Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Fotosearch/Eriko Koga/Comstock/Getty Images; Dan WardSince FDA issued its report, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century—A Risk-Based Approach (1), and its guidance on process analytical technology (PAT) (2) in 2004, academia and industry have been making strides in integrating quality-by-design (QbD) principles and PAT into solid-dosage manufacturing processes. 

PAT and QbD principles both emphasize the need for process and material understanding as a basis for effective control of the process. “This emphasis has stimulated the industry to focus on how to get the information it really needs, which is leading to a productive re-examination of the existing analytical toolkit and an embracing of newer technologies that deliver the goods,” says Tim Freeman, managing director for Freeman Technology. Progress has also been made in integrating PAT into continuous manufacturing of finished-drug products, with the eventual goals of closed-loop control and real-time product release. 

Online PAT is successfully being used to optimize individual unit operations in solid-dosage manufacturing by monitoring on-line critical quality attributes (CQAs). Data from PAT give manufacturers better understanding and can be used to control the unit operation. Moisture content, for example, is used to determine the endpoint of a drying cycle. In tableting, the most common online measurements are near infrared (NIR) spectroscopy, which measures moisture content and blend uniformity, and laser-diffraction particle sizing. 

Bulk-powder characterization techniques, which are performed at-line or in the laboratory, also fulfill the purpose of PAT by providing crucial information in a timely manner. “Precisely quantifying the flow behavior of powders, either as raw materials or as a blend, and other characteristics such as the ease with which a powder entrains and releases air, supports the development of more efficient processes,” explains Freeman. Flow-property measurements are increasingly being recognized as a desirable online measurement, but this technology is not yet available. 

PAT can be used in continuous solid-dosage manufacturing, in which individual batch-processing units are connected in one process train. Advantages of continuous manufacturing include a smaller equipment footprint, production volume flexibility, and higher production efficiency, in addition to the potential for improved quality and process stability as a result of employing PAT. Continuous processing also allows more efficient process development. Because parameter-change effects can be measured in nearly real-time using a continuous setup, dozens of conditions can be tested in hours rather than days or weeks, notes Douglas Hausner, associate director for industrial relations and business development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), which is based at Rutgers, the State University of New Jersey. In most cases, the same equipment used in the development stage can be used in production, which eliminates the need for scale-up. 

Although most solid-dosage processes today operate as a series of independent unit operations, pilot programs for continuous processing have made progress, and commercial implementation could occur within the coming year. The design of a continuous direct-compaction line built at C-SOPS, for example, was recently used to construct a commercial line at Janssen, which will be filed for FDA approval.  

GEA Pharma System’s ConsiGma continuous manufacturing platform is an example of a commercially available continuous-manufacturing system. It can incorporate several different continuous technologies for the production of solid-dosage forms, such as wet granulation, dry granulation, and direct compression. The ConsiGma wet-granulation line consists of a blender, twin-screw granulator, fluid-bed dryer, granule conditioning unit, rotary tablet press, and continuous coater. This new generation of continuous manufacturing technology minimizes start-up and shut-down material losses because steady state can be reached quickly, notes Kris Schoeters, product manager for continuous processing at GEA Pharma Systems. PAT plays a crucial role in the GEA system. In the granulator, online optical systems are used to measure CQAs. Moisture content and blend uniformity are measured using NIR. Particle size is measured using an online laser-diffraction system, and tablet-content uniformity is measured using Fourier Transform (FT)-NIR transmission spectroscopy. Measurement data feeds into a process-control system to reach the goal of closed-loop control. 

Incorporating PAT into a continuous process for solid-dosage drug production has not been a simple task, however. One challenge has been retrofitting the equipment to enable collection of the correct data from PAT devices. Some measurements (e.g., flow, pressure, and temperature) are readily available from inline sensors. Other measurements, such as online NIR spectrometry, are more complex and have required creativity in the physical interface with processing equipment. Enabling the sensor to collect good data, for example, has often required that probes and windows be retrospectively engineered into the processing equipment. 

 “NIR is a reflectance measurement that measures whatever is sampled by the probe. If a sample is stuck to the probe lens, it will be measured repeatedly,” notes Hausner. The C-SOPS line incorporates a window for the NIR measurement in the transfer pipe directly above the tablet press to measure blend content as close as possible to the tablet press. C-SOPS researchers investigated several different designs of modifying the pipe leading into the tablet press. The researchers concluded that plug-flow without turbulence was crucial to minimizing noise and allowing the analysis to run quickly. 

