Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Just before the New Year began, FDA warned the public that criminals were claiming to be agency officials and coercing individuals over the phone to pay fines as high as $250,000 for the illegal purchase of pharmaceuticals. These FDA impersonators somehow obtained records of individuals who had purchased pharmaceuticals online or through telepharmacies and told the individuals that their purchases were illegal. The impersonators asked that a fine be wired, most often to a location in the Dominican Republic.   

The international scam is taking advantage of individuals who seek to buy their medication online rather than from a doctor or pharmacy. Often, online drug products are less expensive and provide more convenience and privacy.  

The purchase of pharmaceuticals on the Internet is legal with a valid prescription. But in a consumer-safety guide on the subject, FDA warns that not all online pharmacies are US state-licensed, protect personal information, or provide accurate medication for the patient's condition. There's also the possibility of counterfeit or expired drugs being sold. 

Fraudulent federal officials capitalizing on the growing business are now giving patients another reason to be paranoid about opting for online pharmacies. The fact is, according to FDA's website, even if a crime was committed, agents and other law enforcement officials are not authorized to impose or collect criminal fines. Only a court can take such action. FDA is working with other government agencies to pursue these criminals, who have also posed as special agents of the FBI, DEA, and more. The scam isn't entirely new. In late 2008, FDA warned of fraudulent special agents that were enticing individuals to buy discounted drugs over the phone—of course, the products were never delivered. 

Although the Internet has provided the world with uncountable benefits, it seems to have opened a can of worms for the pharmaceutical industry—and for patients. 

Articles

FDA impersonators and counterfeit drugs threaten the public's trust in online pharmacies.

Is the Internet to Blame for Unsafe Drug Use?

Since the US Food and Drug Administration finalized its guidance on process analytical technology (PAT) in 2004, PAT tools and applications have evolved (1). FDA defines PAT as a "system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials with the goal of ensuring final product quality"(1). PAT tools may include multivariate data-acquisition and analysis tools, process analyzers or process analytical chemical tools, process and endpoint monitoring and control tools, and continuous improvement and knowledge-management tools (1). To gain a perspective on PAT in solid-dosage manufacturing, Angie Drakulich, managing editor, and Patricia Van Arnum, senior editor of 

gained the input of several industry experts. Todd Strother, applications scientist at ThermoFisher (Madison, WI) and Robert Mattes, application scientist at FOSS NIRSystems (Laurel, MD) discuss near-infrared (NIR) spectroscopy. Craig Dobbs, program manager of process analytics at Waters (Milford, MA), explains the use of ultra-performance liquid chromatography (UPLC). Alon Vaisman, application development manager for pharmaceuticals at Malvern Instruments (Westborough, MA), discusses the use of particle-size analysis. Tim Freeman, director of operations for Freeman Technology (Welland, UK), examines the use of powder-flow property PAT tools, and Janie Dubois, product manager for analytical imaging in the Americas at Malvern Instruments (West-borough, MA), discusses near-infrared chemical imaging (NIRCI). 

How are various techniques (e.g., NIR spectroscopy, UPLC, and particle-size analysis) currently used as a PAT tool in solid-dosage manufacturing and by your company specifically? 

Our Antaris NIR systems are an integral tool for PAT in pharmaceutical and solid-dosage manufacturing from raw-material analysis, to intermediate formulations, to analysis of the final products and tablets. First, the systems are used on the receiving dock to verify the material being brought in is correctly identified and of the quality needed. Good-quality NIR systems are robust enough to withstand the abuses that might be found on the loading dock, including extremes of temperature and humidity as well as vibrations from equipment. The technique is suitable for these conditions and can produce usable data right there on the loading dock without taking samples back to the laboratory for more labor-intensive analysis. 

