT. But it comes at a price. Typically, companies opt to use the older equipment that has already been paid for. New technology is only being used for new products.

	There have been some stumbles, for example with restricted access barrier systems (RABS), which got a lot of hype in the late 1990s and early 2000s. Now, more people are seeing that isolators are more cost-effective.

	If I’ve spent $100 million on a RABS facility, am I going to tear it down and use isolators? I’ll keep going. If manufacturers had made a better decision 12 years ago, we might see more isolator facilities.

: What are the biggest lessons that the industry has to learn, apart from the need to invest?

: We have to invest in our people first. That’s the key more than anything else. The idea that we can make these really complex products without really well trained and well-qualified people and enough of them is a mistake. We need headcount. Companies in Korea, Japan, Taiwan, and Singapore are moving ahead of us because they are investing in humans and in technology.

: How do we solve the problems you’ve cited?

	Agalloco: Industry doesn’t know how to fix what’s wrong. I can see why CMOs are desirable and why they are not going away, but our industry has effectively sacrificed its current products for its future ones. Manufacturing has become a backwater in our industry. It’s something we have to have, but we just aren’t good at it anymore.

	Recently, a major company recalled sodium chloride for particles. We’re talking about water and salt. How easy can it be? That’s the saddest part of all: apart from the complex compounds, many of the generics on the shortage list are very simple to make.

	PDA and ISPE are trumpeting their drug shortage action programs. Why isn’t PhRMA getting involved in some kind of consortium? Why aren’t they looking at the root cause?


	Victor Lee is vice-president of business development at BioTechnique, a cytotoxic sterile injectables contract manufacturer (CMO) that recently bought a fill-finish facility in Madison, WI from the Wisconsin Alumni Research Foundation. Lee shares a CMO’s perspective with Pharmaceutical Technology.

: What lessons has the industry learned from events in the sterile injectables space over the past few years?

: There is no straightforward answer. Within the past 5 years, there seemed to be more emphasis on enforcement of regulations and rules at FDA, and we saw an increase in 483s, warning letters, and consent decrees. Several factors were at play with selective budgetary spending being a major culprit. In the world of generics, margins are very tight, so cost control is a main driver.

	The FDA warning letters pointed out weak quality systems and staffing issues, perhaps because people who are multitasking and overwhelmed are more likely to make mistakes. Also, the degree of microbial contamination reflects the amount of time a company has devoted up front to make its processes as robust as possible.

: Have you seen any improvement in the way sterile manufacturing facilities are run since these problems surfaced?

: In 2010, I worked at Teva when the facility received a warning letter. We had to go through a major process to get back into compliance. During remediation we stopped manufacturing, which resulted in exacerbating certain drug shortages.

	More facilities recognize that people are the number one source of contamination, and FDA has encouraged industry to automate as much as possible, so there has been an uptick in the design and use of isolators, disposable process equipment, and the development of rapid microbial monitoring systems.

	The pharma industry is typically a slow adopter of new technologies, but with isolators and restricted access barrier systems (RABS), early adopters proved to the rest of the industry that new technology is not all that intimidating. But it did take years, and that is how it is with any new technology in the pharma industry.

: What should one be aware of when working with sterile injectable CMOs?
	

: CMOs are typically working in multiproduct facilities. That’s how they generate margins and revenue. So it is essential to ensure that there is no crossover contamination. Cleaning validation has to be robust. This is one reason more people are using single-use technology.

: Have design changes in isolators and RABS made them easier to use or more cost effective?

: Basic isolators and RABS haven’t changed much over the past five to 10 years, but there have been incremental improvements in automation. Within the past two to three years, there has been an increase in multipurpose design, using equipment within the isolator that is multipurpose and can handle various processes. Instead of building separate lines, companies can now use one machine; one day, it can be used to fill syringes, another day, bags, and another day, vials.

Communication, and the sharing of new ideas, needed


	Jacques Navellou, co-founder of Axys Network, aseptic processing consultants, discussess progress in technology, and the need for improved industry/regulator communication, with Pharmaceutical Technology.

: What positive changes have you seen in sterile manufacturing over the past five years?

: The most important changes have been driven by improvement of the sterility assurance level, including best aseptic practices, better operator training in microbiology and practices, barrier technology design, and automation. The fewer people you have making the product, the less contamination you will have.

