Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Three-dimensional printing (3DP) is sometimes called additive manufacturing because it involves precisely adding layer on top of layer to build a 3D object. In discussions in the pharmaceutical industry, 3DP is often linked to personalized medicine. Indeed, 3DP is being used to manufacture medical devices-such as implants and prosthetics-designed for a specific person (1, 2), and FDA’s May 2016 draft guidance on additive manufactured devices includes direction for patient-matched devices (3). Academic researchers are investigating 3DP for printing living cells and organs (4). And researchers at the National University of Singapore envision 3D printing of customized, solid-dosage drugs that can combine multiple types of drugs and different release rates (5).

	A host of challenges, including regulatory and technical issues, must be addressed before personalized, 3D-printed pills can be commercialized, perhaps some time in the future. Today, however, 3DP is being used by Aprecia Pharmaceuticals as a technique for cGMP manufacturing of commercial, solid-dosage drugs marketed through the conventional, FDA-approved regulatory path.

	Aprecia’s Spritam (levetiracetam) tablets for oral suspension for treatment of seizures in adults and children with certain types of epilepsy became the first 3D-printed drug approved by FDA in August 2015 (6). The drug is made using the company’s proprietary ZipDose Technology platform, which it developed from 3DP technology originated at the Massachusetts Institute of Technology. The initial focus for the technology is to produce high-dose medications in a rapidly disintegrating, easy-to-swallow form. 

	“ZipDose is both a formulation platform and process for manufacturing,” says Jennifer Zieverink, senior director of marketing and alliance management at Aprecia. “The three primary benefits we see are the rapid disintegration in the mouth with a sip of liquid, along with taste-masking ability and high drug load. When we look across the landscape of central-nervous system drugs, we see that typically a high-drug dose is needed, often in a large pill that needs to be swallowed intact. Some patients struggle to swallow their medication, however, either due to the size of the pill or due to comorbid conditions associated with their medical issues. In this therapeutic area, we feel there is an opportunity to meet patient needs with a new dosing option.”

	Other fast-melt dosage forms typically range from 50–200 mg of drug load, notes Zieverink. “Spritam is approved and being manufactured up to 1000 mg, and the manufacturing process is capable of going beyond that.”

	Taste masking is easily incorporated in this process. “With a drug that disintegrates rapidly in the mouth, there is a need to neutralize the bitter API taste or even add pleasant taste. Currently we use a spearmint flavor to neutralize the tastes, but in the future could consider other types. The nature of the 3DP process gives a lot of room for adding taste masking. We can even wrap API for extended release, which is in development,” says Zieverink.

	“In our 3D printing process, we put down thin layers of powdered active-ingredient blends, then we spray or ‘print’ liquid onto each layer. The interactions between the particles and the liquid is what creates our tablet structure,” explains Grant Brock, vice-president of engineering at Aprecia. The resulting tablet is very porous, which allows it to disintegrate prior to swallowing. The porous structure is partly due to the fact that the process does not rely on the compression forces used to make traditional tablets.

	One of the drawbacks often noted for 3DP in various industries is a smaller scale with lower output than the corresponding traditional manufacturing method. Aprecia notes that their process has some limits, but that their engineers have “jumped the hurdle of manufacturing at commercial scale,” says Zieverink, while achieving the benefit of the precision manufacturing of 3DP manufacturing. 

	“Our equipment and process has been designed for commercial scale. Our process is really a unique technology using 3DP capabilities but in a custom platform; we produce at tens of thousands of doses per hour,” adds Brock. Because this is still a new technology, greater efficiency may be achieved as the technology evolves. “Continuous improvement is in our DNA. We’ll always be looking at ways to improve our capacity, efficiency, and throughput,” says Brock.

	Although 3DP is often associated with personalized medicine, the FDA-approved drugs made by Aprecia are not personalized; they are made using a commercial-scale, CGMP process and distributed through traditional methods. “Personalized medicine-someone intervening in the manufacture of a drug-is not in the regulatory pathway at this point in time for this manufacturing process. It is a worthy endeavour, but it is years away. Our current process is not used for personalized medicine or printing on demand or printing at home,” notes Zieverink. “With our 3DP platform, we are focused on a unique administration experience-disintegration in the mouth and taste masking-combined with high drug load. However, what’s not different from traditional solid-dosage drugs is that this is a highly regulated process used to make a FDA-approved drug, Spritam, available in specific strengths: 250, 500, 750, and 1000 mg, which are the same strengths as the tablets that are available. We have traditional distribution methods through retail pharmacy, and the patient must get a prescription from his or her physician.”

