Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

, a supplement to its GMP Guide Chapter 4 on Documentation to account for the increased use of and complexity of computerized systems in the drug-manufacturing community. The annex applies to all forms of computerized systems that are used as part of GMP-regulated activities.

Some key points in the new Annex note that computer applications should be validated and that information-technology structures should be qualified. The document also states that when moving from manual operation to computerized operation, it is important to ensure that product quality and process control assurance do not decrease. In the same regard, the overall risk to the process should not be affected when such a change takes place.

The Annex addresses risk management as a tool that should be applied throughout the life cycle of the computerized system, taking into account factors such as patient safety and data integrity. Agreements and working relationships among personnel and third parties are addressed as well. Finally, the revised Annex reviews project and operational phases of drug manufacturing and how computerized systems can play a role in these stages (e.g., by documenting validation, checking for accuracy, and maintaining audit trails).

The updated Annex will take effect June 30, 2011.


Articles

The European Medicines Agency has released a new Annex 11-Computerized Systems to its GMP Guide Chapter 4 on Documentation to account for the increased use of and complexity of computerized systems in the drug-manufacturing community.

EMA Releases Revised Computerized Systems Annex to GMP Guide

In 2004, FDA published a final guidance for industry introducing the concept of process analytical technology (PAT) and redefining pharmaceutical manufacturing and quality assurance for the future. That guidance also addressed a concept known as "real time release," defined as "the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data" (1). The PAT component includes, according to the guidance, "a valid combination of assessed material attributes and process controls," and builds upon the 1985 guidance on parametric release, which is used primarily in heat-based sterilization of drugs.  

A few years later, in August 2009, the parties to the International Conference on Harmonization (ICH) adopted ICH Q8(R2) 

, which used the term "real time release testing" (RTRT). The definition of this term in ICH Q8(R2) shifted the emphasis from the decision to release a batch to the measurements themselves, as follows: "the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls."  

There are many benefits to be gained from RTRT applications. "From an industry standpoint, RTRT approaches seem to have economic benefits from manufacturing efficiency, such as reduced inventory and lower laboratory costs," says Christine Moore, PhD, deputy director for science and policy at the FDA Office of New Drug Quality Assessment (ONDQA), which falls under the Center for Drug Evaluation and Research (CDER). "Quality can also benefit resulting in higher yields or lower rework or rejection rates. From a regulator's and a consumer's standpoint, the integrated real-time analysis and control feasible with RTRT have the potential to provide an increased assurance of product quality."  

Adds Grace McNally, senior policy advisor within FDA's Division of Manufacturing and Product Quality, Office of Compliance, which also falls under CDER, "One of the benefits of on-line or at-line testing is the ability to perform rapid analysis in real-time. PAT tools typically enable nondestructive testing and provide the opportunity for enhanced monitoring during the manufacturing process, and greater product and process understanding."  

Despite the potential gains that can be realized from RTRT, industry still is trying to work out the practicalities of implementing the approach, and therefore, is not yet fully benefitting from its promises. Many questions remain regarding the instrumentation to use, when and where on the manufacturing line to conduct tests, how to evaluate on- or in-line analyzers during manufacture, and what regulatory authorities expect.  

Industry's hesitation toward applying RTRT was abundantly clear during the October 2010 ICH Quality Implementation Working Group (IWG) workshop, held in North Bethesda, Maryland. A breakout session on control strategy addressed RTRT controls and brought up even more questions about its application, such as what to do in case of instrumentation failure, how to differentiate between RTRT and in-process tests, how to describe RTRT in specification, and where to record RTRT information in regulatory submissions, such as the common technical document. 

The issue stretches across the Atlantic. The European Medicines Agency (EMA) published a new draft guideline on RTRT just last year to replace its former guideline on parametric release (2). The new document is meant to align better with the ICH terminology and to allow for real time release tests beyond that of sterility testing, which is the most common real time release practice. 

During the past nearly two years, the ICH Quality IWG has constructed and posted on its website a list of common questions and answers about the organization's quality guidelines (Q8, Q9, and Q10). The current version includes 11 Q&As devoted solely to RTRT (3). As industry moves more toward a quality-based approach, some RTRT questions may fall into place. In the meantime, 

gathered input from industry and regulatory experts already making headway in this area. 

Now that RTRT has moved from a concept to a realistic option for drug products, says Senior Director of Global Manufacturing Services at Pfizer Global Manufacturing Holly Bonsignore, there are many benefits for industry to take advantage of. For example, RTRT can "improve process control by generating more data while the manufacturing process is taking place, as opposed to traditional release testing conducted on small samples after batch manufacture is complete." The availability of RTRT data at the time of batch manufacture can also improve operational efficiency and inventory control by eliminating the time and resources needed to test batches in a laboratory post-manufacture.  

There are a few downsides to the approach as well. Because RTRT is not yet globally accepted by regulatory agencies, explains Bonsignore, manufacturers are caught somewhat in the middle of a paradigm manufacturing shift. Some companies need to continue to use traditional batch-release testing for certain markets even if other markets have approved the approach and even if the company is ready to move full speed ahead with RTRT. 

Bonsignore's colleague, Steve Hammond, a director and team leader in Pfizer Global Manufacturing's analytical sciences group, notes a more technical limitation with RTRT: testing for impurities and stability. "PAT technology is being developed that may be capable of that category of 'stability indicating' analysis, but at this time, there is a gap," he explains. "The approach at Pfizer is to propose RTRT for products for which we have a history of stability (e.g., active pharmaceutical ingredients that do not degrade due to the manufacturing process)." 

Adds Terry Redman, product manager for particle-system characterization at Mettler-Toledo AutoChem, "It is not always feasible or cost-effective to implement direct measurement of all critical process parameters (CPPs) and critical quality attributes (CQAs) with RTRT. In many cases, gaps in measurement technology must be filled with inferred measurements that must be proven statistically reliable," he says. However, that may change in the coming years. New measurement technologies are on the horizon that will improve industry's ability to monitor process control and provide analytical measurements for quality control. 

The key, according to many industry experts, is going to be increased product and process knowledge—a fundamental concept of quality by design (QbD) and the harmonized ICH quality guidelines. As Tim Freeman, director of operations at Freeman Technology, points out, "Although RTRT is the future for efficient, safe and competitive pharmaceutical manufacturing, it relies on capturing more information about the materials being processed and the equipment and configuration employed during manufacturing."  

