process requirements drive innovation; microsphere classification, filtration and drying

PROCESS REQUIREMENTS DRIVE INNOVATION; MICROSPHERE

CLASSIFICATION, FILTRATION AND DRYING

By Craig Patrizio and Michelle Frisch

Case Study of how Innovative Design Solves difficult Process Requirements.

Evolution of Complex Processes Driven by:

Drug Delivery Methods.

Sterile Requirements.

Potency.

Particle Size and Classification.

Environmental Conditions.

Proprietary and Confidential

Identification of Standard Process Equipment and Constraints

Choosing the right equipment to start and how it can morph into specific process needs.

Environmental Conditions: Low RH, solvent laden environments. What are the constraints?

Elimination of or reduction of process equipment required.

Process optimization.

Sterile Discharge.


Microsphere Formulation The Constraints and Solutions

Evaluation of existing equipment technology that might suit the process.

Looking at new innovative designs for standard equipment to suit the process constraints.

Using the right PAT/OPC for optimization.


Background Existing pilot process…

Multiple ways of making polymer microspheres: emulsion (oil/water phases), coacervation/precipitation (solvent competition), etc…



A typical polymer emulsion process has:

– Oil phase: usually dissolved polymer in organic solvent, drug may be co-dissolved in this phase or in another phase known as inner-emulsion.

– Water phase: usually contains surfactants and/or other miscible solvents to modify encapsulation.




– Energy input: either in the form of sonicators, homogenizers, or static mixers. The energy imparted here emulsifies the oil and water phases to create droplets.




– Quenching/extraction: once microspheres are formed, the solvents need to be removed in a very controlled manner. Typically an anti-solvent is used – miscible with polymer solvent, but not polymer.




– Filtration: once an acceptable amount of the polymer solvent is removed, microspheres need to be gently filtered as they are soft and usually “plasticized” by the quench/extraction solvent.




– Drying: once filtered, the soft nascent microspheres need to be gently dried. Good powder flow qualities can be achieved here.




– Re-quench: a second quench/extraction may be needed to lower residual solvents and/or to promote “mobility” in the polymer. Material goes from dryer back to quench tank and then back to F/D.


Background Linear pilot/commercial process with existing Sweco dryers

Sweco 1

Sweco 2

Water/

Cont. Phase

Polymer

Phase

Drug

Phase

1˚ Quench/

Extraction

Water/

Cont. Phase

2˚ Quench/

Extraction

Re-slurry


Problem With existing dryer technology

Sweco was not designed to be an aseptic dryer – needed extensive modification by others (pressure rating, plunger valve seals, by-pass for SIP, drainable, remote sterile in/out filters-N2 and vac).

Requires large surface area of main deck – high DP from product cake will cause screen damage – screen is not supported.

Controlling filtration rate to lower DP would cause settling in lines – no means for high sustained flow with low DP on screen.

Lack of heat transfer from unsupported screen – only heat source is from shallow side walls where product “ropes” around.


Problem

Product “ropes” around circumference of screen at sidewall – sparge carrier gas has little or no contact with product to aid in drying and PAT detection. Sweco vibrates in two planes with adjustable counterweights – not always consistent or reliable – weights would shift, motor stress leads to failure. Mounted instrumentation has short MTBF and high PFD (probability of failure on demand) due to vibration.


Problem

1. Sanitary fittings vibrate loose even with nylon lock nut.

2. Welds fatigue and break.

3. Screen material fixed to circumferential frame with epoxy – epoxy cracks away and contributes to particulate load and loss of product.

4. Vibration can fracture delicate microsphere formation.


Custom Solution Conception of 5 kg Pilot Dryer Standard equipment evaluated.

Standard Filter/Dryers have bottom filtration only – ok for drying but still limits filtration and liquid/wet handling capability.

Need for increased SA, flexible filtration/drying, good liquid/wet/powder handling capability while maintaining good heat transfer.

Candle filtration was considered as a means to increase filtration SA utilizing gravity to clear filter material.


Custom Solution Conception of 5 kg Pilot Dryer THINKING OUTSIDE OF THE BOX!!

Candle filtration, however, impedes powder handling because it interferes with plough and physical turnover of material – it also impedes liquid handling.

Integration of candle filtration into sidewall of filter/dryer vessel was logical next step.


Custom Solution Conception of 5 kg Pilot Dryer SPECIALIZED DESIGN TO SUIT THE PROCESS BASED ON STANDARD EQUIPMENT AVAILABLE

PSL was chosen to build a very unique FD with a customized “ring” featuring vertical sidewall filtration! Many engineering obstacles to overcome.

“Eunice” was born – 5kg prototype FD, nicknamed from Uni-vessel, or one vessel (to be explained later).

Advantages of Integrated Vertical Filtration - covers full depth of product, out of the way of plough/mixing, self-cleaning, N2 injection or vacuum pull through depth of cake, in-dryer cross flow extraction/filtration.


Custom Solution Conception of 5 kg Pilot Dryer

However, a single vertical filtration zone would not pressure filter below top weir of filter area – air would by-pass through filter area and be preferential to liquid.

The solution is….



Multi-Zoned Vertical Filtration. (PATENT PENDING)

1) Simultaneous back pulsing and filtration, if needed.

2) The zones can be shut down as cake depth increases – protects cake from compression, promotes decanting of filtrate.

Sterile with Tilt side discharge. 1) One Vessel.



3) Allow for smaller batch processing by being able to utilize lower sections by preventing air by-pass.