	Aprecia is currently manufacturing only in the US, but is actively evaluating opportunities for manufacturing in other regions. The company has initially focused on central nervous system (CNS) drugs, but says that their process could be applicable to other areas or in the veterinary drug space. “We have more CNS drugs in the pipeline, but as we ramp up and grow we do see an opportunity to branch out across therapeutic areas in the future,” says Zieverink.

		Oxford Performance Materials, “OPM Receives FDA Clearance for 3D Printed OsteoFab Patient-Specific Facial Device,” Press Release, Aug. 19, 2014.	

		University of Michigan Health System, “3D-Airway Printed Splint,”  

https://medicine.umich.edu/dept/otolaryngology/3d-airway-printed-splint

Draft Guidance for Industry and Food and Drug Administration Staff: Technical Considerations for Additive Manufactured Devices 

		Carnegie Mellon University College of Engineering, “Carnegie Mellon Researchers Hack Off-the-Shelf 3-D Printer Toward Rebuilding the Heart,” 

https://engineering.cmu.edu/media/feature/2015/10_23_feinberg_paper.html

		National University of Singapore, “NUS Engineering team develops novel technology to ‘print’ customised tablets for personalised medicine,” Press Release, May 25, 2016.	

		Aprecia Pharmaceuticals, “FDA Approves the First 3D Printed Drug Product,” Press Release, August 3, 2015. 

					Freeform reversible embedding of suspended hydrogels (FRESH) is a method of three-dimensional (3D) printing of soft materials. “Most 3D printers on the market are good for printing metals, ceramics, or plastics, but soft materials (such as living cells) that collapse under their own weight have been challenging to 3D print,” explained Adam Feinberg, associate professor of Biomedical Engineering at Carnegie Mellon University, in an interview with 

. His group has developed a technology to solve this problem by printing one gel inside of another support gel.

					Thermal inkjet printers can be designed to print biomolecules. “Ink jet generates a little bit of heat to vaporize the liquid, but this can typically be tuned so that it doesn’t damage the biomolecules,” says Feinberg, and channels must be designed to be large enough to avoid excessive shear force.  

					In the future, 3D printing could be used to print complete organs. Along with the organ, a vascular-like fluid-transport network is required. “Vascularization is a challenge, because you need to have a system that can get nutrients within 100 to 200 microns of the cell. A lot of research is currently going into how to accomplish 3D printing of this system and linking it to the host during transplant,” says Feinberg.

					For more information, watch a video interview with Feinberg at 

www.PharmTech.com/challenges-3d-bioprinting-0

	When referring to this article, please cite it as J. Markarian, "Using 3D Printing for Solid-Dosage Drugs," 

Articles

Three-dimensional printing allows unique benefits to be built in to solid-dosage forms.

Using 3D Printing for Solid-Dosage Drugs

	Three-dimensional printing (3DP) is one of the emerging technologies on FDA’s radar at its Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER). FDA experts are striving for understanding of the science involved in 3DP of drugs and devices. The agency also aims to provide guidance to companies adopting these new technologies. In the development of Aprecia’s 3D printed drug, “FDA met frequently and worked closely with the manufacturer to make 3D printing technology a reality,” notes Kristofer Baumgartner, spokesperson for CDER. 

 spoke with Baumgartner to gain insight on FDA’s views of 3DP and its regulation in drug manufacturing.

 What are some of the unique challenges in 3D printing of drugs in relation to the regulatory pathway?

: There is no unique regulatory pathway for the approval of 3D drugs, but there are existing approval pathways that are flexible enough to address new technologies, small batches, orphan/expedited review, and personalized medicines. A particular application may use a combination of these programs; the use of multiple programs and pathways is not unusual or unique to 3DP products. Nevertheless, in anticipation of possible unique challenges, FDA is working with drug makers in a new way to help the industry adopt scientifically sound, novel technologies to produce quality medicines that are consistently safe and effective-with an eye toward avoiding drug shortages.

: 3DP is often associated with personalized medicine. Can you comment on what concerns might need to be addressed before there is a pathway for approving personalized 3D printed drugs?

