Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

 of 2007 and 2008? Batches of the workhorse blood thinner supplied by Baxter were found to be contaminated with a synthetic chemical, overly sulfated chondroitin sulfate (OSCS), from a Chinese API supplier. More than 140 patients injected with the contaminated material died. FDA and other regulators launched an investigation, and the US Pharmacopeia and FDA approved analytical methods for assuring legitimacy of material.

	More than anything, the case revealed a new pattern for crime: economically-motivated adulteration of APIs and drugs. Instead of greedy thugs or ignorant traders using the wrong material, the perpetrators had a sophisticated knowledge of chemistry and analytics.

	The case also revealed the need for faster regulatory action, improved communication between different branches of FDA, more collaboration with regulatory authorities outside of the US, and greater vigilance within the industry.

	Today, even drug manufacturers with more advanced supply chain management programs in place admit to being able to see only a few levels down into their supply chains. Complex supply chains involving spot buys of raw materials are extremely hard to control.

	At the same time, the US is sourcing most of its APIs and ingredients from a country that is known as source of illegal counterfeit drugs. The potential for cases like this to recur seems almost limitless.

	Eight years after the heparin recall, there is no room for complacency about the safety of the US (or global) heparin supply. 

sent to FDA Commissioner Robert Califf on March 29, 2016, by US Representatives Fred Upton and Frank Pallone, points out reasons and asks some difficult questions.

	Most significantly, the letter says, the identities of the perpetrators in the first heparin recall remain unknown, although ample evidence was available to help nail them. “Loopholes and exemptions that permit part of the Chinese drug supply chain to operate without outside government scrutiny still remain,” the representatives wrote. 

	Illustrating this sense of entitlement most dramatically was a situation in 2014, mentioned in the representatives’ letter, which involved the heparin API supplier, Beijing Shunxin Meihua Biotech Co. Ltd. Ultimately, the company received a warning letter from FDA, but initially, staff at the factory did not allow FDA inspectors onto the production area or permit them to access inventory records. 

	Eventually, inspectors found that the address for one of Shunxin’s heparin suppliers was identical to that of a heparin supplier that had been put on FDA’s Import Alert list. They also found that crude heparin processed at the facility contained ungulate (i.e., goat or sheep) DNA.

	Another problem pointed out in the letter was the failure of different divisions within FDA to work together and collaborate fully on the case. (Coincidentally, FDA’s 

 this week underscores the need for teamwork at the Agency).


	As the letter explains, FDA’s Center for Drug Evaluation and Research (CDER) and its Office of Criminal Investigations (OCI) failed to communicate or to hand off investigative work as they should have. 

	For instance, the company that sent the problematic API to Baxter, Changzhou Scientific Protein Labs, maintained traceability records for each individual lot of crude heparin. Maintained on spreadsheets, this information would have allowed crude lots to be traced back to individual suppliers back in 2008, the letter explains. However, the OCI did not use the information in its official report, or make it available to CDER at the time, the representatives say.

	After requesting the information separately, CDER received it in 2012 and acted on it, but the companies involved had continued to supply the US market during the four intervening years, the letter says.

	In addition, the representatives say, FDA did not follow up with another “respected government agency” from another country, which had found that the two crude heparin suppliers in China had a less-than-transparent relationship, which, for example, allowed one to export heparin under the other’s label, the letter says, even though the company on the label had not manufactured it.

	This government agency had also found that the owner of one of the companies admitted to falsifying test results, the letter says, and the agency had also found inconsistencies in batch numbering, as well as information and signatures on certificates of analysis.

	The company's owner reportedly admitted to using an unregistered company in Shandong to make crude heparin, some of which was sold to Italy. He was also said to display an “unusually profound and extensive knowledge of modern testing methods (for a trader),” the letter says. Ultimately the agency described the company and owner as untrustworthy, but FDA did not investigate these claims in sufficient depth, the representatives say.


	The letter also faults FDA for failing to respond to evidence that more Chinese suppliers have been using non-porcine materials, derived from cows, goats, and sheep, to manufacture crude heparin. Use of non-porcine derivatives can have an impact on final product efficacy, but beef products in particular present a potential risk of contamination that could cause mad cow disease. 

	As the representatives point out in their letter, there is little known in China about the risk of mad cow disease, and, until 2015, the Chinese Pharmacopeia permitted the use of bovine materials to manufacture heparin. A common practice in China, the letter says, has been to mix porcine derivatives with those from other animals.

Weak quality management systems and traceability


	And, as the letter points out, in December 2015, French regulators found that heparin supplied by Dongying Tiandog Pharma company in China, contained sheep DNA. Weak quality management systems could not provide traceability to the original source of materials.