	Other technology has been validated that will improve quality, including single-use technology, aseptic connectors and tubing, environmental monitoring technologies, and improved sterilization processes, such as pascalization. Regulations are also being improved, on a continuous basis, as evidenced by the European Medicines Agency’s Annex 1.

: What will be needed for the future to maintain progress and prevent the supply shortages and other problems we’ve seen over the past five years?

: We need to see continuous interaction between industry, regulatory agencies, and vendors through technical meetings and working groups, in which they can share their experiences. We also need to work on the concept of parametric release to a point where we won’t need to do traditional sterility testing.

Pharmaceutical Technology Outsourcing Resources Supplement

 When referring to this article, please cite it as A. Shanley, " Industry Viewpoints: Can Sterile Manufacturing Turn the Ship Around?" 

Pharmaceutical Technology Outsourcing Resources Supplement 

Articles

Within the past few years, key players have left the sterile manufacturing business. Can new technology and investment revitalize this critical market?

Industry Viewpoints: Can Sterile Manufacturing Turn the Ship Around?

Repurposing drugs-redeveloping drugs that have already been approved for one use, for another-has been going on for decades. Pfizer’s Viagra was originally developed to treat high blood pressure and angina; Celgene redeveloped the infamous teratogen thalidomide, as a treatment for leprosy and multiple -myeloma.

	In the past, repurposing efforts were usually ad hocor the results of serendipity. Within the past few years, as the cost and time required for coming up with new drugs has risen to new heights, efforts are becoming more systematic and focused. In addition, more companies are exploring the development of repurposed drugs via the 505(b)(2) pathway of the US Food, Drug, and Cosmetic Act, and orphan drug indications.

	A number of companies, including S M Bioech (Barcelona, Spain) and Biovista (Charlottesville, VA), are focusing on drug repurposing, using 

 and animal studies to evaluate potential candidates. In addition, patient groups and nonprofits, notably Chicago-based Cures Within Reach, are working with medical researchers on key projects.

	In the United Kingdom, HealX matches potential repositioning targets to rare diseases. The company recently set up the Cambridge Rare Diseases network to advance this work. Transparency Life Sciences, which calls itself an “open innovation” company is working to crowdsource repurposed drug projects.

	The only way to make a connection between a potential candidate for repurposing, and applications, is by checking the patent literature and data. A number of commercial da-tabases are available, in addition to databases on patented drugs. Consultant Hermann Mucke, based in Vienna, Austria, is a specialist in drug repurposing. He is currently developing the Discontinued Drug and Candidate Database (DDCD) as a reference tool to facilitate the identification of potential repurposing candidates.

	The DDCD uses information going back to the early 1990s, and includes data on APIs discontinued from development or pulled from the market. In addition to chemical structure, international non-proprietary names (INN) and/or research codes, pharmacological activities, key literature, and patent references, the database contains developer statements and analyst assessments. Currently, Mucke’s H.M. Pharma Consultancy is using the database as an internal tool, but he hopes to secure funding to develop and publish the database-ideally, as an open-access tool that would facilitate drug repurposing. Mucke recently shared his insights into repurposed medicines with 

: How did you get into the field of repurposed medicine?

: I have been in the field since long before the term ‘drug repurposing’ was even used. I was involved in the repurposing of galantamine, a drug originally sold in Eastern Europe in the 1950s and 1960s to treat myopathy. The drug also inhibited cholinesterase, which made it an interesting candidate for repurposing when the cholinergic hypothesis of Alzheimer’s disease was advanced in the 1980s. It was only available in small quantities and was very expensive. Eventually, Janssen Pharmaceuticals launched it as Reminyl (later, Razadyne), a treatment for Alzheimer’s disease, in 2000.

: How large is the potential market for repurposed drugs? Has anyone come up with an estimate?

: It’s very difficult to attach a monetary size or market volume/ unit volume to repurposing. My impression, however, is that the market could grow by a factor of 10 without a problem within the next decade. We are going to see developments that we can’t even imagine now. I’d say that, taken altogether, perhaps 10% of the entire pharmaceutical market is in some way related to repurposing.

: How do you find potential candidates for repurposing? What data are already out there?

