Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Studying how a drug dissolves and disintegrates is crucial to understanding how it will perform in the body. The US Pharmacopeial Convention (USP) has established guidelines for testing dissolution in most commercial dosage forms.

	However, especially for pharmaceutical tablets and capsules, the seven traditional test methods and equipment recognized by USP (1) are variations on a single theme: tablet holder, bath, and paddles. They can seem worlds away from the complexities of the human body. 

	As William E. Brown, senior scientific liaison for general chapters with USP explains, the dissolution test distills all the information that is known about the performance of a pharmaceutical in a laboratory setting. “It is highly simplified and intentionally so,” he says. “For manufacturing, you want a test that passes or fails.” 

	To delve deeper into studying bioavailability, complex systems are available that mimic closely the digestive systems in a mammal or a human (2,3). Ishai Nir, small-molecule product manager at Distek, a manufacturer of dissolution test equipment and ancillary products, recalls the TNO gastro Intestinal Model (TIM), a simulator developed by researchers at the Netherlands-based Organization for Applied Scientific Research (abbreviated TNO in Dutch) in the early 1990s. 

	As Nir explains, TIM includes a stomach model with simulated contractions, as well as simulated mouths and intestine, all modeled with the correct pH, flow time of materials, and simulated gastric fluids. Other advanced models include the Institute for Food Research’s dynamic gastric model (DGM), France’s National Institute for Agricultural Research’s (INRA in French) In-Vitro, and Canada’s Laval and Guelph. 

	These models, however, are costly, complicated, and take a long time to use because they involve so many variables, says Nir. “Of necessity, the industry has replaced bioavailability testing with dissolution testing as a simpler QC test for manufacturing,” he says. Companies pick the formulation that showed efficacy in clinical trials and put it through conventional dissolution testing so that it becomes a benchmark for future manufacturing QC. 

	“It’s like goodness by association. We know that this formulation with this property performed well in the clinic trials, so if we keep making tab- lets that have the same dissolution and disintegration characteristics, we can assume they will continue to work well 

	“In fact, in many ways dissolution is largely a reproducibility test that asks whether the last batch is the same as the current one, and whether or not it behaves the same 

as it did in the clinical study where the formulation was shown to work,” he elaborates. 

	But, as formulations become more complex, will that be enough for the future? Researchers are working to improve the correlation between 

testing and to come up with better methods that are more representative of bioavailability and give more information about functionality, says Nir. “For some,” he says, “this effort has become a holy grail.” 

	It began, he says, with using simulated gastric media instead of running tests using simple media such as water or 0.1 Normal hydrochloric acid. Tests would emulate the stomach when full or fasted, and simulate a much broader array of variables than simply pH, he adds. In addition, Nir notes, some innovator companies are examining the properties of compression and its impact on dissolution more closely. Because the stomach works based on muscular contraction, researchers are simulating that (although, perhaps, not to the extent seen in TNO’s TIM), to identify key parameters. 

	A 2016 article (4) coauthored by experts from Bristol-Myers Squibb and AstraZeneca discussed some of the ways that dissolution testing could be made more biorelevant. At this point, however, the industry isn’t exactly clamoring for more biorelevance in dissolution testing. “The test is well understood and well constrained, and makes it easy to compare between batches and between facilities, and to do scaleup without a tremendous amount of work,” says Nir. 

	Dissolution testing has remained largely unchanged for the past few years, says Nir. However, USP continues to update its information. The organization recently drafted a new general chapter on performance testing for mucosal routes, has a new chapter on testing for topical routes, and plans to re-evaluate testing for injectable pharmaceuticals, says Brown. 

	At the same time, draft guidance from FDA may bring some changes. For readily soluble biopharmaceuticals in the biopharmaceutics classification system (BCS) 1 and 3, says Brown, regulators have said that traditional basket/paddle test methods should suffice. “New products in BCS 1 and 3 won’t need new exotic dissolution test methods,” he says. 

	In the recent past, FDA guidance had focused on validation, with the agency advocating the use of mechanical validation alone in validating dissolution test apparatus, without USP’s prednisone “tester tablets.” The argument against using the tablets was that they themselves could be subject to variability, and thus inject more variability into a process that can already be affected by environmental and equipment factors and technician training and experience.

	As Nir says, FDA’s guidance led some companies, particularly some of the larger name-brand companies, to change their approach, and to move to mechanical calibration for validation. However, many manufacturers, and particularly those in developing nations, continue to use the tablet testers for validation, he says.

	“If a manufacturer looks at its own dissolution numbers quite frequently, its products are much more likely to be consistent and to have tighter dissolution profiles, but that doesn’t make a very good diagnostic. The USP intentionally makes its calibrator tablets sensitive to multiple parameters. This way, if there is too much vibration, if component concentricity is off, or problems with other parameters, then this will be indicated by the testing” says Nir.

