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Achieving PAT Goals with Process
Analytics Equipment

Pharmaceutical
manufacturers need to focus on quality and cost efficiency. Traditionally, the
pharmaceutical industry evaluates quality on samples tested in the laboratory.
The FDA has encouraged the industry to implement in-line tools as described in
the PAT initiative, with the goal being to better understand and control the
manufacturing process.

This white paper will focus on a new
technology used to assist the measurement of pH and dissolved oxygen in
bioreactors, as well as in product purification and downstream processing pH
and dissolved oxygen measurement are classical tools. Intelligent Sensor
Management (ISM), a break-through improvement to these measurement parameters,
offers diagnostic tools that aid optimization of the lifetime, performance and
reliability of process analytical equipment. It is much better to predict
problems before they happen, than to have to respond rapidly because a sensor
has failed in service. Intelligent Sensor Management means higher process
safety, higher productivity and less downtime. The pharmaceutical industry is
hesitant to initiate new techniques into their manufacturing processes for a
number of reasons, one being their perception that existing regulations are
unfavorable to the introduction of new systems. Such hesitancy is ultimately
undesirable, as the opposite approach can result in benefits for the industry
in the form of quicker manufacturing cycles, a shorter time to market and
improved drugs. In 2002, the FDA in recognition
of the need to alter the pharmaceutical industry’s belief, launched a new
initiative called “Pharmaceutical cGMPs for the 21st Century: A Risk-Based
Approach.” This scheme has led to the FDA encouraging the adoption of Process
Analytical Technology (PAT) tools, with the goal being for pharmaceutical
companies to better “understand and control the manufacturing process” (http://www.fda.gov/Cder/ OPS/PAT.htm). These PAT
techniques include continuous improvement and knowledge management tools, and
data acquisition and analysis tools. Early discussions on PAT in the
pharmaceutical industry often mentioned adding additional analytical
measurements to processes as a step towards achieving PAT compliance. PAT,
however, is not about improving small aspects of a process, nor about better
control of bad processes. It relates to a greater vision where the entire
manufacturing process is designed, monitored and controlled in an integrated
manner to ensure that raw materials are efficiently and reliably converted into
the highest quality products possible. This does not mean that the FDA expects
drug manufacturers to invest in expensive analytical equipment. “The main
emphasis of PAT is on understanding and controlling the process, and not trying
to find exotic technologies for doing so.” (Ajaz Hussain, former Deputy
Director FDA – Pharmaceutical Technology Oct 2004). As will be shown in this
white paper, process analysis tools for measuring pH, DO, etc., have a major
role to play in assisting pharmaceuticals manufacturers in achieving PAT goals.

Intelligent Sensor Management as a
PAT tool

In pharmaceutical manufacturing, the
downstream-processing phase is usually the most expensive, it is thus a very
interesting area for implementing PAT tools and techniques with a view to
reducing production cycle times, and hence costs. In order to help achieve
this, analytical measurement points must supply accurate, real-time information
to enable the earliest possible detection of drift from desired process
parameters. Further, the sensors should be easy to maintain, have a long
lifetime and be highly reliable, as unplanned production downtimes due to
sensor failure are substantial cost factors. The presence of an
analog-to-digital converter and a memory are a revolution in digital pH and DO
measurement. Sensors with inductive, non-contact plug-in connections are on the
market to avoid problems such as moisture ingress and corrosion. Further, a low
impedance digital signal is not affected by humidity. METTLER TOLEDO’s digital
ISM sensors focus on very sophisticated diagnostics and offer a solution to the
time-consuming task of calibration and maintenance. Sensors with ISM
functionality carry their own specific data on an imbedded integrated chip
along with calibration data and data on the current process, and convey this to
the connected transmitter. ISM technology is able to provide expert information
that is tailor-made for each measuring point. Using the “advanced diagnostics”
measurement function, the ISM system saves all relevant data related to the
sensor and the process, and displays this on the graphical interface of the
transmitter in a detailed yet clear manner. This allows the measurement point
to be optimized on an ongoing basis, as all critical situations can be
predicted allowing action to be taken before production is interrupted. For
example, for pH measurement, monitoring the reference system is essential. ISM
provides in-line glass impedance and reference monitoring. This data is
summarized graphically in a sensor network diagram and displayed on the
transmitter (Fig. 1). Should either or both impedance readings stray too far
toward the center point on the network diagram – an indication of impending
malfunction – the sensor can be replaced before it fails.