FDA's Moore offers a specific example. "By understanding your process and controlling its associated risks through a PAT system, you can monitor and control the process at the most important points," she says. "Some critical quality attributes, such as dissolution, cannot be measured directly by a specific probe. Instead, to utilize a RTRT approach, you need to understand the relation between the desired product attribute and relevant material attributes and process parameters and then monitor and control them accordingly." 

In terms of gaining knowledge before applying RTRT to a manufacturing process, pharmaceutical firms may need to determine which operations, from blending and compaction to tablet coating, are conducive to its use. The good news, according to Pfizer's Hammond, is that PAT applications are now well developed for most all unit operations. "For most products, nearinfrared (NIR) can handle a high proportion of unit operations, and the emergence of light-induced fluorescence instruments with an order of magnitude greater sensitivity than NIR has taken PAT into low-dose products," he says. In addition, he notes that technologies such as terahertz spectroscopy are emerging for coating monitoring and control, but says that further development is required in this application area. 

In terms of tableting and powder processing, Freeman says he has come across several advances in measurement technologies that are driving material and process understanding toward an RTRT approach. "There are now GMP suites for continuous manufacturing of tablets that rely heavily on PAT and that function with real-time, closed-loop feedback on parameters such as size, moisture content and blend uniformity," he says. "For this reason, RTRT has become much more of a reality in the last couple of years. However, there are many material properties that are still not measured routinely at-line or on-line, even though they will influence final product quality."  

According to FDA's Moore, "Many of the sensors used for in-process measurements of pharmaceutical technologies have been well established in other similar industries, such as the chemical or food processing industry. Undoubtedly, there is a sensor available that could be used at every unit operation of tablet or other dosage form manufacturing. Monitoring every step does not necessarily add value though." She adds, "The challenge is to perform the right measurement, at the right time, and at the right location. Furthermore, you want the right control systems in place to make appropriate and timely adjustments to the process based on the information collected." 

Another big challenge to using RTRT is how to approach sampling plans, specifically when and where to take a sample, how much of a sample to take, and whether compendial or risk-assessment issues need to be considered. Explains Alon Vaisman, applications manager of pharmaceuticals for Malvern Instruments, "Usually PAT instruments access larger amounts of sample than would be used for lab analysis. On-line instrumentation would typically utilize automated sampling, in contrast to traditional off-line techniques that tend to rely on grab sampling at the end of the process. Sample preparation is usually relatively limited for PAT systems since this is necessary to achieve the measurement rates required for continuous monitoring."  

As for where to do sampling on themanufacturing line, Real-Time Analyzers President & CEO Stuart Farquharson suggests that RTRT is not limited to tablet or pill manufacturing, but also encompases drug synthesis. In this case, the best place to monitor synthesis is 

, or inside the reactor.  This allows monitoring and ultimately controlling the reaction rate, reaction end-point, and yield. "This can be accomplished using a long rod fiber-optic probe. However, efforts must be made to keep the probe head clean. 

measurements allow for true real-time monitoring, which is significantly better than traditional grab sampling, primarily used to determine when the end point had been reached," he explains. 

According to FDA's McNally, "Manufacturers must determine appropriate sampling for their processes. It is important to remember that compendial tests are standards that any compendial drug must meet if tested. Applicants should consider the claims and disclaimers made by each compendium they reference.  

 28 Reissue), for example, notes that their compendial standards are not intended to make inferences about the larger group of units from which the sample was obtained. The General Notices section also states, 'In all cases, statements about whether the compendial standard is met apply only to the units tested. Repeats, replicates, statistical rejection of outliers, or extrapolations of results to larger populations, as well as the necessity and appropriate frequency of batch testing, are neither specified nor proscribed by the compendia.' So, manufacturers must ensure sampling sizes and plans are statistically sound and representative of the batch. A quality risk-management approach can be useful to develop an appropriate sampling plan."  

Moore adds that the agency is willing to work with applicants to ensure appropriate acceptance criteria for large sample sizes. 

Pfizer's Hammond seems to agree that there is work to be done in the area of sampling. "There is the potential to sample very frequently or to take large numbers of units for a measurement," he explains. Pfizer uses a risk-based approach to determine sampling frequency, including looking at how the data is used, what calculations are performed, and what statistics are used for setting a specification.  

"There is agreement that conventional statistics do not apply when larger data sets are under consideration. The so-called 'large n' approach is needed. Industry and regulators have been debating the best approach for a while now and some sensible approaches seem to be evolving from this discussion," adds Hammond.  

He references a recent PQRI paper published, with FDA input, that describes three possible "large n" approaches. "In terms of sampling of blends during analysis using probe systems, careful control of the amount of sample that contributes to a spectrum is important. Generally the illumination characteristics are engineered to ensure that approximately one unit dose weight of blend contributes to a spectrum. Analysis of tablet cores is generally 

 transmission of light, through the tablet, thus ensuring that most of the material in the tablet core contributes to the spectrum collected." 

Overall, the primary purpose of RTRT, and any PAT or QbD application for that matter, is to understand and control one's product and processes in a manner that ensures quality final product.  

Sampling needs to be sufficient to facilitate real-time control, generate knowledge to allow the control of the next manufacturing step, and measure critical material attributes. With end-of-line testing, according to one expert, the purpose of sampling is to assess what the quality is, and the testing of samples has two roles: one enables control, and another validates the control system and strategy. Within RTRR, therefore, sampling's role is to assure that the controls are appropriate. 

Of great concern among industry is what to do in the event of an equipment or instrumentation failure while an RTRT process or analysis is being run. "Generally, it is not acceptable to discount PAT measurements and return to a conventional approach simply because the PAT fails a batch," says Pfizer's Hammond. "It must be proven that the equipment has malfunctioned in some way. As most PAT instruments now have very sophisticated self-diagnostic procedures, it is better to have the PAT device automatically cease to function if any of the internal diagnostics fail. Thus, suspect results are not generated." 

Furthermore, a manufacturer applying an RTRT test that fails might also use a risk-assessment process to decide how to proceed. "The possibility of using the traditional analytical procedures that are registered for the product is something the industry needs to make PAT a viable proposition. All mechanical electrical systems can malfunction, and pharmaceutical manufacturing needs a way to ensure business continuity if a PAT system does break down," says Hammond. 