	Beyond concerns about source, there are concerns that suppliers in China have been stockpiling heparin contaminated with OSCS, treating it and releasing it into the supply chain, the letter says, faulting FDA for failing to investigate this possibility. 

	On a fundamental level, the letter blames FDA for failing to take into account basic supply and demand within China. According to the representatives’ research, the amount of heparin that China exported could not have been made with the number of pigs available. Back in 2008, there was a shortfall of 100 million pigs, the letter says, and similar gaps were likely for each of the subsequent years, raising concerns that illegal methods are being used to make up for the deficit.

	The letter heightens concerns about the quality and safety of offshore materials and gaps in the industry’s and regulators’ ability to keep up with a massive challenge, and a moving target. FDA officials have said that they will respond formally and follow up directly with the Representatives. Please let us know what you think.

Articles

Unsafe material may remain in the US supply chain, according to a March 29th letter to FDA Commissioner Califf

U.S. Representatives Question the Safety of the Heparin Supply

	The Drug, Chemical, and Allied Trade (DCAT) Association’s annual meeting and conference program in March 2016, featured the usual look at trends driving global markets and innovation. Speakers examined macroeconomics, R&D focus, and the impact that value-based medicine, pricing, and payer models can be expected to have on drug development and manufacturing.

	Leading speakers on the program was IMS Health’s economist Graham Lewis, who channeled Christopher Lloyd’s character, Dr. Emmett Brown, from the film “Back to the Future,” with his talk. It was entitled “Confounding expectations: How pharma reinvented innovation and turned the world on its head.”

	Lewis challenged analysts who pronounced that pharma’s blockbuster business model was dead. High-volume products remain important to the top 20 pharma companies, he said, and last year, just over half of the industry’s sales came from blockbusters.

	“Many of you depend on scale, and revenues from scale,” he told the audience. Of the new chemical entities (NCEs) introduced between 2010 and 2014, he said, eight products were worth more than a billion dollars and one, more than 12 billion dollars.

	Five of the top 10 pharmaceutical companies currently derive more than 30% of their revenue from one therapy area, he said, with 15% of Pfizer’s revenues from central nervous system (CNS) therapies, 21% of Novartis’ revenues from oncologics, 34% of Sanofi’s revenues from diabetes, and 20% of Teva’s revenues from therapies for multiple sclerosis (MS).

	Lewis also questioned whether value-based medicine is limiting innovation. Citing Sovaldi (Gilead) as a case in point, and “only the first of several potential tsunamis to affect the market,” he noted that “The market will accept higher prices if the innovation is there.”

	Overall, the global pharmaceuticals market is growing by 4–7% overall, and should reach $1.3 trillion in 2019, Lewis says. 

	The number of new active substances has been increasing since 1996, and will reach record levels between 2016 and 2020, Lewis said, with 225 expected to be launched between 2016 and 2020, a return to higher levels seen from 1996 to 2000, when 223 were launched, and a dramatic increase from levels in 2006–2010, when 146 were launched. 

	Currently Lewis said, the US dominates launch of NCEs; between 2010 and 2014, pharmaceutical companies in the US launched 121 new chemical entities, with German companies launching 92, UK firms 83, and Japanese companies 67. 

	Three-quarters of new drugs focus on five therapeutic areas: hepatitis, diabetes, oncology, anticoagulants, and autoimmune therapies. As payers try to reduce drug spending and make it more effective, they are also having a problem finding money for all the areas where innovation is coming through,” Lewis said.

	For manufacturers, in turn, value-based medicine has made it more difficult to have a sustainable innovation model, Lewis said, and companies are feeling the pressure. Some major employers, such as Coca-Cola, have launched pilot programs designed to reduce spending on prescription drugs. 

	Intensifying the value-based medicine debate, especially in the oncology field, have been independent groups such as:

		The Institute for Clinical and Economic Review (ICER), which has developed benchmarks for value-based pricing for expensive drugs (and recently released 

 proposes that cancer drugs be priced based on efficacy, toxicity, novelty, R&D cost, disease rarity and disease burden

		The National Institute for Health and Clinical Excellence (NICE), which has introduced the 

 as a means of measuring a drug's value. 

	One of the most dramatic changes in recent years has been the growth of developed markets. “Resurgence of US growth (which in 2012, had been negative, Lewis said, for the first time in IMS’ 57-year history) is the most significant event of this decade,” Lewis said. The US should account for 45% of global growth through 2020, he said, and remain a top market for innovators, growing by more than 7% per year over the next five years, Lewis said.