: There are some good subscription databases, such as those offered by Thompson Reuters and GVK Biosciences, which leverage these companies’ huge data pools for repurposing. H.M. Pharma Consultancy approaches the challenge bottom-up. We are trying to develop a database that would theoretically look at each and every compound that has been reported on. Right now, we have a few hundred core compounds with structures, activities, and research and development history summarized and annotated. We’re using it internally now, and haven’t begun the programming and development work.

: What is the general process, at the start, for repurposing a drug?

: You have the basic strategy of looking for candidates, you have the structure of the molecule, and you build on structural and pharmacological similarities and use your knowledge about biological and biochemical pathways and their interconnections to see where you might pitch your candidate. You try to achieve something that hasn’t been recorded for this particular drug.

	You have to be a clever pharmacologist and connect the dots in new ways. Very often, you just try to think of a new application where you know that the known pharmacological activity should be of some use.

	Repurposing drugs is a universe unto itself, and we have barely scratched its surface. There are enough APIs, in theory, for many, many years, if not decades. This is why repurposing has become such an important strategy in drug development.

: What role do contract research organizations (CROs) and contract manufacturing organizations (CMOs) play in drug repurposing? Are there any new business models that you are seeing in CMOs that work in this area?

: Right now, I think the potential of CROs in drug repurposing is not sufficiently well utilized, which is a shame.

: So, how would a contract services partner fit in?

: With drug repurposing, you have a different starting point than you do for new drug entities, one that calls for a stronger partnership between sponsor and CRO.

	Of course, you can just ask for specific studies from different contract companies and choose the least expensive one. A better strategy is to find a CRO or CMO with a clear understanding of what you want to do and make that company your partner.

	You will want to change the route of administration, or at least the presentation, to prevent cross prescription problems. In most cases, you switch to a new target population, and you don’t know what the acceptable dose is. This is what CROs and CMOs do best.

	CROs’ expertise could be much better utilized if repurposing projects could be treated as true joint development projects, particularly if the repurposing company is a university institute, or a newly established academic spin-off.

: What mistakes are typically made in drug repurposing projects?

: The most important thing to realize is that repurposing a drug does not automatically make its development cheaper or quicker. It reduces risk of failure because the drug has already been investigated, or even approved, in humans. You are not starting from ground zero.

: Where do you see outsourcing service companies working in in repurposing, in the future?

: Many CROs have picked up on the repurposing trend, but they are not typically the largest ones. They are well acquainted with life science aspects of repurposing, from discovery to animal testing and clinical trials. Generally, they are also experienced with regulatory issues. In most cases, however, they are not familiar with the challenges of patenting.

	Questions to ask are: what sort of timeline can you offer? Will this project follow the 505(b)(2) pathway? Will it be for an orphan drug project? You should also know the people at regulatory agencies who have worked on cases like this in the past. Before considering all this, however, you must establish that the patent situation allows, not only for freedom to operate, but also to develop any new intellectual property.

	On the clinical trial side, you might run into some of the same problems that you would have with a new drug, even if you know the mechanism and what the acceptable dose in healthy humans is.

	In theory, you should be able to start at Phase I/II, but you will typically change the route for administration, which will require a new formulation. In any case, you’ll also be targeting a new patient population, which could have quite different pharmacokinetics and pharmacodynamics (PK/PD properties) when compared to the population for which the original drug was first investigated. You must be prepared for surprises all the way along. In the end, it is still less risky to do than a new chemical entity (NCE), but it is not, a priori, cheaper or quicker.

: Is there an issue globally with different regulations?

: Not really. Much has been harmonized. There are two basic ways for repurposing a drug that have been approved, 505(b)(2) in the US, or the hybrid application in Europe. There are some differences between these two approaches, but they share many characteristics, so you can often request a common review, which may involve a few additional studies.

	Also, if the compound had never been approved before, there is no longer a significant difference between Europe and the US, although I don’t know about Japan.

: What business models are you seeing, and where do you see innovation on the business side?

: Smaller companies often work the classical NCE strategy: to develop the drug candidate to the point where they have the greatest leverage they can manage financially (i.e., to the conclusion of Phase II). Then they can try to outlicense it.