	Sometimes product batches will fail because of other factors. “From what we have seen, the single biggest parameter that people tend to get wrong is degassing. Not only are the tester tab- lets sensitive to physical factors, such as vibration, concentricity, and centration, they are also very sensitive to degassing,” says Nir. This can cause perfectly good batches of product tablets to fail dissolution tests.

	“When we respond to calls about test failures, and measure dissolved oxygen in the vessel, we often find that the level is too high. Even if the manufacturer has degassed properly, by the time they get the material into the vessel, they may have inadvertently re-aerated it, and there will be problems with the batch test,” says Nir.

	To get around this problem, Distek offers EZFill, a degasser that degasses and dispenses the media at the same time, providing better uniformity of degassing in the vessel itself to help prevent false alarms.

	Despite FDA’s guidance, USP’s position on calibration is that enhanced mechanical calibration alone is not enough to ensure quality. “Our standards already incorporate mechanical calibration, but we do not agree with the use of mechanical calibration alone,” says William (Jay) Pearson, project director, portfolio and program management at USP.

Mechanical calibration or tester tablets?

	“We suggest use of performance verification tablets because mechanical calibration alone may not be able to address some things that might be intrinsic to the setup of a given dissolution test in a given lab. The tester tablets have been designed to speak to these issues,” he says.

	Brown agrees: “It’s not sufficient to just look at speed and operation of the stirring element and the dimensions of vessel. If we really want to control performance, and variability due to the testing apparatus, we need to put a probe right where the apparatus is working. That is difficult to do by any means, but using a tester tablet is a good way to evaluate performance.”

	Dissolution test methods have been adapted for new formulations such as slow-release tablets. One technology that is becoming more prominent for longer dissolution tests (i.e., those lasting 24 hours or longer) is fiber optics, which, Nir says, can address problems such as evaporation and the need to replace media for sampling.

	The biggest problem with dissolution testing for extended release is that, if you’re running a fairly large number of sample points, you have to control evaporation but still have a way to get liquid in and out. “It’s very difficult to have a sealed environment because you need to run probes and have access points,” says Nir. “Fiber optics is a completely sealed measurement tool and lets you take as many measurements as you want without having to extract and replace media,” he adds.

	Distek purchased fiber optic testing technology from Leap Technologies in 2012. Use of the technology was first published by AstraZeneca in Sweden in 1988 (5), Nir notes.

	A number of companies are also work- ing with process analytical technologies (PAT) for dissolution testing (6). “There have always been projects that use fluorescence, near-infrared (NIR), and Raman spectroscopy. But NIR tends to be very sensitive to physical parameters, which is one of the challenges in implementing NIR for content uniformity. The models work very well until people change the manufacturing site, the compaction, physical parameters, or excipients. Then they have to develop a new model,” says Nir. Raman is great for selectivity, but that’s not a problem with dissolution, he says.

	Between ultraviolet (UV) and high-performance liquid chromatography (HPLC), virtually all bases are covered for dissolution testing, says Nir. One notable exception, however, is in processing nanoparticles, whether they are encapsulated or deposited on nanospheres. “These exotic dosage forms are giving people fits, not because HPLC or UV don’t work but because filters stop working, so the question then becomes: how do you arrest dissolution after you’ve pulled a sample if you cannot filter out all the existing remnant particles in that sample? That’s another area where fiber optics has become the go-to technique because it allows measurements in-situ in real time, eliminating the need for filtration,” he says.

	The use of spectroscopy, however, points to the potential to use principles of PAT and quality by design (QbD) for real-time release (RTR) testing. Recently, notes Nir, the industry has been abuzz since news came that Vertex Pharmaceuticals received approval to release an existing product using a model, rather than traditional dissolution testing (6). “It’s a very specific case, but points out what might be possible in the future,” Nir says. Vertex is doing online monitoring, he says, and applying PAT/QbD, instead of doing dissolution testing. However, Nir notes, the company did a tremendous amount of dissolution testing using fiber optics to get the data needed to develop the models.

	“Of course, one can correlate NIR to dissolution, but part of the reason the company could do this is because the product had been manufactured for many years so there was a tremendous amount of data to work with. It’s not like attempting RTR testing with a brand-new product,” says Nir.

	Innopharma Labs is developing predictive methods that model dissolution to optimize tablet coating for real-time release, as a way to ensure consistent coating despite variability in raw materials and other factors (7). In this approach, an NIR analyzer measures initial particle size at the start of processing. Initial size data are automatically fed to a dynamic process-control algorithm, which defines what is needed to add the correct amount of material per minute to achieve the coating thickness for optimal dissolution, and stops the process once it has reached a predefined growth level.