	Growth in “pharmerging” markets, meanwhile, is slipping, he said. Ten to 15 years ago, many top pharma company CEOs saw all the growth in emerging markets and expected it to remain there. Over the past five years, Chinese annual pharma market growth, for example, has fallen from 17% to between 6% and 9%, Lewis says. It is likely to stay at these levels over the next five years, he adds, while the government sorts out problems such as its huge national debt.

	Pharmaceutical market growth in Brazil, meanwhile, has dropped from 12% per year to 2% per year, he said. Political, economic, and social problems have increased instability in the country and made it more difficult to forecast growth there, he added.

	Major companies have slowed or stopped investing in emerging markets, Lewis said, and some are asking whether they need to form new alliances in order to succeed, since local and regional players seem to be faring better than multinational players.

	Nevertheless, these markets remain extremely important, and should emerge stronger from their current challenges. By 2020, Lewis projects, China will account for 12% of the market, as much as the top five European markets. It will be the second largest pharmaceutical market in the world, followed by Japan.

	Not only specialties, but biologics are becoming a more significant part of the pipeline, and large molecule drugs account for roughly 24% of industry sales. In 2020, by which time many key biologics will lose patent protection, the top 10 pharmaceuticals will likely be biologics, Lewis said. 

	Large molecules make up the following percentages of each phase:

	US biosimilar players are leading in drug development, Lewis said, but markets such as South Korea are becoming important, since they offer tax benefits, and financial and other support.

	Oncology and autoimmune therapies are two important therapeutic areas for biosimilars. At this early stage, 35 biosimilars are in late-stage development (i.e., Phase III and Pre-Reg), Lewis said. Autoimmune therapy is generally an easier target for biosimilars, since oncology treatments usually require the use of combination drugs, he said. 

At DCAT 2016, IMS Health economist Graham Lewis noted that pharma is reliving trends last seen in the 1980s. Despite value-based medicine, he said, the blockbuster model is alive and well.

Who Says the Blockbuster is Dead?

	At a special biopharmaceutical manufacturing track at the 2016 Drug Chemicals and Allied Trades (DCAT) on March 16, 2016, Bill Downey, head of the market research firm, High Tech Business Decisions, shared results from its latest survey on the contract manufacturing of biopharmaceuticals.

	As he said, demand for outsourcing has been growing steadily, from $800 million in 1998, to $2.5 billion in 2014. It’s expected to reach $3.1 billion in 2016 and $4.1 billion by 2019, he said.

	Capacity is growing by about 7% per year, Downey said, and hit 1 million liters in 2015. Utilization rates have moved from 65% in 2011 to 72% in 2016, and should reach 75% in 208 and 76% the following year, based on a survey of contract manufacturing organizations (CMOs) using a weighted average response, Downey said.

	Development projects had declined from 2008 to 2011, but have since increased slightly. When only Phase I and Phase II projects are considered the number has been increasing by 25% since 2010. Companies with multiple sites devoted roughly 25% of their budgets to outsourcing last year, and expect that number to increase to 35% next year, Downey said.

	North America is the largest market for outsourced services, growing by 6% per year, but Europe os growing faster, at 40%.  The rest of the world, particularly Asian markets, may hold 10% of the market or less, but demand is doubling every year.

	Production has moved from 47% commercial in 2011 to 51% commercial in 2015, with Phase III moving from 23% to 24% over the same period and Phase I and II slipping slightly from 25% to 23% between 2011 and 2014, Downey said.

	When surveyed about the importance of biosimilars, 50% of CMOs saw this as an important area, with 17% describing it as very important. The remainder said it was not significant, but Downey expects that to change. As a percentage of revenue, half of the CMOs surveyed said biosimilars projects account for 10-20% of revenues, and 17% of CMOs said biosimilars represented over 25% of revenue in the past year. “Biosimilars may not have a huge impact right now, but, for some CMOs they are already a significant portion of their business,” said Downey.

	Interestingly, where 500 organizations now actively market themselves as pharmaceutical contract development and manufacturing organizations or contract manufacturing organizations (CDMOs or CMOs), Downey said, only 90 have large-molecule recombinant production capabilities.

At DCAT's annual meeting, Bill Downey, president of the market research firm High Tech Business Decisions, summarized results from its latest survey on biopharmaceutical outsourcing.

Biopharmaceutical Outsourcing Continues to Grow

As pharmaceutical manufacturers continue to outsource more manufacturing and quality functions to contract partners, the question of who owns final product quality has become more complex. In the end, the company marketing the product is responsible, but achieving that quality is increasingly becoming a joint responsibility involving contract partners.

	In 2015, FDA released draft guidance (1) that attempts to guide both sponsor companies and their partners in understanding the most important product quality metrics.  The goal behind the guidance is to help the agency schedule plant inspections based on risk, so that companies with the most rigorous quality-assurance (QA) metrics would be inspected less frequently than those with weaker quality systems. Another goal is to help FDA inspectors better understand, and take steps to help address, potential product shortages.

