Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Data integrity is an important issue for pharmaceutical manufacturing. 

 spoke with Oliver Wolf, senior product manager at 

, about some of the benefits and challenges of ensuring data integrity using electronic systems.

 What are the primary data integrity risks associated with paper-based systems and with computerized systems? How can these risks be mitigated?

 The primary data integrity risks associated with paper-based systems are data loss, data accuracy, and process integrity. All of these risks can be reduced or even eliminated effectively through computerized systems. In the physical world, complete data loss can occur through something as simple as losing track of a piece of paper or something as calamitous as a fire. Well-designed computer systems will make complete data loss virtually impossible as long as an effective backup and disaster recovery system is in place.

	Data accuracy can be compromised by honest mistakes or willful tampering with data, whether you are working in a paper or an electronic system. Electronic systems can eliminate many common sources of errors by automating data processing steps, such as data transcription and calculations. When it comes to willful falsification, more automation does mean less opportunity for tampering. In practice, however, most electronic systems still rely on humans to some degree. These systems do improve detectability but nonetheless still rely on strong review and approval processes.

	In FDA-regulated environments, recording who reviewed and approved the data is a crucial element. Paper systems can do a decent job in defining the reviewer/approver, but again rely on human review to catch routing errors that an electronic system may eliminate.

	An added risk in electronic records stems from the easy data access these systems afford, which raises the concern that an unauthorized person could access your data. FDA's approach emphasizes that systems need to be designed in a way that such falsification would require the collusion of at least two people. Simply put, while your database administrator may have the ability to alter data without much of a trace, this role does not typically have the motive to do so. Outsiders’ access to your data still obviously is a concern, and implementing sound security procedures is extremely important.

 How can manipulation of electronic records be detected?

 Well-designed electronic systems have mechanisms in place to ensure that data simply cannot be altered through ordinary means by their users when it is not meant to be changed. So, in these systems you would expect that records, once approved, are simply put into read-only mode. In cases where edits are required after the fact, such systems would only allow edits once the record is revised, or at least is bumped back into an ‘in-process’ state. Either mechanism requires personnel to run through an approval process again. This will generate a full record of the changes made and approvals committed.

 Part 11 outlines a number of requirements that FDA-regulated companies must meet in their use of electronic records and signatures. This includes requirements for user passwords, audit trails, and mechanisms that tie an electronic signature to the record it signs. Although this does not mean that it is impossible to change data, for example by gaining direct database access, even a technically proficient person would have trouble updating all records to avoid contradictory data. If data tampering of this level of sophistication is suspected, a good place to start is to compare date and timestamps between activity logs, audit trails, signatures, and the record itself.

 What are the requirements of/best practices for validating a computer system/electronic records?

In FDA-regulated industries, the entity using a computer system is responsible for validation-ensuring the proper functioning of all aspects of the system. Using a risk-based approach to assess high-risk areas of a given system, and then focusing validation testing on those areas, has become acceptable. It has also become acceptable to rely on vendor documentation for testing of the lower-risk areas, especially when the reliability of the documentation has been confirmed through a vendor audit.

	What the high-risk areas of a given system are depends on many factors, including the types of products a company or facility manufactures and what impact the data processed in the system could have on the integrity of these products. System functionality to focus on would certainly include data access and security, electronic signatures, approval processes, and audit trails. 

 What do you see as the most important thing for companies to do or recognize regarding manufacturing data integrity? 

 The most challenging aspect in the implementation of computerized systems in FDA-regulated industries seems to be finding a solid balance between ensuring your risk exposures are mitigated and not stifling your use of innovative systems by being overly conservative and stringent. This can be especially challenging given that validation and quality assurance activities are often seen as part of a checks and balances system that is almost designed to be confrontational. There are no easy answers here. Every company has a unique culture, but creating one that allows for a cooperative approach can certainly pay dividends.

Articles

Computerized systems can solve some of the data integrity problems with conventional paper-based systems.

Mitigating Data Integrity Risks

	The US government’s National Science and Technology Council (NSTC), which sets national goals for Federal science and technology investments, listed continuous manufacturing of pharmaceuticals as one of five manufacturing technology areas of emerging priority in its April 2016 report on advanced manufacturing (1). As reported in the 

, continuous biopharmaceutical manufacturing and other advanced biopharmaceutical manufacturing technologies are also listed as emerging priority areas. Government support can make a difference in promoting continuous manufacturing of pharmaceuticals, say the report authors, who suggest that, “Future Federal investments may focus on broadly applicable and enabling technologies, demonstrating their return-on-investment required for mainstream adoption” (1).