	USP is evaluating the use of PAT and predictive dissolution methods, although nothing has been incorporated into any specific standards or guidance yet. Nir sees the idea of doing this as very promising. “It’s nondestructive, and allows manufacturers to modify and improve the process. Someday it may even be possible, for example, that if a given formulation develops a problem that it could be fixed in real-time by adjusting some parameter like the compaction, allowing the manufacturer to save the batch,” he says. The question is how sensitive the models will be to future changes and differences in the excipients or manufacturing equipment used.

	Recently, multiple component analysis (MCA), a chemometric technique, was used with UV fiber optics to allow UV dissolution testing to be done on formulations containing two active ingredients (8). Normally, UV spectrophotometry would not be able to provide clear results for formulations that contain more than one active.

	The benefits of this particular form of MCA stem from the fact that it is a closed, rather than an iterative technique, says Nir. “You solve a series of equations and develop the model. Because these are well defined, it makes it easy to validate,” he explains.

	While efforts continue to improve the way the industry approaches dissolution testing, many pharmaceutical manufacturers take an ‘if it ain’t broke don’t fix it’ approach. “Those in the industry who are focused on making product are very happy with the dissolution test as it is,” says Nir.

.
	3. M. McAllister, Pharmaceutics, 7(5), pp 1374-1381, 2010.
	4. X. Lu et al., 

, September 2017
	5. M.Josefson,E.Johansson,A.Torstensson, 

.60 (1988) 2666–2671.
	6. I. Colon and J. Medendorp, “

Novel Approaches and Challenges in Dissolution Testing of Pharmaceutical Solid Oral Dosage Beyond Commercialization

Innopharma Labs Bets on Manufacturing 4.0

,” PharmTech.com, March 21, 2018.
	8. A. Kielt, I. Nir, et al., “Analysis of Two APIs...Using UV Spectrophotometry with Multiple Component Analysis with a Fiber Optic Dissolution Analyzer,” white paper, 


	Vol. 42, No. 6
	June 2018
	Pages: 42–45

	When referring to this article, please cite it as A. Shanley, "Simple by Design," 

Articles

Dissolution testing remains one of the pharmaceutical industry’s most straightforward, least expensive QC tools. Research is focusing on ways to extend its reach, improve in-vitro and in-vivo correlation, and make real-time release testing a reality.

Simple by Design

	Now that global regulators have approved four oral solid-dosage drugs that were made using continuous processes-two from Vertex (in 2015 and 2018), one from Janssen (in 2016), and one from Eli Lilly (in 2017)-equipment manufacturers and early adopters are working to resolve engineering challenges that may be hindering more widespread use of continuous manufacturing (CM). Equipment cleaning and configuration is one such challenge; so is operator training. At a roundtable hosted by 

at INTERPHEX in April 2018, panelists discussed efforts within the industry. 

	Equipment manufacturers are adapting to requirements that have been identified by early adopters. First there was the need to make equipment such as mixers and extruders smaller. Then came the need to automate them. The emphasis now is on simplifying changeover and cleaning, said Sharon Nowak, global business development manager at Coperion-K Tron.

	Coperion KTron, for example, introduced the next-generation of it pharmaceutical loss-in-weight feeder with a smaller modular design that allows easier change-out of feeders and hoppers for greater flexibility and easier cleaning (1).  

	Improving changeover speed will take some effort, given the industry’s trend to process multiple products on the same equipment and to integrate equipment from different vendors on the same line.  “There can be upwards of 1000 individual parts in a continuous processing train as well as a couple hundred tri-clamps-associated gaskets, which makes cleaning and turnover a lengthy process,” noted Dave DiProspero, associate and director of pharmaceutical process technology at CRB.

	The need to disassemble, swab, clean, and reassemble the equipment is a time-consuming and complex process, noted Jose Luis Santos, head of operations for drug product continuous manufacturing at Hovione, a contract manufacturer that is partnering with Vertex. Although cleaning is currently done manually, automated clean-in-place (CIP) systems could be considered for future designs. “In addition to the equipment, rooms need to be cleaned. CIP could enable greater efficiency,” commented Santos. 

	At Vertex’ facility in Boston, however, the company chose not to use CIP because of issues and cost associated with wastewater at that location.  Vertex is, instead, considering an automated washer that will reduce cleaning time dramatically, David Nadig noted in a presentation at IFPAC (2). 

	Like other companies that have adopted continuous processes, Hovione is now measuring the time required for each activity and the sequence of operations within continuous, in an effort to reduce the overall time required and to determine the optimal staffing requirements, said Santos. 

