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TABLE OF CONTENTS
WELCOME ADDRESS
Prof. Dr H. G. Kristensen, Chair of the European Pharmacopoeia Commission ................................ 3
SESSION I: PROCESS ANALYTICAL TECHNOLOGIES:
ROLE OF THE PHARMACOPOEIA
Process analytical technologies in the manufacture of medicinal products: an overview
Mr Silvano Lonardi, GlaxoSmithKline (I)........................................................................................... 9
Viewpoint of the regulators: How can the Pharmacopoeia contribute to regulatory assessment
of PAT?
Dr Jean-Louis Robert, Chair Joint CVMP/CPMP Quality Working Party, (QWP, EMEA)............. 15
The PAT Initiative: PAT and Pharmacopoeias
Dr Ajaz Hussain, FDA (USA) ........................................................................................................... 21
A perspective and overview of Process Analytical Technology (PAT)
Mr Gary Ritchie, United States Pharmacopeia (USP) (USA) ........................................................... 31
Process analytical technologies currently in use, or under development:
What role for the Pharmacopoeias?
Dr Alistair Swanson, Pfizer (UK) ...................................................................................................... 37
PAT experiences in the paper and pulp industries
Dr Ralf Marbach, VTT (FIN) ............................................................................................................ 39
SESSION II: SPECIFIC TECHNOLOGIES/ TEST METHODS TO BE APPLIED
The integration and use of vibrational spectroscopy sensors in PAT Technology
Dr Mats Josefson, AstraZeneca (S) ................................................................................................... 45
Making sense of multivariate data
Prof. Tom Fearn, University College, London (UK)......................................................................... 51
Acoustics
Dr Ron Belchamber, Process Analysis & Automation Ltd. (UK) ..................................................... 55
Processability and functionality of excipients
Mr Steve Hammond, Pfizer (UK) ...................................................................................................... 59
Implementation of PAT in automated tabletting
Mr Ivor Pegington, MSD (UK).......................................................................................................... 63
Use of imaging to understand tablet performance
Ms Fiona Clarke, Pfizer (UK)............................................................................................................ 67
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WELCOME ADDRESS
Prof. Dr Henning G. Kristensen, Chair of the European Pharmacopoeia Commission
On behalf of the European Pharmacopoeia Commission and the EDQM I am pleased to welcome all
of you to this symposium on Process Analytical Technologies (PAT). The symposium has attracted
approximately 135 participants coming from 25 different countries. I will in particular welcome the
invited speakers. Your contributions to our discussion on the role of the Pharmacopoeia in the
development and regulatory assessment of PAT are highly appreciated.
The program for the symposium is organised by a Programme Committee counting members from
the EDQM, the European Pharmacopoeia Commission, national authorities and European
pharmaceutical companies. I will thank each of you for your assistance in developing an interesting
programme.
The Process Analytical Technology initiative launched by the Food and Drug Administration
(FDA) in 2002 encourages the concepts of quality by design, process- and product monitoring
methods through advanced instrumentation and data collection and evaluation. Thus, PAT focuses
on the principles of building quality into the product during the manufacturing process.
The idea of building quality into the product instead of ensuring quality by testing is not new. It has
been practised for years in the field of sterilisation processes, in Europe under the name parametric
release. The reference materials distributed to participants contain the Note for guidance on
parametric release and a copy of Annex 17 to the European Union (EU) Good Manufacturing
Practices (GMP) guide. The PAT concept develops very fast. To day we have available a range of
advanced analytical methods including methods for data processing, which allow the monitoring of
manufacturing processes of solid dosage forms as well as other dosage forms. In the field of food
processing, for example, implementation of process analytical chemistry seems well advanced.
The idea to organise a conference on the impact of PAT on the Pharmacopoeia came up one year
ago, when EDQM organised a meeting on microbiological methods. During the discussions at that
meeting it became clear that there are obstacles to the introduction of rapid microbiological
methods in the production of pharmaceuticals, in particular with regard to validation of modern
methods against the traditional pharmacopoeia methods. You can see it as a kind of conflict
between the performance tests presented in the Pharmacopoeia and the use of alternative testing
methods. The Pharmacopoeia presents in general monographs and specific monographs
requirements on the quality of pharmaceuticals that have to be met in their lifetime.
It has been said that the PAT initiative is incompatible with pharmacopoeia quality standards. I do
not see it this way. General Notices of the European Pharmacopoeia states in its Chapter 1.1 that an
article must comply with all the requirements stated in the monograph, but this does not imply that
performance of all the tests is necessary for assessing compliance with the Pharmacopoeia before
release of the product. It is stated further, that the manufacturer may obtain assurance that a product
is of pharmacopoeia quality from data derived, for example, from validation studies of the
manufacturing process and from in-process controls. Parametric release in circumstances deemed
appropriate by the competent authority is thus not precluded by the need to comply with the
Pharmacopoeia.
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Figure 1: Chemical and physical domain of 20 different manufacturing batches of the same drug
product.
While the product's chemical formula may remain the same, one batch of tablets could have a
different dissolution Prof.ile for example. Differences in production location and atmosphere or
minor plant set-up variations can all result in variances in the properties of the finished product
depending on the plant where it is produced, despite the same processes being applied and the same
ingredients being used, as anyone who has ever tried to make a Pizza in England will know.
Tests carried out on a number of intermediate products showed little variance between the Prof.iles
of batches produced in a European plant and those produced in a Far Eastern plant. Evaluation of
the chemical domain did not reveal any differences. When the physical domain was tested,
however, a variance was found between the two plants. Moreover, the mechanical domain still
showed differences in the spectroscopic response even after the granules had been milled in an
attempt to remove these physical differences. In other words, the resultant process signature
showed that the batches had significantly different Prof.iles.
When applying the PAT philosophy, it will therefore be necessary to evaluate all the fields of
activity over which we have control and to apply this philosophy in such a way to build quality into
drug product or by the design of these processes. These areas will unquestionably include the
product, chemical, physical and mechanical domains as well as the microbiological domain,
measurement technologies, risk assessment techniques and the related skills required.
