1. What is ‘Manufacturability’?
(AZ) Manufacturability Definition: The ability to manufacture and supply a product routinely and predictably to the business requirements for quality, cost and scale in compliance with the appropriate Regulatory Authority and Health and Safety regulations.
(For Pharma) - Patients should always expect medicines to be available when needed and of the highest quality, safety and efficacy
Manufacturers should manage new knowledge well, improve processes and methods continually, introduce new and better technologies, and do their best to avoid manufacturing quality related problems
Manufacturing innovation across the industry has been stifled, which has resulted in ageing facilities replete with outdated process controls and equipment. In many instances of drug shortages, these conditions are the direct cause.

2. Design for Manufacturability
Design for manufacturability is the general engineering art of designing products in such a way that they are easy to manufacture. The concept exists in almost all engineering disciplines, but the implementation differs widely depending on the manufacturing technology.
Describes the process of designing or engineering a product in order to facilitate the manufacturing process in order to reduce its manufacturing costs.
Will allow potential problems to be fixed in the design phase which is the least expensive place to address them.
Other factors may affect the manufacturability such as the type of raw material, the form of the raw material, dimensional tolerances, and secondary processing such as finishing
Addresses inconsistencies that arise during operation
Applied in many areas but not particularly in chemical (pharma) manufacturing

3. So what’s the problem?
Even without introducing new technologies, all companies run into manufacturing problems on a regular basis!
Batch failures due to changes in material properties as a result of scale/site/equipment changes; applies to internal and outsourced supply
It is often necessary for a number of reasons to change the site, scale or equipment used for manufacturing drug substances. These changes can give rise to differences in the physical properties of the products which are not well understood and which can cause difficulties in downstream processing.
Importantly, these issues will likely not go away, even with the advent of new technologies designed to deliver consistency

4. Some examples of equipment

5. Some examples of equipment

6. Some examples of equipment

7. The Challenge!
Insufficient understanding and control of our manufacturing processes in respect of Physical Properties!
Changes in the physical properties of both drug substances and excipients can influence downstream processing in formulations. Understanding of these particle properties (eg size, shape, surface properties), bulk properties (eg density, flow) and performance (e.g. fracture, compression, interactions) would allow for more reproducible manufacturing processes….
What is it about material and particle properties that influence bulk properties?
What techniques are most appropriate to characterise particle and bulk properties?

8. ‘Centre for Manufacturability Design’ Aims and Objectives
To increase significantly the fundamental understanding in this area, the Centre for Manufacturability Design has been established by the University of Leeds in partnership with industry (starting with AZ, but now being extended to other companies)
The Centre is a managed academic-industry funded initiative; in the first-place for 5 years with a focus on Pharma and related manufacturing.
Gain Scientific understanding to eliminate batch failure in commercial manufacture due to changes in material properties that arise as a result of changes in site, scale or equipment of manufacture.
Aims to maximise value within drug substance manufacturing processes by enhancing understanding of e.g. work-up, isolation, drying, particle size reduction, which in turn influence their material and particle properties.
Better control of physical properties will allow improved flexibility and predictability of drug substance and drug product manufacturing processes.
Ensure that industry aims to reduce costs and waste, and improve consistency and reliability will be achieved, alongside UoL objectives to create excellent research outputs and demonstrate impact.

9. Vision: Strategic Partnership across key areas
Co-ordinate current activities
PDRAs working on problems from both operations and development.
Utilisation of facilities at both Leeds and AZ
Develop AZ/Leeds network
Engage other companies in joint projects
Link to other activities of interest (eg CMAC)
Enhance utilisation of DIAMOND LS
Applications for external funding
Leveraging the knowledge of academic staff to identify new approaches/tools for use on projects
(Secondments between AZ/Leeds to improve project understanding)
A fully networked centre in collaboration with other industries e.g.pharma/agrochem/FMCG/ Universities/funding bodies
Formation of national centre
Spoke in UK Formulation Centre
EU/Innovate funded consortia projects
Renewal of funding
Horizon 3
A “Centre for Manufacturability Design”
Horizon 2
‘Drive value for Industry partners
and Leeds’
Horizon 1
‘Establish the centre’

10. Manufacturability Process Isolation and Work-Up Process Engineering
Crystallisation/
Particle Science
Solid form, powder,
bulk behaviour
Catalysis

11. Facilities and equipment

12. Scanning Electron Microscopy
(SEM)

13. X-ray Diffraction Measurement
X-ray Diffraction comparison
X-ray Diffraction Measurement

14. (Mastersizer, LD wet analysis)
Size Measurement
(Mastersizer, LD wet analysis)
A SOP was developed after extensive study and the results are shown in the following slides for most suitable solvents.