	Multiple US government agencies already involved with projects include the National Science Foundation (NSF), National Institutes of Health, National Institute of Standards and Technology, Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), and FDA’s Center for Drug Evaluation and Research (CDER). FDA has often stated its support of continuous manufacturing, which it sees as having the potential to contribute to quality. FDA’s guidance, 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base

 (2), published in December 2015, outlines how CDER’s Emerging Technology Team (ETT) is working with companies to facilitate understanding of such technologies in order to appropriately regulate it, Michael Kopcha, PhD, RPh, director of FDA’s Office of Pharmaceutical Quality, told 

 (3). Some potential regulatory concerns, such as the definition of a batch, have already been resolved, and two continuous manufacturing processes for tablets have been approved for commercial production: a Vertex process is described in the report (1), and approval of a Janssen process was


	One of the most significant achievements in developing continuous processing for pharmaceuticals has been using a science-based approach to developing engineering systems, says Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic–industry consortium that has been working on continuous manufacturing with NSF support for the past ten years. “This approach to formulation is different from the old way of looking primarily at pharmacokinetics; now we’re looking at materials characterization and how minor changes affect manufacturability as part of a system,” Hausner explains. “Modeling is a key tool in development of these systems; it can show you where variability exists and what the failure modes are so that you can control the process.” C-SOPS has worked closely with developers, regulators, as well as users in both academia and industry to help drive this technology forward. While there is currently a gap between the cutting-edge of research and what is available commercially for modeling software, this could quickly close as adoption picks up and as regulators look to use this as a communication tool for relating process understanding, says Hausner.

	“Models allow you to understand how materials and processes relate. This greater understanding is valuable because it allows more rapid development. You can potentially ‘skip’ some of the traditional process development steps. Some of our current work, for example, involves using multivariate analysis to elucidate similarities between processes and determine how many tests you really need to do to get to an answer,” says Hausner. The ability to have faster development, which can translate to the business benefit of market exclusivity, is a potential driver for greater use of continuous manufacturing.


	Experts agree that a broader understanding of continuous manufacturing is needed to drive greater commercial use. A 2015 FDA grant included funding for training at C-SOPS. “Part of this training includes hands-on, intensive training, initially for FDA’s ETT team, and then for the broader industry. Trainees will gain experience running the integrated line at the Rutgers University C-SOPS lab. We want to give people exposure to this and thereby grow the level of continuous manufacturing expertise in the industry,” says Hausner. 

	A template or “road map” for development, based on the experiences learned by early adopters, would help the industry adopt continuous manufacturing, suggests Hausner. Regulatory science is another challenge, although progress is being made in understanding the risks and developing appropriate requirements for continuous manufacturing. Equipment, including having more standard connections and communication between PAT and processing equipment, is another challenge that will need to be overcome.

	Another step forward for equipment for continuous processing was the development and installation of a prototype 

Portable Continuous Miniature Modular (PCMM)

 system for tablet production in Pfizer’s Groton, CT facility in 2015. The prototype was built as a collaboration between Pfizer, G-Con, and GEA, and the system won the International Society for Pharmaceutical Engineering Facility of the Year 

Equipment Innovation Category Award in 2016.

Executive Office of the President, National Science and Technology Council

 “Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government,” by the Subcommittee for Advanced Manufacturing of the National Science and Technology Council (April, 2016).	

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base  

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM478821.pdf

FDA Insights on Quality in Solid Dosage Manufacturing

," Sidebar to S. Haigney, "Ensuring Quality in Solid and Semi-Solid Dosage Forms," 

		PharmTech, “FDA Approves Tablet Production on Janssen Continuous Manufacturing Line,” 

www.pharmtech.com/fda-approves-tablet-production-janssen-continuous-manufacturing-line

A US government report on advanced manufacturing promotes continuous manufacturing of pharmaceuticals, which has had recent commercial success but faces challenges for widespread adoption.

Next Steps for Investment in Continuous Manufacturing Research

Revised versions of ISO 14644 Parts 1 and 2 introduce changes to sampling procedures and monitoring plans for cleanrooms and clean zones.

Revised ISO Cleanroom Standards Improve Air Cleanliness Classification

	Continuous manufacturing is beginning to be used commercially to produce traditional tablets. In March 2016, 

 that it would install a commercial-scale continuous solid-dosage manufacturing facility as part of an agreement with Vertex Pharmaceuticals. And in April, 

 FDA approval for using continuous manufacturing to make its PREZISTA (darunavir) 600 mg tablets in its Gurabo, Puerto Rico facility. This approval was the result of years of development, which included building a full-scale test line at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at the Rutgers University School of Engineering, as described in a 

	At INTERPHEX 2016, Doug Hausner, Associate Director for Industrial Relations and Business Development at C-SOPS, described the advantages of being able to do more rapid process development using continuous manufacturing. Using continuous manufacturing, points in a design of experiments can be performed in minutes rather than days and use significantly less API. Rapid development can help companies improve speed to market, noted Hausner. Continuous manfuacturing is still not broadly understood, which is a roadblock to greater adoption, but upcoming training programs aim to increase industry exposure.  

