Molecular Spectroscopy Workbench - Report from the 19th IFPAC/PAT Initiative Conference

March 1, 2005

Attendees from the pharmaceutical industry and FDA discussed a range of topics, including new spectroscopic analysis techniques, chemical imaging, calibration, and current efforts at ASTM.

Recently I attended the International Forum for Process Analysis and Control (IFPAC 2005) in Arlington, VA (January10-13, 2005). As usual, it was hectic with several simultaneous sessions. The forum, originally started as a showcase for chemical analyses, has become a showcase for pharmaceutical (process) analyses, as well. A mere five years ago, there was a single session in the morning and one in the afternoon on pharmaceutical analysis. With the introduction of FDA's Process Analysis Technologies (PAT) initiative, the number of sessions has exploded.

Among the co-sponsors of the event were the Center for Process Analytical Chemistry (CPAC), Measurement and Control Engineering Center (MCEC), the Center for Pharmaceutical Process Research (CPPR) (along with the Particle Technology and Crystallization Consortium [PTCC]), Duquesne Center Pharmaceutical Technology (DCPT), the Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP), the National Institute of Standards and Technology (NIST), and FDA's Center for Drug Evaluation & Research (CDER). All participated and contributed to the overall success of the meeting.

Of course, the once "roaming" meeting, known for its warm-weather locations each January (Florida, Arizona, Nevada, and Southern California), has found a home in Virginia. It has eschewed the golf tournament for proximity to the Food and Drug Administration. This has paid off handsomely: the participation of FDA personnel has made the conference a "must-attend" for pharmaceutical scientists with any interest in doing process analyses.

After a Tuesday morning plenary session, there were five afternoon sessions: "PAT — A Systems Approach," "NESSi Update — 2nd Generation," "Advanced Instrumental Concepts for Process Analysis," "Mass Spectroscopy — Novel Innovations," and "Homeland Security — Chemical & Biological Agent Detection." The conference never slowed down after that.

One way to look at the papers is by "type" of talk; there were talks on the legalities of PAT, the "philosophy" of PAT, the hardware and software of PAT, and the "systematic" approach. This was a good mix, because all these need to be addressed for PAT to be a success in any company. As Ajaz Hussain has been saying from the beginning: "PAT is not about the hardware." I will adjust that to, "PAT is not just about the hardware." The general categories of the meeting now are presented in no specific order (actually, I'm a hardware person, so I will lead off there). There is, of course, no way to discuss all or even most of the papers given throughout the meeting, so the papers mentioned will highlight the diversity of topics addressed.

Near-Infrared

As the "grandfather" of multiple pharmaceutical analyses (raw materials ID since 1984), NIR had a major portion of the talks at the meeting. Used for liquids, powders and solids, NIR has the attractive benefit of no sample preparation. This makes it ideas for process measurements. The line between a specific piece of hardware and a specific application is sometimes difficult to draw, so I will not attempt it.

PAT of dry granulations. Ke Hong and Martin Warman (Pfizer, Morris Plains, NJ) discussed some interesting work with a Corona (wireless) system attached to a moving blender. They compared a "large spot" measurement for blend uniformity and a "small spot" attachment for troubleshooting purposes. Pfizer obtained the first patent for measuring mixing of powders in a moving blender and continue to lead the way in this field.

Dry blend measurements of direct compression mixtures. Nathan Pixley of Merck (West Point, PA) addressed this topic. Because there is no second step of liquid addition and granulation to assist in the distribution of materials, the uniformity of the blend can even be more critical in a direct compression formulation. The methodology, endpoint criteria, and validation also were covered in the talk.

In-line monitoring of moisture in fluid bed dryers. This was the topic of a talk by a group from Merck, the key point of which was that most similar previous applications have been at the university level. In this talk, several commercial-level successes were reported. Both 65- and 300-liter pilot-scale and 600-liter production-scale models with data were shown. The presenters also discussed the effects of sampling on-line. Indeed, when performing any on-line measurement, how and where samples are taken for reference will make or break the method.

Content uniformity of tablets. Seetha Ananthaiah (Bristol Meyers Squibb, New Brunswick, NJ) discussed the use of NIR for this application. The ability to continuously monitor the drug content is especially valuable in narrow therapeutic index (NTI) products. This is where the efficacy of the active is defined within small parameters: too high and toxicity is a concern; too low and it might be ineffective. Such products are not well served by the "traditional" plus or minus 15% window of USP standards. Technology transfer from lab to process plant was also discussed.

On-line tablet monitoring. Bruker Optics (Bellerica, MA) showed some of its work using a system that combines transmission content uniformity analyses with tablet weight, thickness, hardness, and diameter. This approach does more to determine the "goodness" of tablets than merely assaying them for active ingredient.