: Emerging technologies such as 3D printing can be an enabler of personalized medicine by promoting agile manufacturing, an approach to production that is focused on meeting the needs of a specific patient while controlling manufacturing efficiency. 3D printing technologies have the potential for producing final dosage forms that allow patients to be given a personalized regime, which could include multiple active ingredients, either as a single blend or potentially as layers in a multi-layer printed tablet, based on their treatment needs. Due to the potential in these cases for the 3D printing equipment to be portable and distributed, and to be used to make multiple medical products, other factors may need to be evaluated as part of the regulatory process, such as robustness against shipping and changing environmental conditions or cross-contamination potential, to ensure the consistent production of high quality pharmaceuticals from such processes.

	The Emerging Technology Team (ETT) is a specialized group with representation from CDER’s Office of Pharmaceutical Quality (OPQ) and the Office of Regulatory Affairs (ORA) that works directly with various external stakeholders to help identify and resolve scientific issues for new technologies. Pharmaceutical companies can have early discussions with the ETT regarding manufacturing design and development issues and obtain FDA’s recommendations for regulatory submission content related to new manufacturing technology, as clarified in a draft guidance (1). What makes this approach novel is that this dialogue can occur during early technology development prior to the submission of a drug application to FDA. Such early engagement enables FDA to proactively identify and address potential roadblocks and helps eliminate potential delay in the adoption of promising new technologies. In addition, when regulatory submissions involving novel manufacturing technology are received by FDA, the ETT will work collaboratively with the pharmaceutical quality review offices to ensure timely assessment of the submission. The continued involvement of ETT from the early technology development to application review will help ensure the consistency, continuity, and predictability in review, including the facility inspection, of emerging technology.

: What other research is FDA conducting in 3DP?

: CDER/OPQ’s Office of Testing and Research (OTR)’s Division of Product Quality Research (DPQR) has established a manufacturing science research program with the goal of enabling innovation and advancing the understanding of the risk and benefits of novel technologies, including process analytical technologies and 3D printing, to support FDA’s regulation of pharmaceutical quality.

	Other regulatory science and research projects within CDER, funded by a Critical Path grant, seek to advance the understanding of the relationship between material properties and process parameters on product quality for 3D-printed drug products. These initiatives will encourage the adoption of innovative approaches to pharmaceutical manufacturing by ensuring that FDA quality experts understand the science and application to enable meaningful and appropriate regulatory oversight, from application review through facility inspection, of manufacturing technologies likely to improve product safety, identity, strength, quality, and purity. 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base 

	When referring to this article, please cite it as J. Markarian, " FDA and the Emerging Technology of 3D Printing," 

A Q&A with FDA to gain insight on FDA's views of three-dimensional printing and its regulation in drug manufacturing.

FDA and the Emerging Technology of 3D Printing

annual survey asks finished drug-product manufacturing equipment users in both parenteral and solid-dosage manufacturing about how equipment is meeting their needs and how new technology and initiatives are shaping the industry. Respondents were from diverse companies that manufacture products around the world (see 

 Equipment and Manufacturing Survey targeted individuals in production and engineering. The survey was conducted by email in May through July 2016 and had 132 respondents. Approximately 35% were from innovator pharmaceutical companies, 32% were from generic-drug companies, and 18% were from contract manufacturers. The remaining respondents (fewer than 6% each) included consumer healthcare companies making over-the-counter products, equipment or machinery vendors, excipient and raw material suppliers, and consultants. Respondents included solid-dosage manufacturers (60%), parenteral drug manufacturers (30%), and those who participate in both areas (10%). Companies represented by the survey manufacture products in: the United States (61%), Canada (23%), Mexico/Central/South America (24%), Europe (53%), Asia (38%), and other regions (11%), which included Africa and Russia; respondents could choose more than one region. 

	Survey results suggest that, as in past years, equipment users are typically satisfied with existing equipment and with the level of innovation in most equipment areas. Although continuous solid-dosage manufacturing is viewed as a crucial area for innovation and is being used to some extent, significant commercial growth in use of this technology has not yet materialized. Equipment metrics are widely used and seen as valuable. The following summarizes some of the findings from the 2016 survey. 