	The guidance would assess certain measurements as a baseline and consider data from both sponsor and contract labs and manufacturing organizations including the number of out-of-specification (OOS) results, the number of lot-release and stability tests, and whether annual product reviews are published on a timely basis.  

	FDA’s draft would also assess corporate commitment to quality by requiring that senior quality executives review and sign off on documentation, evaluating the effectiveness of the company’s corrective actions and preventive actions (CAPA) programs, and checking on how well it is using process capability analysis to look at critical product quality attributes.  

	Industry’s reaction to the draft guidance was strong and immediate, with some companies and trade groups voicing criticism and calling for revisions (2). For contract laboratories and sponsors alike, the draft guidance reaffirms basic benchmarks and offers new reasons to assess programs and interactions, and establish best practices.  

 interviewed quality assurance consultant Susan Schniepp, chair of the Parenteral Drug Association’s (PDA) regulatory affairs and quality advisory board, as well as Eurofins Lancaster Laboratories’ quality assurance specialists Art Pezzica, senior director of quality assurance, and Brittany Cloud, senior quality assurance specialist, for their views on best practices, as well as industry reaction to the draft guidance.  

 In its draft guidance on quality metrics, FDA seems to be focusing on the basics, such as OOS.  Without having sponsors micromanage their partners, what do you feel should be reported for optimal results and to justify a sponsor’s comfort with a contract laboratory?

 For contract laboratories, FDA is only looking for unconfirmed out-of-spec results, but there are other metrics that laboratories monitor that can provide a certain comfort level for sponsors. These might include operator errors, unconfirmed deviations, and misreported data. Data quality is very important. It’s our laboratory’s product.

 Quantitative data, such as invalidated OOS rates and CAPAs, are very important, but so is qualitative information. For instance, does your contract partner have any Six Sigma or Lean projects underway? These can speak volumes as to how far the company is willing to go to achieve continued excellence or success.  

	If a contract partner is making positive changes, how is it handling change control? Is it investing in improving infrastructure or adding new employees?  These questions provide insights into the overall quality culture of the firm, and go beyond the compliance statistics to give a picture of what is going on.

 CAPA has been a compliance challenge for many companies. Complexity would seem to increase with the number of functions being outsourced and the number of contract partners involved. How should concerns about CAPA influence reporting metrics?

 The key is having a dynamic and transparent relationship in which both partner and sponsor can speak openly. This involves not only reporting on open or completed CAPA items, but also looking at effectiveness trends to see whether any special programs and initiatives that the lab has established are actually working.

	It is also important to hold regular quality meetings with the client to review CAPA. These meetings allow the contract partner to develop best practices to address client issues, but also to learn from clients. In some cases, we’ve been able to implement some of our clients’ best internal and external audit practices to improve our overall quality assurance.

	Communication should be dynamic, and should go beyond merely reporting metrics.  Ideally, it becomes a fluent discussion that improves not just the way you operate your lab, but the overall relationship as well as the quality of the product that eventually reaches the consumer.

 With CAPAs, clients should share more information on their investigations with contract partners.  As a contract lab, you are typically just one part of a CAPA investigation. You run your tests and report results to the client, but you often don’t learn what the final results were. That information could be very helpful in improving your understanding of the client’s process and what can affect it. It would be helpful to have that information loop back, to help you improve your systems.

 Data integrity has been a crucial issue for manufacturers and their contract partners, and many contract partners are falling short of FDA’s expectations. How should contract labs and sponsors work together to ensure that requirements are being met?

 It’s crucial to have a strong validation program in place, and to focus on ethics and training. We know that we have good systems, but, due to the recent cases of insufficient data integrity affecting the industry, we recently formed a team to reassess our electronic systems. This team has implemented a risk-assessment program that is reviewing all our electronic data systems to identify any potential risks that might affect data integrity. Once the analysis is complete, we plan to focus on the top 20 potential risk areas and assess each electronic system for any potential risk to data integrity.

	We also have an ethics program in place and emphasize the importance of training. We make sure that our employees are fully aware that, while human error may occur, any attempt at falsification would be grounds for immediate dismissal.  It is essential for any contract lab to ensure that its employees divulge errors and strive to maintain the highest quality data results.

 Do you find that you have to work with clients to help them better understand data integrity requirements from global regulatory agencies, and the need to assess risks?

 I routinely host audits and have found the level of expertise varies among sponsors. Some clients are experts in this area and can share best practices with us. Others may know very little about regulators’ expectations for data integrity, while other clients are in between. Our job is to work with companies of all types to ensure that they understand requirements and can be comfortable with their data.