	“Companies are going through each stage to identify bottlenecks and areas where they can reduce the amount of time required,” said Doug Hausner, associate director for Industrial Relations and Business Development with the Engineering Research Center for Structured Organic Particulate Systems located at Rutgers University. “As a result, cleaning is becoming part of the initial equipment design stage for continuous processing.”

	In addition, he noted, ergonomics is becoming a more important design factor.  For example, Eli Lilly optimized placement of feeders in its continuous processing suite, and placed them on tracks and turntables to cut down cleaning, maintenance, and changeover time.

	Human resources and training will be crucial. Currently, processes are typically run by PhD-level engineers, but eventually will need to be run by process engineers and trained operators. Despite a great level of automation in continuous manufacturing rigs, operator intervention and close monitoring are key for success. “You can’t have someone running the process from a control room. You need the process engineer on the floor, giving close attention to several different unit operations at the same time,” said Santos.

	It will also be important to change the approach to standard operating procedures (SOPs), which, today, can run in the thousands of pages for each unit operation.  “You want to digest this information so that it can be used in the field, for example, with checklists highlighting the most important steps to take,” said Santos. Then, if a user is not familiar with the process, they can be referred back to the relevant SOP, without carrying tomes of paper. Technology such as making SOPs available via human-machine interfaces or mobile devices could be used to get information to the operator at the right place and time. 

	Despite these challenges and others, those involved with CM implementation say that the opportunity for benefits of a flexible, efficient process that offers greater speed of development, scaleup, and tech transfer and can run under a high level of control is well worth the effort. Panelists see continuous manufacturing becoming increasingly important for orphan drugs and rare disease therapies, as well as for generics.  “We’re working with a number of generic-drug companies on business cases…it is my belief that once cleaning and some of these other hurdles are cleared, more companies will put continuous processes in their facilities,” said Nowak.

New Compact and Modular Pharmaceutical Feeder Design at Interphex 2018,

	2.  D. Nadig, “Industrialization of Continuous Manufacturing,” Presentation at IFPAC, (Arlington, VA, Feb. 2018).

As more continuous processes move toward commercialization, users and equipment vendors are working to speed changeovers and address other needs.

Addressing Continuous Manufacturing’s Growing Pains

Despite its importance to the pharmaceutical industry, lyophilization has seen relatively little change since it was introduced in the 1940s. This has led to a disconnect between current practice and market needs. LyoHub, a consortium of pharma and biopharmaceutical manufacturers, equipment designers and suppliers, researchers, and academics with participation from regulatory bodies, is trying to address this problem. LyoHub is now working with the American Society for Testing and Materials International’s E-55 Committee to make its proposed best practices into industry standards.  This article gives insight into E-55.05’s goals for optimizing lyophilization.

Pharmaceutical Technology’s Biologics and Sterile Drug Manufacturing 2018

 Biologics and Sterile Drug Manufacturing 2018

	When referring to this article, please cite it as A. Shanley, "Can Standards Help Pharma Modernize Lyophilization?" 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 2018 

ASTM’s E-55.05 committee aims to turn best practices into industry standards in order to eliminate variability and allow a 70-year-old process to leverage 21st century tools, technologies, and practices.

Can Standards Help Pharma Modernize Lyophilization?

As single-use processing equipment becomes a more prominent part of biopharmaceutical development and manufacturing, a clear understanding of risk management and testing requirements are needed. Regulatory guidelines are not prescriptive, forcing manufacturers to develop clear strategies that will ensure that product safety and efficacy are maintained during shipment.

	A thorough understanding of the distribution cycle and potential transportation risks is required. In this article, Elisabeth Vachette, senior product manager, and Jean-Marc Cappia, vice-president of marketing, both at Sartorius Stedim Biotech FMT, Aubagne, France, share with 

some of the key issues and challenges involved, and how to meet them effectively.

:Which regulations and standards govern long-distance shipping of liquids in single-use systems? 

:Currently, there is no dedicated regulatory guidance on the subject. FDA, the European Medicines Agency (EMA), and other regulatory bodies require that companies have qualified processes and can prove that the process will meet the quality standards of the final drug product.

	[Neither FDA nor EMA] provide very specific requirements. They want end users to be in control of their processes.  What they say is that the process of drug making should be qualified, whether that involves filtration, bag or virus inactivation, transportation, or storage space during manufacturing.

	It is up to end users to establish documented evidence providing assurance that processes are under control and meeting specs and defined quality attributes (i.e., that the process is stable, robust, and free of any leakage or contamination).The Parenteral Drug Association’s (PDA) technical report TR66 recommends that shipping systems be qualified for intended use through “proper design and testing in consultation with a packaging engineer.”
	