	Respondents who use solid-dosage equipment indicate relatively high satisfaction with the equipment they are currently using. As shown in 

, in six categories (mixing/blending, encapsulation, tablet compression, feeding/dispensing, granulation, coating, and packaging), 90% or more said equipment utility was "excellent, completely satisfied" or "good, but see areas for improvement." More than 80% of respondents indicated that packaging and powder transfer/materials handling were excellent or good. In-process testing/process analytical technology (PAT), integration with manufacturing and business systems, and process control/automation ranked slightly lower, with 65–70% of respondents indicating excellent or good performance. These rates of satisfaction are similar to rates in the past two years surveyed (1, 2). Satisfaction with innovation in all the areas surveyed paralleled the respondents’ satisfaction with current equipment.

Approximately 40% of the respondents who use solid-dosage equipment indicated that they employ continuous processing either overall or in select unit operations. In past years, most respondents indicated that they expected continuous manufacturing to advance. In an open-ended question in this year’s survey, nearly 10% of all respondents listed continuous manufacturing as the most important area for innovation in pharmaceutical manufacturing. The percentage of respondents using the technology, however, is the same as in 2014 (1). Cost (e.g., to invest in needed equipment) was noted by 72% of respondents as a barrier to implementing continuous manufacturing. Other barriers selected by respondents (multiple answers allowed) included insufficient expertise to adapt processes (45%), insufficient PAT available in the market to enable continuous processing (41%), concern over regulatory acceptance (39%), lack of equipment available in the market (33%), and lack of appropriate documentation systems in place (30%).

satisfaction with equipment used in parenteral manufacturing was generally good; 80% or more respondents indicated "excellent" or "good" for all categories except one. More than one-third of respondents noted significant problems with existing equipment in the area of integration with manufacturing and business systems. More than 90% of respondents were satisfied with the level of innovation in most areas. Two areas where some noted a lack of innovative solutions to problems were in system integration (15% of respondents) and process control and automation (13%).  

	Respondents in both solid-dosage and parenteral manufacturing who use containment for high-potency drug production employ various strategies, and combinations of strategies, including personal protective equipment (63%), dedicated production areas (55%), restricted area barrier systems (55%), and isolators (47%). When asked to choose the one most challenging area for high-containment/high-potency, responses were diverse, as shown in 

	Measuring and tracking equipment and operational effectiveness is strongly supported by equipment users, as indicated by those surveyed in 2015 (2) and 2016. More than 90% of respondents to the 2016 survey believe that metrics and trend analysis enhances the ability to improve equipment operation. More than three-quarters of respondents work in a company culture that encourages use of manufacturing metrics, and 78% use trend analysis to evaluate equipment performance. Nearly 60% have metrics to measure unplanned downtime or equipment failure.

Just under half of survey respondents, in both solid-dosage and parenteral equipment areas, were aware of equipment failures that had led to significant downtime or quality problems in the past year. Contamination or cleaning problems were the most frequently indicated root cause of failure indicated by 48% of solid-dosage manufacturers responding and 58% of parenteral manufacturers responding. Other causes of failure included utilities and process validation (approximately one-third of respondents each) and nonconformance (approximately 20%); equipment age was also noted as a root cause.

	This year respondents were asked for the first time to reveal how various initiatives would improve equipment uptime or efficiency. Approximately 90% of respondents thought preventive maintenance, investing in new equipment, more metrics and management focus on equipment, and/or renovating facilities would have some or significant positive effect. Approximately 80% also indicated that more regulatory focus on equipment or switching to continuous manufacturing would help. Other factors that respondents thought would improve efficiency or uptime included improved automation or software upgrades and lean manufacturing concepts.

	PAT, which measures characteristics of in-process materials, is an enabling tool for continuous manufacturing, process automation, and even equipment metrics and continued process improvement (3). In the five equipment areas surveyed (see 

), 24­­–45% of respondents use PAT and another 25–33% plan to implement PAT use in the coming year. Although these responses indicate growth, use and intended use of PAT among survey respondents has not shown a significant increase but has been consistent for the past three years. 

When asked to identify the most important areas for innovation in pharmaceutical manufacturing, several respondents listed continuous manufacturing and PAT. Automated processes and real-time release were also noted, along with process efficiency, lean manufacturing, and operational excellence. Several other respondents indicated quality control or quality assurance improvements as the most crucial, including enhanced methodology and rapid microbial testing. Others noted streamlined R&D, regulatory changes, cleaning, and maintenance as key. Although no respondents listed “internet of things (IoT)”, IoT does play a role in several of these areas.

