Friday, September 30, 2016

The 'Doers' in CM meet in Ireland in February 2017

You'll know from previous posts that FDA-AIChE organized a first successful workshop on adoption of CM in Besthesda in February 2016.  That is to be followed just under one year later by a second workshop in Ireland on 22-23 February, 2017.

Like the first workshop, this one will bring together the 'doers' in adopting CM; that is:
  • site leaders and senior managers from pharma manufacturing sites; 
  • leading scientists and engineers driving adoption from HQ and locally; 
  • regulators including reviewers and inspectors and members of emerging technology teams; 
  • and leading investigators from collaborative research centers worldwide.
We will spend two days together hearing the latest updates and progress from industry practitioners, regulators and principal investigators, and in breakout sessions and a tour of a  live operating CM facility for drug substance.  All talks and discussions will address three core themes:
  • Regulatory considerations: expectations for filing and process validation across the product lifecycle (especially how CM differs from batch)   
  • Control strategy, including application of PAT 
  • (Opportunities for) Industry / academic collaboration for shared learning and to address open questions.
Those interested in progressing CM filings, the future of pharmaceutical manufacturing and looking to have an influence or make a contribution in this field will find this workshop valuable and informative.  We look forward to seeing you there.

Online registration and further details of the program will be available shortly.  If you'd like more details in the meantime, contact contact co chairs Mark Barrett (APC) and Joe Hannon (Scale-up Systems).

Tuesday, September 6, 2016

Crystallization Toolbox continues to generate great feedback

Thanks to all the users who worked with us on crystallization projects, especially during 2015, and received training in 2015 and 2016 on the new cooling and antisolvent crystallization toolbox.

For our part, we've been making some of the requested enhancements and the latest version includes additional options for automatically generating cooling and/or addition rate profiles to reach specific process goals.  If you haven't taken a look for a few months, watch this video preview of the quick design sheets and if that whets your appetite, download the toolbox and take the training exercise.

This two-minute video preview shows rapid generation of a solubility curve and quick calculation of potential cooling and/or addition rate profiles and their impact on the rate of crystallization.  [Main steps shown with captions - musical accompaniment by Beethoven :)]

Tuesday, August 30, 2016

Funnel plot helps define control strategy for continuous process

At the FDA-AIChE Continuous Manufacturing (CM) workshop in Bethesda this year, I enjoyed the talk by Ahmad Almaya of Lilly on drug product CM, especially the part introducing 'funnel plots'.

These are a tool to determine for a given CM system and line flow rate the range of disturbance sizes and durations that can be handled before exiting product would drift out of specification. Disturbances could be caused by factors such as equipment failure or changeover in raw material properties; higher amplitudes are harder to deal with.  Disturbance duration reflects how long it takes for such a problem to be detected and the control system response to be put in place; a quick response is obviously best.

In late June, we held a webinar to introduce our latest tool for CM, which calculates the residence time distributions of a sequence of operations (e.g. telescoped reactions and/or workup and isolation for Drug Substance; a sequence of Drug Product operations; or an end to end process).  We simulated the response of the product stream to a series of disturbances and then generated the funnel plot shared below.
Funnel plot for a CM process:
Disturbance amplitude (here labeled 'deviation') on the y-axis and disturbance duration (min) on the x-axis.  Any disturbance in the 'green zone' in this case keeps product in spec while the red zone results in OOS material.
We think this is a very useful representation for use in filings and tech transfers and it's also easy to generate.

Tuesday, June 21, 2016

Links to some good recent Continuous Manufacturing (CM) talks

Unless you've recently returned to earth from a distant planet, you'll be aware of the momentum behind adoption of continuous manufacturing (CM) in pharma and its close relative, Flow Chemistry.  Our team have been active in this area for more than two decades and if you're part of our user community you will know about the relevant equipment, properties and kinetic modeling tools we provide.

Simulation of the response of a CM system to disturbance, using CM synthesis of Ibuprofen as an example.
We've been attending some of the higher profile CM events and also developing additional tools to help manage specific risks.  Here are some links to talks we saw at two events this year that we hope you find useful:

From the ISPE one-day meeting, CONTINUOUS MANUFACTURING – THE FUTURE OF PHARMACEUTICALS?, held in Cork, Ireland in late May:

From the FDA-AIChE Workshop on Adoption of Continuous Manufacturing: held in Bethesda, Maryland at the end of February:

Monday, May 9, 2016

New DynoChem cooling and antisolvent crystallization toolbox released

We were delighted to release in April our new crystallization process design toolbox, having spent much of 2015 working with customers to better define requirements and piloting the toolbox as it developed in several live sessions.

Inspired by the user interface of our successful solvent swap model, the Main Inputs tab serves as a dashboard for designing and visualizing your crystallization process.

You can get a good intro to the toolbox from the preview webinar we recorded in January 2016.  In short, we combined several of our popular crystallization utilities, enhanced them and then automated the building of a crystallization kinetic model in the background.  That model is ready to use for parameter fitting and detailed process predictions if you have suitable experimental data.

As you might expect, you can generate a solubility curve within seconds of pasting your data.  You can also make quick estimates of operating profiles (cooling and/or addition) for controlled crystallization.  And you can estimate the final PSD from the seed PSD and mass.  That's all within a few minutes and before using the kinetic model.

The toolbox supports both design of experiments (helping make each lab run more valuable) and design of your crystallization process, especially in relation to scale-up or scale-down.  There's a dedicated training exercise that walks you through application to a new project.

We'd be delighted to hear your feedback in due course.

Wednesday, May 4, 2016

Continuous Manufacturing: A tide in the affairs of men

A lot of the good 'flow' puns and quotations are already well used by us and others.  However, the words of Brutus in Shakespeare's Julius Caesar do seem quite apt for the current momentum behind continuous manufacturing / aka 'flow chemistry'.

Scale-up Systems was delighted to attend Flow Chemistry III in Cambridge, UK, March 14-16, where an international group of practitioners from academia, industry and continuous reactor vendors assembled to share state-of-the-art work in this area.

Numerous university researchers, including Prof. Oliver Kappe of Karl-Franzens University, talked about how this technology is allowing them to work in conditions not possible with traditional round bottom flasks and to approach new chemistries in this way.  While industrial speakers mainly concentrated on the benefits and practicalities of operating continuously.  These ranged from Jesus Alcazar of Jannsen who presented their roll-out of “Flow Chemistry as a tool for Drug Discovery” through to Malcolm Berry who’s plenary detailed GSK’s journey in “Industrialisation of API Continuous Processing, from Lab to Factory.  What have we learnt along the way?” 

A strong take home for Scale-up Systems was an oft-repeated message that DynoChem and reaction kinetics are key tools for implementation of Continuous Manufacturing of APIs.   Prof Frans Muller of Leeds University made a presentation that covered in detail how kinetic motifs can be used to explore the Design Space with limited experimental data and this message was echoed by Malcolm Berry who noted that a wealth of process knowledge was obtained with a kinetic model that would not have been possible via a DoE approach.

You can find relevant tools in our online library with this link.  Watch out for a new utility coming shortly for modeling a sequence of unit operations based on residence time distribution models.

Wednesday, February 24, 2016

Mitigating the Risk of Coprecipitation of Pinacol during Isolation from Telescoped Miyaura Borylation and Suzuki Couplings ...

We thought we would highlight this recent reference as one that is worthy of your attention.

It's a nice combination of different types of process model and experimental data to understand an unexpected problem and find operating conditions to ensure high purity product.

The elegant approach spans multiple unit operations, as shown below.

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