 Figure 1: An in-process optical probe enables process analytical technology (Lighthouse Probe, GEA Pharma Systems).GEA Pharma’s self-cleaning Lighthouse Probe, developed with J&M Analytik, was designed as a solution to the problem of sample adhering to the lens (see 

). The viewing windows can be cleaned during the process, and a self-calibration feature indicates if a window is contaminated. 

Work at Pfizer included developing solutions for sampling, such as screw transfer devices that enable sampling points to be inserted in flowing powders and developing heated probes to avoid material sticking, notes Steve Hammond, senior director and team leader of Pfizer’s Process Analytical Sciences Group. Pfizer also conducted experiments to determine reflective properties of powders, depth of penetration, and return of radiation in loose and compressed powders. Other aspects of sampling, such as mass of material contributing to a measurement, integration times for scanning, and the effect of reference scanning had to be extensively studied and understood, adds Hammond. 

The next step after integrating PAT into the continuous process as a monitoring tool is to incorporate the data from PAT into process control. In a feed-forward/feed-backward or closed-loop control system, critical process parameters (CPPs) are dynamically adapted and fed to the controller to keep the process within specification. In today’s batch processes, unit operations are operated as “islands of automation,” but the goal of continuous processing is to control multiple, single units as one unit by using an overarching process-control system. 

Closed-loop control has been used successfully for many years in other process industries. “The frightening part for the pharmaceutical industry is moving from manual control with people making decisions to advanced process control, in which process data and modeling software automatically control the process,” comments Jonathon Thompson, senior manager of Compliance Services Consulting at Invensys. “PAT can give you a lot of data, which you need to turn into information about the process and whether it is within the CQA parameters,” he explains. “Process-modeling software compares real-time data to an ideal or ‘golden’ batch profile, identifies what parameters need to be changed to meet the ideal, and feeds this back into the control system.” 

Researchers have been addressing several issues while integrating process control. One issue is that although some process equipment (e.g., newer feeders) is typically already instrumented for control, other equipment may require retrofitting. The tubular blender used at C-SOPS, for example, had a simple motor with a tachometer to control the speed, and C-SOPS engineers added instrumentation to allow more sophisticated control of the blender speed.Integration of instrument software with plant equipment is a challenge. Some installations that require simple endpoint or on/off control could use simple, analog 4–20 mA connections, says Hammond, but the most valuable applications generally require more sophisticated control that involves developing either direct communication with the manufacturing equipment’s control systems or communication with plant supervisory control and data acquisition (SCADA) systems. 

 “Ten years ago these communication links were custom developed for each piece of equipment. In recent years the development of “open architecture” software has simplified this aspect of instrument integration,” explains Hammond. Open-architecture software (e.g., OPC) uses open standards that enable connectivity. This software meets the need for communication protocols to enable analytical instruments to communicate with control systems, says Hammond, who notes that, after working with instrument vendors and control-system companies over the past five years, most of Pfizer’s vendors’ instruments now communicate via OPC. 

Another challenge has been ensuring that data from PAT flows into the process-control system quickly enough to enable meaningful control of process fluctuations to keep CQAs within specification. “If the measurement takes longer than the residence time of the material—for example, 30–45 seconds of residence time in the blender—then the measurement can not be used for process control,” explains Hausner. He says that available NIR instruments are adequate for some applications, but faster analysis may be needed for other applications, such as smaller doses or lower percentages of API, which would necessitate more scans to obtain a measurement. C-SOPS continues to investigate solutions for NIR measurement in its production-scale Continuous Pharmaceutical Advanced Manufacturing Laboratory (CpAML). Analysis costs are part of the equation, notes Hausner. For example, a current CpAML project is comparing the use of one, fast (i.e., expensive) spectrometer with an array of slower but more economical spectrometers. An alternative method is inferential sensing, in which offline laboratory data is used with known correlations to give the control system the data it needs, adds Thompson. 

Tracking material flow through the system is a crucial aspect of process control. A SCADA system tracks the location of a “product plug” as it moves through the process and adds this context to the PAT data in the process-control modeling software, explains Ivo Backx, manager of business and project development for the pharmaceutical industry at Siemens Industry Automation Division. “In tablet production, for example, multiple variables control the CQAs and you need to know what these attributes are and the correlation between them at specific points in the process,” says Backx. “For example, you need to know that the material in the tablet press now had a certain content uniformity at the blender.” Material tracking through the system is linked to requirements for traceability, notes Backx. 