	When referring to this article, please cite it as J. Markarian, "Measuring Equipment and Manufacturing Trends," 

PharmTech’s 2016 survey shows general satisfaction with existing solid-dose and parenteral manufacturing equipment, and slow adoption of continuous manufacturing processes.

Measuring Equipment and Manufacturing Trends

	A good understanding of the properties of the plastic materials used to make single-use biopharmaceutical manufacturing system components is crucial. Polymers can vary in their barrier properties, whether physical properties change at extreme high or low temperatures, in their ability to hold up under sterilization conditions, and in extractables and leachables. Polymers used for single-use bio/pharmaceutical systems can include polyethylene (PE), polypropylene (PP), polycarbonate (PC), and-more recently-fluoropolymers. 

 spoke with Eric Isberg, director of Life Sciences at Entegris, which recently introduced its Aramus single-use bag assembly made from a gamma-stable fluoropolymer, about considerations for single-use materials.   

 Are there temperature limitations for single-use materials?

 Most single-use bag assemblies are limited to a temperature range of -20 to 40 °C. The limitation is mostly due to the bag film itself. Below this range, the materials become brittle and fail, and above it the materials soften and can melt. Rapid changes in temperature, temperature cycling, or temperatures below -70 °C can cause delamination of the film layers and film failure due to cracking.

	The Aramus single-use bag assembly is designed and tested from -85 to 40 °C. However, the film and bag boat fitment are made from a single layer of fluoropolymer material that is suitable for use down to -200 °C and as high as 200 °C.

 What are the concerns with single-use materials affecting cell growth?

 All additives-whether they are by-products or purposely added chemicals like antioxidants, UV stabilizers, or processing agents-are potential leachables that can have a negative effect on processes and products.  For example, certain purposely added chemicals have been shown to negatively affect cell growth. Our fluoropolymers have none of these by-products or additives that can leach out into the process.

 What are the concerns with particulates coming from the materials? 

 Both foreign particles, as well as particles native to the bag assembly materials, which are generated during manufacturing, are potential process contaminates. Aramus single-use bag assemblies are manufactured in an ISO Class 5 environment, greatly reducing the potential for particulate contamination. The advantage of manufacturing in an ISO Class 5 environment is a reduction in foreign particles from both the manufacturing environment and the manufacturing process itself. Utilizing sufficient laminar air flow across the parts during manufacture can sweep away any airborne particles that are generated. Also, controlling the dryness of the air, combined with other static-elimination methods, can keep airborne particles from sticking to surfaces, including the surface of the single-use components being assembled. Lastly, reducing the number of penetrations on the interior of the bag reduces the chance of particles being introduced. Fluoropolymers are not inherently better than other plastics in terms of native particle generation during manufacture. It is a matter of how those particles are reduced using these steps as well as other proprietary methods, including post-processing procedures.

Gamma-stable fluoropolymers are an alternative material for single-use bags and assemblies in biopharmaceutical manufacturing.

Considering Single-Use Materials

Data integrity, which refers to the completeness, consistency, and accuracy of data, is a key part of CGMP compliance for drugs, said FDA in its April 2016 draft guidance (1). The agency said at a 2014 conference that it anticipated more enforcement of data integrity issues, including warning letters, product seizures, import alerts, and broader injunctions (2), and indeed, several warning letters since then have focused on data integrity.

	Regulatory and industry organizations have tried to clearly spell out what data integrity means. Several other regulatory bodies have also published guidelines and guidance regarding data integrity. The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) published a guidance for industry defining data integrity in March 2015 (3). The United States Pharmacopeial Convention (USP) proposed a new General Chapter <1029> on good documentation practices (4). And in June 2016, the World Health Organization (WHO) published a guidance on good data and record management practices (5).  

	Data integrity should be thought of as a whole system, says Rebecca Brewer, strategic practice lead for Quality Executive Partners. “All components of the system-organization, culture, and oversight; training and performance management; data management; physical controls; and documentation practices-must be working effectively to provide the highest level of assurance of data integrity.”

	"Management must align expectations with the capability of a process, site, or even a person," adds Monica Cahilly, president of Green Mountain Quality Assurance. "If the infrastructure or the resources aren't there-for example, to achieve a certain throughput-errors may result and there may be a greater risk for falsification of data to try to meet targets. Establishing and staying within the boundaries of a design space that yield a safe and effective product is fundamental to meaningful data integrity and data governance programs."