	FDA has expressed support for continuous manufacturing, and in 2015, 

 $4.9 million in grant funding, administered by the National Institutes of Health (NIH), to C-SOPS institutions. Part of this grant is going to the New Jersey Institute of Technology (NJIT), a C-SOPS partner institution, to support the development of regulatory science for continuous manufacturing of strip-film based drug-dosage forms capable of real-time release. Rajesh N. Davé, professor at NJIT and the project's leader, spoke at INTERPHEX 2016 about the thin-film technology. He demonstrated that film technology can be used for poorly soluble APIs by using particle engineering and embedding particles in the film matrix using slurry casting instead of the conventional solvent casting. Davé also showed how process analytical technology, such as Raman or near infrared spectroscopy, can be used to monitor drug content and film thickness.

	Arjun Giridhar, staff scientist at Purdue University, which is another C-SOPS partner institution, also spoke at INTERPHEX 2016. He described a different processing technology-drop-wise additive manufacturing of pharmaceutical products (DAMPP), which deposits a drug (in liquid drops) on a film or tablet. Using liquids has several advantages, including avoiding problems associated with powder handling. Giridhar explained the importance of depositing the drops precisely and consistently as well as precisely measuring drops. The research group has had success in consistent production with 1% or less variation.      

The benefits of continuous manufacturing of solid-dosage drugs are beginning to be realized.

Continuous Manufacturing Ramps Up

	Although manufacturing tablets and filling capsules are well-established processes, there is always room for improvement, whether through optimizing current operations or investing in new equipment. For those looking for new equipment, INTERPHEX 2016 is a good place to be. A wide range of solid-dosage equipment is on display at INTERPHEX 2016, including several North American product launches.


	On the opening day of INTERPHEX 2016, Fette unveiled its brand new FEC40 capsule filler, with a maximum output of 400,000 capsules an hour, which is double the output of the current state-of-the-art capsule filling equipment, the company said during a press conference. This capacity increase, while maintaining a small footprint, is enabled by the use of Fette’s Duplex Concept, which the company adopted from its efficient FE55 tablet press. The same engineering knowledge used to develop Fette’s tablet presses was used to develop the new capsule filler, yet it is based on “tried and true capsule filling principles,” said company representative Matt Bundenthal at the unveiling. An intelligent drive system allows independent adjustment of each subprocess, which increases productivity by allowing optimization for the requirements of each product. The capsule filler incorporates Fette’s Tri-Easy concept with 360-degree access and ease of maintenance, service, and changeover.

	MG America (booth #2221) is displaying three new machines for capsules: the PLANETA 200 Capsule Filler, the Anritsu KWS Capsule Checkweigher, and the Antares Vision TCI Tablet & Capsule Inspector. According to the company, the 

 produces up to 200,000 capsules per hour; its modular design can be configured for a variety of production requirements, fitting several dosing units simultaneously and enabling one capsule to be filled with differing products.


	PharmaTechnology Inc. (booth # 2671) is introducing its enhanced PharmaFlex iSeries Deduster to the US market. The latest model features 20% greater output, a more efficient dedusting process, and enhanced resistance to prolonged heat, alcohol, and industrial detergents exposure, says the company. The iSeries uses the PharmaTechnology Inc. design that allows dust extraction to take place on the spiral’s outer circumference, as close as possible to the path of the tablets, to increase capacity compared to traditional units. “Dust is one of those seemingly minor issues that, if not properly managed, can exponentially affect an entire operation, particularly by necessitating unacceptable duration and frequency of downstream (post tablet compression) cleaning,” explained Nic Michel, General Manager, North America for Pharma Technology Inc., in an 

	Korsch (booth #3341) is presenting the XL 400 MFP [Multi-Function Platform] Tablet Press, a flexible tablet press that can produce single-layer, bi-layer, tri-layer, and core-coated tablets, of any size and shape, on a single machine platform. Fred Murray, President of Korsch America, Inc., recently shared his expertise in an article titled, “

,” which provides a practical approach to maximizing output and product quality. 

	GEA (booth # 2421) is introducing its MODUL Q rotary tableting technology to the North American market at INTERPHEX 2016. A new version of GEA’s Exchangeable Compression Module (ECM) offers a higher level of containment performance. The MODUL Q uses a new control system. It also incorporates the Exchangeable Die Disc, which was only previously available on the PERFORMA P press. “Operationally, the MODUL Q has a bigger pitch diameter and, in terms of size, will be positioned between the MODUL P and MODUL S. The use of A-type tooling is now possible, which allows 51 punch stations to be incorporated and an output of up to 367,200 tablets per hour to be achieved,” the company said in a press release.

New equipment for manufacturing tablets and capsules are on display at INTERPHEX 2016.