	This approach requires high capital investment, but it is still manageable to work with a CRO to get to Phase II. Unless they are working towards an orphan indication, or perhaps a tropical disease where the World Health Organization (WHO) might help with financing, they will not advance to Phase III.

	Another small-company strategy is to work in silico, to develop unique algorithms and run them against compounds with known structures. They can then work with a CRO to try to substantiate these initial in-silico hits in animal studies. This approach doesn’t require much investment, but doesn’t provide much leverage either.

	And then there are those who work with Big Data--they mine the literature, patents, and side effect data to identify potential repurposing candidates. If you are with a large pharma company, you might want to repurpose your own universe of unexplored compounds. Big Pharna has the patents, undisclosed test results, and the expertise.

	So, unless you are with Big Pharma the options are not so different from what you would have with a NCE: -identify and sell early-stage repurposing candidates, or push the work to clinical proof-of-principle, and then attempt to out-license it, perhaps to the original developer.

: Are foundations showing any interest in repurposing drugs?

: There is Cures Within Reach, a foundation that is focused on drug repurposing. There are also companies such as Transparency Life Sciences, that try to crowdsource drug repurposing, or just put out a repurposing idea and see what creative life-science people can contribute. This approach, however, requires settling any unresolved patent problems early.

: Are there any particular therapeutic areas where you’re seeing a lot of potential for repurposing?

: There are several hot spots, including tropical and orphan diseases, because these are relatively neglected fields where a project can be advanced to initial stages without investing too heavily. These would include malaria, West Nile, and the Coronavirus.

	In more conventional applications, a big area would be in neurology, the next most popular would be cardiovascular drugs. Any neglected diseases would also be a ripe area for focus.

: When referring to this article, please cite it as A. Shanley, " Recovering the Value of Repurposed Drugs,

" Pharmaceutical Technology Outsourcing Resources Supplement

Currently, pharma has only scratched the surface of the potential value of repurposing drugs, says consultant Hermann Mucke. Contract service partners are playing a more prominent role, but could play an even larger one in these efforts.

Recovering the Value of Repurposed Drugs

As concerns about drug product safety have increased, national governments worldwide have been setting deadlines for implementing traceability and tracking of pharmaceutical products.  Requirements vary, with many countries requiring a GS-2-compliant solution and 2-D barcoding. The US deadline is now just a little more than two years away. Yet, consultants say not all pharmaceutical companies are prepared. 

	At a time when more of them are outsourcing key functions in manufacturing and packaging, many pharmaceutical manufacturers are not involving their contract development and manufacturing partners (CDMOs/CMOs) in planning and implementation. Some consultants have guessed that manufacturers may be counting on the deadline for serialization to be postponed, because the last time a major serialization deadline was set, by the California Board of Pharmacies, it wound up being pushed back three times.

	Assuming that the 2017 deadline is elastic would be a serious mistake, consultants warn. Developing a workable strategy will require top-down support from senior management, buy-in from operators and the ground floor, and a cross-functional approach.

	Especially important are the program charter, the establishment of a steering committee involving all disciplines that will be affected by serialization changes, and strong user requirement specifications (URS) with technology vendors, according to Steve Peterson, project manager with CRB Consulting Engineers. Peterson, who has worked on serialization projects with pharma companies of all sizes, shared advice and best practices with 

: What are the biggest issues that sponsors and CMOs need to keep in mind when working on serialization through the lifecycle of this type of project? 

: The biggest issue that we see right now is one of, I wouldn’t call it nonchalance, but inactivity. If any manufacturers or CMOs have not started the gap assessment process, then they are way behind. This process requires studying the equipment and infrastructure they have now, and the processes in place, how well they work, and comparing each of them to where they will need to be, not only for the 2017 but the 2023 requirement.

	As the deadline approaches, available resources will become extremely scarce, both from consultants, vendors, and even within their own companies. Equipment deliveries are up, stretching out for the next six months, and we’re not even into the heat of the installation and procurement period yet. 

	There is too much focus on November 2017, in isolation.  In reality, one needs to back that date up by six months, give or take, to take Murphy’s Law into account, because things never go exactly as planned. We’re more than halfway through 2015, so there are only 24 months left, realistically. Every bit of that time will be taken up by IT infrastructure, equipment purchasing, design, validation, and startup.