NIR also has been found to be highly valuable throughout the formulation process. Small portable units such as our Target systems are fitted onto powder blenders to determine when blending is complete and to guard against overblending, which will ruin a batch and cost a substantial amount of money. These units will typically communicate their data wirelessly and draw their power from rechargeable battery packs or slip rings. Other areas in the process can be monitored on-line or in-line in real time, including batch reactors, storage tanks, dryers, and even pipe lines. NIR light is easily ported through many meters of fiber-optic cables and probes to access areas that challenge other techniques. This ability, of course, allows every aspect of the process stream to be monitored and ultimately controlled for deviations in the process. High-quality and well-utilized systems can interface with process-control software to automatically set off alarms, open valves, or add components at precise times to make sure the manufacturing process behaves properly. 

Dynamic powder characterization using the Freeman Technology FT4 Powder Rheometer. (Courtesy Freeman Technology) 

NIR is an exceptionally good tool to nondestructively monitor the quality of the final solid-dosage form. The light can penetrate deeply into and through most tablets to determine total amounts of the active pharmaceutical ingredient (API). Transmission-type measurements collect this NIR light that travels through the solid forms and provide information on the internal materials while reflection-type measurements provide information on tablet coatings and thicknesses. All of this can be done automatically and nondestructively 

The FOSS MasterLab includes a transmission NIR option designed specifically for solid dosage form analysis. It has been adopted by major pharmaceutical manufacturers because it can be used at-line to measure content uniformity of active ingredients in capsules and tablets. The MasterLab can be placed next to the tablet press to ensure the quality of the cores and/or the finished product. Process NIR instruments are designed to be used in-line to measure residual granulating liquid in fluid-bed dryers or single-pot granulators. Mean particle size and polymorph conversion can be monitored at the same time. 

Industry and regulators alike recognized very soon after the PAT initiative began that NIRCI was a unique laboratory technique that could help determine which product parameters should be monitored on-line and at what stage of the manufacturing process. Indeed, analyses of blends, intermediates, and finished tablets have provided pharmaceutical manufacturers with information about the critical quality attributes that affect quality and performance. 

Similarly, the correlation between size, shape, and chemistry in granules has been shown to be important in understanding product performance. Interestingly, however, this correlation has led many to conclude that, in most cases, online monitoring of size only is required once the size-chemistry relationship is understood. While not in itself a PAT sensor, NIRCI can be used to deploy PAT sensors where it matters in the process. It can also be used as a risk-assessment tool for factors such as ingredient sourcing and process modifications. 

Throughout a therapeutic compound's life cycle, liquid chromatography (LC) is routinely used in discovery, research, development, manufacturing, quality control and release, and post-shipment stability monitoring. It is imperative that such LC analytical data be secured, easily archived and searchable, quickly cross-referenced, overlayed, and instantaneously available. The concept of a long-term historical database focused specifically on full characterization of a therapeutic molecule is at the core of FDA's quality-by-design (QbD) initiative. LC permits disparate analytical data from different process stages to be compared. 

The manufacture of an API is invariably a solution-phase-based process, which is the ideal sample matrix for LC analysis. Whether the sample matrix is aqueous, organic, or a mixture, analytical LC testing of in-process material (IPM) is routinely performed today in an off-line manufacturing quality-control (QC) laboratory to monitor reaction progress or to specifically measure individual parameters such as IPM purity or concentration. During a single in-process LC analysis, a breadth of information can be extracted: raw-material consumption, IPM purity, IPM concentration, and low-level or trace concentrations of impurities as low as 0.01% 

What has kept LC from being adopted directly onto the manufacturing floor is that LC analysis simply takes too long to generate a result. LC may produce data with breadth, specificity, sensitivity, and accuracy, but off-line QC laboratory sample-to-answer times are typically in excess of 4 to 6 hours. That reality is rapidly changing. With new at-line and on-line analytical LC tools, manufacturers can make a measurement, generate information, and make a decision in real-time, or under 5 minutes. Waters introduced UPLC technology (Acquity UPLC System) in 2004 to provide real-time LC capability. The technology is available for automated direct on-line and at-line IPM analysis on the manufacturing floor with a process analyzer (Patrol UPLC, Waters). 