 Figure 2: A continuous, high-shear granulation and drying systemin operation at the GEA test center (ConsiGma, GEA Pharma Systems).Traceability is simple in a batch system because it is assumed that all the product from one batch is the same.  “For a continuous operation, traceability becomes much more important because not all the product is submitted to the same process at the same time. Using a first-in/first-out (FIFO) principle is, therefore, very important,” says Schoeters, who notes that GEA has adapted the unit operations of mixing, granulation, drying, compression, and coating in such a way that the product is traceable throughout the production line and back-mixing is limited as much as possible. The ConsiGma system, such as the line shown in 

, continuously monitors CPPs to keep them in control and maintain product quality. This includes measurements using PAT (e.g., particle size, moisture, uniformity), but primarily involves monitoring of and control-feedback loops on machine parameters. Torque of the granulator screws, for example, is continuously monitored, and a deviation from the set value triggers actions and alarms. 

High equipment costs and restrictions on capital spending are currently barriers to implementing PAT and continuous processing technologies. In addition, revised European regulatory guidance requires refiling of NIR instruments after calibration updates (3). “This new guidance on NIR is very restrictive. It does not allow for changes in raw materials, instrument maintenance, and all the routine occurrences that require calibration maintenance,” notes Hammond. 

Although real-time release (RTR) is a goal for industry and for regulators, only a few companies have achieved it as a commercial reality. In RTR, product quality assurance is based on online analysis, and the product is released as it is produced rather than a batch being held while waiting for quality-control testing. RTR could be implemented for batch processing, in that a batch could be released if there were no deviations throughout the batch. In continuous processing, product could be released continually given no deviations. Theoretically, online measurement would identify out-of-specification product and allow it to be segregated or even identify a change in CQAs before the product goes out of specification (4). 

A new program, Accelerating Innovative Research (AIR), builds on the C-SOPS infrastructure at Rutgers and is focused on working with existing PAT as well as partnering with companies to move RTR testing technology forward. The program will involve working with large pharmaceutical companies to run specific formulations as case studies in an effort to build up a toolbox of knowledge on how spectroscopic data can be used for RTR testing. 

Implementing closed-loop control is a step towards RTR. “Intelligent processes that are proactively controlled to ensure the expected outcome are inherently capable of supporting a RTR strategy. Regulators have always stated that tight control of the unit operations leading up to final product is the best way to ensure quality of the product and enable a RTR filing,” says Hammond, who notes that Pfizer’s Chantix RTR application is now filed in all major markets and most of the rest of world.  “The value of RTR has been reduction in laboratory testing. The focus in the future will be on enabling a modern supply chain, with flexible response to a pull from the market, and maintaining lower inventory.” 

Many in industry and academia say that continuous manufacturing using online PAT with closed-loop process control and real-time release represent the future of solid-dosage manufacturing. These concepts are part of a “seismic shift in culture change within the pharmaceutical industry, which continues to put the spotlight on manufacturing in a way that has been absent in the past,” concludes Freeman. 

Pharmaceutical cGMPs for the 21st Century—Risk-Based Approach: Final Report

Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance

3. EMA, EMEA/CHMP/CVMP/QWP/17760/2009 Rev2, “Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations, draft” (London, 2012), www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500122769.pdf, accessed March 4, 2013. 

FIGURES ARE COURTESY OF GEA PHARMA SYSTEMS

Articles

Industry is moving toward closed-loop control of continuous processing.

Process Analytical Technology and Process Control in Solid-Dosage Manufacturing

	Representatives from Merck, Pfizer, and Novartis shared their recent efforts in applying quality-by-design (QbD) concepts to analytical methods, and Todd Cecil from USP explained the related new draft USP chapter in a symposium at Pittcon on Monday, March 18, 2013. The session, “Understanding Analytical Method Variance and the Impact for QbD Filing for Pharmaceutical Products,” was sponsored by the American Chemical Society’s Division of Analytical Chemistry (ACS ANYL) and the American Association of Pharmaceutical Scientist’s  Analysis and Pharmaceutical Quality Section (AAPS APQ).

	In recent years, scientists have begun applying QbD concepts to analytical methods. An article in the March 2013 issue of 

The Role of Analytical Science in Implementing Quality by Design

,” discusses this topic and reviews the conclusions of a Parenteral Drug Association (PDA) workshop from March 2012 that provided a forum for stakeholders to explore the implications of QbD on analytical science. A QbD approach “highlights the potential to re-examine the way methods are developed and validated, in the same way that application of QbD to manufacturing processes has driven a revision in thinking of how process development and validation are performed,” say the article’s authors.