: So how do you develop a strategy?  What do pharmaceutical sponsors need to do, and how should CMOs work on their own strategies, since they have so many customers in different therapeutic areas and parts of the world?

: The first thing that any owner company needs to do is to understand the work streams within its own operations, to get down to the SKU level and to understand where each of those products go and where the data come from. They also need a thorough understanding of the types of equipment that are online, what type of print technology is being used.

	Serialization offers an opportunity for people to look at their operations and processes, and ask what else they can do to offset the efficiency losses that will result from changes to the lines for serialization. The same applies for CMOs. They have the additional challenge of needing to maximize flexibility, because they are going to be receiving data and different requirements from different owners. Understanding their processes comes first, so that, when owners come to them with their different requirements, they can communicate clearly. 

: At the INTERPHEX conference in New York City last spring, you told the story of a six-month pilot project taking 18 months. Is that time frame typical? What are the typical reasons for time, scope, and cost creep?

: I would love to say that there is a perfect project management process, but there isn’t. Because these types of projects are so new and so extensive, initially many people have a mindset of ‘all you have to do is put a code on a bottle.’ Then they miss things.

	Yes, at the end of the process, one must put a code on a bottle, but there is a need to take a step back and consider the much bigger picture. Where are those numbers coming from?  From another software package?  Where does that software reside, onsite or in the cloud?  What types of IT systems does the company have, and what types of backup and recovery systems?

	It is also important to consider potential changes when you are dealing with vendors and setting up user requirement specifications (URS).  The other thing that most companies don’t take into consideration is the impact that work on serialization will have across the entire organization. 

	With a typical packaging line, you inspect the equipment, procure it, install it, and start it up.  For this type of project, you are going to have an impact on regulatory and legal departments, and on your labeling systems. You may be changing artwork on your unit labels. You may be changing labels on cases and even pallets.  You’re changing standard operating procedures (SOPs) for your operations, and changing the fundamental operating line.  

	Questions come up such as, ‘When can they take bottles off the line?’ or ‘How does quality control take a case out of the pallet to run tests on it?  When do you release pallets?’

	It’s all-encompassing, not just a simple coding project out on the manufacturing plant floor.  Success comes back to understanding your systems now and what you need to do, whether that means adding fields in master data for exemptions or determining why you are, or aren’t, coding.  It’s much bigger than most people start out thinking.

: How do you ensure cross-functional input? 

: You need to have buy-in from senior management, and their commitment to having a steering committee for the project that represents all the key functional departments within the organization--not just engineering, but regulatory, legal, operations, and manufacturing, CMOs. They all must be represented there. 

: How do you engage people on the plant floor?

: The sooner you do this, the better. If you do not engage them, if you don’t ask for their reality check on your plans and ideas, you will see a real, negative impact on your line efficiency. 

	The most important thing to communicate to them is the reason why serialization is being undertaken in the first place.  Once they understand that the project will help preserve the integrity of medicines and the supply chain, they are usually very supportive. They’ve also told us that ideas we thought were great, weren’t. ‘Why don’t you do it that way, instead?’  It’s important to listen to them. 

: These projects are costly. How do you discuss return on investment (ROI), if you need additional senior management support?

: Some people understand numbers, others need key performance indicators, but the lifeblood of any company is being able to distribute and sell its products. If they’re not ready in time, they won’t be able to ship products. Executives cannot afford to see serialization as just an engineering issue, but a total company issue.

	ROI is difficult to quantify, and with any serialization program, you are going to take a hit, economically. But efforts highlight areas for improvement. For instance, as a result of serialization work, one company replaced two slower and less efficient lines with one brand new line. Is that due specifically to serialization?  Maybe not, but by looking at their strategic long-term plan, they were able to see opportunities to improve efficiencies.

 When referring to this article, please cite it as A. Shanley, " Serialization: Are You Prepared? Why this time is different," 

Sponsors and contract partners alike should not assume that upcoming US federal deadlines will be as elastic as California’s were.

Serialization: Are You Prepared?  Why This Time is Different

	As the time and investment required to develop new therapies continues to climb, a strategy that has been around for some time is gaining momentum: repurposing APIs that have been discontinued or abandoned, and developing them for new indications. Examples include Pfizer’s Viagra, which was originally developed to treat angina and hypertension, and Celgene’s thalidomid, a treatment for leprosy and multiple myeloma that repurposed thalidomide, a morning sickness treatment that was found to cause birth defects and banned.