To provide the maximum return on investment, a PAT tool should provide the user with accurate and precise results in an automated fashion without compromising process performance or quality. These results must be available in timeframes that allow the user to make process decisions and facilitate real-time release (RTR). The results must be available in a standardized format to allow integration into plant-control systems. And finally, the PAT tool must be designed to comply with current good manufacturing practice (GMP) guidelines and be robust enough to last. 

Compared with various imaging and chord-length measuring techniques, laser diffraction, a well-understood method throughout industry, offers the user precision as well as high statistical significance of an ensemble technique. Instruments such as Malvern Instruments' Insitec On-line Particle Size Analyzer are capable of producing up to 4 complete results per second while analyzing a large fraction (several kg/h) of the product. Compliance with the OPC data access specification enables this analyzer to communicate with most commercial plant-control systems and devices. Because the analyzer can produce results in real time, it is an efficient tool for pharmaceutical milling, spray-drying, and roller compaction applications. By producing absolute-size information rather than trend monitoring alone, Insitec enables closed-loop process control and on-line quality control. For example, when installed on a discharge of a hammer mill, the analyzer can be used to control the speed of the milling rotor by reporting particle-size parameters to a mill programmable logic controller (PLC). The PLC will adjust the rotor speed to maintain constant size, which results in stronger product consistency. At the same time, the analyzer data can help produce cumulative batch results. 

For formulators of solid oral-dosage forms, or tablets, it is essential that the properties of the [powder] blend be such that they can be manufactured in an efficient way. For example, a certain number of fines may be an advantage when it comes to expediting dissolution. These fines, however, may cause the blend to behave in a more cohesive manner, which could result in flow problems during manufacture. It goes without saying, if a formulation can't be processed into a final product, its suitability for optimum final-product properties is irrelevant because it can't be manufactured in the first place. 

Although powder-flow measurements are not taken in-line, they provide new and valuable at-line information about the powder and its suitability for processing. For example, at-line powder-flow measurement tools can help verify the 'end-point'" of a wet granulation process, identify batch to batch variability of raw materials or intermediate product, or ensure that the final blend powder characteristics are suitable for processing through the hopper, feedframe, and into the die, before final compression in a rotary tablet press. 

Traditionally, techniques such as particle-size distribution and tapped density have been measured to try to correlate these parameters with powder behavior in process. Today, with the introduction of techniques that can simulate the conditions imposed in the process environment and measure the powder's response, performance can be measured rather than inferred. This new information enables [a formulator] to establish a database of flow properties for each product and provides a platform on which new products can be introduced with greater confidence. The formulator will know 

which powders will work well in the planned process, and which powders may be problematic. Armed with this information, formulators can engineer new products to have characteristics that are similar to those of powders that have previously demonstrated desirable process behavior, and avoid powders with properties that have been shown to cause trouble during manufacture. This, of course, is the essence of quality by design. 

What are challenges in using PAT tools and how are these resolved?  

NIR instruments are widely used in PAT applications simply because there are fewer challenges in implementation than other techniques such as HPLC or mass spectrometry. NIR instruments are considerably more robust and less finicky than other analytical instruments. Also, multiple components in a mixture can be measured simultaneously from a single collected spectrum. 

That being said, there are a few challenges facing users who depend on NIR for process information. NIR isn't as sensitive as other techniques and dispersive instruments are somewhat slow and don't provide the highest spectral resolution. One way to improve on sensitivity, spectral resolution, and speed is to use a Fourier-transform NIR instrument. The nature of these instrument designs allows them to collect a large amount of high quality spectral data rapidly in just a few seconds. 

A second challenge is in interpreting the spectral data to provide answers and results. Spectral peaks and information that identify a specific component and concentration aren't as obvious to the human eye as with mid-IR spectra or mass spectroscopy. Fortunately, we can take advantage of common computers to perform chemometric statistical analysis on the NIR spectra. This approach allows us to tease out subtle spectral features that would otherwise not be obvious. Relying on computers to perform the Fourier transform and chemometric analysis leads to a secondary advantage in that these instruments become very easy to use. A good software package will allow a user to just push a button to collect a spectrum and return a result. Even better for PAT applications is that the instrument can be integrated in the process-control system and work autonomously without need of human interface. 