	Speakers at the Pittcon symposium described some of their work in applying the systematic approach and formal risk-assessments of a QbD approach to analytical methods.  Beth Junker of Merck, for example, described an “analytical target profile (ATP)” and talked about determining critical and key method attributes together with end-users of the method.  Design of experiments (DOE) can help optimize methods. Dr. Junker noted that because most design of experiments (DOE) training and guidance materials are intended for process scientists, her group found it useful to assemble a design of experiments toolkit, including software training, specifically for use by analysts. She added that QbD for analytical methods can aid with planning method lifecycle activities and reduce unplanned resource demands. James Morgado from Pfizer described the “Method Operable Design Region (MODR),” and explained that defining the ATP, performing risk assessments, and conducting DOEs to determine risk results in the MODR.

	Todd Cecil, vice-president of Compendial Science at the United States Pharmacopeia (USP), weighed in on defining acceptable analytical method variation and setting system suitability requirements. He described a new chapter, USP<1200>, with a working title “Requirements for Compendial Variation,” which introduces alternate tests (e.g., detectability instead of limit of detection) and reduces the total number of tests needed. Cecil noted that other industries (e.g., the food industry) have moved to this approach already and it will take time for it to be accepted by FDA, but that USP is moving forward.

Representatives from Merck, Pfizer, and Novartis shared their recent efforts in applying quality-by-design (QbD) concepts to analytical methods, and Todd Cecil from USP explained the related new draft USP chapter in a symposium at Pittcon on Monday, March 18, 2013.

Experts at Symposium Promote Quality by Design for Analytical Methods

FDA alerted healthcare providers and patients of a voluntary, nationwide recall of all sterile drug products from Med Prep Consulting, a specialty compounding pharmacy licensed by the state of New Jersey, in a March 18, 2013 FDA 

. Med Prep Consulting initiated the recall because fungus particles were identified in bags of magnesium sulfate intravenous solution after healthcare providers at a hospital in Connecticut observed the floating particles. The New Jersey State Board of Pharmacy entered into an interim voluntary consent order with Med Prep Consulting, under which the company temporarily halted all production operations. 

“Giving a patient a contaminated injectable drug could result in a life-threatening infection,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research, in the press release. “We do not have reports of patient infections. However, due to a lack of sterility assurance at the facility and out of an abundance of caution, this recall is necessary to protect patients.” FDA’s investigation is ongoing, and FDA is working with the Centers for Disease Control and Prevention and state officials in New Jersey and Connecticut to determine the scope of the contamination. 

Med Prep Consulting’s Tinton Falls, NJ facility prepares sterile products for intravenous administration in hospitals and physician’s offices or clinics. 

Last year’s fatal fungal meningitis outbreak was attributed to lack of sterility assurance in injectable products produced by a compounding pharmacy in Massachusetts. 

The New Jersey-licensed specialty pharmacy recalls magnesium sulfate products and halts all production operations.

FDA Investigates Med Prep Consulting for Contaminated Intravenous Solution

Process analytical technology (PAT) is being successfully used to improve understanding and optimize pharmaceutical unit operations, but greater value can be obtained by integrating PAT with overall process control of a continuous manufacturing system. 

 spoke with Ivo Backx, manager of business and project development for the pharmaceutical industry at Siemens Industry Automation Division, to gain insight on the issues involved. 

 What is involved in using the data from PAT measurement to control a pharmaceutical process?

 Regulatory authorities are pushing the pharmaceutical industry to better understand the manufacturing process and to measure the attributes that are critical to the final quality of the manufactured product, with focus on the therapeutic effect of the medicine. Critical to quality attributes (CQAs) must be measured and monitored against deviation limits. Parameters that are critical to the process (CPPs) must be controlled in order to keep the CQAs within the design space and continuously produce the right product with the right quality.

In the SIEMENS PAT quality data management system (SIPAT), the first step is to collect all relevant data from different sources, such as multivariate data from spectroscopy instruments as well as univariate data from classic instrumentation. The spectrum from an analyzer can be read out over a direct interface. Univariate data is typically already available in the process control system and can be collected from there. Data from off-line laboratory tests may be of interest as well and can be obtained over an interface to a laboratory information management system (LIMS). Principally, data from the different sources must be collected and integrated. In this process, time alignment is very important as the data are collected at different sample rates in the different systems. Context data (e.g., equipment identification, product-plug identification, batch or lot identification) are retrieved from the process control system and added to the data, thus allowing for product tracking and process data mining.