	When we work on product risk assessments with clients, we always share our standard operating procedures (SOPs) when that is requested, so that clients will know that we are following our procedures and policies.

	In some cases, we will even visit client sites to discuss our processes and how we incorporate quality into our data integrity systems. We have to take a holistic approach to meet the needs of all our clients, since they come from so many different areas of the business

 Do you see a lack of understanding of what documentation processes should be?

 Some clients may not understand differences between various regulatory agencies’ expectations. They may, for example, only want to follow FDA or European Medicines Agency (EMA) or, in the UK, the Medicines and Health Regulatory Agency (MHRA) guidance. In these cases, we must impress upon them the need to be ready on all fronts, and be ready to defend that position and our practices.

	Whenever a discrepancy comes up with a client, we need to triage it first and ask two crucial questions:  

		Could performing this function this way cause us to violate a regulatory requirement?  

		Would we be violating any of our own SOPs?

	If we can confidently say that we’re not failing on either front, then we are meeting the goals of that intended practice and procedure, and there is no need to change it.

 Clients should have a clear understanding of contract lab realities. A process that may work at a client’s manufacturing facility that is producing 10 or 20 products may be difficult to manage at a facility where thousands of different products are being tested using different analytical methods and test procedures.

	We always try to accommodate client requests, but we must also ask some hard questions:  Can we implement that process here and do it correctly all the time?  Does the change in process increase, even slightly, the potential of creating more errors? If so, we discuss our concerns with our customers.

	If the procedure or process will add value, but also add costs, is it a cost that all clients are willing to absorb, or will it be a single client-specific request? In the end, it is really a balancing act. We always need to assess the potential impact on our operations and whether it will add value. Managing client-specific requests will always make a project more difficult and add costs to our operation.

 How can both sides balance the need for maximum transparency with realistic expectations?

 We meet twice a year with some of our larger customers, and always include both of our quality departments, to discuss any issues that come up. For some clients, we’ll follow their OOS procedures instead of our own, but their request has to be reasonable, and involve something that we can be successful doing. Whenever differences of opinion come up, we discuss and resolve them.

 As a contractor, you’re often in a tough spot. This is especially evident with early reporting. You want to tell clients when numbers start trending in a certain way, to warn them, like Paul Revere, that something may start to go wrong.  

	However, in reality, when you do that, clients can overreact and take over, to a point where they can get in the way of root cause investigations and other lab work. Over time, if this keeps happening, a contract laboratory might not want to tell its clients about anything too early, before they have something concrete to report. But then, clients may be angry that they weren’t given advanced warning. It is definitely a difficult balancing act.

	You’re between the proverbial rock and a hard place.  I used to address this by calling clients and managing their expectations and fears with a ‘Don’t panic yet.’

 Transparency is so important to any contract lab-sponsor relationship. If a contractor is transparent and builds quality into its relationships with clients up front, clients tend to trust them. Having quality assurance involved, on both sides of the team, is very important, and this involvement is needed as early as possible.

	I do a lot of onboarding, and we tend to find that, when the quality assurance department is involved early and clients can put a face to a name, trust will be built and will make any challenges easier to manage if and when they come up. In this type of relationship, you can call or email each other at any time, even for things that may seem relatively trivial. Proactive communication can help avoid problems, and also clarify boundaries and prevent micromanagement.

 For any investigation that we do, we notify our clients within 24 hours. At that point, we are open to discussion, and we ask them to share additional inside knowledge about the product. We find that most clients are comfortable with this approach. At times, some have made unreasonable requests, but we’ve been able to rely on our knowledge of FDA and other regulatory agency requirements to enable open communication.

 Can you give any examples of unreasonable scope requests?

 Sometimes, we get test results that may not be what was expected, but still within specifications. The company may want us to invalidate the result, even though results were within specifications, and all method requirements were met.  In the end, we may agree that the result might be considered out of trend, but the data do not support invalidating the result.

 Some companies may try to set unreasonable expectations through quality agreements. For example, a company might require monthly metrics reporting of many different metrics, or dedicated QA personnel just for their investigations, as well as daily status reports on any investigations and CAPAs. Excessive levels of reporting and custom requests would have a negative impact on our operations without adding value for our clients.

 Are more pharmaceutical companies building IT connections to facilitate data reporting?

 With some larger companies, we record data and results directly into portions of their laboratory information management systems (LIMS).  A few companies may have special data acquisitions systems that they want us to use, so we’ll bring them onsite and work with them. We’ve even had clients recommend certain systems for instruments and equipment that we’ve brought online.  

	As a contract partner, flexibility in adapting to client needs is important to sustaining the relationship. We’re open to working with different data and IT systems.