At present, 75% of products tested are non-sterile products and the remaining 25% sterile. Of the
non-sterile products, 65% are solid and 35% semi-solid. These products/processes drive the
selection of the different available measurement technologies. Current laboratory test practices
enable the chemical domain to be tested but do not provide sufficient information on the other
aspects of the product Profile. It is expected that the use of on-line Near-Infrared (NIR) technology
will increase in the coming years to cover approximately 60% of process technologies in order to
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Microbiological testing concerns only sterile products and are only laboratory based. When we
look back on how sterility tests are performed today, we are likely to consider they were a rather
hit-and-miss affair. One need simply consider, for example, that every time a batch of 100,000
units is produced, only 20 samples are taken for microbiological tests, in accordance with
Pharmacopoeia requirements, to demonstrate that there has been no microbiological contamination.
Whilst there is little probability of any existing contamination being detected (see Figure 2), the
tests are at the same time also very time-consuming both in preparation and analysis. Additionally
only around one-third of existing microorganisms grow in the culturable media currently used for
performing these tests; therefore a different approach is not only desirable but also essential.
20
10
Sample size
30
Probability Curves
0.5
1.0
1.5
2.0
Contamination %
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DISCUSSION
Question from the floor: The axes on your figure risk analysis of actual stability test what
would the axes be?
Dr S. Lonardi: It is .005 is the probability curve in percentage. It is the percentage of the products
at the point of manufacture that are delivered right first time with no defects. Any recycling,
blending or other adjustments are excluded from the right first time.
Mr G. Ritchie: I have an interest in the spectroscopy, the part that you showed where you
attempted to remove the physical effect of the offset of the spectroscopy by milling. One of the
purposes of using the technology is to be able to come to a quicker conclusion of root cause
analysis. Have you been able to solve that? Do you know why that off set still exists, even after
milling?
Dr S. Lonardi: We look at 2 different processes, the Far East and the European, just because there
wasnt a need to build another one and basically the performance of the Far East process was better
than the European one. It has not been possible to determine exactly the reason why one plant was
working better than the other. It was probably a series of combinations. Basically the accurate set
up of Far East plant, rather than a European plant was the explanation of this.
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ICH Q8:
Discussion on Regulatory Flexibility
Traditional process limited
knowledge 3 batches, any change
needs new data and new approval
Var X
New paradigm: influence of
factors explored creating
knowledge. Risk analysis of
impact of change possible.
Approval to move within defined
area post-approval could give
flexibility for continuous
improvement without need for
further approval
Var Y
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DISCUSSION
Prof. Dr H. G. Kristensen: I think the most provocative slide you had was the question whether
regulators represent a barrier to PAT and of course you say no. In a very fast, rapid changing
environment you have to be very cautious, therefore I agree with you also and your comments
whether the Pharmacopoeia should or could do anything now. We need to be very cautious because
there is a need for flexibility. The point I made in my introduction is that in the future with a better
understanding of PAT and PAT systems we can run into a situation where we need to express
ourselves differently. You had a slide with the same viewpoint - Pharmacopoeia Specifications to
be accepted by the regulators. If such a change should be made, we have to begin to think now
because it will be a very long development.
Question from the floor: Im just interested to hear what kind of co-operation is with the FDA
PAT team from this European PAT team you have now established. I have seen that a lot of work is
going on in both places and as we are supplying our products to the whole world it would be
beneficial if we work on the same track. I see from your presentation here that we are actually
working on the same track, but could you elaborate about the co-operation and how you think the
future will be between USA and Europe?
Dr JL. Robert: When we had our meeting last Thursday we had a teleconference with Dr A.
Hussain and his FDA colleagues. So there is a collaboration with the FDA on this level. In Q8, the
ICH process, we collaborate with the US and Japan and I think also there we will also address these
PAT issues. This is one of the topics on our next agenda. In our first full meeting in March 2004
understanding but specifically the PAT issue will be discussed. So we have already in a certain
sense a global collaboration here. The PAT team is of course dedicated to having an international
collaboration. But of course we have also 25 member states since few days now and we have to
make sure we also harmonise within the European Union, so it goes in two senses, regionally but
also with Japan and the FDA together with industry of course.
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DISCUSSION
Question from the floor: Just a question concerning where you the think the USP is at this point in
time. Are there any movements that the expansion of the acceptance criteria to a more statistical
based approach is going to happen in the near future, for example for continuity conformity or even
more importantly for dissolution?
Dr A. Hussain: I think this question should be asked to the USP speaker after me, but Dr
Woodcock made a presentation to our FDA science board. We are not waiting for the USP to make
the changes, we will be making those changes ourselves, in terms of how we enforce and how we
interpret these things. We are moving very quickly towards the approaches to manage that. Again
we have a clear distinction of what is a market standard and what is a release standard. We are
focused on the release standards and any other specifications from that will be addressing it from
that perspecive.
Question from the floor: What is your interpretation of the legal impact of such as dual standard
situation?
Dr A. Hussain: I think its not a dual standard per say. It is a standard which is a minimal standard,
because I think that PAT from a process understanding and design perspective, the minimal
standard is the least of your worries. Youll achieve a higher quality standard and legal standards,
which are enforceable when you take somebody to court, you really have to, from a science
perspective, violate that legal standard, which is a minimal standard.
Prof. Dr H. G. Kristensen: In slide number 4 you showed drug code of high quality but the second
point is high burden on FDA resources. You didnt comment on that point, but one can get the
impression from the slide that you think there is a high burden on the FDA resources today and
PAT could diminish them. Is that your opinion?
Dr A. Hussain: PAT will diminish the need for our resources, yes. That is the point in a sense,
because of a lack of sharing of knowledge and the focus on testing to document quality.
Unfortunately I think the challenge is from a validation and release perspective if we do minimal
testing. So the FDA approach has been as if everything is suspect, you have to scrutinise every step
and with the increasing number of products and the increasing number of companies, our resources
do not matter at that level. The PAT process is, if there is more sharing of knowledge, more
science-based approaches and PAT focused process understanding, then these companies, which
achieve a higher standard would be recognised from a risk-based perspective and our FDA
resources would not have to be spent on those companies and so from an inspection perspective, a
review perspective. We want to shift our limited resources to high-risk areas. So companies that
have understood the processes would be at lower risk and those thats have that information with us
would be lower risk.
Dr J. Berridge: You mention a number of times standards and the ability of companies to reach
higher standards. You also talked about the FDA developing a quantitative tool to enable risk
assessment of presumably firms or firms and products or products. Would you like to comment on
how you think these standards will actually be developed and agreed and how industry and
regulators might agree that they are appropriate standards and how they would be applied? How
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DISCUSSION
Prof. Dr H. G. Kristensen: It seems that the USP is thinking along the same lines as I outlined in
my opening. There is a basis for international harmonisation in this field.