4) Cross-flow filtration – keep material in dryer while cross flowing quench.

5) Heat conducting fins provide heat to all filtration surfaces during liquid and powder handling.


Redesigned 5 kg Pilot Dryer* *Winner of the Innovation Award

ACHEMA 2016 Mechanical Processes


Custom Solution An Unexpected Twist: The Unfortunate Truth!

The new dryer arrives, uncrated, installed and placebo batches are successfully run from 1-3 kg – good dead-end filtration (see Optimization).

With successful placebo batches under our belt it was time for active material – the next logical step.

The first active batch ran well, all in-process sampling looked good for PS, solvent ratio, etc – then it was time for filtration.



Filtration went well for the first 30 seconds and then came to a dead stop – roughly 200g out of 2kg.

We tried every trick in our bag and nothing worked. – visualization confirmed that the material was settling and forming a very thin layer on sidewall filters – normal based on placebo – why wasn’t it filtering?

As children, we all played with corn starch and water, right?



GOOD – then we all would have recognized sheer thickening when we saw it.

The BAD news is that no additional force was going to help, only hinder, and that this filtration rate was unacceptable for scale-up.

An acceptable filtration solution was needed ASAP – sustained acceptable filtration rate, quick enough for processing and to prevent settling in transfer lines/tanks.


Custom Solution A Call Home, a Pot of Coffee, and a Late Night

Keep the material moving at a high enough rate

to prevent settling in transfer lines.

Utilize fast moving flow stream to clear filtration

screens and allow fines to pass.

Create DP to provide filtration driving force that

is independent of pump speed.

Use recirculated quench material to suspend

quench tank contents – prevent settling.

Filtration Solution!


Custom Solution A Call Home, a Pot of Coffee, and a Late Night

The quench material is pumped from the BQT and injected into the dryer tangentially to the vertical filtration area. The high speed injection clears the screens and allows fines to pass into filtrate. The suspension is allowed to return to the BQT via a dip tube.

Illustration of rapid dewatering and high speed screen clearing in existing dryer.


Custom Solution Conditioning Phase: set BQT, in-line heat exchanger

(optional), and FD to -xC while recirculating – wait for temperature to homogenize (<xC).

Dewatering Phase: open side filtration valves to initiate dewatering taking pressure drop at valves, not screen – continue until BQT runs out or becomes too concentrated, initiate settling in dryer by reducing speed.

Pressure filter remaining heal in dryer and then wash/rinse from BQT.

Enable vacuum control set to xTorr, enable N2 flow set to xSLPM, plough control, MS sample control, and temp ramping control.


Optimization

Several placebo and active batches were run until we were comfortable with our upstream process and filtration scheme. All conditions mimicked 20 kg commercial scale, with the exception of lowering filtration temperature for primary and secondary filtration. Initial attempts at “normal” temps produced Bit-O-Honey (discovered secret recipe).

Several side studies were performed and adjustments were made to pilot scale to hone in on particle size, solvent extraction profile, drying conditions (vacuum and temperature profile), etc…


Optimization

Use of PAT (process analytical technology) was key to discovering and exploring process space (window) – lead to upstream formulation and process parameter adjustments.

IR, NIR, Raman, and mass spec were all used to characterize and explore the process window, including quantification of individual solvents removed and correlation to drying event real-time (removal of which solvent ratios triggered solid state conversion).

Each piece of PAT involved further customization of the dryer and PLC/HMI to accommodate its needs (data collection, sampling, coordination of PAT with PLC).


Data

Pilot lab had 2 full racks of native I/O and a 5-rack remote I/O cluster (via ControlNet) for monitoring and control – free reign over PLC programming and HMI development.

Every process entity was well fitted with bulk temperature, cooling temp in and out, pressure and vacuum sensors, mixer control and speed (if applicable), infrared temperature, full dryer control, discrete and proportional valve control, pressure control loops, load cells, and 6 independent temperature control sub-loops.


Data

All data and process state information was collected and synchronized with PAT data via OPC (OLE for Process Control).

This was not an easy task and created large data files – who ever thought that you could have too much data?

Imagine viewing a vacuum drying profile and having vacuum and solvent levels overlaid with crystallinity data from Raman.


Unified Process: Microspheres never leave FD until harvest

Waste

PMT

WMT WMT

DMT

FD1 PET

Emulsion stream enters dryer, external recirculation provides screen clearing concurrent w/ dewatering and fines removal.

Extraction takes place by recirculating quench through dryer w/ external recirc.

Microspheres never leave dryer until harvest. Proprietary and Confidential

Every Good Process Dreams of Growing Up

The 5 kg pilot dryer design was considered a success – design was used for a more immediate need and was fast-tracked.

A 15 kg GMP commercial version was designed, built, delivered, installed, IQ, OQ, PQ, and validated. - Fall ’06 through Dec ’07.

Very first batch had >80% recovery, within 3 batches of active we achieved >98% yield.


15 kg Commercial Dryer With Support Skid


Summary of Filter Dryer Capabilities

Rapid dewatering. Screen clearing w/ fines removal. Multi-part vertical filtration for “decanting” and

pressure filtering. Excellent heat transfer – bottom, sides, agitator. Excellent powder and liquid handling capabilities. Efficient drying – N2 can be directed through depth

of powder. All processing can take place in dryer w/ cross-flow.


Questions?

Thank you!

For more detailed information please contact us!


process requirements drive innovation; microsphere classification, filtration and drying

Health & Medicine