According to FDA's McNally, "In the event of on-line or in-line equipment breakdown, the control strategy provided in the application can include the use of alternative tests or monitoring in case of equipment failure. The alternative approach could involve use of in-process and end product testing or other options, while maintaining an acceptable level of quality."  

 Of note, EMA's new draft guideline on RTRT includes very similar language with regard to dealing with equipment failure (2). Overall, both regulatory authorities seem to agree that testing or monitoring equipment breakdown needs to "be managed in the context of a deviation under the quality management system and can be covered by GMP" (2).

This may be particularly important for those PAT systems that can produce false negatives, such as those using spectroscopy and chemometric methods, adds McNally. "The manufacturer should ensure an effective calibration program is in place. This includes procedures to follow in the case of an out-of-specification (OOS) result from a PAT tool and steps to be taken to maintain and recalibrate the calibration model." 

 Some of the ICH questions and answers on real time release address this issue in more detail (3).

To date, the pharmaceutical sector seems to be moving forward with RTRT but at a slow pace. The concept "is no longer treated as an unobtainable goal," says Malvern's Vaisman. "Many companies in industry and in academic research centers are making significant inroads in implementing continuous manufacturing trains and RTRT. That said, RTRT is not yet the norm," he adds.  

Cost may be a factor in the rate of implementation, point out GE Analytical Instrumentation's Richard Godec and Jonathan Yourkin, new product development manager, and global pharmaceutical product manager, respectively. Because analytical tools are still being developed and many companies' senior management and quality teams are not yet on board, RTRT is a bit of a double-edged sword. "The main advantage of RTRT is the cost-effective control of the manufacturing process to meet all quality and product specifications. The main disadvantage, however, is that there is an initial investment required to achieve RTRT of finished drug products," they say. 

On the regulatory side, FDA "has reviewed and approved several applications using RTRT approaches, but the numbers are still small," says Moore. "The applications containing RTRT approaches have been challenging to review; they not only include new science but also have new approaches to fulfilling regulatory requirements. We (the FDA) are still learning, and every application has different nuances. We strongly recommend that companies looking to implement RTRT request a meeting with the FDA to discuss their proposal prior to submission." 

Be sure to check out the online only features related to this article on 

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

Guideline on Real Time Release Testing (formerly Guideline on Parametric Release)

Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers 

Draft Guidance for Industry, Process Validation: General Principles and Practices 

Industry and regulatory experts discuss the challenges and benefits of implementing real time release testing in a pharmaceutical manufacturing environment.

Real Time Release Testing

The US Pharmacopeia has been helping to improve the quality of healthcare in developing countries for some time. Its most recent program, supported by the US Agency for International Development (USAID), is called Promoting the Quality of Medicines (PQM).  

The five-year program began in 2009 and focuses on improving access to quality medicines for people around the world. PQM picks up, in part, where the pharmacopeia's Drug Quality and Information Program leaves off—that program began in 2000 and ended this past December—with the additional benefit of building national capacity to monitor drug quality from the product's manufacture to the end user.   

PQM staffers work with local governments, USAID missions and partners, the World Health Organization, the US Centers for Disease Control and Prevention, and the Global Pharma Health Fund, to advance strategies to improve drug quality and use; to increase access to current, evidence-based drug information; and to provide technical leadership. The program is running in 32 countries, which are based on USAID's list of priority countries across four regions (Africa, Asia, Latin America and the Caribbean, and Europe).  

PQM starts by assessing a country's ability to ensure drug quality and thereby, secure the public health. Scientists associated with the program look at things like regulation, registration, laboratory control, and distribution. Once the evaluation is complete, PQM staff members work with policymakers and country authorities to address weaknesses in the drug quality monitoring system.  

Because it's hard to monitor and control important information about drug usage as well as on adverse events in the developing world, PQM also works with national authorities to produce workshops on pharmacovigilance. Anticounterfeiting workshops and public awareness campaigns (see 

 for video demonstrations) are also part of PQM's work.  

According to USP, the greatest challenges in improving health outcomes in developing countries are the lack of access to quality assured medicines, the irrational use of life-saving medicines, and the accompanying potential consequences, such as developing resistance to those medicines.  

"The lack of adequate pharmaceutical systems to manage the storage and distribution of needed medicines to remote areas in a timely manner impedes their effectiveness in rural settings," says Patrick Lukulay, director of PQM. "In addition to pharmaceutical interventions, hygiene, and nutrition are also critical in effecting positive health outcomes." 

Further efforts that would be helpful to address these barriers, says Lukulay, are coordination of donor efforts for maximum impact within countries and a focus on building sustainable country systems.  

"Putting effective mechanisms in place increases country capacity to manage pharmaceutical commodities and encourages country ownership of major transformational initiatives," he adds. 

USP helps to improve drug quality in 32 countries.

Global Healthcare on the Ground: USP

As part of this month's special report on real time release testing [see full story here], 

talked to experts at analytical companies throughout the industry to gain their perspective on how RTRT can be done on a practical basis. Participating in the virtual roundtable are: Richard Godec, new product development manager, and Jonathan Yourkin, global pharmaceutical product manager, both at GE Analytical Instruments; Alon Vaisman, applications manager of pharmaceuticals for Malvern Instruments; Terry Redman, product manager for particle-system characterization at Mettler-Toledo AutoChem; and Stuart Farquharson, president & CEO of Real-Time Analyzers.

Where does the industry now stand in terms of understanding and applying real-time release testing (RTRT) for finished drug products? Would you say that real-time release of a finished drug product is still at a nascent stage or is it further along? What are the advantages and disadvantages in real-time release of finished drug products?  

Godec and Yourkin (GE Analytical Instruments):

 They are just beginning to study the problem. Almost no older manufacturing facilities are doing RTRT and very few new facilities are implementing RTRT for the finished products. There is more activity on in-process measurements at critical points that can help prevent final product quality failures. It is company dependent, but in general, RTRT of finished drug products is still in the nascent stage. The main advantage is the cost-effective control of the manufacturing process to meet all quality and product specifications. The main disadvantage is that there is an initial investment required to achieve RTRT of finished drug products. 