MEMS-based miniature spectrometers. Larry McDermott and Richard Crocombe (Axsun, Bellerica, MA) presented a couple of papers about their work with these devices. They described the new superluminescent light emitting diodes (SLEDs) used as sources for their equipment. The crux of the hardware talk was that most other types of equipment use full-range NIR, because that is the nature of their sources. The Axsun claim is that, because only a shorter portion of the spectrum actually is used, the instrument provides maximum illumination over the needed range, using far lower power requirements and with a longer source life expectancy.

The applications covered were simple, previously demonstrated assays. The difference was that Axsun used their quite small instrument to generate similar results. If this proves to be a rugged instrument, it will go a long way to bringing about the next generation of smaller, more durable instruments for PAT.

Real-time fermentation monitoring. This was described by Ingrid Maes (Siemens, AG). The company's bioreactor not only monitors the individual components, but is set to refresh materials through feedback mechanisms. This allows the batch to be kept within "optimal" conditions, assuring optimal yield each time.

Pharmaceutical (transdermal) patches. Fred Long (Spectroscopic Solutions, Randolph, NJ) shared the work he has done with these patches, explaining that the work needed to prepare the instrument and software for compliance before proceeding to the actual analysis mode. While early work on patches dates to the late 1980s, this is the first report on process analyses of them.

Mid-Range IR (FT-IR)

The Mid-IR has not gone out of style yet. While (apparently) lacking the versatility of NIR, it still remains much better at "cleaner" spectra, allowing specific interpretations.

David Peters (Hamilton Sundstrand Systems-AIT Group) used FT-IR to determine "key" constituents in a fermentation process. The group measured glucose, ethanol, sucrose, lactic acid, and citric acid in a simulated fermentation system.

Raman

One of the fastest growing techniques for PAT is Raman spectroscopy. Shih-Ying Chang, representing a group from Bristol-Meyers Squibb's (BMS) Pharmaceutical Research Institute presented the group's work on monitoring solid dosage forms via Raman.

Polymorph transformation was the subject of a talk by Dimuthu Jayawickrama (BMS, New Brunswick, NJ). The BMS work was used to describe polymorph transition from a hydrate to neat form in a water/glycol slurry. The model was transferred to a second instrument and has even been used to assess solid forms. The details of model building and method transfer were discussed.

Raman was combined with energy dispersive X-ray fluorescence (EDXRF) microscopy in a talk by Fiona Clarke (Pfizer, Kent, UK) in consort with Fran Adar (Horiba Jobin Yvon, Edison, NJ). They explained that He Raman allows for high spatial resolution (1 µm) hyperspectral images for particle size and chemical distribution in a granulation. EDXRF allows for rapid hyperspectral images with 10 µm spatial resolution. A number of images were used for illustration.

Gas monitoring of bioprocesses was the topic of a talk by Ronald Rich (Atmosphere Recovery, Inc., Plymouth, MN). The set-up consisted of a 45-cm detector module, using a low-power laser with chemically specific optical filters. The system was capable of performing a gas composition analysis every 50 milliseconds. It was seen that one instrument could monitor several bioprocessors.

Chemical Imaging

Of course, chemical imaging (CI) is not,

per se

, a single technique. The session consisted of (the above mentioned) Raman/EDXRF, NIR-CI, Terahertz Pulsed Imaging, diffuse reflection techniques, and enlisting a tunable laser light source. The contributors were from instrument companies (Spectral Dimensions, Olney, MD; OPOTEK, Inc., Carlsbad, CA; TeraView Ltd., Cambridge, UK), academia (Duquesne University, Pittsburgh, PA; Insitute fur Angewandte Forschung, Germany), government (FDA), and industry (Pfizer, US and UK). This subject is large and important enough to warrant an entire issue and is merely mentioned here.

Chemometrics

It is inconceivable that the massive amount of data generated by PAT could be interpreted

without

chemometrics. (The mass of data once was referred to as "an insurmountable opportunity.") Several speakers addressed various aspects of the concepts of chemometrics.

Broad overview. Charles Miller (DuPont, Houston, TX) gave a picture of the changing philosophy of process measurements. He showed that in the "good old days," process measurements were univariate: pH, pressure, temperature, flow rate, sample level, etc. Now, samples are recognized to be the result of complex interactions among all the potential influences within a system. In a real process, "ideal" ideas such as holding all parameters constant and only allowing one to change do not truly monitor a "real" system. Instead, all the parameters are monitored throughout one or more runs and the product is then evaluated in light of all the parameters using chemometrics. Miller explained how formerly lab-based instruments can be used in a process environment when statistical and chemometric (multivariate) methods are employed.

Software. Brian Rohrback (Infometrix, Inc., Bothell, WA) spoke about a new Microsoft-driven software, called ActiveX. It supposedly allows any system to access a chemometrics computational engine without reading or writing files. Its basic purpose is to seamlessly combine software from various sources and allow data to flow uninterrupted.