 We offer our clients secure access to their data through our online portal, LabAccess.com, which provides a window into our LIMs, and scans and links raw data so that clients can see how all the data support the final COA report.  They receive a full data package, including any investigations related to the group of samples that was submitted for testing. Each client can only see its specific data. The software also allows us to control who receives the data, for instance, in cases where we may be working on multiple projects with different divisions of the same company, those data could be restricted to specific individuals from the different divisions.

	Some clients review all of the raw data. We use this system to provide companies the assurance that we’re showing them everything that we did. This is important for data integrity and compliance.

 Are you becoming more involved in customer operational excellence programs?  Do you have one in place at your company?

 Throughout the years, we’ve had a process improvement program, where anyone in the company can suggest lean or process improvement projects, which are taken on not just by management but by quality, data review, lab, document control, and other departments. Anyone can be involved in this program throughout the lifespan of a project.

	In one of our most effective recent projects, we renovated a raw material wet chemistry lab to reduce human error significantly. We like to share this information with our clients, because we feel that it enhances our relationship and improves the quality of the final products overall. Numbers alone don’t measure quality.

 Do you find that more of your pharma and biopharma customers have continuous improvement programs in place?

 A few of the larger companies do, but most do not, apart from executive-level programs. By definition, such programs don’t go into the trenches and ask the people working in the labs to suggest improvements.  

 You can’t manage what you don’t measure. Our QA department leaders meet with all department directors and managers to review all quality metrics.

	We ask them to come prepared to explain trends, whether positive or negative. This allows us to assess issues as well as solutions so that we can improve our processes.

	Currently, we do this quarterly for 18 different departments, analyzing a series of metrics such as OOS, report reprints, client complaints, and various other quality indicators. We find that the results are worth the investment in time and effort that this approach requires.  

	We have also just implemented a new quality program that we call ‘Integrated QA.’ We’ve hired and transferred QA people who will be physically located in technical departments so that they can observe operations and eliminate potential problems or errors.

	In the traditional approach, QA staff is in the office.  They perform audits and problems or issues are generally brought to them. We want to reverse this, so that QA goes to problems to help identify and prevent them. We also want to give our analysts guidance on how to document issues that might occur. In two years, when somebody looks at these data, they need to tell the entire story of how they were generated and any decisions that were made based on them. They need to be able to stand on their own.

Request for Quality Metrics Guidance For Industry

Draft Guidance (CDER, July 2015), accessed Jan. 19, 2015.
	2. R. Hernandez, “

Overwhelming Response from Industry on FDA’s Guidance on Quality Metrics

,” December 7, 2015, BioPharmInternational.com, online, accessed Jan. 19, 2015.

:
	When referring to this article, please cite it as A. Shanley, “Quality Metrics and Best Practices for Working with Contract Labs," 

Pharmaceutical Technology Partnerships in Outsourcing Supplement

Although final product quality is the responsibility of the marketing company, achieving quality is a joint responsibility involving contract partners.

Working with Contract Labs on CAPA and Quality Metrics

Shipping temperature-sensitive pharmaceuticals such as biological products, has never been easy. Today, changing global requirements and a more complex supply chain are driving more conservative approaches to temperature control. For products such as cell therapies and tissue culture, cryogenic shipping is now preferred.  Other biopharmaceuticals are being shipped at lower tempertures, and even small-molecule-based pharmaceuticals that might have been shipped at ambient temperatures a few years ago, must now be kept at controlled temperatures.

	Transport has become much more than simply moving product from one place to another.  It’s now being seen as a “mobile form of storage,” says Volker Kirschner, director of temperature control solutions for World Courier Management Co, part of Amerisource Bergen. This is especially true in Europe, he says, where the European Union (EU) began strengthening its good distribution practice (GDP) guidelines three years ago.

	Nothing can be taken for granted.  “From political unrest to pandemic concerns, the possibility of changes in shipping patterns and logistics strategies is quite real,” he says, and developing a global transport strategy has become more complex.

	Specialists in cold-chain shipment are responding to regulatory challenges and uncertainty by investing in new technology and IT, and strengthening partnerships with specialty logistics providers. For their pharmaceutical and biopharm customers, they caution, careful risk-assessment is the only way to avoid costly product shipment problems. Many are adding services and products to help make this task easier.  


	The most pronounced recent change in the cold-chain market has been more complex global regulations, from the EU’s GDP guidelines for pharmaceuticals to the Drug Supply Chain Security Act in the United States. “It can be difficult for companies, especially smaller ones, to know where to begin, and how to revamp compliance processes to stay ahead,” says Wanis Kabbaj, director of global healthcare strategy for UPS.