 In my opinion, RTRT is no longer treated as an unobtainable goal. Many companies in industry and at academic research centers are making significant inroads in implementing continuous manufacturing trains and RTRT. That said, RTRT is hardly the norm today and constitutes a very small percentage of quality-control activities. 

Advantages of RTRT are in streamlining production, minimizing delays and potentially eliminating out-of-spec product. The downside is that implementing RTRT can be a costly and resource intensive process that requires the thorough understanding and control of production activities. 

 It appears that industry is making real progress in the understanding and implementation of many of the core elements of RTRT. Various PAT tools are being used earlier in development to assist the principles of quality by design (QbD), and these are facilitating the adoption of process monitoring and control concepts throughout scale-up and manufacturing. QbD enables a more thorough understanding of the relationships and interactions between critical process parameters and critical quality attributes, and this in turn allows for more effective strategies to mitigate risk and produce quality product by design. This improved process understanding, in combination with improved process analytics, is necessary for identifying the critical quality attributes and developing the methods for at-line or in-line measurement. 

Although there have been successful examples of real-time monitoring and control of specific quality attributes such as granule size at the outlet of a roller compaction, or nearinfrared (NIR) spectroscopy for monitoring tablet dosage uniformity, it seems there is still a lack of holistic solutions that can reproduce or replace all of the necessary quality-control (QC) tests that would ensure a safe and effective product in its final packaged consumable form. 

The main advantage of RTRT is simply business efficiency. Real-time assurance of quality, and the avoidance of storage or quarantine of intermediates and drug product while awaiting test results, will enable much greater efficiency throughout the process.  

 The pharmaceutical industry clearly understands the value of RTRT. However, there is risk in applying RTRT, the greatest being incorrect information supplied by PAT tools used to implement RTRT. And consequently, I believe that RTRT is still in the nascent stage. 

One of the main advantages of RTRT is being able to monitor and control the quality of a drug during manufacturing (e.g., optimizing polymorph type during synthesis, crystallization, blending). This allows the manufacturer to: improve conformity of final product to specifications; minimize the need of testing every capsule, tablet, or vial of the finished product; and identify out-of-specification batches early and eliminate further manufacturing steps (e.g., tableting of out-of-specification powder).  

What are the key technical barriers to implementing real-time release of a finished drug product overall?  

Godec and Yourkin (GE Analytical Instruments): 

We believe the primarily barriers (not necessarily in order of priority) include the following:  

The inability of adopters to present a strong business justification to management that can justify the additional expenditures necessary to do final product RTRT. The lack of strong FDA regulatory action on non-RTRT process is probably a major cause of this. The basic business question for companies, therefore, is, Why pay the extra expense of using RTRT if a highly reliable manufacturing process can be established without it? If FDA were to require RTRT, then there would be no business doubt.

The analytical tools for RTRT implementation are still being developed.

Many pharmaceutical quality systems are still focused on producing pharmaceuticals using detailed standard operating procedures, such as recipes, temperatures, and timings with a three-batch process validation. It is difficult for many quality departments to allow the use of flexible process controls because they require additional subject matter knowledge that is, in many cases, unknown. Quality personnel therefore may perceive that they will have to cede control to the manufacturing department. 

There is a general lack of direct experience in RTRT projects throughout industry. Only a few pharmaceutical companies have done the required development and research to automate unit operations (processes), which is needed to implement a finished drug product RTRT system. 

Quite a few pharmaceutical companies are taking small steps in the implementation of automated controls and real-time sensors within their facilities' operations. A good example is the adoption of online total organic carbon (TOC) and online conductivity sensors for pharmaceutical waters. But even in this case, companies generally focus on the high return on investment by decreasing the number of required laboratory samples using information provided by the on-line analyzers. The additional cost of the required quality systems for real-time release of the TOC or conductivity water quality attribute is much more expensive and time consuming than can be justified with the decrease in laboratory samples. There is a new ASTM E55 standard practice, 

Real-time Release Testing of Pharmaceutical Water 

for the TOC attribute. This standard may change the number of companies that perform RTRT of their water for the TOC attribute because it addresses the technical issues involved. However, the standard does not address how to make the required quality-system changes.

 In-process measurements often produce results that differ slightly from QC laboratory results. Process analytical technology (PAT) equipment may be different from instrumentation used in the laboratory, and materials therefore, may often be characterized in a different state as it flows through the process. Addressing the issue of specification transfer can ease the transition of an analytical technique from development through to commercial manufacture. 

In addition, RTRT often demands the successful integration of a number of analytical and manufacturing devices, a process hampered by the lack of collaboration between equipment suppliers and the existence of few applicable standards. The relatively new OPC Foundation's Analytical Device Integration (ADI) standard will help in this area but there is still work to be done. 

The key technical barrier I see is the integration of measurement technology with appropriate process modeling and control algorithms for holistic model-based control of the critical quality attributes (CQAS) through direct manipulation of the critical process parameters (CPPs). There is certainly room for improvement in existing measurement technologies to directly monitor CQAS and greatly enhance RTRT capabilities. However, with sufficiently reliable control of the CPPs, RTRT does not have to rely on relocating the quality assurance/quality control laboratory for in-line and at-line analysis. With true QbD, the burden of testing can theoretically be reduced to a minimal level by ensuring product quality through monitoring and control of the process itself. 

 The technical barriers associated with RTRT are tied to the PAT tools being used. In addition to material property tools, spectroscopy tools, specifically Raman, NIR, and infrared analyzers, are being used to monitor the synthesis of a drug or determine the composition of a pill. Each has advantages and limitations.  

For example, Raman and NIR can be interfaced into reactors via highly transmitting fiber optics, IR cannot; Raman and IR provide exceptional specificity (e.g., distinguishing polymorphs), NIR less so; NIR and IR can measure trace quantities of chemicals while Raman is typically limited to 0.1% chemical concentrations. In all cases, the variability of the measurement must be much smaller than the variability of the process. The former depends on the dynamic range and precision of the measurement (e.g., a spectral peak used to determine concentration that changes intensity significantly is better than an unresolved peak that changes very little). It also depends on the stability of the analyzer. For this reason, interferometers have dominated chemical plant installations. A shift in the x-axis, a potential problem with dispersive Raman analyzers, can result in incorrect analysis and decision making.  

The key limitation for these technologies is measurements that do not correctly represent the process or product, such as the contents of a reactor or the composition of a pill.  