Not to be outdone, Chris Ambrozic (Umetrics, Kinnelon, NJ) discussed a real-time chemometrics package wherein real-time data can be processed from multiple analyzers in a straightforward approach.

William Doyle (Axiom Analytical Inc., Irvine, CA) discussed a computer architecture, compliant with 21 CFR Part 11, based upon an SQL database. It was designed to work with multiple instruments and integrate the resultant data into coherent files.

General PAT Approaches

Since the concept of PAT was put forth by the FDA (even prior to the Guidance), there were a number of approaches espoused by different people. A number of people believe that PAT is the total understanding and control of an entire system for each drug product. They think that a company should place sensors along an entire production line from the beginning. At the other extreme, a number of more conservative voices suggest that individual processes be understood and controlled first: raw materials, bending, drying, compression, etc.

Several FDA and industry speakers spoke about PAT as a "systems approach." These speakers included Rebecca Rodriguez (DFI/ORO/ORA/FDA), Gerd Fischer (Aventis, Kansas City, MO), Gordon Muirhead (GlaxoSmithKline, Wirral, UK), and Ron Miller (BMS, New Brunswick, NJ). All gave their own perspectives of PAT as an integrated system of instruments, software, new data treatment and storage approaches, and as a means of understanding the pharmaceutical process, prior to controlling the process.

Pat Picariello, of the American Society for Testing and Materials (ASTM), gave an update on Committee E55 (Pharmaceutical Application of Process Analytical Technology). The committee has been in existence since January 2004. Its members include representatives from industrial, government, and academia involved in pharmaceutical manufacturing. The talk covered some of the work toward standardization to date; the main focus was on the scope and structure of the committee (ASTM is not known for hasty decisions. It is a consensus organization, by its very nature.) It also coordinates with ASTM International, Committee F38, and FDA to streamline standards for the industry.

One particular study was quite detailed was presented by Tim Stevens (BMS). His presentation covered the major steps of PAT:

a. Instrument selection

b. Feasibility study

c. Chemometric modeling and model building

d. Mechanical installation

e. Data collection and verification

f. Software/hardware system integration

g. Control, product release

h. Long-term continuous plant use

This model was presented for Loss on Drying (LOD) in a production setting across a period of over six months. The methodology used and results obtained were presented. This is one of the most complete models presented at a PAT meeting. While the chemistry of drying is trivial, the model presented was a working model for PAT, in general, for any PAT process.

Knowledge Management

The explosion of chemometric methods and the flood of data generated by PAT has proved a trial for IT personnel. The acquisition, evaluation, storage, and retrieval of PAT data have proven to be major projects for "computer-jockeys." Performing logical data handling procedures in light of 21 CFR Part 11 is no trivial task. Some of the papers involved both software and approaches for data storage, so there were few clear-cut "management" talks.

Gawayne Mahboubian-Jones (Optimal Industrial Automation, Yale, Bristol, UK), did address "knowledge management" per se. Several problems and some solutions were offered.

James Duckworth (Thermo Electron Corp., Minneapolis, MN) gave a nice talk about the data file standards needed for successful data storage and management. Some of the topics covered were

a. Business drivers for common instrument data formats

b. Historical efforts, i.e., JCAMP, AnDI, and SPC

c. Shortcomings of these attempts

d. Current efforts and technology, for example, XML

Summary and Comments

It is amazing how complex the IFPAC meeting has become. To say that it is a PAT meeting is like defining the terms "doctor," "chemist," or "teacher" in simple terms. A doctor could be a specialist in the nervous system, internal medicine, eyes-nose-throat, blood, or orthopedic surgery. In the same way, PAT cannot be defined simply as "process analysis." PAT, as can be seen from above, is an amalgam of computers, analytical instruments, software, chemometrics, spectroscopy, pharmaceutics, physics, microscopy, and, of course, engineering. As long as the workers in the field recognize all the parts are equally important, PAT will be alive and well.

Having observed all the positive parts of the PAT meetings, there is still one flat note: the wrong people come to these meetings. While the quality of the talks and speakers remains cutting edge and of high quality, it is "preaching to the choir." The people who ultimately will decide the success of PAT are by and large missing from the attendance roster. The financial officers of the companies often have no idea of why and what PAT is. They see nice profits and might not understand why we want to change things.

What will make PAT a full success is not more of the same (although the quality of what was presented was top-notch), but getting the decision-makers to sit and listen to what PAT is, why it is necessary, and what it can do to improve both products and profits. PAT is a great "product," but the "buyers" aren't getting the information in a timely manner. I want it to thrive, because it will improve the products and will strengthen the industry.

Emil W. Ciurczakworks as a consultant with Integrated Technical Solutions, 77 Park Road, Goldens Bridge, NY 10526. He can be reached via e-mail at: emil@ciurczak.com

Emil W. Ciurczak