© Institute for International Research, Inc All rights reserved. Module 4: Process Analytical Technology

2 international Module 4 Purpose and Objectives  Module Purpose:  Examine PAT in the context of lyophilization  Module Objectives:  After this module, you will  Have been introduced to the instrumentation used in lyophilization  Argue for or against PAT proposals

3 international Process Analytical Technology  A desired goal of the PAT framework is to design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing process. Such procedures would be consistent with the basic tenet of quality by design and could reduce risks to quality and regulatory concerns while improving efficiency. Gains in quality, safety and/or efficiency will vary depending on the product and are likely to come from:

4 international Process Analytical Technology  Reducing production cycle times by using on-, in-, and/or at-line measurements and controls.  Preventing rejects, scrap, and re-processing.  Considering the possibility of real time release.  Increasing automation to improve operator safety and reduce human error.  Facilitating continuous processing to improve efficiency and manage variability  Using small-scale equipment (to eliminate certain scale-up issues) and dedicated manufacturing facilities.  Improving energy and material use and increasing capacity.  Reference: 

5 international Feedback Control Do something with the measurements to cause a change during the cycle.

6 international Measurements  Thermocouple Data – Old and still useful  Pressure Rise  Manometric Temperature Measurement  Pirani gauge  Dew point indicator  NMR  Mass Flow Meter  IR  Weight  Sample thieves

7 international Thermocouples (Gold Standard)  Measure Temperature  Placement is an issue as may be uniformity of results.  Does the measuring tool interfere with the measurement?  Useful to obtain end of primary drying?  Useful to know how close the ice temperature is to the collapse temperature.

8 international TC Placement in a Vial

9 international TC Placement on a Shelf

10 international TC Feed Back Action  If end of primary is detected, then advance cycle? Need sophisticated algorithm to determine ‘end of primary’.  What might be required to validate?  If temp is low or high compared to collapse, then action is to change shelf temperature.

11 international Pressure Rise Test  Method to determine end of primary drying.  Isolate chamber and watch pressure rise. When the test results in no rise, or a significantly small rise, then primary is complete.  Action: Advance to the next segment when the test is passed.

12 international Manometric Temperature Measurement  Similar to a Pressure Hold test – measurement made in Primary measurement is a chamber average.  Fast data collection following fast valve closure.  Data analysis is complex  Action: Adjust shelf temperature or chamber pressure to control product interface temperature near collapse.

13 international Pirani gauge  Measure thermal conductivity of gas across a gap.  Use a heated wire in a vacuum and measure the electrical resistance of the wire. As less molecules hit the wire, a constant power will heat it more and increase its resistance.  Air / Water Vapor / Nitrogen all have different conductivity and return different results.  As Water Vapor goes away, one can guess the end of primary drying.  Often these gauges are not put into the chamber, but rather between the condenser & pump !!

14 international Pirani at end of primary

15 international Pirani Technique  Since the Pirani sensor is based on gas conductivity, it will see water and nitrogen vapor as different. However, it will see EtOH or IPA as particularly conductive. Take advantage of this to find leaks. A spray of IPA onto a suspected leak will result in a spike in the Pirani gauge a few seconds later.

16 international Dew Point  Dew Point is a Temperature at constant pressure that moisture in the air must be cooled to in order for it to condense or frost.  e.g. Slowly cool a mirror. When it suddenly clouds, that is the dew point temperature.  Dew Point is the temperature that would cause the air to be saturated with water vapor.

17 international Dew point indicator  A low dew point means there is very little water in the air (or Nitrogen atmosphere). Water vapor penetrates the gold layer and into the Aluminum Oxide Dielectric. Capacitance is proportional to the water absorbed.

18 international NMR  BOC Edwards has developed a non- contact check weigher (NCCW) that is being proposed to lyophilization users. It does not function inside the lyo. Purpose is to check weigh each unit out of the lyo with its stopper in place and before capping.

19 international Mass Flow Meter Functions by measuring the temperature on either side of a heater that is in a laminar flow. The gas stream is a side stream on the flow and the output is proportional to the mass within the sample at all times. Research Method – Not yet in prime time.

20 international NIRS Spectroscopy In Situ  Near Infrared Spectroscopy (NIRS) Research Method – Not Yet in Prime Time

21 international NIRS Spectroscopy In Situ  Advantages to NIRS  Non-invasive  Works in a sterile environment  Obtains rate data  Observes freezing/primary/secondary  Correlates well with Karl-Fischer end points.

22 international NIRS Spectroscopy In Situ  Negatives about NIRS  Novel  Build may be totally custom and a good design is not yet commercially available.  It is a single vial method, although at a greater expense, multiple probes can be used.  Probes will interfere with shelf loading.

23 international Mass Spectroscopy  Has been done by placing the mass spec sample collection near to the isolation valve.  Could be made sterile by putting a sterile filter prior to the sample port.  Advantage: Virtually perfect to assure the end of drying.  Disadvantage: Expense. Proposed in the literature – not in practice

24 international Weight Robotic balance that periodically picks up the vial and determines its weight. Currently used only for development.

25 international Weight  In food applications, one can suspend the shelves on load cells and obtain a continuous weight measurement.  Ideal for determining an endpoint.  Hasn’t been engineered for vials which have to be stoppered in the sterile chamber.

26 international Sample Thieves  Air lock with robotic arm to retrieve samples without drying interruption.  Off line, any testing can be conducted.  Not used on commercial driers.

27 international Using the data  Choices  Advance to the next segment  Change the shelf temperature  Change the chamber pressure

28 international PAT Actions - 1

29 international PAT Actions - 2 *Most dew point measurements are notoriously inaccurate

30 international PAT Actions - 3  What methods are commercial? PAT is a commercial manufacturing concept.  Thermocouples  Pressure Rise  Mass Flow Meter (after some more development)  What about these methods?  Pirani gauge (can’t be sterilized and hold calibration)  Dew point indicator (insufficiently reliable as currently manufactured)  NIRS (expense, lack of widespread availability – interferes with stoppering)  Weight (interferes with loading and stoppering)  Sample thieves (slow. Considered a development tool only)  Manometric Temperature Measurement (current valve technology is not scaled up – but could be.)

31 international PAT Actions - 4  What about using the sensors to change the shelf temperature or chamber pressure?

32 international Exercise 4.1:  Participant Exercise Directions: Split into pairs and prepare to answer orally.  A new lyo facility has automated loading equipment that negates the use of product thermocouples.  Besides the normal machine parameters, what additional sensor(s) could you recommend to both observe product changes and act to reduce the cycle for variation in lot sizes?

33 international Module 4 Summary  PAT implies taking action from measurements made during the process event in order to maintain product quality.  That action might be as inconsequential as an alarm or direct to include modification of equipment parameters.  The challenge is in knowing what to measure and what to change.