With regard to solid-dosage manufacturing, is it now feasible to apply process analytical technology (PAT) throughout all unit operations or are certain operations not conducive to on-line or at-line testing?  

 Not only is it possible, it is being done. A wide variety of PAT equipment is already commercially available for monitoring, for example: homogeneity, composition, particle-size distribution, density, moisture content, and other parameters. These technologies are being applied across the spectrum of unit operations used by the pharmaceutical industry. While certain applications are particularly exacting in terms of the demands they place on an analytical technique, I believe progress is being made in almost all relevant areas. 

 PAT has applications in every unit operation, and is achievable with existing measurement technologies. It is not always feasible or cost-effective to implement direct measurement of all CPPs and CQAs. In many cases, gaps in measurement technology must be filled with inferred measurements that must be proven statistically reliable. 

We expect to see improvement in measurement technologies across the board though, which will continue to improve the ability to monitor for process control purposes and provide analytical measurements for quality control.  

Can you offer some specific examples of PAT being applied in solid-dosage manufacturing? How would the data used at this particular step be used for the real-time release of a finished solid-dosage product?  

 A common unit operation in the pharmaceutical sector is milling, to produce actives and excipients of defined particle-size distribution for subsequent processing, and/or formulation. On-line particle size analysis enables the automatic control of a mill and provides continuous monitoring of the exiting material. 

In "A PAT Solution for Automated Mill Control," published in 

s January 2010 issue, the authors describe the use of on-line laser diffraction particle-size measurement to automate mill control at a commercial site. The generic solution developed has widespread application. With automated control in place, the operator selects a particle size set point for the product. The speed of the mill rotor then varies automatically in response to real-time particle-size data, so that the specification of the exiting material is consistently maintained, even during fluctuations in the feed. The result is better product quality, higher throughput, and less waste.  

This solution could be directly applied for RTRT provided that correlations between laboratory QC and the process instrument are in place. This is a readily achievable goal with laser diffraction particle-size analysis. 

 In solid-dosage manufacturing, the size distributions of particles and granules are known to be critical parameters affecting final product quality (i.e., influencing critical powder properties such as compressibility and flowability, which in turn impact the tableting step that determines final product quality attributes such as dissolution rates and bioavailability.) Recently, in-line techniques, such as focused beam reflectance measurement (FBRM) and at-line techniques such as laser diffraction, have been shown to provide the capability to measure the progress of size enlargement processes by roller compaction, high-shear wet granulation, and fluid-bed granulation. The ability to monitor particles in real time permits the control of continuous roller-compaction processes through the manipulation of roller speed, gap size, and roller pressure. Likewise, batch processes, such as high-shear or fluid-bed granulation can be monitored until the granule distribution hits a predetermined endpoint. In either case, measuring the particles in-line or at-line provides the ability to control the granule-size distribution. 

 We have used Raman spectroscopy to monitor drug synthesis and crystallization (kinetics and yield) in-line, and polymorphism at-line, steps that precede compaction, tableting, and so forth. We have also used chemometrics, full spectral analysis, to relate process parameters to product quality (e.g., product to by-product ratio). The greatest advantage of RTRT is the ability to identify when a process/manufacturing step is heading out-of-control so that corrective action can be taken. Even if an out-of-specification product is made, savings can be realized by not continuing with the remaining steps. For example, blending an out-of-specification active (e.g., too much byproduct) with the incipient, followed by compaction, coating, and so forth, can be a substantial financial waste. 

How does analytical-methods development change when working in a PAT environment? What are some of the challenges that might arise in scaling up a process from a laboratory scale to the manufacturing scale? 

Analytical methods, if properly validated to the requirements of the International Conference on Harmonization Q2(R1) guideline on analytical validation, and for their intended use, will not generally change. Analytical methods can be subject to scaling problems, however. For example, scaling problems can occur when the automatically collected or measured sample is not representative of the bulk-material analyte concentration. 

 Method development for a PAT system must take into account a wider scope of parameters than just the measurement system and material. In particular, the process interface must be carefully considered to ensure representative analysis. Techniques where results can be affected by multiple variables tend to cause more difficulties during scale up, and in many cases, a new method must be developed for larger scale.  

For example, contrast the example of particle-size analysis by laser diffraction and by ultrasonic extinction. The former technique is based on first principles and is relatively insensitive to variations in environmental factors. Laser-diffraction results will change only if the particle size of the product changes. On the other hand, the results produced by ultrasonic extinction are dependent on multiple factors, including temperature, moisture, bulk density, and others. Should any of these factors change during scale up, the result will be affected even if the monitored value (particle size) has stayed the same.  

 The greatest challenges in scaling up a process is maintaining yield and minimizing byproducts. This difficulty is largely due to the fact that mixing and heat are not uniform at larger scales. Consequently, a laboratory-based analytical method may not be easily transferred to the process. For this reason, Raman and IR may be preferred over NIR because of their greater information content, and because the analysis may need to be changed. If complex models are used, such as chemometrics, model transfer from analyzer-to-analyzer may be an issue. X-axis stability and resolution must be maintained. The latter is problematic if a dispersive analyzer is planned for the process, but an interferometer-based Raman analyzer was used in the laboratory. It is also worth stating that full-scale reactors are not always as pristine as laboratory-scale reactors, and fluorescence interference can occur when using 785 nm lasers to generate Raman.

How should sampling plans be approached when using PAT and RTRT compared with traditional sampling methods?  

 Usually, PAT instruments access larger amounts of sample than would be used for laboratory analysis. On-line instrumentation would typically use automated sampling, in contrast to traditional off-line techniques that tend to rely on grab-sampling at the end of the process. Sample preparation is usually relatively limited for PAT systems to achieve the measurement rates required for continuous monitoring.  

(i.e., inside the reactor). This can be accomplished using a long-rod fiber-optic probe. However, efforts must be made to keep the probe head clean. 

 measurements allow for true real-time monitoring. This is significantly better than traditional grab-sampling, which is primarily used to determine whether the end-point had been reached. This, of course, can lead to incorrect analysis and action, specifically if the reaction is running hot or cold (i.e., high yield or low yield).  

What is the best practice to date for handling an equipment or analytical instrumentation failure during RTRT?  

The implementation of analytical backup procedures is a requirement, and can be achieved by using redundant equipment or backup laboratory procedures.  