Dr J. Kincaid: USP traditionally has really stayed away from getting involved in new technology.
Its something that weve been told over and over again, that they really want to look at things when
they are well developed, well understood and well in place in industry. So, why is the USP trying to
push forward now in this area when theres so much going on within the regulatory bodies and
within industry, instead of taking a step back and waiting and seeing what happens and looking to
see what your role would be?
Mr G. Ritchie: I think the leadership that the USP has in trying to orchestrate a well balanced
approach and dealing with, as Dr A. Hussain alluded to, some of the past issues which are still
outstanding with respect to standard setting activities, but in looking forward the perception now is
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DISCUSSION
Dr A. Hussain: I think the key aspect is when it comes to an assessment and regulatory approval,
unless you look at PAT as a system, you will actually be doing extra work for nothing and I think
thats the reason why its very important to look at PAT as a system for assessment because all
regulatory decisions depend on the intended use. The focus becomes the intended use and
regulatory flexibility comes from that. No matter how you look at PAT it boils down in the end as a
system and not just tool.
Dr A. Swanson: I think this is a terminology thing. The part of the pyramid I call quality by design
and process understanding gives that system framework. Its surely just a case of deciding whether
were going to call all of that PAT or just the bottom bit of it.
Dr S. L. Ali : On one of your slides I saw the different PAT technologies you put together with the
P agent at PLC, NIR and FT-IR, etc.. Do you think that colour is also an important aspect and a
characteristic? Is it a new PAT candidate to instrumentally monitor the colour of your product,
Active Pharmaceutical Ingredient (API) or an excipient?
Dr A. Swanson: I think if you can show that there is some link between colour during a process
and the quality attributes that you care about in the product down stream or the process ability
further down stream, then yes. Thats why we deliberately created a very broad definition there of
process measures that lead to understanding. Now if its the case that colour is incidental on the
way through, then in that particular case no it wouldnt be.
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A very important, first step when starting a PAT development project is to select the right
technology for the needs of the customer. VTT has broad experience in the mainly used NIR, IR,
and Raman; spectroscopic hardware techniques and has developed commercialized instruments
based on all of these. In order to give an overview and rough comparison of these mainly used
technologies, we have done the comparison chart shown in slide 7, page3, PAT-SessionI.pdf,
EDQM internet site.)
The various technologies shown in slide 7, session I file, EDQM internet site were shortly discussed
in the presentation and some of their practically important limitations were mentioned. Also,
example PAT instruments used in PPI and based on several of these technologies were shown. Of
particular interest to the pharmaceutical industry may be latest developments in the area of imaging
spectroscopy, which can be utilized to realize very high sampling rates (by realizing 100
spectrographs in the size of one, so to speak). VTT was very actively involved in the development
of the first commercial product based on this technology, which was launched to the paper industry
in 2002 and which realized a very significant increase of approx. 5% in paper machine
"runnability." Another potentially useful technique, wireless data transfer from "mobile" PAT units,
was not mentioned in the talk but is a specialty of VTT Electronics.
In every PAT development project there is a pattern of key issues or milestones, which tends to
repeat regardless of the details of the application. These key issues come about whenever optical
methods are applied to "real" on-line processes, and include:
1.
2.
3.
4.
Instrumentation
Process interface
Calibration
Closing the loop
(The list above assumes that the R&D-ish part of the project is completed and that the key
specifications for the application are available.)
Issue 1: Instrumentation concerns the core of the hardware of the instrument, i.e., the principle way
of realizing the spectroscopy. Issues here include: Cost; performance (SNR, spectral resolution,
long-term stability of calibration, etc.; robustness (dirt, temperature, humidity,etc.); amount of
required maintenance (cost of ownership); and availability of key components (number of
component suppliers). Infrared detectors are typically among the critical components, both from a
cost of direct material point of view and from an availability point of view. One important remark
here is that as soon as some volume of units is involved, say, 100 units as a very rough rule of
thumb, component suppliers tend to become interested in OEM supply and many of the availability
problems can be solved in this way.
Issue 2 Process Interface concerns the interfacing of the PAT instrument to the manufacturing
process. Cost is critical again here. Another goal is to cause as little change to existing pieces of
manufacturing equipment as possible. Last but not least, performance is also very important here,
because the accuracy of a PAT instrument is usually not limited by electronic noise, but rather, by
variations in the on-line sample and/or the sampling process. Design of the interface optics is
therefore often far from trivial, and detailed understanding of the physical environment and the
optical properties of the sample is desirable. The ability to perform relatively quick and relatively
inexpensive feasibility studies on the "real" process is a key tool in the design of the interface. VTT
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Issue 3 is calibration of the instrument. Whenever possible, VTT employs newly developed
calibration methods based on multivariate measurement science, as opposed to multivariate
statistics. These methods reduce the cost of calibration dramatically and they are also more
transparent and reliable. Specificity of response can usually be guaranteed. Issue #4 is how to close
the loop, i.e., how to actually use the output of the PAT analyzer for closed-loop process control or
quality monitoring.
Conclusion
The paper & pulp industries are advanced in the areas of PAT and on-line process control.
Technologies have been proven in these industries, e.g., imaging spectroscopy for very high
sampling rates, or today's possibilities for efficient manufacturing of complicated opto-mechanical
assemblies, which have strong potential also in the pharmaceutical industry.
In addition to paper & pulp, VTT has PAT experiences also in other manufacturing industries,
including the chemical, food, and steel industries. The pharma industry seems to be a special case in
the following sense. Ideally, the manufacturing industry should be able to buy all PAT related
equipment and know-how from outside, i.e., from specialized companies of the Measurement,
Control and Automation industry. This is indeed the case, e.g., in the paper industry. The pharma
industry, on the other hand, at this point in time seems to get relatively little support from the
instrument supplier companies. This situation is not completely unlike situations in other industries,
in the presence and past.
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DISCUSSION
Mr G. Ritchie: It seems like you a great advantage not being hand strapped by the regulatory
burden of data collection. You must have a very direct path and know precisely what data to collect,
what data to analyse, what data to discard (that word which we dont like to say here.) Just data
management in general, you must have a clear perception of that and it would be good to hear some
of the insight.