	Conditions for international shipment must be defined. They can be based on international standards such as the American Society for Testing and Materials’ (ASTM) D4169 or the International Safe Transit Association (ISTA) 3 series (

). The level of severity for test conditions must be based on real-world shipping conditions.  We recommend a holistic, four-step approach (

: What major technical challenges do pharma and biopharma companies face when shipping liquids in single-use systems over long distances by air or sea?

: The first and main challenge is preserving product integrity within the bag, and the robustness and integrity of the system. Any leaks or bacterial ingress must be prevented.

	During shipping, bags can move, resulting in water hammer and stress. The challenge for the supplier is, first, to design systems that can pass these tests. Currently, single-use systems use better films and technologies than they did in the past, so the bags can more readily pass ASTM test requirements, which are very aggressive.

	Once the integrity and robustness challenge is overcome, end users must monitor the shocks and temperature variations that the pharmaceutical product can experience when it is shipped to its destination.

: For liquid shipping, there is a need first to understand the distribution cycle, what is really happening, and what kind of shipping transportation means you are using. By knowing the distribution cycle, process validation will integrate severe conditions over the normal distribution cycle in order to provide correct and meaningful qualification. This approach allows end users to validate processes in worst-case conditions. 

	ASTM’s testing involves worst-case conditions, and also requires monitoring that enables the complete traceability of product, which might include tracking temperature.

	The responsibility is to define the distribution cycle. End users select a supplier of transport services and a means of transporting the product (i.e., dedicated shipment, during which product is passed in a controlled way).

	For exceptions, they will use a dedicated truck with cold-chain management. The approach that is used depends on the transportation supplier, although our company offers contract supply chain management and testing services for this type of process validation.
	 

: Which aspects of testing and data collection can be outsourced for single-use shipping?

: We have qualified on ASTM standards and can supply technical data to provide a view of the regime and the constraints and stresses we have applied during testing, in terms of vibrations, shocks, and shakes. 

	In addition, when manufacturers are simulating shipping conditions, they can send us the bags to check for integrity. We can either make a pressure or ink tests on the bag, or perform bacterial ingress tests on the bags. We offer these services to support customer validation, since they must simulate shipping conditions and ensure that results are within the proper framework.

The industry’s understanding of shipping requirements varies

: Are most biopharmaceutical companies already aware of what they need to do to validate single-use shipping for liquid products, or are they leaving any vital steps out of the plannint process?

:  The level of understanding varies. Some companies, for example, the large biotech companies, are very well prepared and understand exactly what they need to include in their validation efforts.  But that is not the case for all of the smaller and mid-sized manufacturers. As a vendor, we believe that we can play a role in educating manufacturers on what is required, and providing the testing services themselves if and when needed. 


	Vol. 42, No. 5
	May 2018
	Pages: 55–57, 61

	When referring to this article, please cite it as A. Shanley, "Best Practices for Shipping Single-Use Systems," 

Shipping biopharmaceuticals in single-use containers requires a thorough understanding of the distribution cycle and potential transportation risks.

Best Practices for Shipping Single-Use Systems

	Tracelink recently released results of its latest Drug Supply, Safety, and Traceability Report, which looks at how effectively the links within the pharmaceutical supply chain-pharmaceutical manufacturers and contract manufacturing organizations (CMO) and distributors-are implementing serialization and traceability programs (1). Because 2018 is the last year that companies have to meet serialization requirements set by the US Drug Supply Chain Safety Act (DSCSA), the report’s findings were somewhat unsettling. “Despite goodwill efforts by industry and regulators to meet compliance on time, the industry is extremely behind in being ready for serialization,” wrote Tracelink’s CEO Shabbir Dahod in the report’s introduction. 

	Analyzing survey responses from 660 pharmaceutical companies, CMOs, wholesale distributors, hospitals, and pharmacies, the study found that only one-third are confident that they are ready to meet serialization requirements set by the DSCSA and the EU Falsified Medicines Directive. 

	In addition, none of the respondents had finished all the groundwork required for serialization. Only half of the pharmaceutical manufacturers and CMOs, for example, had prepared their internal packaging lines for serialization or projected the number of units to be serialized annually, wrote Dahod. 

	The readiness gap between pharmaceutical manufacturers and CMOs appears to be “staggering,” Dahod noted. “Pharmaceutical companies are troubled about connectivity to their CMO partners, while CMOs appear to be overstating their actual serialization readiness,” he wrote.

	Of the 660 respondents to the survey, 174 were from pharmaceutical manufacturers; 155 were from CMOs; 50 from wholesaler distributors; 195 from hospitals; 75 from pharmacies; and 11 from third-party logistics companies.  Of the pharma company respondents, 32% were at director level and 25% at manager level.  

