Emil W. Ciurczak, DoraMaxx Consulting11.09.16
In another installment of my close-ups on tools that now may be implemented by CROs, CMOs, and generics, I am focusing on chemical imaging. The technology began as a Near-Infrared (NIR) tool, but has expanded to other wavelength regions (diffuse reflection) and fluorescence, as well. The first really comprehensive NIR Chemical Imaging (NIR-CI) unit was developed by Spectral Dimensions, later purchased by Malverne. It was good, rugged, contained and run by incredible software, and, sadly, was a bit expensive largely due to the expensive components used. It is no longer sold, but was topping $500,000 at the time it was discontinued. It was wonderful, so all the companies (read: large Pharma) that could afford it, purchased one and are still using it. The smaller companies (generics) didn’t obtain one, mainly because it was difficult to justify the price: that ended an era.
Fortunately, in the last few years, several other instrument manufacturers have introduced less expensive, yet well-built and efficient pieces of CI equipment. I will use some applications of chemical imaging to highlight a few instruments. The equipment for this work is currently available in both Europe and the U.S.
Basic theory, hardware and software
The driving force for developing chemical imaging (CI) was that the idea that the amount of API and excipients in a tablet is only one part of a proper dosage form. Their distribution and agglomeration within the tablet is what controls tableting/dissolution/bioavailability. The CI is made in several ways, but all involve either scanning with monochromatic light (prior dispersal) or filtering the emitted/reflected radiation (post-dispersal) and directing the light onto a diode-array (planer or linear). The diode material depends on the wavelength range scanned, usually Silicon (Si) for visible and short-wave NIR (350-1100nm) and Indium Gallium Arsenide (InGaAs) for long-wave NIR (1100-2500nm). The source is usually a Tungsten (Wolfram, for our European readers) halogen lamp, with light emitted throughout the visible and NIR regions.
The result is a 2-dimensional array—position of chemical at each x-y coordinate or pixel—for each wavelength scanned (see Figure 1). When the slices of individual wavelength images are combined, the resultant 3-D hypercube contains both spectral and spatial information. By investigating which wavelength most represents each ingredient, the cube may be scanned to highlight each material. The resultant pictures allow the software to count the pixels—the number may exceed 35,000—that contain a particular chemical and estimate the percentage of each chemical (see Figure 2). Basically, the math is: # pixels with API/ # total pixels X 100% = % API]. Of course, the software needed to get to this point is sophisticated.
The software also generates a faux color or RGB (red-green-blue) image for visual inspection. It usually can generate the statistics of assays between tablets, distribution of agglomerates—how well dispersed the individual components are, particle size distributions, etc.
This RGB depiction may be also generated for fluorescence imaging or FI (see Figure 3). This approach may be more sensitive than NIR for low-dose drugs, where the APIs and or excipients cannot show individual, specific wavelengths in the NIR, or as an adjunct to NIR or IR imaging. In FI, the target sample is illuminated with one set of wavelengths, perhaps UV, and measures the resulting light emitted, which is usually visible. These CI spectra may be generated at a rapid rate, so the information may be gathered at a normal process speed.
Examination of solid dosage forms
There are a number of reasons to use CI to examine a solid dosage form. One is during formulation to assure well-dispersed API(s), lubricant, etc., in the experimental batches. Clearly, as seen from the Figures 2 and 3, a formulator is able to perform preliminary comparisons on newly formulated dosage forms even before lab results—content uniformity, dissolution—are available. This speeds up the formulation process and allows for manipulation of process parameters to achieve uniform, well-lubricated tablets.
Used properly, a CI device may be integrated into a Design of Experiments program to quickly evaluate each dosage form, again faster than the conventional lab results are available. A continuous manufacturing set-up, used for determining the efficiency of each module can be enhanced with the spatial information from chemical imaging.
For example, the uniformity of the powders in a blender is currently done with a running standard deviation versus time. With CI, a more accurate distribution may be discerned. The output of a ribbon compactor is currently evaluated with Raman, NIR, or TeraHertz, but again, on a macro scale. CI could allow the operator or formulator to see the distribution in greater detail.
As part of an OOS (out-of-specification) investigation, samples from throughout the run are analyzed to determine where and what may have changed to cause problems—assay, sticking, chipping, or dissolution times. Not only can the imaging technology show more information than classical lab evaluations, but a large number of doses may be examined, non-destructively and rapidly.