Dr R. Marbach: Actually Im not the expert of that. Our prime customers are these MC&A
companies that I just talked about. Although we also do a lot of one c two c types of instruments for
end users. Prime customers are these MC&A companies and they actually close the loop. They are
the ones who know best how to make use of the measured data and how to control the process very
quickly. It is a close loop process control and things can happen as fast as on, say second time scale
and they will set valves or change pressures or angles of roads downstream and they will wait for
that to return to normality. These are the core competences that the MC&A companies have and
with which they compete with one another. I would not be able to say much about that.
Dr C. Potter: Excuse my ignorance of the paper industry, but how easy is it to get the measurement
and control right first time and how much change is made when we get to manufacturing, both in
the measurement and the production process?
Dr R. Marbach: From our point of view as far as building the hardware, the hardware is actually
tested on pilot plans. So the hardware that we built pretty much ends up in the final stage. As far
how much time the MC&A companies spend in the pilot plan and what routines they go through, to
simulate future expected events, I could not comment on that. All I can say is that the instruments,
when we build them are ready for use, they are calibrated, they are ready for installation. How
much work has been done on the application side to make sure that this instrument covers then
everything, how much testing was done, I could not say. But the time frame is typically two years.
Two years is a typical time to get ready before moving it out. These people also have a reputation
they want to keep.
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80
60
40
Timestop
20
NIRstop
Spectral residual
Figure 1, Film coating process monitoring. Upper trace: thickness calculated from
in-line NIR spectra, Lower trace: Magnitude of Partial Least Squares residual at
calculation of thickness. See reference (6) for full details.
The monitoring of a coating process using diffuse reflectance NIR is shown as an example in the
lecture, detailed information regarding this application can be found in reference (6). Here a
multivariate quantitative approach is taken to monitor the growth of the coating film thickness
during the process. In addition to the film thickness, a spectral residual is obtained from the
chemometric model. The size of this signal acts as a quality control indicator for the calculation of
the film thickness at each time point taken during the process. In Figure 1 one example is shown
where only half the amount of starting material is charged in the fluidised bed. The chemometric
model correctly found the target thickness at a shorter process time. In this way we could go from a
constant time process to a situation where we measure the maturity of the product in the process
step and end the process at 100 % maturity.
At initialisation of the process there is a section of high spectral residuals. This indicates that the
measurement at this point is not reliable due to the start-up of the process. Nevertheless reliable
measurements are obtained after the initialisation phase. Those indicate a process on track that
yields a good quality product. When we run multivariate monitoring tools like this, we will
encounter situations where we have to decide were in the process we want the most precise
measurements. In this case it is technically hard to get those at initialisation. In other cases such as a
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DISCUSSION
Dr A. Swanson (Pfizer): I was interested in the model free approach where you were using
chemometrics to look at the variants in the data. Can you say a bit more about that and when you
might be able to apply an approach like that? The follow on to that is how would you show people
that what you are actually measuring is meaningful?
Dr M. Josefson: In the presentation I defined model free as a situation where you do not create a
chemometric model before the individual process for one specific batch. A merit is that time is
saved because no chemometric model has to be developed before the production of a batch. A
drawback is that it is not possible to build in previous process knowledge in the chemometric
model. This way of working is useful e.g. for early R&D batches when the formulation is developed
and the conditions may change. Examples of model free methods are standard deviation, moving
windows standard deviation, and Evolving Factor Analysis (EFA).
If Design of Experiments (DoE) is applied, there will still be a DoE model on an upper level for the
relations between batches in an experimental design, but each individual batch may be
independently monitored with a chemometric tool on a lower level in the model free way.
EFA can be applied by doing a principal components analysis when a few multivariate observations
are available after the start of a batch process and then automatically calculate a new model for
every acquired observation. The diagnostic information from the series of models may be used e.g.
for homogeneity measurements at powder mixing or granulation. You will then see that e.g. the
score plot variations are diminishing with time for a properly adjusted process.
EFA used in this way is useful to gain understanding of what happens in single process runs in new
situations, but is not the ultimate tool for comparison of variations between process runs. We have
been using that in the R&D phase, it is a good tool because the operator and the experimenter can
use it and look at the diagnostics without doing modelling work before the batch run.
An answer to the follow on question: When DoE has been used to define the allowed variations
inside the specification that still yields an approved product, it will be possible to judge if e.g.
standard deviation is an important parameter to monitor. DoE then also makes it possible to set
trend limits for the same standard deviation.
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DISCUSSION
Mr G. Ritchie: Heres what I would suggest. You have been involved for a period of time now
writing a very good series of columns in NIR News and I think theres enough information in there
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To make a measurement it is necessary to attach an acoustic emission sensor to the outside wall of
the process vessel. Ultrasonic sensors use a small piezoelectric disc to convert the acoustic
emission wave into an electrical signal.
An acoustic emission system consists of a number of acoustic emission sensors, preamplifiers,
intrinsic safety interface, and a signal-conditioning unit. A personal computer is used to acquire
and analyse the signals. The preamplifiers allow the sensors to drive very long cables, which mean
that the signal conditioning unit and computer can be located in a control room away from the
granulation suite.
Many factors influence the acoustic emission signal including particle hardness, particle size and
the flow regime.
We have extensively used acoustic emission, outside the pharmaceutical industry, to monitor the
performance of very large fluid beds. An example is the manufacture of polyolefins granules.
Occasionally, this material will agglomerate causing major process upsets.
We can correlate change in the acoustic emission signals with changes in the particle properties i.e.
when we change the temperature and the particles become softer and more cohesive.
Using this approach we have been able to detect changes in large fluid bed behaviour up to 24 hours
before a major agglomeration incidents occur.
High-shear granulation is good application of acoustic emission monitoring.
During high shear granulation different acoustic emission signatures are obtained during dry
mixing, wet granulation and wet massing.
Acoustic emission signals are very rich in information. We have used a number of different
strategies for analysing and characterising acoustic emission signals. The simplest method is to
convert the signal to a DC level. This works well for simple applications such as detecting
particles passing through the outlet of a cyclone. Other methods of analysis include time series
analysis, which has been used for kinetic studies.
In most case we use a Fourier transformation step to convert the acoustic signals into the frequency
domain. The resulting spectrum is characteristic of a certain process state. The spectra are then
further analysed and characterised using multivariate statistical methods including Partial Least
Squares (PLS) to provide quantitative information and by Soft Independent Modelling by Class
Analogy (SIMCA) to provide qualitative information (e.g. has the end point been reached?).