Pressing Forward with Solid-Dosage Innovations

	Advanced biopharmaceutical manufacturing technologies, including continuous biopharmaceutical manufacturing, are among the "emerging priority" areas highlighted in an April 2016 report, “Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government,” by the Subcommittee for Advanced Manufacturing of the National Science and Technology Council. The report lists a range of advanced manufacturing technologies that the US government believes will improve the economy and create jobs. Federal funding is already going into research and development of these areas, with many projects ongoing. 

	"A vibrant manufacturing sector, especially one invigorated with the latest technologies, requires focused investments along the entire technology innovation pipeline," wrote Tom Kalil, deputy director for Technology and Innovation Office of Science and Technology Policy, in the report. "An innovation pipeline stocked with ideas, from the laboratory bench to the manufacturing shop floor, is required to 'make it here' so that we can 'sell it everywhere.' The advanced manufacturing processes and products we desire-the types that lead to greater economic prosperity-is the result of knowledge, accumulated through research and development, translated systematically into know-how.”


	One of the emerging priority areas is engineering biology-designing and tailoring biological systems to manufacture products. This field evolved from bioprocessing expertise in the US, says the report. Engineered cells produce proteins for biopharmaceuticals, as well as fuels, chemicals, and biomaterials. Designing reproducible, robust, and stable processes in a bioreactor is a challenge that will require multiple approaches. The report notes, "These approaches include a clearer understanding of the biological mechanisms underlying DNA stability and repair, epigenetics, and evolution, as well as development of quantitative tools that enable the prediction of complex biological designs in a manufacturing environment.”


	A second emerging priority area related to biologics is regenerative medicine. "Regenerative medicine, and the clinical use of stem cells, has the potential to repair or replace dysfunctional, degenerating, or absent cells, tissues, and organs. … Additionally, engineered cells can be used to redirect immune function and enable the emergence of 'immuno-oncology,'" says the report, which adds that the US government invested $2.89 billion between 2012–2014 in regenerative medicine, primarily for the development of therapeutic techniques and technologies. A focus on process engineering is crucial to achieve manufacturing reproducibility. The report describes several challenges:

“Manufacturing cell and tissue products is significantly more challenging than manufacturing biopharmaceuticals. This is because manufacturing release criteria for bioengineered cells, tissue, and organs are largely undefined; the mechanisms by which these living products produce their effects are poorly understood; and they contain active cells which continue to grow and evolve. Additional challenges for manufacturing cell-based products stem from the complexity of the product and the bioreactor process. These challenges include appropriate design of bioreactors for adherent cells; characterization of the product with measurements that predict the clinical effectiveness of the product; determining tolerances of variation in cell types; how to store, ship, and deliver product with a very short (hours-long) shelf life; and how to assess the purity of the product in minutes or hours, instead of days. Development of methods to address the long-term storage of cells as manufacturing inventory is essential to increase their flexibility, reliability, and cost-effectiveness.”


	A third area of emerging priority in the report is continuous manufacturing for both small- and large-molecule pharmaceuticals. Regarding biopharmaceutical production, rhe report notes that continuous perfusion and fermentation systems are being used, but needed improvements include "the development of robust and stable cell lines that maintain high productivity over prolonged time periods (e.g., 2–3 months), design of media formulations to support high cell density, and optimization of bioreactor conditions to provide the high cell density at high viability and positive growth rates. Various enabling technologies, such as automatic cell density control, efficient oxygenation and ventilation, and foam control, must be developed and optimized." Work is also needed in continuous downstream purification for improved scale-up and development of continuous viral inactivation and removal. According to the report, "An important design requirement for all continuous downstream unit operations is that they must operate over prolonged periods under stringent sterility control conditions, which will require novel and unconventional solutions."

	Continuous manufacturing processes require real-time analytics. In biopharmaceutical processes, process analytical technology (PAT) is needed for attributes such as activity, aggregation, glycosylation, and impurity level. PAT for biopharmaceutical processes today is often customized, which restricts widespread adoption, says the report.

	Several federal programs are involved with developing continuous biopharmaceutical technology, including NIST, Defense Advanced Research Projects Agency (DARPA), and Biomedical Advanced Research and Development Authority (BARDA). The DARPA program aims to "enable timely response to patient needs and emergent threats by developing miniaturized and distributed manufacturing platforms to produce multiple small-molecule active pharmaceutical ingredients and protein therapeutics on demand." Exploratory studies under contract to BARDA are also investigating continuous manufacturing processes. Representatives from BARDA will be speaking about medical countermeasure manufacturing as part of a 

session on reducing drug shortages at INTERPHEX on April 27, 2016

The Subcommittee for Advanced Manufacturing of the National Science and Technology Council highlights biopharmaceutical manufacturing as an emerging priority.