	Additional requirements (e.g., for controlled room temperature) have increased compliance challenges. Many drugs that were once shipped at ambient emperatures must now be shipped at 15°F to 25°C, increasing costs at a time when most pharmaceutical companies are trying to reduce logistic and supply chain operations budgets, says Ariette Van Strien, chief commercial officer at Marken Global Life Science Supply Chain Solutions, which specializes in cold chain and logistics.  

	Compliance has become especially challenging for clinical trial supply shipments, she says, noting that suppliers must scrutinize their global network, enhance tracking capabilities, and improve quality standards.

	Of utmost importance, says Kirschner, are quality management systems (QMS) and documentation, personnel and training, and risk management, especially regarding standard operating procedures (SOPs); facilities and storage requirements; and transport. “Quality departments within manufacturers’ supply-chain operations are gaining more and more influence,” he says, noting that regulatory agencies expect pharmaceutical manufacturers to take a risk-based approach and enforce audits and quality agreements.


	The most critical aspect to maintaining stability and integrity is choosing the most appropriate temperature conditions for the product and, consequently, the best packaging for maintaining those conditions, says Mark Sawicki, chief commercial officer at the cold chain specialist, Cryoport.

	A perfect example, Sawicki says, is the distribution of critical biomarker samples. Under currently accepted practice, these samples are shipped on dry ice. However, he notes, this shipping method has been connected with a 15-30% product compromise or failure rate. As a result, more companies are opting to use cryogenic temperatures to ship biomarkers, to help eliminate potential risks associated with transit times and temperature excursions.

	PCI Pharma Services, a diversified contract services firm that offers cold-chain expertise, has seen a dramatic increase in demand for storing product at ultra-low temperatures, from -40°C down to -196°C, and has adapted its products and services to focus on supporting these temperatures for storage, packaging and shipments, says Samantha James, associate director of clinical services.

	Pharmaceutical manufacturers need to conduct more critical, comprehensive shipping studies on all materials transported in support of a clinical program, says Sawicki, not only looking at sample failure but the impact of the selected transport medium on assay or product performance.

	“We consult with every client to select the best system and temperature-control solution, whether dry ice, liquid nitrogen, or phase-change materials (PCMs) to ship pharmaceutical products, diagnostic specimens, biotherapeutics, and tissue samples, says Van Strien.  

	Generally, the most crucial factors to consider include therapeutic indication, route, mode of transportation, and product sensitivity, she says. “Because a pharmaceutical’s stability is not always known in early trial phases, additional caution may be necessary, and protection for any changes in environmental conditions.”  

	Van Strien advocates developing a thorough risk assessment to help ensure product stability from origin to destination, including studies of the following:

		Potential risks and mitigation strategy

	For clinical products that are only available in small samples, incorrectly handled shipping and transportation can put millions or even billions of revenue dollars at risk by compromising clinical studies, potentially delaying product commercialization, notes Kirschner. When minimizing risk, it is important for manufacturers to consider the package type and choice of temperature-control mechanisms, environmental concerns, value of the ingredients in the product, temperature requirements and variables, and overall shipping costs.

	Suppliers need to master nontechnical issues as well, including local politics and security issues, especially when conducting clinical trials in new geographic markets. Proactive planning is required, Kirschner says, to help protect the integrity of products and, ultimately, the safety of patients who use those pharmaceuticals.

	Generally, he notes, up-to-date methods should be used to assess risk.  For example, he says, failure mode and effects analysis (FMEA) can be conducted, and risk priority numbers (RPNs) assigned, based on the probabilities and severities of certain adverse events occurring during transport.  These RPNs would help determine whether mitigation is required, and what type would work best for the specific product, market and application.

	Temperature is not the only variable to consider. Many pharmaceuticals and biopharma manufacturers require a great deal of stability protection from temperature, shock, vibration, humidity, and light, explains Kabbaj.  “Healthcare logistics has little room for error, so specialized packaging, advanced temperature and location monitoring leveraging global control towers, and in-transit intervention are all critical.”

	In addition, Kabbaj says, extended time in transit when product is being transported inland may expose the packaging to temperature fluctuations that increase risks. Ocean transportation risk factors include container placement on the vessel, sunlight exposure, container insulation, and dwell time on the dock -- all introducing additional packaging stressors.  

	He suggests that pharmaceutical manufacturing professionals take the following steps to ensure that they are covering all the bases required for risk mitigation:

Test packaging, including seals, for endurance, and put prototypes through compression, impact, vibration, temperature, humidity, and shock tests.

 Package optimization should include validation through design qualification, operational qualification, and performance qualification protocols.

Optimize packaging and transportation together.