SIMCA is a powerful pattern-matching algorithm. It is based on principal component analysis and
models classes of signals. It enables unknowns conditions to be classified as belonging (or not
belonging) to previously defined classes.
SIMCA provides a statistic called the SIMCA distance. This is usually expressed in terms of
standard deviations and tells how well a particular unknown (acoustic emission signal) fits a
particular class.
We have used this statistic to monitor the approach to end point in high-shear granulation, fluid bed
granulation and fluid bed drying.
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DISCUSSION
Dr G. Cook: One of the challenges with high sheer granulation is scale-up and applying the
learning say from a small-scale piece of equipment to a larger piece of equipment, how is that
addressed in acoustic emission technology?
Dr R. Belchamber: You certainly see similarities between small-scale equipment and large-scale
equipment. Im doing an experiment on small-scale granulation and the equipment is actually quite
difficult, really due to the size of the material, your sample size. It is quite possible that in very
small granulator to have 50 % of the material for instance sticking on the walls. So scale-up is quite
difficult. I would say you see similarities, at this moment you cannot build models, I believe on a
small granulator and expect to be able to transfer them to a larger granulator. The calibration stage
for qualitative modelling is actually reasonably straightforward. Its easier than doing a quantitative
model, so its probably not too difficult. But I think there are quite a few challenges in that area and
Im sure there are going to be some developments, but at the moment you would not be able to
transfer a model, although you can actually learn quite a lot.
Prof. T. Moffat: Can you actually go out and buy these things? Or is it very much cut and stick
yourself?
Dr R. Belchamber: You can do both. There are a limited number of manufacturers of systems,
complete monitoring systems and as I said at the beginning, acoustic emission has quite a long
history of non-destructive testing, so it is actually possible to go and buy components. The
companies that supply equipment for non-destructive testing, some of the systems could probably
be applied to some of these things, but are not exactly ideal and it would probably involve you
going to a number of different suppliers, to build a complete system. It could be done, I mean thats
where we all started.
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DISCUSSION
Dr S. Wolfgang: Could you comment more on the surface area findings that you had and also on
your feeling about the functionality characteristics and specifications for instance, the fact that the
USP and Ph.Eur are requiring for surface area testing, yet its possible the measurement of surface
area alone will not allow for selection of materials properly.
Dr S. Hammond: Its certainly taking the last question first. I think that one thing we do know, that
if we do want a magnesium sterate thats going to work for a particular product, then we are relying
on surface area measurements, if they are actually performed and thats an interesting thing. A lot
of plants will just rely on the certificate of analysis for surface area that they get from a supplier and
one another thing, I think its something malencrot need to be very aware of, your gas disorption
measurement is not discriminating enough to tell us whether we have a good surface area. I think
the problem there is that you measure the pore size of the crystals and that has no relevance to
manufacturing. What were interested in, is the actual surface area thats available for a big lump of
micro-crystalline cellulose to interact with. I think the specifications for things like magnesium
sterate in the Ph.Eur and the USP need totally revising. At the moment I feel that they are not really
relevant to process understanding or good control of manufacturing.
Prof. Dr H. G. Kristensen: I mentioned in the morning that the Ph.Eur has decided to introduce
functionality related tests and what I want to emphasise is that we are fully in-line with your
recommendations here. What the Pharmacopoeia should do in this field is to standardise or provide
users with tests which will give the possibility to use the test in developing your specifications, but
a non mandatory system completely free to use, a flexible system. The Pharmacopoeia has really, in
my opinion, a role in the provision of standardised test methods, which can be used by the supplier
of excipients as well as the user of the excipient. But the real reason I want to make a comment is
because you say that impurities are not a problem, they are well controlled. I thought that
processability and many formulations were influenced by impurities in excipient materials. There
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DISCUSSION
Dr M. Josefson: I would like to ask you about those distributions in the last slide. Where does this
negative come from?
Dr F. Clarke: I believe that the negative value comes from the fact that the spectrums are totally
dominated by the lactose. When we do are match factors we dont see any.
Dr M. Josefson: How do you calculate those?
Dr F. Clarke: Basically we have been doing a classification PLS through to the pure group
excipient library.
Dr M. Josefson: Then I understand that they are different in the beginning.
Dr R. Marbach: I have one question. About the scatter co-efficient, if I look at my skin, I cannot
see details in my skin because its scatter. If I just do straightforward looking the smallest 3D
resolved element is determined by the scatter co-efficiency. In your measurement pixel size 20 x 20
microns chosen to be matching with the scattering characteristics above your samples. Is that why it
works so well?
Dr F. Clarke: Good question. I dont honestly know the answer to that. I would have to give it
some thought. In terms of the mapping system the size of the area where we collect information
from is defined by a set of apertures. In terms of the global imaging system its defined purely by
our magnification and all we believe we are limited by is the diffraction. So in terms of the global
imaging systems we can get down to about 5 microns per pixel. I dont know in terms of scattering,
the relationship.
Dr R. Marbach: I wasnt interested about the technical details of the imaging. If I think Im sitting
at one particular side of that tablet and I count the photons coming out at exactly that side, those
photons have a history of traversing neighbourhood material and my question is, how big is that
neighbourhood? What is the smallest technical resolution that makes sense?
Dr F. Clarke: We believe that the smallest object we can actually see is 20 microns. Having done
some experiments through my PhD studies with Prof.. Moffat we believe that if we actually set two
things side by side and go from one to the other the contribution of one from the other is no more
than 20 microns. We no longer see the spectrum contribution in terms of a lateral resolution.
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25
20
Concn. (%)
15
Lab
10
Plant
90
10
0
11
0
12
0
13
0
14
0
15
0
16
0
17
0
18
0
19
0
20
0
21
0
22
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
30
0
31
0
70
80
50
60
30
40
0
10
20
-5
Time (minutes)
20.00
% concn.
15.00
Interm plant
10.00
Product plant
Interm Lab
Product lab
5.00
272
266
260
254
248
242
236
230
224
218
212
206
200
194
188
182
176
170
164
158
152
146
140
134
128
122
116
110
104
98
0.00
-5.00
Minutes
25
Concentration (%w/v)
20
15
Saturated
ketone
Unsaturate
d ester
Saturated
ester
10
0
0
50
100
150
200
250
300
350
400
-5
Time (mins)
DISCUSSION
Mrs L. Lundberg: Thank you for presenting some very interesting things here, I like your
examples. A practical question, the example you gave of the different PAT applications in API
production: are they fully installed? Are the operators the ones to make the decision? How have you
managed to train the staff to cope with these new technologies?
