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What is ‘Manufacturability’?

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Presentation on theme: "What is ‘Manufacturability’?"— Presentation transcript:

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Manufacturing innovation across the industry has been stifled, which has resulted in ageing facilities replete with outdated process controls and equipment.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


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