Implementation of instrumentation on-line or in-line is a challenge in a regulated environment due to limited access and production schedules. Training of facility personnel as well as operators and developers helps to expedite the implementation cycle. The training is also important to minimize the down-time of the process. 

To offer a specific example of resolving challenges in UPLC, the Patrol UPLC system began as a collaborative effort between Waters and a major pharmaceutical company to bring real-time LC to the manufacturing floor. This pharmaceutical company required that the Patrol UPLC System operate in an at-line mode, where a manufacturing floor operator simply would drop a barcoded sample tube into the system, and in an online mode, where the system automatically would draw sample directly from multiple manufacturing slipstreams. The company also required that the Patrol UPLC system have the automated capability of switching analytical methods and columns based on information from the sample vial barcode and/or instructions from the factory's distributed control system (DCS). Remote access to the system was also of critical importance to enabling monitoring the system from anywhere in the facility or from any of its worldwide facilities. 

In another case, the customer stipulated that there could be no deviation from the existing workflow. The preexisting workflow consisted of the operator drawing a sample from a process-scale reactor into a barcode-labeled vial and transporting it to the off-line QC laboratory and waiting 6-10 hours for an actionable answer from QC. With the at-line version of the Patrol UPLC system, after the sample is drawn, the operator presses a green start button on the touchscreen, which unlocks a sample introduction port door, into which the sample tube is placed for analysis. The system immediately reads the barcode to confirm chain of custody and validates with the DCS and laboratory information management system that the loaded sample is a correct sample during the designated time window. If the sample is appropriate to analyze, the system will take custody, complete the analysis within 60 seconds to 5 minutes, calculate the results instantaneously, and send them to the DCS. The entire analytical process can be reduced from over 6 hours using an off-line laboratory to less than 15 minutes. Also, if an incorrect sample is mistakenly placed in the analyzer, the system will notify the operator immediately after the barcode is read 

the touchscreen interface. If the vial is not removed after a specified time period, the system will send an email notification/error message to a specified list that may include the operator, a process engineer, and the line manager. 

Another important characteristic is that the online version of the Patrol UPLC system runs under full automation without operator interaction. The system receives a signal from the DCS to begin the automated sample-extraction process from the manufacturing slipstream. Once the system aspirates the sample, it may require some sample preparation in the form of a dilution (usually up to a 1:50 ratio of 1 part sample to 50 parts of diluent), a solvent exchange, solubilization, or a derivatization reaction. Automated sample preparation is completed in under 90 seconds if no hold times are programmed, and the sample is analyzed. Like the at-line version, analysis can typically be completed within 60 seconds to 5 minutes. Results are calculated instantaneously and sent to the DCS. 

Rather than being a ruggedized modification of a laboratory analyzer, Insitec is a true process system with continuously purged optics, modular design, and no moving parts in operation. This compact system can be easily integrated into pilot-and production-scale operations. 

An extremely important part of analyzer integration is ensuring the 'representativity' of the analysis. Any analyzer, be it an in-line probe or on-line slip stream is dependent on representativity of the sample it actually sees. Moving powder often tends to segregate, so to ensure sampling representativity, flow conditions must be evaluated and, frequently, the use of a flow homogenizer will be necessary to counter segregation. 

 Powder-flow tools are used at-line and, therefore, require an operator to sample the product from the process before measuring the powder-flow properties. In-line technology maybe more desirable for PAT, but PAT should ideally focus on identifying measurement techniques that provide the most relevant and representative data. For instance, a process engineer doesn't care if the particle's size changes from batch to batch, as long as they can process the powder through to final product while ensuring the tablet's quality attributes are met. The at-line measurement of powder-flow properties will help the engineer predict subsequent process behavior and if the measured data deviate significantly, variation in process performance should be expected. 