	Driving renewed interest is, not only competitive pressure, but the rise of patient activism, as well as the benefits offered by orphan drug filings and the 505(b)(2) approval pathway in the U.S.

	Currently, between 5–10% of the pharmaceutical market is connected to repurposed active ingredients, and the industry has “barely scratched the surface” of its potential, according to Hermann Mucke, a consultant based in Vienna, Austria, who has specialized in repurposing, and was involved in repurposing galanthamine, a plant-based drug that had been sold in Eastern Europe decades ago as a treatment for myopathy, and eventually was commercialized by Janssen as an Alzheimer’s disease therapy.

	The challenge is knowing what to develop and where to find it. For individual companies, that means being able to find what Kevin Rivette, founder and CEO of the IP asset management firm, Aurigin Systems, Inc., called “Rembrandts in the Attic.”

	There is a huge amount of data available in the public domain, but mining it is “backbreaking,” says Mucke, who is editor of a new journal, Drug Repurposing, Rescue and Repositioning, which is being published semi-annually as part of the peer-reviewed Assay and Drug Development Technologies. The publication covers in-silico techniques for identifying potential targets, data mining, reformulation and new delivery modes, and other topics.

	Mucke has also been hard at work at the Discontinued Drug and Candidate Database (DDCD) as a reference tool to facilitate the identification of potential repurposing candidates.

	The database contains information on 100 compounds so far, going back to the early 1990s, with data on APIs discontinued from development, or pulled from the market. In addition to chemical structure, INN names and/or research codes, pharmacological activities, key literature and patent references, the database contains developer statements and analyst assessments.

	Currently, Mucke is using it as an internal tool, but he hopes to secure funding to develop and publish the database, ideally, as an open access tool that would facilitate drug repurposing.

	Repurposing requires a mix of scientific knowledge and intuitive sense. “You have to be a clever pharmacologist, use your knowledge to connect the dots in new ways. Very often in part of repurposing you just try find a new application where you know that the known pharmacological activity should be of some use. Then you must project that there is another pharmacological activity, direct or indirect, that hasn’t been reported yet, that you can take advantage of. You can work from your own data, or from data that you mine from larger resource, patent literature,” Mucke says.

	There are also legal considerations, as addressed in 

	Not only economic reasons, but patient-centered strategies, could motivate more repurposing of drugs. The practice puts patent extension in a very different light from the typical “me too” and evergreenining strategies that have been seen in pharma. 

 is crowdsourcing potential repurposing research projects, which could result in more commercial projects.

	In Cambridge, UK, a recent startup called 

 is using advanced informatics to mine pharma's IP for potential cures for rare diseases, and establishing links with key patient groups. 

	If these efforts are not in the mainstream right now, continued competitive pressures may make this standard practice in the near future. Trillions of dollars have been spent to develop these discontinued compounds. Why not get the most out of that investment?  

	The process is not exactly a slam dunk, but eliminates a great deal of the risk that traditional drug development requires.  For an interview with Mucke, stay tuned to PharmTech’s August Outsourcing Supplement, which will be out soon. 

Competitive pressures are driving more companies to repurpose APIs that had originally been developed for other indications. The industry has only "scratched the surface" of what might be possible, says consultant Hermann Mucke

Needle in the Haystack, or Rembrandt in the Attic? Drug Repurposing's New Strategy

birthday of Nigeria’s anti-counterfeiting pioneer Dora Akunyili today,

 came news of another fake drug reaching African supply channels, this time in central Africa.

	The World Health Organization reported (in 

) that tablets of counterfeit diazepam had surfaced in the Democratic Republic of Congo, in Central Africa. The tablets did not contain the active ingredient at all, but rather, 10-20 mg of haloperidol, an antipsychotic drug often used to treat schizophrenia.  The drug can cause dystonic reactions in the face, neck and tongue, and would pose danger if administered to children.

	 Ms. Akunyili, a pharmacist and former director general of Nigeria’s FDA-equivalent, the National Agency for Food and Drug Administration and Control (NAFDAC), had put her life on the line for years to protect the safety of that nation’s pharmaceutical supply. 