Clinical trials and production filling
There are reasons for monitoring an entire lot in its blister packs through imaging technologies.
In clinical trials, the different test tablets or capsules are made to be visually similar. The reason, of course, is to maintain double-blind integrity of the test. Unfortunately, since the blister packs are filled by hand, there is always a chance of human error. Only a couple of the packs are sacrificed for analysis, assuming that, if those are correct, the entire study is considered correct. Aside from non-compliance by patients, incorrect dosing can ruin a clinical study, potentially eliminating a good product from coming to market.
Using CI technology, the filled packs are moved under the instrument at a reasonable rate of speed, allowing the software to determine and generate pictures for the records that the proper doses are in the proper order for clinical trials (Figure 4).
A number of FDA warning letters and recall notices are based on improper filling—wrong dosage level or API. Since the vast majority of packaging areas do not have monitors—hand-help NIR or Raman spectrometers—the bottles and blister packs are filled, based solely on faith in the labels, which are often hand-written or, at least, hand affixed, on the bulk containers. A CI device can show the veracity of the dose and active before a large number of packaging materials and drug product is wasted in false fill.
Machine-vision, or simple cameras, monitoring of the filling line is most effective after a spectrophotometric ID and dose level check of the bulk is first performed. For blister packs, the same cameras may be used to determine 100% filling and integrity of the dose—no cracking or chipping during filling.
Some product containers are designed to contain more than one type of material in a single package, most notably birth control tablets, where the placebo and active are placed in the order to be taken during a woman’s cycle. They are supposedly placed into numbered spots in the order in which they are to be taken.
However, there have been cases where the misplacing of doses—patients are often inattentive as to color of tablets—caused unwanted pregnancies, resulting in expensive lawsuits. A simple CI device on the filling line could save its purchase cost, many times over by assuring the proper doses are in the proper slots (Figure 4).
Final comments
The versatility of chemical imaging is only limited by the imagination of the users. One application I have seen is by generic companies to better understand the formulation and process parameters of a soon-to-be off-patent dosage form, sometimes called “reverse engineering.” Chemical imaging, as well as many other technologies deemed too expensive and/or sophisticated for smaller companies have both come down in price and been made simpler to operate and interpret.
There are fewer and fewer reasons for CROs, CMOs, and generic houses not to come into the 21st century with modern methods of monitoring and control for manufacturing and packaging. The Cost of Goods Sold (CoGS) needs to become lower, especially since so many countries are demanding lower retail prices. The cost of modernizing is small when compared to the increased efficiency and productivity.
References
Emil W. Ciurczak
DoraMaxx Consulting
Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.
Fortunately, in the last few years, several other instrument manufacturers have introduced less expensive, yet well-built and efficient pieces of CI equipment. I will use some applications of chemical imaging to highlight a few instruments. The equipment for this work is currently available in both Europe and the U.S.
Basic theory, hardware and software
The driving force for developing chemical imaging (CI) was that the idea that the amount of API and excipients in a tablet is only one part of a proper dosage form. Their distribution and agglomeration within the tablet is what controls tableting/dissolution/bioavailability. The CI is made in several ways, but all involve either scanning with monochromatic light (prior dispersal) or filtering the emitted/reflected radiation (post-dispersal) and directing the light onto a diode-array (planer or linear). The diode material depends on the wavelength range scanned, usually Silicon (Si) for visible and short-wave NIR (350-1100nm) and Indium Gallium Arsenide (InGaAs) for long-wave NIR (1100-2500nm). The source is usually a Tungsten (Wolfram, for our European readers) halogen lamp, with light emitted throughout the visible and NIR regions.
The result is a 2-dimensional array—position of chemical at each x-y coordinate or pixel—for each wavelength scanned (see Figure 1). When the slices of individual wavelength images are combined, the resultant 3-D hypercube contains both spectral and spatial information. By investigating which wavelength most represents each ingredient, the cube may be scanned to highlight each material. The resultant pictures allow the software to count the pixels—the number may exceed 35,000—that contain a particular chemical and estimate the percentage of each chemical (see Figure 2). Basically, the math is: # pixels with API/ # total pixels X 100% = % API]. Of course, the software needed to get to this point is sophisticated.
The software also generates a faux color or RGB (red-green-blue) image for visual inspection. It usually can generate the statistics of assays between tablets, distribution of agglomerates—how well dispersed the individual components are, particle size distributions, etc.