The best approach is to have internal analyzer diagnostics. For example, we use a process Raman analyzer that constantly monitors a number of parameters, such as the laser power and the unit temperature. It is also possible to implement diagnostics to avoid other failures, such as issuing a warning if the analyzer indicates a constant value due to a coating forming on the optical interface.  

A roundtable moderated by Angie Drakulich.

Real Time Release Testing: Analytical Methods and Innovations

acknowledges the growing emphasis throughout the pharmaceutical outsourcing arena on being a strategic, or preferred, provider. We gathered input from leading contract-service providers to understand the drivers behind this trend and how it's affecting outsourcing. Participants include: David DeCuir, director of fine chemistry R&D at Albemarle; Brik Eyre, general manager of Baxter's BioPharma Solutions business; Paul Josephs, vice-president of sales and marketing at DPT; Hans Engels, president of DSM Pharmaceuticals; Michael J. Kosko, president of Pfizer CentreSource (PCS); R. Ananthanarayanan, president of Pharmaceutical Services and Active Ingredients (PSAI) at Dr. Reddy's; Mark Cassidy, vice-president of SAFC Contract Manufacturing Services; and Peter Soelkner, managing director of Vetter Pharma International GmbH.  

There seems to be an overall trend in recent years by pharmaceutical companies to consolidate their supplier base (i.e., to work with fewer and more strategic suppliers). Have you observed this trend, and if so, what factors are driving the change? Are large pharmaceutical companies primarily pursuing this business model or is it prevalent among smaller drug companies as well? 

Yes, we have observed this trend, or at least have heard major pharma companies talk about this. I believe it has to do with difficulty of cultivating working relationships with multiple suppliers. In addition, there is always a learning curve when working with new suppliers and some pharma companies are on a very tight production schedule. We see it mostly from larger pharma, although many smaller companies continue to work with just a few suppliers because occasionally, they lack the staffing to find and develop new suppliers and may be unwilling to devote extra resources if their needs are being met.  

David DeCuir, director of fine chemistry R&D at Albemarle 

We're in the midst of a great deal of change in the global economy. Pharmaceutical companies are assessing the effectiveness of their strategies with limited resources, while still achieving the commercialization objectives for their pipeline.  Regardless of the company size, use of external resources has long been embraced as an effective strategy to gain efficiency and flexibility, but we have seen a shift from the utilization of service providers to the integration of service providers. In the past, utilization of external vendors was driven by the perception that service providers were essentially interchangeable. This perception is why so many pharmaceutical companies maintained ties with a large number of service providers for long periods of time. Coupling the economic crisis with the increased scrutiny on oversight of partners, managing multiple suppliers proves to be a costly and complex task that is no longer viable. Therefore, the adoption of supplier management standards and increased need of a broader set of services from a consolidated set of strategic partners is occurring.  

Brik Eyre, general manager of Baxter's BioPharma Solutions business 

Within the sterile drug-manufacturing marketplace, in particular, manufacturing is capital intensive.  As a result, many companies have chosen to access this competency by partnering with a supplier that has a demonstrated track record within the specialized manufacturing process to avoid investments in this aspect of commercialization. This is especially true of certain types of molecules, such as cytotoxics or highly potent compounds, which have considerable containment and safety standards. In addition, by selectively partnering with a supplier with a broad portfolio of solutions, companies gain access to a range of options across a product's life cycle.  

In our experience, there continues to be an understanding that external partnerships provide the most value when objectives are clearly understood and aligned. This allows the service provider to elucidate the objectives of the partner and provide tailored and applicable solutions. This mindset dictates a closer working relationship so that the most value is provided to each party. Because of this increased commitment, the logical extension of this philosophy has been a reduction in the number of relationships maintained among pharmaceutical companies and their partners.   

We have observed the trend of pharmaceutical companies consolidating their supplier base, primarily due to mergers among major pharmaceutical companies. In many cases, the mergers led to an initial growth of the supplier base. Since that situation is unsustainable, there is a conscious effort to reduce the supplier base down to a manageable level and use preferred suppliers. Increased pressure in the industry to reduce costs and lower overhead has also factored into consolidation.  

Paul Josephs, vice-president of sales and marketing at DPT 

Although the true preferred-provider relationship concept has been talked about for several years, it's really taken off in the past one to two years. I would say large pharmaceutical companies are driving the trend because they have more products to leverage. Smaller companies are more concerned with finding an expert with regard to a certain technology.  

Consolidation of vendors is a definite Big Pharma trend and the reasons behind it are the drive for efficiency and more leverage for the big pharmaceutical firms to get things done in a way that they desire (e.g., approach to quality and compliance and additional cost leverage). The typical approach is to reduce the number of suppliers by 50% or more. An unsolved challenge of this consolidation goal as a result of mergers and acquisitions is how to handle new products with an established manufacturing base.  

Hans Engels, president of DSM Pharmaceuticals 

Pfizer CentreSource has seen a strong trend during the past few years toward pharmaceutical companies reducing their number of vendors, and our business development colleagues have seen this trend apply to both large and small pharmaceutical companies with locations in the US, Europe, and Asia. One factor driving the approach is industry consolidation. Acquisitions have brought together companies with different sourcing philosophies and supply chains. Efficiently managing these merged organizations going forward requires that this issue be addressed. Additional drivers for vendor consolidation include the pursuit of improved performance in the areas of supply, quality, and service as well as cost.  

Michael J. Kosko, president of Pfizer CentreSource (PCS) 

We have observed a strong trend, particularly among mid- to large-sized pharmaceutical companies to consolidate their supplier base and to work with more strategic suppliers. From our interaction with customers and with the industry, one of the significant reasons for the consolidation is to incorporate an outsourcing strategy that creates a more intimate relationship with the supplier. This allows the pharmaceutical company to understand the suppliers' operations in a more detailed way, influence how the operations are being run, and enhance cost effectiveness along the way.  Other organizations that are less strategic in their outsourcing efforts are reducing the number of suppliers that they work with as a mean of controlling their own internal resources, such as staff to manage suppliers and tighter control of their spend. While this is not a new concept, over the past couple of years, the effectiveness of the pharma organizations to execute against this kind of strategy has evolved.  