In general, NIRCI is not used on-line or in-line, but rather at-line. Numerous studies have shown that the product and process understanding obtained with this technique often enable the use of 'simpler' sensors on-line to monitor markers of specific phenomena. This approach has proven to be economically beneficial because it provides the monitoring required to ensure product quality, without requiring the financial investment and technical challenge that might arise from acquiring chemical imaging in real time or in moving systems. 

What are recent advances in instrumentation to apply PAT in solid-dosage manufacturing? 

 In addition to the development of Fourier transform NIR, the more significant advances in the industry probably relate specifically to blending applications. There are several companies that have instruments designed to attach to blenders to monitor a mixture of powders to ensure they are properly mixed without becoming 'overblended.' 

There is also ongoing work to improve integrating NIR as part of a total analysis system. We've worked with organizations that would like to run a battery of tests on solid-dosage forms ranging from weight, hardness, and other physical properties to more in-depth chemical analysis from NIR. We also have found that NIR can also be used to accurately predict some physical properties such as particle size, crystalline polymorphs, hardness, and density. 

The latest technology is digital dispersive NIR. These instruments are fast and accurate and are not sensitive to vibration as Fourier-transform (FT) instruments can be. Due to higher noise levels, FT instruments require more co-added scans for a complete spectrum. FT instruments claim higher resolution but this is not an advantage in the NIR spectral region, where absorbance bands are broad and where using the higher resolution only makes the FT instrument signal-to-noise poorer. New applications are developed all the time. For example, digital dispersive diffuse transmission methods have been applied to prolonged release tablets for the prediction of dissolution profile, which can greatly reduce analysis time. The FOSS MasterLab has proven to be robust in harsh manufacturing environments and delivers extremely accurate and reliable results providing manufacturing with real-time feedback on content uniformity, moisture and other quality attributes. 

Automation of data acquisition and processing has allowed the rugged solid-state SyNIRgi (a Malvern NIRCI analyzer) to be brought to the process line for data acquisition at various sample thieving points. Minimally-trained personnel can now collect data enabling thorough process understanding. 

Recent advances in integration and control software have significantly simplified embedding on-line size analyzers into manufacturing equipment. An embedded on-line analyzer, with fully integrated controls, serves to convert a traditional batch-manufacturing unit into a continuous operation with higher throughput, less waste, and better product quality. Availability of streaming on-line data reduces or removes the need for off-line sampling saving time and resources. 

As mentioned above, the measurement of powder flow and other behavioral characteristics, in a process relevant way, is relatively new. As a result, advances in powder and process understanding are continuing at a rapid rate. Most leading global pharmaceutical manufacturers are employing this technology in process, development, and quality-assurance environments. 

Guidance for Industry: PAT-A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance 

Leading experts share insight on the current and future direction of process analytical technology. This article contains bonus online material.

PAT: A New Dawn for Drug Product Quality

The US Pharmacopeial Convention (USP) is recalling 

, multiple monograph errors were introduced into the publication when it was converted into a new format and published on 1 November 2009.

28 to go into effect was 1 May 2010. According to a public notice of 12 January 2010, the redesign of the publication, including all 4000 monographs, encompassing more than 4100 pages, was "intended to improve ease of use, streamline presentation, and update and harmonize terminology, but was not intended to change any of the monograph requirements…. While many of the monographs were successfully redesigned, a significant number contained errors."

 on an ongoing basis is inefficient for the current problem, thus necessitating the recall of 

Other official texts related to the recalled publication remain available and may be used with confidence, including the 

USP Dietary Supplement CompendiumFood Chemicals Codex

, Second Edition, and its supplements; and the 

. In addition, Accelerated Revisions posted on the New Official Text section of the USP website are not affected by the recall and are official as of the dates indicated on the 

USP will reissue the online and CD versions of 

28 in March 2010 with an official date six months after reissue. Only new and revised monographs available since the 

27 will be in the redesigned format. The convention will also reissue a print volume of new and revised monographs and other official text available since the Second Supplement to 

27.  The monographs will appear in the redesigned format. This smaller volume, combined with official text in 

27 and its supplements without redesign will serve as the print version of 

28. Its official date will be the same as the official date of the electronic versions. Finally, USP will release the first supplement to 

Until the publication and its related supplements are reissued, says USP, industry should continue to use 

 "provides access to official standards enforceable by the US Food and Drug Administration for drugs and related products manufactured and marketed in the United States." Official revisions to the pharmaceutical monographs are published annually or as supplements (twice yearly), as well as in the 

28 was made available in English in three formats  print, CD and online.