	She died last year, but her example and hard line against counterfeiters spurred other African nations to take action. It also revealed the ugly, mob-run nexus of the fake pharma market, not only in Africa but around the world. It is amazing how little we know about it, and, despite increased access to inexpensive advanced analytics technology and interpretive software, how ill-equipped we are to deal with it.   

	The counterfeiters, as usual, preyed on consumer confusion and trust, including the names of two manufacturers, and even stamping the bottles in red type “Government of Uganda, For Public Use Only. ”

	The fakes were found in two forms, one sold as Solina, with a batch number of SBG038 and an expiration date of August 2017, and the other as Diazpam, Batch #2332 with an expiration date of October 2016.  Tablets, meanwhile, were printed with the name of a drug manufacturer, AGOG, that does not manufacture diazepam, and containers of the drug both referenced the manufacturer CENTAUR, which manufacturers diazepam but not halperidol. 

	Although progress is slow in understanding the scope of the world’s drug counterfeiting and substandard and tampered drug presence, important research is under way that promises to strengthen enforcement efforts and public outreach and education programs.

	Late last year, researchers looked into the need for better public outreach and education on the potential risks of taking any medication (including substandard and potentially counterfeited or adulterated drugs), 

published last December by University of Maryland economics professor Ginger Zhe Jin focused on differentiating between substandard and counterfeit drugs, drawing attention to a paper that will soon be published in the 

Journal of Economics and Management Strategy.  

	These studies may be limited by academic budgets but they are critical to improving our understanding of the size of the global counterfeit and substandard/adulterated drug problem, and to refining distinctions between problems that share common characteristics.  The key will be focusing on chemical content, since API loading is the best way to distinguish between drugs that were intentionally adulterated or counterfeit, and shoddy, substandard drugs reflecting inadequate cGMP compliance.

	Only by understanding what we are up against can we come up with comprehensive solutions for regulation, enforcement, public outreach and use of modern analytics and technology.

Important research is under way that will help us understand the extent of the presence of substandard, adulterated and counterfeit drugs around the world, and, thus, strengthen enforcement efforts and public outreach programs. Future studies will focus on the API and overall chemical content

Understanding the Extent of the Counterfeit and Substandard Drug Problem

leaning is such a basic concept that it may be difficult to view scientifically, but getting it right, and validating the approach taken, is critical to patient safety and drug quality. Some pharmaceutical manufacturers may still approach cleaning validation in a somewhat random way, using imprecise and outdated methods.

	Andrew Walsh, principal and owner of the PharmaClean Group, LLC and an industry professor in Stevens Institute of Technology’s Pharmaceutical Manufacturing and Engineering program, has been an outspoken advocate of changing the status quo. He urges pharmaceutical industry professionals to apply risk-based principles and science, and concepts such as Lean Six Sigma and Process Analytical Technology (PAT) to their cleaning validation programs. 

	Walsh led the global multidisciplinary team that drafted the science, risk and statistics-based Cleaning Process Development and Validation for ISPE (1).

 spoke with Walsh about the guidance, which is expected to be published in 2015.

 What’s wrong with the idea of limits, as they’re currently defined and used by pharmaceutical manufacturers?

 First, companies are applying them inconsistently. Back in 1992, the Pharmaceutical Manufacturers Association (now PhRMA) surveyed industry professionals and found that they were using 44 different criteria, based either on dose (e.g., 1/10th of a therapeutic dose or 1/1000th of the lowest dose, or 1/50th of the maximum therapeutic dose), or on default limits (e.g., no greater than 1 ppm or 3 ppm) (2).

	Fourteen years later, the Parenteral Drug Association (PDA) surveyed its members and found the same disparity in practice, with respondents using dose-based only, or a combination of dose-based and default. Most used 1/1000th as the dose limit and a majority used 10 ppm as the default limit.  

	But the limits themselves are inconsistent. In some cases (for some compounds and at some facilities), these limits will leave large amounts of API residue, and in others, small amounts nearly impossible to measure. The 10 ppm default was added to account for this problem, but this value is arbitrary and some companies even have trouble meeting it.

 Do dose-based and default cleaning validation limits differentiate between compounds, based on potential risk to the patient or operator?