R. Ananthanarayanan, president of Pharmaceutical Services and Active Ingredients (PSAI) at Dr. Reddy's Laboratories 

In recent years, SAFC has definitely observed a trend for medium and large pharmaceutical companies to consolidate their supplier base and move toward identifying and selecting strategic vendors. There are certainly cost savings in managing and working with fewer suppliers. Also, the trend for many companies is to take more of a partnership approach with suppliers, as opposed to basic outsourcing of activities. To achieve better results and efficiencies, selecting vendors that will fit into the strategic partnership model is an important factor in the overall program. For example, when outsourcing GMP active pharmaceutical ingredient manufacturing, it becomes much more efficient to have two or three strategic contract manufacturing organizations (CMOs) already identified, with master service agreements, clearer expectations, communication standards, and relationships in place to complete the work more quickly and efficiently.  

Mark Cassidy, vice-president of SAFC Contract Manufacturing Services 

We have noticed that strategic partnerships have become even more important for pharmaceutical and biotech companies. They are increasingly interested in working with partners in long-term and strategic projects and have begun setting up programs to assess and choose preferred suppliers. In the process, manufacturers are continuously screening suppliers, creating databases, and using electronic bidding with the goal of creating a base of two or three qualified service providers. They also evaluate existing suppliers with scorecards and key performance indicators, such as adherence to cycle time, supply-plan adherence, or compliant-closure adherence.  

Peter Soelkner, managing director of Vetter Pharma International GmbH 

Several factors have led to this development. First, a number of product patents will be expiring in the coming years. This is exacerbated by the fact that the pipelines of many companies are simply unable to compensate for this loss. They are trying to find a solution by acquiring or merging with other companies. Competitive pressure is increasing as well, leading many companies to look for growth in the emerging pharmaceutical markets. For the established markets of the US, Europe, and Japan, growth is expected to continue. Therefore, to take advantage of opportunities and savings potential, manufacturers are banking on preferred suppliers. Even the smaller biotech firms and start-ups are increasingly recognizing the advantages of strategic partnerships. For them, what's more important are CMOs that are able to support them in the development of new products. This level of cooperation and partnering allows a more seamless transfer to commercial manufacturing after products have passed clinical studies.  

Preferred provider–sponsor company relationships 

From a contract-service provider perspective, how has supplier consolidation affected the pharmaceutical contract environment, including the expectations and nature of the outsourced relationship? When a contract service provider becomes a so-called preferred provider, how might its relationship with the sponsor change?  

In this case, the service supplier has more opportunities, but occasionally this means that the sponsor's need is outside the supplier's core expertise. Frequent communication is key and must be combined with a positive working relationship, including among technical staff. It is important to stay abreast of future trends and products. Having a larger presence with a customer, however, can be a double-edged sword.  On the one hand, your customer becomes more valuable to you, but on the other hand, your importance to the customer increases and that changes the balance of power somewhat in your favor.  

A strategic relationship requires an increased level of commitment from both parties. In our view, this needs to be considered as an investment by both parties with the goal of establishing a relationship that provides both organizations with additional value. These types of relationships are not simple and require a high degree of experience and knowledge, as well as clear communication practices to ensure proper alignment of goals.  

What hasn't changed despite the trend is the fact that pharmaceutical companies still have clear commercialization objectives and are focused on results. Therefore, delivering on commitments—whether development milestones or commercial-scale manufacturing targets—is crucial for creating mutual reliability in such a collaborative relationship. We see pharmaceutical companies seeking more assurance that their projects will be managed diligently, and service providers providing support to maintain budgets, timelines, and quality. As the partnership evolves, it becomes increasingly synergistic and both parties realize increased benefits by periodically revisiting alignment of strategies and goals.   

For the preferred-provider model to be successful, increased attention must be paid to metrics. New metrics may be needed to assess the effectiveness of the partnership and provide data that can be used to drive mutual continuous improvement.  

The practice has provided significant opportunity for a contract provider like DPT. The preferred-provider environment forces both the contract provider and the client to look at the relationship in a different paradigm. You go from looking tactically at one or two different opportunities, where you manage them in a specific way, to managing a relationship or partnership on a strategic level. There is more transparency on both sides with regards to future volumes and commitments. On the provider side, there's more transparency and commitment with regard to capacity, resources, and so forth. 

In addition, a preferred provider tends to complement the customer rather than being a general supplier. This level of integration drives inefficiencies out of the system. Where it was once a transactional, buy–sell relationship, it becomes an integrated relationship with access and visibility in the customer supply chain.... For example, with an integrated supply chain, we have access and visibility into our customer's network and are working as a complement to our customer. From a development perspective, we also have dedicated resources proactively working on development projects for our customers, so we are not working on an opportunity-by-opportunity basis but actually have staff working on multiple projects for our partners. 

One major impact on the industry from supplier consolidation is a more aggressive pricing structure. The governance structure between suppliers and sponsors also becomes more sophisticated (e.g., annual relationship, trend assessment meetings) and supply-chain planning becomes more integrated.  

When a supplier enters into a preferred-provider partnership, it is crucial that each party have a clear understanding of the arrangement. In our experience, having agreed-upon metrics to evaluate performance is key. In addition to developing metrics (e.g., delivery performance), the performance evaluation should contain a dialogue on the customer pipeline that addresses how both companies can increase the span of their relationship with new opportunities. In our more developed partnerships, for example, PCS regularly schedules sessions involving key executive leadership from both organizations.   

In our experience, once a service provider has been invited into the fold of strategic suppliers, the relationship evolves rapidly. Access to senior management on both sides is much more evident, and the information flow between the parties is more free-flowing. This information goes beyond the technology needs, and by revealing more sensitive information, parties can align to ensure success on both sides. The desire for both parties to succeed tends to have a far greater priority than what we normally observe in a more tactical relationship. More objectives are set between the parties to define what success means as well. Even the language we use and the titles we assign to each other are different. For the very tactical projects, we could be referred to as a "vendor." For something bigger we are usually a "supplier." When we get involved on a strategic level, we become "outsourcing partners." Language says a lot in our experience. If you are being called a supplier, you probably are one.  

The expectations are high regardless of whether a strategic relationship is in place. However, most service providers desire a more strategic relationship with their key customers and an expectation that comes along with these relationships includes longer range planning, more transparent communication, preferred capacity utilization, and well-defined plans for escalating issues that affect product quality or team cohesion.  