Dr C. Killen: Good question. The first example I talked about, what we actually did with that one
was that, we were putting data through to the plant control screens. Not controlling the process, but
going through to the screens, so that the operators would get warnings if anything was out of
specification as far as our process should be running. In that case what they would do, they would
call a chemist. On a couple of occasions I was actually called in because the thing wasnt running
properly, to verify what the data meant. In that case they didnt really need any knowledge, they
had to make decisions about calling the appropriate person who had that knowledge.
The second application was a temporary installation that was run by technical staff, so the operators
werent doing anything there. We put a mobile unit on there to get process understanding and it
didnt justify putting a permanent installation in there.
Concerning the third installation, we are at the point where we are training up the operators. Two of
the points there we will actually go closely upon. So the operator wont need to interact with that. It
will actually take the process forward in the appropriate way. What it will be doing, it will be
looking at a waste stream and we concentrate up to a certain extent, when the concentration is
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Filtrated
1 volume 2
(Q2 ml)
200
Result
Q1
Result
Q2
Interpretation
Conclusion
+
+
> 10 org./100 ml
10
200
+
-
10
200
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DISCUSSION
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2.
3.
DISCUSSION
Dr I. Unlusayin:Vibrational analysis techniques are less informative than compared to mid IR or
other techniques. More mathematics, statistical matters have to be used, such as PCA, PLS, MLH.
You can use more capital letters if you want. I mean chemometrics. Since limited availability has
invalidated so fair packages, especially for chemical imaging techniques. We have already seen
negative results yesterday on some slides. Remembering to keep-it-simple principle, how do we
convince them if we have an audit by the regulatory agencies? Without clearly defined procedures,
basic requirements or acceptance criteria? Like defining other analytical methods?
Dr C. Cottini: I think we have to change our point of view. We have to begin to collaborate with
the regulatory bodies to put this new approach in place because the real point is how confident we
are in our software. If we need a higher level of confidence, we need to move towards these tools
and I hope the regulatory bodies will follow us.
Dr A. Hussain: I think in terms of software validation the concept pharmaceutical software is not
as complicated as some of the software we have been looking at from our department of defence to
the aviation industry and so forth. I think there are a lot more examples out there on how you can
focus on the reliability of software rather than validation of the software, I think there are a lot of
lessons to be learnt from the other sectors.
Mr F. Despagne: Dont you have a concern that implementation of this certification approach will
just add a huge multiplying factor to the cost of the projects? It would certainly require a significant
amount of money on the pharmaceutical companies side and also on the vendors side. I think the
model is nice but Im just trying to see how you can implement that realistically within the next
years without just bankrupting the instrument vendors?
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SRM 2035 at
16cm-1
Water
vapour
2 cm-1
0309011-final PPU
0309011-first PPU
0309002-5th drum
0309005-composite
0309011-first PPU
0309002-5th drum
0309011-middle PPU
0309002-3rd drum
0309011-middle PPU
0309005-composite
0309002-3rd drum
0309002-1st drum
0.09
0.45
0.04
-0.01
0.4
-0.06
-0.11
0.35
-0.16
Dihydrate
-0.21
0.3
-0.26
variation
monohydrate
0.25
-0.31
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
0.2
0.15
0.1
Needed Linearity
0.05
0
1150
1350
1550
1750
1950
2150
2350
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Cells of two or 3
pathlengths could
monitor linearity
Detector
Etalon &
Gas Cell
Detector
Probe
Tunable
Light Source
Sample
Beamsplitter
Beamsplitter
Detector
Figure 3 shows the proposed optical system for continuous performance verification in the Axsun
spectrometers.
For routine performance checks the S\N ratio is one of the most important calculations we can
make. This becomes particularly relevant if we use the sample we want to measure as the reference
material. This is a simple measurement to perform and can tell us a lot about the relative
performance of an installed on-line instrument. Particularly with the rapid scanning diode array
instruments available today.
Conclusion.
The pharmacopoeias need to introduce flexibility and science based testing into the procedures for
qualifying analytical instruments that are to be used in the process environment.
The pharmacopoeias need to think in terms of recommending strategies for testing the performance
of on-line instruments. Suggest what might be measured, but must at all costs avoid
recommending how. There must also be a recognition that the idea of a traceable standard is just
not realistic, in the light of the variety of instruments and sample interfaces that exist now, and
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DISCUSSION
Prof. T. Moffat: Id like to just discuss the last point you had about traceable standards. One of the
great things about traceable standards is that they are the same across the whole of the world. I
dont see any reason at all why you shouldnt start off with a traceable standard whether it comes
from NIST or somewhere else and use your own secondary standard to match against that and from
that moment forward your practical samples become traceable back to NIST. All you need to do is
to start off with a traceable standard and then match everything to your own secondary standards. Is
that not a possibility?
Dr S. Hammond: Its a nice idea but the problem is that the traceable standards out there dont
cover the wavelength range you need, you have peaks missing where you need them or the worse
case is the resolution you can achieve with them just isnt good enough. If NIST decided to validate
something like acetline as a traceable standard that would be a good thing. If NIST decide to take it
upon themselves to very quickly keep up to date with what are the standards that industry use, then
again thats not a problem. The problem I have is that they develop a standard, which has poor
resolution and doesnt fit the purpose and even if you did decide to use it its almost impossible to
get. If NIST produce standards that are applicable then thats fine but if NIST are not capable or
cant move fast enough to do that, which is their experience, then they become a real drag on what
were trying to do.
Mrs I. Maes: I can indeed agree with what you propose and I encourage this approach of using real
samples as the kind of reference. Also perhaps in other industries this kind of discussion has already
taken place 10 15 years ago. Perhaps Tom Fearn can confirm that and in the food industry theres
a discussion of using real samples compared to reference samples. It has already been discussed so
we dont have to re-invent the wheel every time and just look to these kinds of conclusions, which
have been made in other industries earlier. Another remark I would like to make is by using these
internal gas cells as standards, we are checking the performance of the instrument but normally the
configuration of the instrument consists of spectrometer often also fibre and a probe. How do we
test the performance of that part of also the instrument? That means measurement of real samples is
really something we have to do, because then you are also checking the fibres and the aging of the
fibres and the probe.