	"In large-molecule production, with all the complexities of this technology compared to small molecule, companies must be mindful of what targets can be realistically achieved given the variability of the technology. Saying we can hit a target that we can not is a mistake," says Cahilly. Regulatory guidance documents are beginning to acknowledge this with more realistic targets specific to large-molecule testing. For example, a 2013 FDA draft guidance on bioanalytical methods (6), which revises a 2001 guidance, gives broader acceptance criteria (e.g., for accuracy and precision) for ligand-binding assays, notes Cahilly. 

	As companies work to improve data integrity, computerized systems and electronic records are playing a key role. The International Society for Pharmaceutical Engineering (ISPE) GAMP Community of Practice started a data integrity special interest group (SIG) in January 2014 due to the high interest in this area, says Michael Rutherford, the GAMP global chair and sponsor of the SIG. The group has published concept papers and offered education sessions to help members get a handle on data integrity, including challenges with electronic records.


	Recent attention to electronic records is primarily because these systems have not yet been as closely examined as traditional paper systems, says Cahilly. But whether records are paper or electronic doesn't really matter, say experts; the core principles of ALCOA+ (data must be attributable, legible, contemporaneous, original, accurate, complete, consistent, and enduring) apply to both. 

						Rebecca Brewer, strategic practice lead for Quality Executive Partners, explains some of the concerns with electronic records.

 Part of ALCOA+ is ensuring an available and enduring record. What risks are associated with this aspect of electronic records?

 The systems from today may not be fully compatible with the systems of tomorrow, and it is a constant struggle to ensure that not only the data, but also the metadata, are available in a readable, retrievable format for the duration of retention period of that data. Although batch release data may have a limited shelf-life in terms of archival, data in support of development, technology transfer, stability, validation, and continued process verification may be required for the full life-time of the product itself.

						Mitigation of these risks depends on effective planning for obsolescence. At the time of computer system/automation design, it is not too early to begin thinking about how records will be maintained in an accessible format after the system has reached obsolescence.

		“Manual systems most commonly suffer from failure to be a contemporaneous record, and may not be original, accurate, and complete,” notes Brewer. “Since the inception of GMPs, the industry has been emphasizing the importance of good documentation practices, yet today we still see occasional ‘pencil whipping’ of records, where an employee finishes a series of tasks and then signs for all of them (rather than completing the entries as the tasks were accomplished) or occasions where one employee signs for another employee’s activities.” Automated, electronic systems can be better if they restrict access and ensure that entries are attributable.

	Making sure records are original is key in both paper and electronic versions. "There is a trash can on the computer just like a trash can in the lab," notes Lorrie Schuessler, a co-leader of the GAMP SIG. "Controls must be in place for computers to prevent deleting or renaming files or changing a record's date. Inspectors are trained to detect the specific ways that data changes can be covered up in computer systems just as they look for fraud in paper records."

	"Sometimes people change records intentionally, but sometimes they may just be trying to make it less sloppy, for example," notes Rutherford. "Any time you have a human in the process, we make mistakes. Someone might not strictly follow procedures, and there might not be strict enough controls that force good data integrity."

	One challenging area is having controls to prevent 'orphan data', which are results that are acquired but not reported or reviewed. "A good example of orphan data is when there are 'test' injections performed under the auspices of an investigation or in preparation for running a sample on a chromatography system, where these samples are never included in the formal investigation or run report," explains Brewer. "These unreported sample results can, intentionally or unintentionally, prevent failing data from coming to light or serve as a way in which an operator can change the operating conditions to ensure a good result. Management oversight should include a combination of policy, procedure, training, monitoring, and metrics. 'Trust but verify' should be the watchwords for the program, with frequent inspection to look to ensure that no orphan data are detected and to ensure that all operations comply with the intended policies and procedures.”

	Self-recorded data (i.e., data that are not captured directly from a networked automation system) is another concern. "In these cases, it is important to think carefully about when the 'four eyes' principle should be employed and when a 'second check' is required," suggests Brewer.

	A special concern for electronic data is security-changes should be made only by authorized personnel and these changes should be recorded. "Making a change on paper is more obvious, because you can easily initial, date, and note a reason for the change," notes Rutherford, but with electronic records, systems need to be set up to control changes. "Shared accounts or roles are common in manufacturing control systems, but this is a challenge for data integrity because, for example, six different engineers could change a parameter. Regulatory agencies would prefer to not have shared accounts. But for situations where they are necessary, such as for running a test over a 24-hour period, there must be other ways of showing the integrity of the data."