Statistical data regression models are applied to the collected data using chemometrics software runtime engines. The result is a value of the CQA (e.g., moisture content or particle size). The derived CQA can then be aggregated to calculate standard deviations and averaged values and can be monitored over time in a trend display. The aggregated values of the different CQA data over different unit operations of the total manufacturing process are the basis for advanced process control for closed-loop, model-predictive control, which steers the CPPs in the process control system. The different calculated CQAs are stored electronically and are the basis for real-time release evaluation.

 How are these systems being used today in finished solid dosage processes (e.g., tableting)?

 Today, PAT instruments are often used on single unit-operations to measure a CQA. Often, they are applied for closed-loop control but isolated to a single process step. For instance, moisture content is measured to determine the end point of a drying cycle. Hardness and thickness are measured and controlled in the tablet press. The concentration of the active ingredients may be verified basing on NIR analysis of tablet samples after the press. 

In order to get in-specification product the first time and all the time, however, the control strategy must be to take all the CQAs into considerations and deploy a feed-forward/feed-backward process control strategy over the complete manufacturing process. 

 Are there any other issues that limit the use of PAT in process control?

 Today, PAT instruments still have dedicated, proprietary interfaces. Now a new interface standard, the OPC UA ADI (Object Linking and Embedding for Process Control Unified Architecture for Analytical Device Interfaces), exists, but few instrument suppliers support it.  Another problem is that spectroscopy instruments are quite expensive. They are typically applied in laboratory environments and require more robustness to support a commercial manufacturing. This situation, however, is changing fast as new instruments come on the market. Another issue is that multidisciplinary teams are required to develop and maintain the PAT solutions, which is a challenge for most organizations. 

Process equipment suppliers often have a single PAT solution integrated in their equipment controls, with local data management on the local equipment human-machine interface. Validation of isolated, single operation solutions is a pain; tighter integration is a must. Platforms that integrate all CQA data from different sources (i.e., online, inline, at-line and off-line) into one central quality data management tool and deploy the overall control strategy from a central system should be used.

Ivo Backx is manager of business and project development for the pharmaceutical industry at Siemens Industry Automation Division, 

Process analytical technology (PAT) is being successfully used to improve understanding and optimize pharmaceutical unit operations, but greater value can be obtained by integrating PAT with overall process control of a continuous manufacturing system. Pharmaceutical Technology spoke with Ivo Backx, manager of business and project development for the pharmaceutical industry at Siemens Industry Automation Division, to gain insight on the issues involved.

Incorporating Process Analytical Technology Data into Process Control

Daiichi Sankyo warned that a product being sold online to consumers in Malaysia and Indonesia is illegally using Daiichi Sankyo’s name, logo, and registered trademark and is not manufactured or sold by any Daiichi Sankyo Group companies or subcontractors. The package of the falsely represented product, Glutax 4G Premium, is similar to one of Daiichi Sankyo’s Asian prescription-drug products, the company reported. Daiichi Sankyo placed advertisements in Malaysian and Indonesian consumer publications to warn consumers of the deceit. 

Daiichi Sankyo said that the advertisements were published because protecting consumers is its highest priority. The advertisements were published in Malaysian newspapers at the end of January and in February magazine issues, as well as in Indonesian newspapers at the end of February and in March or April magazine issues. The company is preparing to take legal action and is consulting with Malaysian authorities, the company announced in a 

Product sold online in Malaysia and Indonesia infringes on the companyâ€™s trademark.

Daiichi Sankyo Condemns Falsely-represented Product

 from GBI Research reviews the current opioid-product market, analyzes the development pipeline, and reviews industry merger, acquisition, and licensing deals to develop a picture of the market through 2018. The increase in opioid use has led to an increase in abuse and consequently to increasing concern from doctors and regulators. As a result, approved drugs are differentiated increasingly by abuse-resistant technologies. 

Many companies are working to develop abuse-resistant formulations of extended-release (ER) opioid analgesics, notes GBI Research. Most recent marketing approvals for ER opioids in the US have included risk evaluation and mitigation strategies that require license holders to provide physician training and raise patient awareness of opioid abuse. In many cases, post-marketing studies are required to examine the efficacy of abuse-resistant formulations. Initial post-marketing data reports for Embeda, which was launched in the US in 2009, are positive. 

The current opioids market has a broad and highly diversified product profile, reports GBI Research. The developmental pipeline is small, however, and the market is relatively stagnant. Competition among abuse-resistant products is expected to be the driving factor in this market. 

A GBI Research report says the opioid market will be driven by development of new products and post-marketing studies designed to reduce abuse risk.