Dr S. Hammond: Thats exactly the point. I think youd use internal gas cells to check the stability
of the instrument, but thats only 50% of what you want to do. Using real samples and measuring
the signal to noise and wavelength repeatability using the samples is exactly that. You test the
system rather than the spectrometer.
Mr G. Ritchie: Im happy to say that your pleas have not fallen on deaf ears since the F-PAT
meeting. I went back, discussed earnestly some of the issues that you raise and since the last
meeting of the PAT project team is at the top of the list and the number one priority is to address the
issues of the chapter of 11 18. That being said theres two things, which stand out in my mind.
One of them is along the lines of what Prof.. Moffat was suggesting. There are current applications
that are robust and are used day in and day out in the laboratories with the current configuration of a
lab instrument. They have to continually be supported and I think one of the issues I am aware of is
the lack of the standard, especially the wavelength standard needs to be addressed to support current
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API + Excipients
At-line, In-line..
water content
homogenenity
PP
Granulation
Excipients
PP
At-line, In-line..
content (active)
homogeneity
...
Blending
PP
Tabletting
PP
Coating
PP=Process Parameters
At-line, In-line..
content (active)
homogeneity
water content
At-line, In-line..
film thickness
...
QC
QA/release
Figure 1. Example of a typical manufacturing process for a tablet formulation
Relationship of PAT based information to the final product quality
The material/process information collected during the manufacturing process is most often related
to the final specification clauses as a combination of information elements and not as a single
direct correlation as illustrated in Figure 2. For example the resulting uniformity of dosage units is
often a combination of in put material characteristics (e.g. particle size distribution of drug
substance) and how it is processed (e.g. granulation and tabletting). To predict the uniformity of
dosage units for a batch only the relevant in process information are used.
Info 1
Info 2
Info 4
Specification
Item 1
Item 2
Item 3
.
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DISCUSSION
Mrs C. L. Heinze: In the beginning of your presentation you stated that the real time release will
come sooner than later. How far do you think we are from real time release and what will it take to
get there?
Dr A. Torstensson: I think there are interactions already with our regulatory colleagues and of
course we shouldnt run too fast. I think as we have heard there is an open mind, an acceptance for
the concept. But finding the proper way, the right documentation etc.. and to fit into the current
system it will take some time. I dont see that there are any barriers any more. I think we have to
be careful about ourselves, that we dont ourselves build barriers.
Dr A. Hussain: In terms of harmonisation and innovation, when you have a standard, when you
have harmonised standards, how can you be innovative? That was the question in my mind. Talking
to Jean- Louis Robert, the EUPAT team and FDA PAT team, the way I think we have approached
that is not to harmonise the guidance, but more in terms of how you would approach that. If you
really look at the PAT Guidance, it is a very high level framework guidance. It doesnt tell how to
do anything except gives you a signal that we are ready to work with you and here is a flexible
regulatory process. The way to support harmonisation is a direct communication between the EU
PAT team and the sponsors and the FDA PAT team and their sponsors. That probably is the most
efficient way to support innovation and harmonisation already because its more science based. It is
more case by case, rather than writing a standard or writing a general chapter.
Dr S. Wolfgang: I just want to make a couple of comments: One on behalf of the quality people
from my organisation who are not here. How are going to deal with the possibility of having out of
spec results and the need perform investigations of 00S results? This in the realm of real time
release is one issue that I see and another is in terms of the sampling and testing and verification of
homogeneity of your batch or lot? I see that theres a lot of technology there, but some of the
practical concerns like this need to be addressed.
Dr A. Torstensson: If I may comment on the out of spec situation, I think that first of all you
should have specifications, which are needed, dont write specifications on everything because then
you run into problems. If you have out of spec specifications for critical attributes, you have to deal
with that as you deal with that today. I dont think thats a different situation.
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DISCUSSION
Abstract: Process Analytical Technology (PAT) is a strategic area of new technology that will have
a major impact on the Pharmaceutical Industrys future way of operating and that is likely to lead
to major changes in regulation of Drug Product Quality. PAT enables quality of materials and
processes to be assessed both in real-time and in more depth. The enhanced process understanding
provides new opportunities for advanced process control and prediction of product quality. In all,
this will reduce long production cycles, improve quality consistency and improve manufacturing
efficiency. However, it will also enable smarter development, and predictive scale-up and tech
transfer of new drug products. Indeed, manufacturing inefficiencies are often locked in before
phase III development which is why the major benefits from PAT require PAT to be integral to new
product development.
In this context, the presentation will discuss design and implementation of Quality systems based on
PAT. It will emphasize that PAT is not a goal itself or, a matter of only interfacing analyzers to
manufacturing processes. Rather, it is a holistic approach towards in-depth process understanding
from Pharmaceutical Development and onward. As such, the new paradigm shifts the emphasis
from current Quality Control and rigid GMP compliance to the assurance that the right product
will be made through better control of drug manufacture throughout its lifecycle. Because of
slightly different perceptions/interpretations of PAT in the current discussions there is, however,
some confusion on the impact of PAT for future Quality systems. The aim of this presentation is
therefore to clarify key scientific elements and outline how the will provide the basis for progress in
Drug Quality. Topics needed to be further discussed will be addressed.
Dr S. Folestads slides are available on page 24 of the PAT-SessionII.b2.pdf;
http://www.Ph.Eur.org/site/page_dynamique.php3?lien=M&lien_page=4&id=2
DISCUSSION
Dr G. Fischer: You mention several time a supporting structure, which is important, would you go
so far as to give recommendations, what would be the key elements in terms of structure,
organisational settings etc that have to be there for a company that wants to be successful with PAT
implementation.
Dr S. Folestad: Generally speaking it takes some 3 5 years to build a support structure, not
because of recruiting or getting the right competences and skills in place, but its very much about
changing mind sets, changing conscience, changing ways of working and it requires the holistic
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DISCUSSION
Dr J. Timmermans: In looking at your last slide I recognise very much the need for recognition by
regulatory agencies and pharmacopoeias for new technologies. However, in the past the role of
pharmacopoeias specifically has really focused on established technologies, for example the HPLC
chapters really appeared 10 15 years after HPLC was commonly used within the industry.
Personally I foresee that we are at the onset of the use of PAT and a lot of the technologies and
applications are still being developed. So, why do you believe its beneficial right now to get
technology and potentially even application specific guidance, when we dont really know yet in
which direction we are going to take this?