	"Ideally there would be a technological solution to the problem of having shared accounts by keeping track of who to attribute data to," adds Schuessler. "If an electronic solution isn't available, sometimes the way to deal with this situation is a paper log."

	"Whether you use a computer or paper, you can have data integrity issues," concludes Rutherford. "The key is to manage and control the risk so it doesn’t affect patient safety. Doing this includes having a quality culture, proper procedures, and making sure people are reviewing data properly and catching problems before they impact product quality and ultimately patient safety."


	A data integrity program should include a review of an audit trail, in which critical data points are reviewed. FDA's data integrity guidance promotes a risk-based approach to reviewing the content of the original electronic record, with a focus on changes to critical data, explains Cahilly. It is important to understand that the entire original electronic record is considered the original, even if only a subset of it is printed. "Regulators and quality units are now starting to understand where to find meaningful data and metadata and make more informed decisions about whether products are safe and effective," says Cahilly. "The challenge is to facilitate an efficient review by thinking through what is critical when you’re validating the system."

	In addition, people need to be trained to review audit trails to find problems in electronic data, says Cahilly. "On paper, reviewers are already trained to look for cross-outs and focus on the ones that may represent significant changes that could affect process, or method, or product, for example. In computer audit trails and metadata, reviewers would also look at audit trails and other meaningful metadata to determine whether a change to data was appropriate and properly investigated, if required. A review that is risk-based requires process understanding and thus would focus on changes to data potentially impactful to process rather than those of indirect or no impact. For example, was a datapoint changed, or was the change to correct a misspelling? Audit trails in process control systems in manufacturing may track alterations to recipe parameters, some of which may be significant. A focus on prevention makes less work in detection. For example, by securing the recipe to prevent alteration of significant parameters, there will be less metadata to review.”

	Electronic records can be an advantage in the review process, because the data are more accessible than with paper. However, "Reviewing all data all the time is impossible," notes Rutherford. "Review by exception allows you to focus on what is most critical. Computerized systems do this well by flagging unusual conditions to be reviewed."  A manufacturing execution system (MES) can flag when numbers are modified, for example, or when set-up parameters are out of specification. "If there are too many flags, they may be ignored," warns Rutherford. "It gets back to understanding the process and knowing which ones are important to flag."

	Current coding systems often have audit trail or "history" features, but they may need to be turned on. In some cases, software systems don’t have what is needed, such as the ability to capture data at the time of the analysis or activity, so some redesign of software is occurring as the industry's understanding of good documentation practice grows, notes Cahilly.

	Because process understanding is crucial, audit trail review should be done by the business function-by the operators, engineers, or laboratory analysts-rather than by the information technology (IT) group. "The quality group can oversee the review and IT can implement a system, but the business needs to own the data and its integrity," says Rutherford.

	The business group, not IT, should also be doing validation of flags and the audit system. "Validation is proving that the system meets your needs and is fit for purpose-that it provides technological control of data integrity," says Rutherford. "Some consider validation merely a documentation exercise, but really it comes down to whether you care if it works. You should know what a flag is supposed to do and test to show that it functions that way." Periodic reviews and a change-control process are also important.

	A practice that can be used in addition to audit trail review is a forensic audit, which involves selecting high-risk targets based upon triggering criteria. "These targets are then reviewed and traced from initial data source to final data output-an end-to-end evaluation-to detect any wrong-doing," explains Brewer. "Forensic audits can be used either proactively, as part of the monitoring associated with the site management controls, or in response to a specific known failure or suspected wrong-doing.”

Draft Guidance for Industry: Data Integrity and Compliance With CGMP

GMP Data Integrity Definitions and Guidance for Industry 

Proposed General Chapter <1029> Good Documentation Guidelines 

Annex 5 Guidance on good data and record management practices, WHO Technical Report Series No. 996

Draft Guidance for Industry: Bioanalytical Method Validation

:
	When referring to this article, please cite it as J. Markarian, "Data Integrity Challenges in Manufacturing," 

Designing systems using the principles of good documentation practice, including validated audit trails, is a key piece of a manufacturing data integrity program.

Data Integrity Challenges in Manufacturing

	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.

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