This RGB depiction may be also generated for fluorescence imaging or FI (see Figure 3). This approach may be more sensitive than NIR for low-dose drugs, where the APIs and or excipients cannot show individual, specific wavelengths in the NIR, or as an adjunct to NIR or IR imaging. In FI, the target sample is illuminated with one set of wavelengths, perhaps UV, and measures the resulting light emitted, which is usually visible. These CI spectra may be generated at a rapid rate, so the information may be gathered at a normal process speed.
Examination of solid dosage forms
There are a number of reasons to use CI to examine a solid dosage form. One is during formulation to assure well-dispersed API(s), lubricant, etc., in the experimental batches. Clearly, as seen from the Figures 2 and 3, a formulator is able to perform preliminary comparisons on newly formulated dosage forms even before lab results—content uniformity, dissolution—are available. This speeds up the formulation process and allows for manipulation of process parameters to achieve uniform, well-lubricated tablets.
Used properly, a CI device may be integrated into a Design of Experiments program to quickly evaluate each dosage form, again faster than the conventional lab results are available. A continuous manufacturing set-up, used for determining the efficiency of each module can be enhanced with the spatial information from chemical imaging.
For example, the uniformity of the powders in a blender is currently done with a running standard deviation versus time. With CI, a more accurate distribution may be discerned. The output of a ribbon compactor is currently evaluated with Raman, NIR, or TeraHertz, but again, on a macro scale. CI could allow the operator or formulator to see the distribution in greater detail.
As part of an OOS (out-of-specification) investigation, samples from throughout the run are analyzed to determine where and what may have changed to cause problems—assay, sticking, chipping, or dissolution times. Not only can the imaging technology show more information than classical lab evaluations, but a large number of doses may be examined, non-destructively and rapidly.
Clinical trials and production filling
There are reasons for monitoring an entire lot in its blister packs through imaging technologies.
In clinical trials, the different test tablets or capsules are made to be visually similar. The reason, of course, is to maintain double-blind integrity of the test. Unfortunately, since the blister packs are filled by hand, there is always a chance of human error. Only a couple of the packs are sacrificed for analysis, assuming that, if those are correct, the entire study is considered correct. Aside from non-compliance by patients, incorrect dosing can ruin a clinical study, potentially eliminating a good product from coming to market.
Using CI technology, the filled packs are moved under the instrument at a reasonable rate of speed, allowing the software to determine and generate pictures for the records that the proper doses are in the proper order for clinical trials (Figure 4).
A number of FDA warning letters and recall notices are based on improper filling—wrong dosage level or API. Since the vast majority of packaging areas do not have monitors—hand-help NIR or Raman spectrometers—the bottles and blister packs are filled, based solely on faith in the labels, which are often hand-written or, at least, hand affixed, on the bulk containers. A CI device can show the veracity of the dose and active before a large number of packaging materials and drug product is wasted in false fill.
Machine-vision, or simple cameras, monitoring of the filling line is most effective after a spectrophotometric ID and dose level check of the bulk is first performed. For blister packs, the same cameras may be used to determine 100% filling and integrity of the dose—no cracking or chipping during filling.
Some product containers are designed to contain more than one type of material in a single package, most notably birth control tablets, where the placebo and active are placed in the order to be taken during a woman’s cycle. They are supposedly placed into numbered spots in the order in which they are to be taken.
However, there have been cases where the misplacing of doses—patients are often inattentive as to color of tablets—caused unwanted pregnancies, resulting in expensive lawsuits. A simple CI device on the filling line could save its purchase cost, many times over by assuring the proper doses are in the proper slots (Figure 4).
Final comments
The versatility of chemical imaging is only limited by the imagination of the users. One application I have seen is by generic companies to better understand the formulation and process parameters of a soon-to-be off-patent dosage form, sometimes called “reverse engineering.” Chemical imaging, as well as many other technologies deemed too expensive and/or sophisticated for smaller companies have both come down in price and been made simpler to operate and interpret.
There are fewer and fewer reasons for CROs, CMOs, and generic houses not to come into the 21st century with modern methods of monitoring and control for manufacturing and packaging. The Cost of Goods Sold (CoGS) needs to become lower, especially since so many countries are demanding lower retail prices. The cost of modernizing is small when compared to the increased efficiency and productivity.
References
- Innovació i Recerca Industrial i Sostenible, S.L. (known as IRIS), Barcelona, Spain
- Middleton Research, Madison, WI, USA
Emil W. Ciurczak
DoraMaxx Consulting
Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.