 The current method of limit setting is not science-based. Some manufacturers will take the lowest dose of any given API or drug, divide by a thousand, and set limits based on the results, even though they may not really be safe.

	Most of the time, however, the limits are set too low, so that cleaning validation runs fail when there really is no need and the residue levels present absolutely no risk to the patient.

	But setting cleaning validation limits is a big deal.  The industry has set them incorrectly for years, using reverse logic. That’s why the ISPE publication is so important, especially the sections dealing with statistical analysis. Also important are the concept of measuring the level of risk through process capability.

	Today, many manufacturers use an acceptable daily exposure limit of 1/1000th but that fails to take into account potential product risk.  As a result, a 1/1000th limit set for low-dose aspirin is much lower than the limits that have been set for some drugs with potentially teratogenic or immunogenic effects.  

	The pharmaceutical industry is unique in that it has an enormous amount of data on its compounds available from toxicological and clinical studies and these can be used to set appropriate limits for patient exposure. So it’s important to have a toxicologist and pharma manufacturing professionals work together on setting limits based on real risks and plant floor realities, and not just by simply taking a dose and dividing it by a number.

	Concepts from ICH Q9 and ISPE’s RiskMaPP guide will also be very important in setting science-based limits for API and detergent residue.

 Should toxicologists be working more closely with manufacturing and quality teams at pharma companies?

 At some companies, they already are, but other manufacturers are not using their expertise enough. I would like to see a closer connection between Toxicology departments and QA and validation.

	Pharmaceutical toxicologists are mainly PhDs, and tend to be a tightly knit group. Many have known each other for decades. They actually all meet once a year, and have done a lot of work on how to set limits, but they tend to publish in their own specialized journals, which does not get the message out to the rest of the industry.

	Generally, toxicologists are getting more closely involved in GMP issues today, but more of them need to be given the GMP perspective, and some better understanding of how the GMP world works, from people in that world.  A cross-functional perspective will be very important in many situations, for example, in setting limits for early discovery compounds. 

Scientific approach to cleaning validation

 Are more companies embracing the more scientific approach to cleaning validation?

 I see it starting to happen.  I also see a move to risk-based tools using statistics, and drawing from the FDA’s revised process validation guidance. But I also feel that many workers don’t have a strong mastery of statistics or a clear understanding of risk and how to measure it, and are reluctant to revise their standard operating procedures (SOPs).

 What role do you see Lean Six Sigma playing in cleaning validation and cleaning?

 Lean Six Sigma concepts are very applicable to cleaning validation; so applicable that the original name for my company was ‘Clean6Sigma’ and we even trademarked and use the term.

	The key goals for Lean Six Sigma are eliminating waste and reducing variability, and that can apply to cleaning validation and cleaning, too. More manufacturers need to ask themselves such questions as ‘Why are we rinsing for 15 minutes?’  

	I have made Value Stream Maps of cleaning processes, and there is clearly a lot of wasted time and water in most cleaning processes. For example, why should a procedure take an hour when it could easily be done in two minutes? Many companies are discovering that capacity issues are closely tied to cleaning, so there is a real need to shorten cycle times, but it can be challenging, since it requires revalidation.

 What role could process analytical technology (PAT) play in cleaning validation, and cleaning in general?

 PAT has a lot of potential.  We have been doing some work with GE Analytical Instruments (Sievers) in the area of total organic carbon (TOC) measurement, using their portable system. This way, instead of taking swab samples to the lab, you take the lab to the line. With their instrument, there is a real promise of parametric release of equipment after cleaning, and this is one of the goals of the ISPE guide.

 What other analytical techniques should be used to improve cleaning validation?

 High-pressure liquid chromatography is commonly used and also a good tool, but so is simple visual inspection in low- to moderate-risk situations. We are working with companies right now on a simple, cost effective program using standard coupons for qualifying operators to release equipment visually.  TOC, conductivity, and visual inspection used together in a comprehensive program could save pharmaceutical manufacturers a lot of time.  

	There is a definite need to move away from the old ‘three batches’ and dose-based approach, towards continuous monitoring where necessary. TOC, conductivity, and visual inspection will help lead the way.

An ISPE guidance document, four years in the making, brings risk-based thinking, statistics, and Lean Six Sigma to cleaning validation.