Dr D. Rudd: Its a good question. I think the answer is that a lot of the so-called new technologies
that we are talking about are maybe new in terms of pharmaceutical applications, but I think a good
example is acoustic emission that Ron talked about yesterday. Thats a very mature technology, not
in pharmaceuticals but in other industry sectors. If you argue that the role of the pharmacopoeia is
not to talk about the applications but simply to provide a framework for the principles of the
methodology, then I think you could argue that a number of so-called new technologies are actually
mature enough to be included. Acoustics is a very good example of that. In contrast some of the
newer technologies, some of the imaging technology, some of the tomography things I have
mentioned. I think that isnt necessarily as mature as we would like and it may be very much
premature to think about monographs for those techniques. So I think we should simply put
emphasis on those techniques that are mature even though the applications to pharmaceuticals may
be novel.
Dr J. Timmermans: Do you not believe that if you were to generate a chapter on acoustic emission
you would recognise that as an acceptable PAT? But by not having a chapter on imaging, we slow
the acceptance of an implementation of those technologies?
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Prof. Dr H.G. Kristensen: Thank you for being back on time - still we are a little delayed. I will
make sure that we close this session 3 on PAT and the European Pharmacopoeia in time, which
means quarter past 3 at the latest.
We have one hour to, what in my opinion is the most important part of this symposium, namely to
identify how to proceed from now. I have a panel here containing some distinguished speakers: the
2 regulators, Ajaz Hussain and Jean-Louis Robert, two people representing industry, John Berridge
from Pfizer and Chris Potter from AstraZeneca. They are both very much involved in the ICH
process and Tony Moffat who has joined the NIR working group. Finally we have two people
representing the Pharmacopoeias, Gary Ritchie the USP and the European Pharmacopoeia.
We have had 1 and a half days with presentations on PAT and very good talks, wonderful speakers.
They have addressed the item which they were asked to do namely what is the impact of PAT on
the pharmacopoeia and pharmacopoeia standards and what can the pharmacopoeia do in the future
to facilitate the development and regulators acceptance of PAT. We have also heard very diverging
proposals and viewpoints from the speakers. I hope we can catch up a little in this final round
discussion. The aim is to reach some conclusions, may be not very specific, but conclusions on how
to proceed from this point.
I have had my lunch together with the panel and we agreed that we will start by giving the panel
members the chance to make general statements and after that Id like to have a discussion with the
panel and also with you on how to proceed from today and from this point. So, not to waste too
much time on my talking I will ask the panel if any of you want to make statements now on how to
proceed.
Dr J-L. Robert: Yes, thank you chairman. I would like to apologize because I will have to leave a
little earlier and so I am grateful that I can start.
Firstly I would like to congratulate the organiser for this meeting and if I can make a first
conclusion - very straightforward we have a lot to do. As we are more focusing on the role of
Pharmacopoeias on PAT in the future, I will therefore not go into detail of all the different
contributions. But as I already stated yesterday in my talk, I said of course Pharmacopoeia is, has
been and will always be, a tool for standardisation and harmonisation, a fact you should be aware of
and we should also really take advantage of it. PAT concept is a vast, very fast moving field where I
think it is very important to maintain flexibility in this area.
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BIOGRAPHICAL NOTES
Dr Ron Belchamber graduated in Chemistry from Imperial College, London in 1975. He obtained
his PhD in Analytical Chemistry from the University of Alberta, Canada in 1981. After doing
postdoctoral work at the University of Swansea, Wales he spent 9 years at BP Research Centre as a
Team Leader, specialising in process analysis. For the last 11 years he has been Managing Director
of Process Analysis and Automation Ltd, Farnborough UK, his main area of interest is acoustic
process measurements.
Dr John C. Berridge is Vice President Pharmaceutical Sciences, Pfizer Global Research &
Development at Sandwich, Kent, UK. He received his BSc in Chemistry and Maths from the
University of Reading in 1971 and a PhD in Organic Photochemistry in 1975, also from Reading
University. He joined Pfizer Central Research in 1974. His research interests have been directed
towards high performance liquid chromatography, with special emphasis on the use of
chemometrics to aid method development. Over 40 papers and a book have been published and this
research has been recognised by the award of the Chromatographic Societys Jubilee medal in 1989.
More recently Dr. Berridge has been involved in the ICH processes, representing Europe in the
Quality topics, initially in the development of the guidelines on impurities in drug substances and
their dosage forms, more recently as Topic Leader for the Common Technical Document (Quality).
At FIPs 55th World Congress in Stockholm in 1995 he was presented with an IPS award for his
outstanding contribution to industrial pharmacy and in September 1997 he was awarded the Royal
Pharmaceutical Society Chiroscience award for his services to the pharmaceutical industry for his
work within ICH.
Mr Bob Chisholm is International Technology manager based in AstraZeneca Engineering in the
UK. Bob graduated BSc (Hons) electrical and control systems engineering from Glasgow
University in 1970 and joined the ICI then the worlds third largest chemical company. His career
has spanned a number of ICI Businesses and he moved from the petrochemical division to the then
ICI Pharmaceuticals division in 1989 to set up and manage the engineering science and technology
development group. Bob initiated technology initiatives in the area of spectrometry, chemometrics
and real time computing and this led to the adoption of such techniques, particularly Near Infra Red
Analysis in Zeneca (the successor to ICI Pharmaceuticals) which merged with Astra two years later.
The company sanctioned a potent tablet facility (PTF) in Germany in 1990 and Bobs technology
teams were responsible for the technical project management including the equipping of the facility
with cradle to grave on-line NIR analysers ethernet networked via a server to a data management
computer system, effectively the first fully equipped PAT facility in operation. The PTF will be
submitted to regulatory authorities in 2004Q2.
Ms. Fiona Clarke obtained her degree in Forensic and Analytical Chemistry from the Strathclyde
University in Scotland. She studied for her PhD at the School of Pharmacy, University of London
under the supervision of Prof.. Tony Moffat. Since 2001 she has been Manager of the Root Cause
Analysis Team in Pfizer investigating production issues utilising novel technology, including NIR
chemical imaging.
Dr Ciro Cottini is Manufacturing Technology and PAT expert within Engineering department of
GlaxoSmithKline Parma, Italy. He is graduate in Physics at Padua University with a thesis on bidimensional correlation algorithm for infrared spectroscopy. He joined GlaxoSmithKline 4 years
ago working on computer and compliance validation department.
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