15. Size Measurement
(Morphologi G3)

16. Flowability Assessment
(Schulze Ring Shear Tester)

17. Flowability (Shear cell)
ffc
Classification
<1
Not Flowing
1-2
Very Cohesive
2-4
Cohesive
4-10
Easy Flowing
>10
Free Flowing
The Schultze shear cell

18. Differential scanning calorimetry
DSC measurement

19. Auto-Agglomeration
Tendency for auto-agglomeration was assessed using fixed vibration condition for different time periods using the equipment below.
The equipment for measurement consists of a narrow box (i.e. with a shallow depth) which is mounted on a vibration unit K2007E01 Miniature shaker (PCB Piezotronics, Inc. Hertfordshire).
The vibration settings, i.e. amplitude and frequency are controlled by an electrometer, TG315 function generator.
This device has an operational frequency range of 0.03 Hz to 3 MHz and voltage range of 2 mV to 20 V

20. Operation modes Funding
H2020, Spire, Innovate UK, direct, university leveraged funding
Management
Project pipeline management and prioritisation mechanism
Dissemination
Collaboration agreement IP
Wider interactions
UK National Formulation Centre
CMAC

21. Example 1 - API from two
Sources. SEM source 1 21

22. Example 1
SEM source 2 22

23. Easy flowing- free flowing
Example 1
Shear Cell Test
Powders
Flow Function, ffc
Evaluation
XYZ (1)
Easy flowing- free flowing
XYZ (2)
XYZ (3)
XYZ (4)
Very Cohesive
XYZ (5) 23

24. Tribo-electric charge
Example 1
Tribo-electric charge
Test were done at 3 bar dispersion pressure.
Copper foils were used for dispersion.
Conclusions
The sample from Source 2 has a charge to mass ratio which is approximately three times higher than the Source 1 sample.
The charge to mass ratio of the Source 2 sample is one of the highest recorded for API’s1.
The value of hardness and Young’s modulus are comparable to Aspirin2
Šupuk, E., Zarrebini, A., Reddy, J., Hughes, H., Leane, M., Tobyn, M., Timmins, P. and Ghadiri, M. (2011) ‘Tribo-electrification of active pharmaceutical ingredients and excipients’ Powder Technology , 217,
Olusanmi, O. (2009) ‘Milling of Organic Solids’ Doctoral thesis, University of Leeds.

25. Example 2 – API from two Sources
Auto-agglomeration

26. No auto-agglomeration
Example 2
Auto-agglomeration
No auto-agglomeration
Auto-agglomeration
Supplier 2
Supplier 1
1 min
3 min
5 min
1 min
3 min
5 min
Supplier 2
Supplier 2
1 min
3 min
5 min

27. Agglomerate Crushing Strength
Example 2
Agglomerate Crushing Strength
A single agglomerate was carefully mounted on the base plate.
The load-deformation profiles were recorded for several agglomerates of each batch for Supplier 2
The maximum compression force at which a sharp reduction takes place was regarded as the crushing strength of the agglomerate.
Loading rate: 1mm/min

28. Agglomerate Crushing Strength
Example 2
Agglomerate Crushing Strength
The average crushing strength of the agglomerates as a function of the number of test.
The moving average crushing strength of the agglomerates is within a reasonably narrow band.

29. Access to Diamond Light Source: The UK Synchrotron facility
An opportunity to use cutting edge techniques on projects and scientific challenges
Sven Schroeder (Leeds) sits on the Diamond Leadership Board and a good working knowledge of facilities available
Opportunity to enhance our presence at Diamond
0.2 PDRA for AZ at Diamond
Industry influence at “DISCo” (Diamond Industrial Strategy Committee)
Identification of how Diamond can help current projects
Mostly around surface characterisation
Longer term opportunities in imaging in processes in real time

30. Processability of an
Active Pharmaceutical Ingredient

31. Origin of surface colour
Conventional techniques provide no answer

32. Origin of surface colour

33. Summary
Higher level of scientific input to our development and manufacturing
Knowledge transfer between Industry and Academia
More reproducible and portable processes which are better understood
Fewer batch failures
Reduced waste and cost
Reduced risk of failure to supply to patients