 Do not develop a cold-chain solution sequentially with assumptions based on transportation, and then the transportation solution that comes with pack-out expiry. Pairing a lighter and cheaper cold-chain packaging with expedited air transportation, for example, may prove to be more effective than opting for a slower mode of transportation (e.g., ground shipping) with complex, heavy, and bulky packaging.

Innovate continually to create better efficiencies.

 Optimize the shipping carton, minimizing unused space, and select more precise packaging configurations.

	“Pharmaceutical manufacturers that do not continually review, evaluate and update packaging best practices leave themselves open to product risk and cost inefficiencies,” Kabbaj says. “Leave room for new ideas, material innovations, and new packaging manufacturers by engaging cold chain partners in a collaborative mode.”


	Cold-chain service providers have been developing new technologies to help pharmaceutical companies better manage risk and respond to problems.  “New requirements are driving developments in packaging and monitoring technologies,” says Kirschner.  As an example, he points to newer semi-active packaging technologies that allow for longer durations of temperature control with lighter materials that have less environmental impact.

	In addition, he says, passive packaging  solutions have been developed that can provide proven temperature control over long distances. Independent testing has shown these solutions to perform five to seven times more efficiently than semi-active solutions, he says. Kirschner also points to new phase-change materials (PCMs), comprised of paraffin or salt-based solutions, that allow for more precise temperature control to maintain product stability over long distances or through extreme climates.

	Many packaging manufacturers are now developing their own vacuum-insulated panel (VIP) containers, combined with PCM solutions, for easier handling and storage. Additionally, he says, on the monitoring side, developments in global positioning software (GPS) and tracking equipment now include automatic start-up and shutdown mechanisms that can provide a real-time view into a shipment’s status. Many technology providers have invested in real-time, GPS-enabled data loggers. Combined with improved data access, through customer portals and better IT, the technology offers immediate insights into bottlenecks and delays.


	“These data loggers provide the ability to track both condition and chain-of-custody, in real time,” says Sawicki.  They can track, not just temperature, but also monitor the impact of external influences on container integrity including orientation and package damage, he adds, and can also tell whether the container has been opened.

	Examples of new cold-chain data loggers include Sensitech’s TempTale and Nexleaf’s ColdTrace systems. Contract service suppliers are also offering enhanced IT connections. PCI Pharma Services, for instance, has developed a portal to allow clients to access real-time data, 24/7. “They can monitor stock levels, and view and trace all live shipments associated with their project, with direct links to courier tracking,” says James.

	Last year, Marken introduced Sentry, a GPS-enabled sensor platform, designed specifically for pharma with real-time track and trace capability through custom-designed software that monitors, records, and reports on location, temperature, motion, shock, exposure to light (i.e., when the box opens), atmospheric pressure, and remaining battery life. The device transmits in real time and communicates through customized cloud-based software that connects with Marken’s Maestro IT system, says Van Strien.

	Today, major cold-chain trends include increased use of temperature- managed shipping, and an interest in evaluating transport  methods and equipment critically, to maximize sample integrity, says Sawicki. There is also an increased emphasis on protecting the products of cell, gene and immunotherapy, says Van Strien, and the complex supply chain logistics that these products require.


	A growing number of biopharm companies must now ship cell- and gene-based therapies, says Kabbaj.  Such products require cryogenic storage at temperatures -238°F and below. In the past, shippers relied on dry ice (which performs best at approximately  -108.4°C), he explains, but dry ice emits carbon gas, which can damage proteins in biologic shipments, and might be harmful to handlers and to the environment. “Not only is dry ice shipping subject to a wide range of international regulations, it simply does not provide a cold enough temperature for many new specialty therapies” he says.

	Yet another important trend, says Van Strien, is increased demand of remote shipping, for example, of clinical trial dosages to patients’ homes. “We will continue to develop further services to allow patients to participate in clinical trials from home, or remote sites of their choosing,” she says.  

	Marken has also introduced an enhanced online booking app for investigator sites that is pre-programmed by study. It has also integrated enhanced scanning technologies throughout its global network. “More mobile technology will help treat patients at locations of their choosing,” says Van Strien.  

:
	When referring to this article, please cite it as A. Shanley, “Cold Chain: Going the Extra Mile," 

Cold-chain shipping for sensitive pharmaceuticals benefits from real-time GPS technology, better IT connections, and more conservative, controlled shipping temperatures.

Trends in Temperature-Controlled Shipping

Today, some of the most advanced computer-based models are being used for early research.  However, the move to continuous processing has stimulated interest in process optimization and control. This article explores two commercial platforms, and touches on a new program underway in the UK.

’s 2016 Solid Dosage Drug Development and Manufacturing eBook.

This article explores two commercial platforms, and touches on a new program underway in the UK.