Pharmaceutical Drying: Technologies for the enhancement of process understanding during drying in agitated dryers

To understand the drying unit operation in the pharmaceutical industry, it is desired to collect real-time data over the course of the drying process.  The current state of real time data collection suffers from limitations of existing PAT tools, process measurements, and/or material sampling technologies. Ultimately, the concern with the limitations in the current capabilities for real time data collection during drying is the inability to collect meaningful data for the development of closed loop control systems, model validation/verification or to pursue the design of effective scale-down equipment.

ETC is seeking to work with companies interested in supplying equipment that can be used for PAT, process characterization, or sampling to address this need.

Download the Request for Information and submit your response.

RFI issued March 6, 2017

Responses due April 3, 2017

Questions Received (Updated March 24, 2017)

  • Can the team provide a detailed workflow for the steps involved in drying API – starting with discharge of crystals from a vessel and moving through filtration, washing and drying ending up in discharge from the dryer? (the RFI highlights challenges with the unit operation). Can more detail be provided on the "mechanics" of running drying experiments?

APIs and intermediates are isolated by filtering the slurry and washing the resulting cake in a Nutsche style filter or centrifuge. If an agitated filter dryer (AFD) is used, filtration and drying take place in the same vessel. If a Nutsche style filter without drying capability or a centrifuge is used, the wet cake is manually transferred to the dryer.

Further information and descriptions of workflow are readily available in literature. The chapter on filtration and drying (17) in Chemical Engineering in the Pharmaceutical Industry is a great starting point:

The focus of the PAT project should be on the drying step explicitly, starting once deliquoring of the cake is complete and transfer to the drying vessel is complete, if applicable. As the paper (The Pharmaceutical Drying Unit Operation: An Industry Perspective on Advancing the Science and Development Approach for Scale-Up and Technology Transfer) describes, workflow addresses 3 main categories:

- Chemical and physical stability (thermal stability of the compound and it’s crystal form/lack of crystal form)

- Drying kinetics (rate of solvent removal, rate of heat transfer, and rate of dehydration/desolvation or form change)

- Physical property control (agglomeration and attrition, particularly during agitation)

  • Perspective on specific gaps and challenges in this workflow would be useful. Please refer to the “Current Technology and Knowledge Gaps” section of the paper for this question.

  • Description of the most common apparatus and equipment used to do this. Each company has developed their own approach and tools, so there isn’t necessarily a “common” apparatus used. Lab scale agitated filter dryers, vacuum ovens modified with load cells, mixer torque rheometers, and a few other tools are described throughout the paper.

  • Types and brands of dryers used in the lab would be useful - along with their pros and cons (tray, filter, vacuum, filter, etc.). We cannot disclose brands of dryers we currently use in the labs, and much of the equipment used is customized. We suggest doing a general search for lab drying equipment and come prepared with designs/dryer styles as a discussion point during interactions with the team to determine the ideal designs to target. The dryers used in the lab and manufacturing scales include agitated filter dryers, vacuum ovens/tray dryers, tumble dryers, and conical dryers. Chemical Engineering in the Pharmaceutical Industry captures pros and cons of different dryer styles in table 17.3.

  • The RFI and associated journal article highlights the need to obtain process measurements during the drying process. The focus appears to be on the utilization of PAT tools to achieve this. However the dryer itself needs to be controlled and parameters needed to be recorded.
    • Is the RFI requesting PAT tools and sampling devices that fit existing dryers (retrofitting is mentioned in the RFI)?
    • Or is the RFI requesting new dryers that can more easily control and record relevant parameters – and integrate PAT tools more easily (standardized scale down equipment is mentioned in the journal article)?

For large scale equipment, the PAT tool will need to be able to retrofit existing dryers.  There would be more flexibility on the approach for lab scale dryers including options for dryers with designs that better integrate PAT tools more easily.   

  • What type of dryer is most suitable for experimentation in the lab? Are different types of dryer needed for the characterization of different mechanisms? No, not necessarily.  Ideally a single lab dryer capable of capturing the different mechanisms is preferred, but often due to the complexity associated with scaling down individual mechanisms are often studied using different systems.  Drying is investigated in the lab either through scaled down drying equipment e.g. lab scale filter dryers with or without agitator, or equipment specifically designed to look at specific aspects of drying. These are detailed in the paper and include vacuum oven plus load cell to look at drying kinetics, mixer torque rheometer to look at agglomeration, attrition cell to study attrition. There are also scale down, e.g. conical dryers which can be used at kilo lab scales.
  • For example can drying kinetics and attrition/agglomeration be studied in the same laboratory dryer? Yes, and it is preferred if this is most representative of the large scale process.

  • Is drying studied and analyzed for every experiment where material is isolated? Or for some experiments is API simply dried slowly and carefully in order to obtain material for analytical testing? Drying is not studied for every experiment where material is isolated.  In cases where drying kinetics are being studied, analysis of a drying curve is often done in a specialized drying apparatus.  Larger scale experiments and plant runs may be less common and as such are more likely to collect information during drying. A scientist may verify a given laboratory technique (time, pressure, and temperature) provides sufficiently dry material and replicate that technique outside the specialized drying apparatus for much of their routine experimentation.
  • In the journal article intermediates are mentioned – and physical properties are deemed important. How often are intermediates isolated? And how often is drying performance characterized for intermediates?

While physical properties of the final dried API are important (because they may impact the drug product formulation), physical properties of isolated dried intermediates are generally less important.  The physical properties of intermediates must be such that the solids can be successfully dried and are amenable for processing in the next step of the API synthesis process.  Other properties that are important for API drying are also less important for an intermediate. For example, for an API that is a desolvated compound, it is important that the drying step achieves complete desolvation (e.g., by application of sufficiently high temperature). However, for an intermediate, it is less of a concern if the dried compound contains organic solvent as a crystal solvate.

In general, several intermediates are isolated in the chemical pathway of a validated process producing an API from regulatory starting materials. This affords control of impurity levels and enables shipment of well-characterized intermediates between production sites.

Drying performance characterization of intermediates is more limited and less rigorous than for APIs. The focus is on properties of the solid particles of the intermediate that may impact processability in the next synthetic pathway step (there is no need to consider impact on drug product formulation for intermediates). In general, a subset of the tools employed for characterization of API drying are used for characterization of drying of intermediates. For many APIs, it is important to minimize agitation that may cause attrition and/or agglomeration; so, it is important to understand API drying well to achieve a reasonable drying time with limited agitation during drying.  Since particle attrition/agglomeration are typically less of a concern for intermediates, less product-specific drying knowledge is needed for intermediates.