	Of the 146 respondents from pharmaceutical companies that must meet DSCSA requirements, only one third said they felt very ready. 90% had prepared for master data management; 80% said they will be shipping serialized product by the deadline, and 72% felt confident that they understand the legal requirements behind the DSCSA and European Union Falsified Medicine Directive regulations.  In addition, 62% say their organizations began preparing for serialization 13 months before the deadline; 55% say they will use the proper electronic forms; and 55% say they have estimated the number of units that will be serialized each year. Another 51% plan to eliminate 81–100% of paper forms by November 2018.

	However, at this point, only 8% had integrated serialization processes with their CMOs, and only 11% said their CMOs were ready to ship serialized product, while only 12% said they had ordered and installed the equipment required for serialization on their internal packaging lines.  As a result, the study says, only 25% of respondents whose companies must meet requirements by November 2018 are ready for serialization and have taken the necessary foundational steps. 

	The survey found that half of all pharma CMOs felt very ready and have taken the basic steps required for serialization.  For European pharmaceutical companies and CMOs, one third of respondents said they felt very ready for serialization requirements.  13% of respondents said that most CMOs were ready to ship serialized product and 46% said that internal packaging lines had been readied for serialization. In addition, 94% of respondents from this group say they have begun preparing for master data management; 54% have projected the number of units that will need to be serialized, while 48% said they have integrated serialization efforts with their pharmaceutical company clients. However, the research found, only 15% within this group were found to be on the true path to readiness, suggesting that more work and more coordination will be needed this year.

	The study found that pharmaceutical companies had hired more staff in 2017 to help with serialization efforts, with 21% of respondents saying that they had hired or were planning to hire more staff. In 2016, only 9% responded that way.


	Tracelink’s research also found that aggregation efforts were in full swing; nearly 75% of respondents from those pharmaceutical manufacturers and CMOs that must meet DSCSA requirements had already begun to aggregate product or were planning to implement aggregation by the November serialization deadline. Within that group, 20% of pharmaceutical companies and 31% of CMOs reported that they were already aggregating product, while 33% of pharma respondents and 20% of CMO respondents said they would be aggregating by November 2018.  

	Tracelink’s study also found a disconnect between the pharmaceutical manufacturing and distributors in the chain. 60% of wholesalers who responded to the survey said they are requesting that their pharma partners aggregate product, yet one third of pharma company respondents said that their trade partners haven’t been asking for aggregation yet.

		Tracelink, “Drug Supply, Safety, and Traceability Report,” (April 2018).

INTERPHEX session on serialization and blockchain

INTERPHEX Keynote Series: Information Technology Trends and Best Practices for blockchain technology and serialization 

to be held on Wednesday, April 18, 2018. The series includes a 1:30 pm session on the industrial internet of things, blockchain, and smart contracts and a 2:15 pm presentation on serialization. The sessions will be held on the show floor at the Innovation Stage and are open to all show attendees.

Most pharma companies still aren’t ready for serialization, and only a few have coordinated traceability efforts with their CMOs, according to Tracelink’s latest readiness report.

Serialization: So Close and Yet So Far

Certificates of analysis (CoAs) are a tangible, and important, manifestation of a manufacturer’s relationship with its suppliers of APIs, excipients, and the other materials used to make drug products. Provided by suppliers to customers as a matter of course, these documents operate at the point where materials, laboratory control systems, and manufacturing intersect. These are three of the six crucial domains governed by any good pharmaceutical quality system (1). The right approach to managing and evaluating CoAs is also key to maintaining data integrity, an area where many pharma company compliance strategies continue to fall short (2).

	CoAs summarize key information on product quality testing, including test conditions and parameters, specifications and requirements, results of tests (both qualitative and quantitative), and approval signature and date. They also provide information on the chain of custody, including such basics as the manufacturer’s name, address, telephone number/email and other identifiers that allow the material to be tracked throughout the supply chain.

	Despite CoAs’ importance, some pharmaceutical manufacturers have begun to take them for granted. In other cases, they may be relying on them too much. As spectroscopist and consultant Emil Ciurczak notes, “They might be better off heeding the old Russian proverb: ‘Trust, but verify,’ which former US President Ronald Reagan often used in arms control talks with the former Soviet Union.”

	In fact, given the complexity of outsourcing chains today, taking a defensive approach, and cutting straight to “verify” might be an even better strategy.  Ciurczak recommends taking a systematic approach and, in addition to thoroughly testing all incoming materials, randomly testing APIs a second time, on a rotating basis, to validate data in the CoAs.

	In general, many pharma companies don’t do a good job in their annual verification of supplier CoAs, notes Irwin Silverstein, consultant to the International Pharmaceutical Excipients Council (IPEC).  “Their focus seems to be only on whether the sample they test annually meets the monograph. They should instead investigate any measurements that differ significantly from what was reported on the CoA. These differences may be due to differences in test method or sample preparation, lack of homogeneity within the excipient lot, or erroneous test results,” he says.