What does it take to be a preferred provider? What would you identify as the critical success factors?  

First, and foremost, one must have a positive track record with the customer. Then, the contract-service provider must be able to provide a variety of technology options. It may difficult for niche technology players to become key suppliers.  

A contract service provider has to demonstrate a proven track record in three key areas: delivery (i.e., the expertise and ability to deliver on commitments); service (i.e., a robust customer-centric philosophy and committed, engaged project teams); and integrity (i.e., a culture of "doing the right thing" that fosters confidence in the partnership). Trust and reliability are the foundation of any partnership. And in the most effective partnerships, each party contributes unique services, expertise and technology.  

Within Baxter's BioPharma Solutions business, we have a systematic approach to partnerships that starts from project initiation through the mature phase of a project through conclusion. All aspects require diligent alignment of expectations and monitoring of critical success factors. We have increased our investment in customer-service training and certification programs for our project managers, built communication-sharing tools, and developed improved metrics-tracking programs to better enable our teams to meet the needs of our clients and produce optimal results. 

Transparency is critical, as is trust. And, goals that are mutually beneficial are vital because there has to be incentive for both the sponsor and the contract provider. When I talk about transparency, I mean transparency not only through today but three years down the line.  

Critical and fundamental success factors in today's environment are financial stability, a solid quality track record, and proof of capability. A customer is not going to take a risk in this environment with somebody who doesn't have a quality track record. That's your ticket into the game. Proof of capability comes from your ability to execute.  

At DPT, we have implemented these things with all of our partners so that there is an ongoing scorecard. We are measuring month by month, quarter by quarter, so we are on track, and if we are not on track, we identify how we are going to get back on track. 

Good reputation (primarily through common history), flexibility (i.e., delivery of products and services, contract design, and pricing), and sound financial sustainability. 

Critical success factors required to take a vendor from a status of "supplier" to "partner" include supply assurance, regulatory compliance, product quality, service, and cost. A supplier's ability to innovate will also set it apart from the competition. A strong focus on relationship development is essential to building strong, enduring and collaborative relationships. Expanding the relationship to include marketing, technical service, regulatory affairs, finance, customer service, and leadership can deepen the partnership and promote ongoing collaboration.  

Attaining a preferred-supplier status usually involves a fairly significant journey over a period of time. Typically, there are a series of information exchanges that occur in the beginning to ensure that the two parties are compatible with respect to service offerings and strategic needs.  Once the determination is made that the two organizations are indeed compatible, then function-to-function and person-to-person relationships are evaluated. Both parties need to know that they are able to not just meet each others' needs, but are able to work together harmoniously. Mutual respect must be achieved or the trust needed to evolve a strategic relationship will never come to fruition. Trust must be earned through proven execution. Most often, smaller projects are awarded to the supplier to test performance, and if successful, more projects to prove performance are awarded. Typically, it is when a dependable track record established, that a discussion about being a preferred supplier occurs.  

Critical factors would include having the appropriate capabilities to match the sponsor's needs; trust and communication; excellent service, quality, compliance, and safety record; experience and/or expertise in the specified service area; an understanding of the sponsors' expectations; excellent project management and competitive pricing 

The demands made on CMO partners are clear: quality, reliability, flexibility, and punctuality are among others the most important factors necessary to achieve a successful partnership. At Vetter, for example, we invest in high-quality materials and aim to achieve the highest possible safety and cGMP standards. We implement a highly structured project-management approach. This, combined with ongoing direct communication, serves to reinforce mutual trust. 

Most important, a CMO has to know and understand the needs of its clients, and meet them accordingly. For Vetter, it is important to know what a client needs today, but it is also crucial for us to understand what support they will need in the future.  

A contract-service provider roundtable, featuring Albemarle, Baxter, DPT, Pfizer CentreSource, Dr. Reddy's, SAFC, and Vetter. Read this and other preferred organization articles in this special issue.

Strategies for Becoming a Preferred Provider

 for industry on Jan. 18, 2011, about the size of beads within drug products labeled for sprinkle. Beads are often included in capsule products that contain labeling that indicates patients can break the capsule and sprinkle its internal beads on soft foods to swallow (without chewing) as an alternative administration technique. According to the document, this type of administration is common with extended- or delayed-release characteristics. The concern lies in whether patients can swallow the beads with the soft foods without chewing the product. If the beads are chewed, the drug product may be absorbed and released too quickly into the body.

The guidance specifically calls for a maximum bead size of 2.0 mm. This is based on approved product information and human studies that demonstrate food is chewed to approximately 2 mm in median particle size before swallowing. “We recognize the specific importance of a maximum size limit for modified-release products, where unintentional chewing of beads may lead to pharmacokinetic differences. It is our belief, however, that maintaining a consistent maximum size of beads for all drug products labeled for sprinkle is prudent. Taste and performance issues that may arise from inadvertently chewing beads labeled for sprinkle may lead to noncompliance and decreased drug product efficacy,” states the draft document.

The guidance also provides current FDA thinking on delivering capsule beads 

 an enteral feeding tube as well as its recommendations on bioavailability and bioequivalence.

In terms of submission information, the draft guidance recommends that bead-size distribution be provided in a common technical document (CTD) application, specifically in section 3.2.P.3.3 (Description of Manufacturing Process and Process Controls) or in section 3.2.P.5.1 (Specification). The maximum bead size can be provided in the CTD 3.2.P.1 (Description and Composition of the Drug Product) section or 3.2.P.4 (Control of Critical Steps and Intermediates) section.

The draft guidance does not apply to bead products already on the market, but only to applicants of new drug, abbreviated new drug, or new biologics licensing applications (NDAs, ANDAs, BLAs). “Currently approved NDAs, ANDAs, or BLAs that contain beads that are greater than the recommended 2.0 mm need not modify their product specifications (unless the product has issues that are affecting public health),” states the draft guidance. However, an ANDA that references a currently approved reference listed drug (RLD) may propose a bead size equal to or less than the size of the bead used in the currently approved RLD, according to the document. Such data should be provided to support the size(s) of the beads in the ANDA product within a CTD submission.   

Comments on the draft guidance are due within 90 days of the document’s publication.

FDA issued a draft guidance for industry on Jan. 18, 2011, about the size of beads within drug products labeled for sprinkle.