Determining sensor wear

A diagnostics parameter called “sensor wear” gives
an indication as to how much the exposure of a sensor to a process has altered
the sensor’s condition (Fig.2). As in the impedance example above, sensors with
high wear can be replaced preemptively before they fail during operation, resulting
in less frequent unscheduled downtimes. The level of maximum tolerable wear can
be set for each measurement point individually, adapting to the level of
confidence required for the process. As a result, maintenance strategy can be
changed from a passive, costly and unpredictable workflow, to a fully proactive
and optimized procedure. This is an example of continuous improvement – an
element of the PAT initiative. Part of the function of the sensor wear
parameter is to monitor the frequency of CIP and SIP cycles. These are critical
to proper function of pH and DO sensors in batch processes; however, they can
be detrimental to a sensor’s slope and lead to improper measurements and
early-stage sensor failure. To overcome this, plant operators would
traditionally turn to manual documentation of a sensor’s history and rely on
this to schedule maintenance. ISM sensors have a built-in CIP and SIP counter
which detects when the sensor is exposed to heat cycles. This data is stored in
the imbedded chip and is automatically uploaded to the transmitter. When the
maximum set number of cycles is exceeded, an alarm condition is raised. As a
result, using a sensor that could potentially fail in the process can be
avoided.

iSense Asset Suite

As the signal from ISM sensors is digital, a simple
connection via a USB port to a PC or laptop is possible. This allows the sensor
to interface with METTLER TOLEDO’s iSense Asset Suite software, which provides
access to various analysis, calibration and documentation tools. The Key
Performance Table allows the evaluation of the condition of an ISM sensor at a
glance, without the need of a transmitter. The iSense software has a further
useful feature; it allows a sensor to be calibrated via the PC / laptop. As an
accurate pre-calibration in the lab yields better sensor performance in the
field, this is a significant advantage to large bioreactors and provides
another step towards achieving the goals of PAT.

Optical oxygen sensors

During fermentation processes, air feed and agitator
speed are adjusted on the basis of the measured DO concentration value in order
to achieve optimal growth conditions for the microorganisms. Mammalian cell
cultures – the use of which is on the increase in the pharmaceutical industry –
are much more sensitive to changes in their environment than are bacterial
cultures, and their growth is significantly slower. It is precisely in the case
of batch runs of up to five weeks that optical oxygen sensors can fully demonstrate
their inherent strength, namely negligible drift over time. The stable
measurement enables batchto- batch consistency – another goal of PAT – and the maintenance
of optimal growth conditions. The new optical oxygen sensor from METTLER TOLEDO
can be used in small, autoclavable bioreactors as well as in production-scale
vessels. The built-in ISM technology in the sensor llows for quick startup thanks
to the “Plug and Measure” feature and offers the advanced diagnostics mentioned
above. ISM helps in deciding whether a sensor is safe for reuse in the next
batch or whether it is advisable to carry out maintenance such as membrane
replacement. Furthermore, the optical sensor offers maximum availability, since
no prepolarization time is required as is the case with polarographic sensors.

Measuring point verification

An ISM verification kit allows the qualification of
the measuring point independently of the sensor, as required by GMP rules. A set
of five devices simulate two fixed values at different temperatures as well as
various error states. Important ISM parameters such as the SIP / CIP counter
and the Dynamic Lifetime Indicator can also be verified.

Turbidity sensors

In situ turbidity sensors deliver a real-time
reading of the amount of light scattered by a suspension of cells. The
correlation with an optical density measurement is excellent, as the turbidity
of a cell suspension is directly related to cell mass. Knowing turbidity means
that the microbial activity in a continuous culture can be controlled via the
regulation of nutrient feed and withdrawal rate of the culture from the
bioreactor. If this activity is modeled into the process, then in situ
turbidity measurement is also consistent with the goals of PAT.

Conclusion

The recommendations in the PAT initiative are just
that, recommendations; they are not stipulations. However, this does not mean that
the pharmaceutical industry should maintain their hesitant approach to
implementing new  procedures until
legislation forces them otherwise. As shown above, the use of METTLER TOLEDO
process analytical sensors with ISM technology can bring about a better
understanding of bioprocesses, and better in situ monitoring, which are pre-requisites
for feedback control and consistent quality. It is the understanding and use of
the data which METTLER TOLEDO technology provides that makes it compatible with
PAT. Further, ISM sensors help improve batch quality, reduce unscheduled
production downtimes and lessen the maintenance burden, all of which are also
commensurate with the PAT initiative.