	“Best practice would be to make CoA verification part of annual overall verification. It would require sending the excipient manufacturer a copy of the CoA they have received and asking whether their copy is genuine,” Silverstein says. In addition, manufacturers should review the CoA with attention to the reference to the test method. Where the method listed is not compendial, they should request a copy from the manufacturer, says Silverstein.

	A systematic approach to CoAs, and vendor data management, is extremely important. In finished drug products, FDA has clearly been stepping up its enforcement of current good manufacturing practices (GMPs) for over-the-counter (OTC) products. In February 2018, the agency issued a warning letter to an OTC antacid manufacturer in Mexico, which was found to have distributed product even before receiving CoAs on finished product test results from its third-party testing lab (3). 

	The company had not tested for identity of incoming APIs and ingredients, and failed to verify supplier CoAs.  In some cases, FDA found, operators made up yield results in batch records for weighing, filling, and label reconciliation because there were no established methods or calculations used to determine yields.

	Cellex-C International, a Canadian OTC manufacturer, received a warning letter from FDA in 2017 (4) for failing to test incoming APIs and ingredients. Regulatory inspectors found that the company relied almost entirely on its suppliers’ CoAs for evidence of identity and product conformance data (5). 

	As FDA’s letter stated, “You must conduct at least one specific identity test to analyze all incoming components. You may not rely on your supplier’s CoA to verify the identity of your components.”

	In addition, the company was cited for failing to test product identity, strength, and other specifications. Cellex-C  had outsourced lab testing for APIs in finished drug products, but FDA inspectors found that its managers had no action plan or timelines in place for testing products and supervising that outsourced testing. 
	In India, Kim Chemicals, a manufacturer of OTC chest rubs and other treatments was penalized for data integrity deficiencies related to CoAs (6).  As FDA investigators wrote, “You had no records to support the analytical testing results that were reported on your CoAs.”

	Technicians would document finished product analysis on a piece of paper, transcribe the test results onto a certificate of analysis, and then destroy the paper with the original test results. As a result, there was no record verifying that tests had been run in the first place.

	In 2014, FDA issued a warning letter to CBSCHEM, an API distributor in Hong Kong, for inconsistent documentation and failure to record manufacturer’s identity, address, batch number, purchase, receipt, transportation, distribution, and CoAs and provide this information to customers (7). In addition, CoAs did not include batch or lot codes, laboratory testing information, expiry or retest dates, and other relevant information.  The facility was also found to store unlabeled APIs inside inadequately labeled totes.

	But these issues pale when compared to problems that FDA inspectors discovered more recently.  In 2017, the agency issued warning letters to three API and ingredient distributors that created false CoAs (8,9,10). The following passage was almost exactly duplicated in FDA warning letters sent to Lumis and Su Zhou Pharmaceuticals in China, and Sal Pharma in India. 

	“For many APIs, you generated CoAs by copying and pasting analytical results from the original API manufacturers, replacing the manufacturers’ information with your letterhead, then issuing these CoAs to your customers. You omitted critical information, including the original manufacturers’ names and addresses and the names, addresses, and telephone numbers of laboratories that performed the testing,” read one such letter. One of the companies also held unlabeled material, which was reportedly offspec and due to be destroyed, in its “released for shipping” area.

	In addition, Sal Pharma was selling APIs from two suppliers that were not registered with FDA, calling itself the manufacturer. According to the FDA letter, company’s staffers would pick up API from suppliers, relabel it with Sal Pharma’s information in the car, and then drop the API off to its clearing agent without knowing whether the material would be stored in a temperature-controlled environment.

	Su Zhou Pharmaceutical Technologies was found not to have a quality unit onsite, or written procedures for quality activities.  Instead, FDA inspectors found, salespeople signed CoAs as “QC directors” and as quality testers. Among other problems, including nonexistent temperature controls, the company distributed supplies from a manufacturer that was on FDA’s Import Ban list, under its own name.

	Such problems, and penalties, can only be shared by unwary pharmaceutical clients. Tamara Felton-Clark a former acting district director within FDA’s Office of Manufacturing Quality, pointed out one case (1) where a manufacturer worked with multiple contract manufacturing organizations (CMOs) to make various drug products.  Several of these CMOs had received FDA warning letters for cGMP problems with API manufacturing, but the manufacturer did not take action.

	The manufacturer’s quality control procedures involved checking whether a CoA was present for each material, rather than testing that the material and verifying information within the accompanying CoA. As a result, product made using the ingredients was problematic, with some lots failing stability tests and customers complaining of problems with the product.

	FDA issued the company a warning letter for cGMP deficiencies, including inadequate CMO oversight by the quality department.  “Manufacturers are responsible for the quality of their products, and the reliability of associated test results, regardless of who tests them,” Felton-Clark said.