Additional information can be found on the 

The US Pharmacopeial Convention (USP) is recalling USP 33?NF 28.

USP recalls latest monographs

, multiple monograph errors were introduced into the publication when it was converted into a new format and published on Nov. 1, 2009.

28 to go into effect was May 1, 2010. According to a public notice of Jan. 12, 2010, the redesign of the publication, including all 4000 monographs, encompassing more than 4100 pages, was "intended to improve ease of use, streamline presentation, and update and harmonize terminology, but was not intended to change any of the monograph requirements…. While many of the monographs were successfully redesigned, a significant number contained errors."

The United States Pharmacopeial Convention is recalling USP 33?NF 28.

USP Recalls Latest Monographs

The US Food and Drug Administration released a

to the public on Dec. 29, 2009 about criminals posing as FDA special agents and other law-enforcement personnel as part of an international extortion scam. The impersonators target individuals who have previously purchased drugs over the Internet or through telepharmacies.

 The impersonators claim that purchasing drugs online or by phone is illegal and tell the individuals they must pay a fine of $100 to $250,000 via wire transfer (usually to the Dominican Republic). Individuals who refuse to pay the fake fine are threatened with physical harm, arrest, or property searches. The impersonators have also used the victims’ credit cards for fraudulent purchases.


 "Impersonating an FDA official is a violation of federal law," said Michael Chappell, FDA acting associate commissioner for regulatory affairs, in a press release. "The public should note that no FDA official will ever contact a consumer by phone demanding money or any other form of payment.”


 Individuals who receive calls from potential agency impersonators can report the information by phone to the FDA Office of Criminal Investigations Metro Washington Field Office at 800.521.5783. Other criminals have been posing as agents of the Federal Bureau of Investigation, US Secret Service, US Customs Service, and US and Dominican prosecutors and judges. 

The US Food and Drug Administration released a warning to the public on Dec. 29, 2009 about criminals posing as FDA special agents and other law enforcement personnel as part of an international extortion scam.

FDA Impersonators Threaten Public Safety

The European Medicines Agency (EMEA) recently released a 

 regarding the involvement of patients and consumers in the agency’s activities. The agency issued a similar report in March 2008 to the EMEA Management Board and agreed to work with patient and consumer organizations in a more structured manner. The reflection paper proposes actions to further carry out this engagement.

The reflection paper notes that some of the current framework of interaction has been implemented (such as patient participation in scientific committees for orphan medicinal products and for pediatrics) but also notes areas that need more structure such as a procedure to systematically assess the need to involve patients in the Committee for Medicinal Products for Human Use (CHMP). The areas in which patient and consumer involvement have not increased generally are those areas that lack a legal basis for supporting patient interaction.

“The added value of patients and consumers in the scientific process of benefit/risk evaluation is [that] they enrich regulatory outcomes by complementing them with the views of those directly affected by regulatory decisions,” according to the paper’s executive summary. In addition, patients’ and consumers’ contributions build trust in the regulatory process because they foster higher levels of transparency.

The paper also discusses the compensation of patients and consumers who participate in agency activities. Currently, such work is done on a voluntary basis. Patients and consumers participating in an EMEA questionnaire confirmed their interest in remaining active in agency activities, including at the CHMP level, according to the paper.

Ultimately, the paper asks EMEA Management Board to revise “the framework of interaction between the agency and patients’ and consumers’ organizations” so that the legal basis for patient involvement is extended, and to “provide financial support to experts and delegates in need of it under certain conditions.” 

The European Medicines Agency recently released a reflection paper regarding the involvement of patients and consumers in the agency's activities.