	In another case, Felton-Clark pointed to a finished drug manufacturer that found high levels of impurities in raw materials.  These impurities resulted in an up to a 75% rejection rate for some compounds and generated customer complaints, but no action was taken. Failure to test and document problems and to verify CoAs resulted in warning letters, recalls, a multimillion dollar fine, and, eventually, a permanent injunction, she said. 

	Manufacturers may often fail to consider the importance of document control, auditing, and data review, to reduce the risk of data integrity failures, as consultant Magaly Aham told attendees at a PDA Pharma Industry Trends conference in Brazil in 2017 (2).  This can often be a function of inadequate training, pressure to increase output, and a misunderstanding of priorities, she noted.

	Often, when regulators note these problems during inspections, Aham said, the deficiencies will fall under 

), for “failure to establish an adequate quality control unit with the responsibility and authority to approve or reject all components … in process materials and drug products.” She recalled cases where one company’s quality control (QC) department allowed the use of adulterated API manufactured by another company.  The department had approved CoAs for six APIs as well as finished products before running QC and release tests, while the production manager signed and dated the “prepared by” and “checked by” sections in the CoA. 

	Depending on the product involved, such omissions might have fatal results, especially when potentially hazardous materials are being formulated for sensitive patient populations.  The level of risk involved was clear in a recent case where FDA inspectors found that a CMO of homeopathic infant’s teething tablets accepted raw materials without validating data in CoAs or performing adequate material testing. These failures resulted in product that contained varying levels of the API belladonna, and a warning letter to Raritan Pharmaceuticals (11) in June 2017. 

	In the end, compliance problems will only be shared by all supply chain partners if they are not accounted for, and prevented. Strong supplier quality agreements and clear delineation of roles and responsibilities are a key first step, especially where production involves several different outsourcing partners, according to quality expert Sue Schniepp.  She recalls a situation where a CMO was making clinical trial quantities of an API for a drug manufacturer (12).

	As the sixth manufacturing run of clinical materials was about to begin, the CMO noticed that the API looked different than it had in previous runs, although the API supplier’s CoA showed that it met specs. The manufacturer had contracted with a third-party lab for API release testing, so the CMO could only run an incoming material identity test, Schniepp explained.

	After the manufacturing run, product was sent to another testing lab, which found that the material was out of spec. The CMO asked for permission to talk with the API manufacturer to address the quality issues, but the drug manufacturer would not allow it, so the clinical trial batch was placed on hold.
	Then during a regulatory inspection, all problems were revealed and, as a result, the CMO, client, and API manufacturer all received 483s and product approval was delayed.

	As Ciurczak says, pharmaceutical quality by design (QbD) offers partners an opportunity to supplement and go beyond the CoA, to prevent quality problems from the start.  Once manufacturers get results from design of experiments and design space work, they can then specify optimal ranges of values such as moisture content, crystallinity, and particle size distribution to API and raw material suppliers, and offer to pay a premium for product that meets those criteria.

	In the end, buyers must still test product, and validate CoAs, to mitigate data integrity and drug safety risks. In a complex, interconnected global supply chain, trust alone just won’t cut it, as more manufacturers are discovering.

,” a presentation made at Regulatory Education for Industry: Focus on cGMPs and FDA Inspections, FDA and Small Business and Industry Assistance Program, Silver Spring, MD, July 15, 2015.
	2. M. E. Aham, “

,” a presentation at the PDA Pharma Industry Trends Conference, March 14, 2017, Sao Paulo, Brazil.
	3. FDA, Warning Letter to Prosana Distribuciones Sa de CV, Dec. 18, 2017.
	4. Pharmaceutical Technology editors, “

Canadian Manufacturer Receives FDA Warning Letter

,” Aug. 14, 2017.
	5. FDA, Warning Letter to Cellex-C International, August 2, 2017.
	6. FDA, Warning Letter to Kim Chemicals Private Ltd, October 16, 2017.
	7. FDA, Warning Letter to CBSChem Ltd, January 13, 2014.
	8. FDA, Warning Letter to Lumis Pharmaceuticals, March 2, 2017.
	9. FDA, Warning Letter to Su Zhou Pharmaceuticals, January 16, 2017.
	10. FDA, Warning Letter to Sal Pharmaceuticals, April 20, 2017.
	11. FDA, 

Warning Letter to Raritan Pharmaceuticals


	Vol. 42, No. 4
	April 2018
	Pages: 60, 64, 66, 69

	When referring to this article, please cite it as A. Shanley, “Certificates of Analysis: Don’t Trust, Verify,” 

Taking vendor product data at face value puts pharmaceutical manufacturers and their supply chain partners at risk.