Introduction to the concept of the
Manufacturing Classification System
1 AAPS Denver 15-Nov-2016
Michael Leane, BMS
APS Manufacturing Classification System Working Group
Tableting
Dosage form
London
PharmacopoeiaBritish Pharmacopoeia
1824 1885 1898 1914 1932 1948 1963 1980 1988 2010
Pills 3 21 20 18 7 5 0 0 0 0
Tablets 0 1 1 1 1 49 177 257 381 380
Capsules 0 0 0 0 0 0 7 50 73 90
Black box
The Tableting Process
Drug
Excipient
Inside the black box
Tableting
Same form – Different tableting characteristics?
Size chart
‘Nature’ does not like or produceDry particles <10 microns
APIs or excipients? determinants of performance
API Common excipient
Size, properties Small,
Hydrophobic
Large,
HydrophilicInvented for Curing maladies Facilitating tableting
Commercial experience
‘Never seen in nature’
40+ years
Tablet Size
9
Tabletting Issues
Biopharmaceutics Classification System (BCS)
I
High Permeability
High Solubility
II
High Permeability
Low Solubility
III
Low Permeability
High Solubility
IV
Low Permeability
Low Solubility
High
Low
Pe
rme
ability
Development Classification System (DCS) Butler & Dressman (2010) provided animportant advance on this as it discriminates particle size and dissolution rate
Amidon GL, Pharm. Res., 12 (3), 1995. - Guidance for industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. August 2000, CDER/FDA.
JAMES M. BUTLER, and JENNIFER B. DRESSMAN Journal of Pharmaceutical Sciences, Vol. 99, 4940–4954 (2010) The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development
MCS: Why have one?
• Borrowing from BCS, use properties of particles to form a new
classification to aid drug product manufacturing.
• Defines the “right particles” and “best process”.
• Assist in particle engineering to provide targets for API
properties.
• Aid development and subsequent transfer to manufacturing.
• Provide a common understanding of risk.
• Fits with QbD principles. Potential of obtaining regulatory relief
by demonstrating that the properties of the ingoing API and
excipients are within established ranges for the process.
The MCS as part of a Regulatory System?.
Resolve
Identify differences
Discuss impact of differences
Framework for assessment
13.
‘Difficult’ API
“Good” API
APS Joint Focus Group Meeting
BCS to MCS: From the particle to drug product: Predictions from Material Science through to manufacturing
May 13th and 14th 2013, East Midlands Conference Centre, University of Nottingham, UK.
• Mat Sci and PEFDM focus groups
MCS: Initial discussions
..
MCS Based on Processing Route
Direct compression
Dry Granulation
Wet granulation
Procedure
• Working group assembled comprising members from industry and academia.
• Subteams established to determine current best practice for DC, RC and WG.
• Short-term aim: Publish a peer-reviewedwhite paper to:
– Summarise current knowledge and provide a frame of reference of level of risk vs process type.
– Publicise this initiative to gain feedbackfrom the wider pharmaceutical community
White Paper
• Industry and academic collaboration• International contributions• Feedback questionnaire rolled out
Parallel Co-ordinatesCharts
Abstract: next steps
“ This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process.”
24
Continuous Manufacturing:Where would the MCS sit?
25
Real example of Factory Of The Future :
.
Presentation title 26
.
Continuous Dispensing, Wet Granulation , tabletting and coating
Image Courtesy of GEA Pharma Systems
Table 2: Properties of an Ideal Direct-Compression Material
Are these appropriate for Continuous?
28
Property Value Target Value
Particle Size and Shape D 4,3 (mean volume diameter) > 80µm D 10 (10th percentile diameter)
D 90 (90th percentile diameter) Aspect Ratio
> 30µm ≤ 1000 µm
< 1.5 Blend Uniformity Blend Potency <2% relative standard deviation
Powder Flow Effective angle of internal friction
< 41°
Powder density True 1.0 - 2.5 g/mL Bulk > 0.5 g/mL
Tableting performance Dwell time sensitivity Low Precompression force Low Compression stress
(at ~ 0.85 solid fraction) 20 - 125 MPa
Compact mechanical properties Tensile strength > 1.0 MPa (at ~ 0.85 solid fraction) Brittle fracture index < 0.2
Indentation hardness 75 - 250 MPa
Adapted from McCormick 200534 from a talk given by BC Hancock “Identifying candidates for direct compression using material-sparing formulation tools” presented at AAPS November 2004
IFPAC 2015 (Washington DC) 25-28 Jan 2015: Regulatory Input
UK Pharm Sci 2015 (Nottingham UK) / FIP 2015 (Dusseldorf) 28 Sept -3rd Oct 2015 EU input
AAPS 2016 Global input
APV 2017
Pre-competitive data sharing? Precedents in other areas.
Events for Input
Electronic Inputs
• Comments please plus volunteers for data gathering!
• At forthcoming meetings.
• By use of E-mail Address : [email protected]
• Via Survey Monkey
• https://www.surveymonkey.com/s/57GGL8K
• Quarterly TC
Acknowledgements
• Iris Ziegler (Corden)• Kendal Pitt (GSK)• Gavin Reynolds (AZ)• Jamshed Anwar (Lancaster
Uni)• Stuart Charlton (BMS)• Abina Crean (SSPSC, Cork)• Richard Creekmore (AZ)• Conrad Davies (Pfizer)• Tomas DeBeer (Ghent Uni)• Marcel De-Matas (AZ)• Abdenour Djemai (GSK)• Dionysius Douroumis (Uni of
Greenwich)• Simon Gaisford (UCL)
• John Gamble (BMS)
• Linda Hakes (UCB)
• Bruno Hancock (Pfizer)
• Elaine Harrop Stone (Merlin)
• Anne Kavanagh (AZ)
• Yarolsav Khimyak (Uni of East Anglia)
• Peter Kleinebudde (Heinrich-Heine Uni)
• Chris Moreton (FinnBrit Consulting)
• Amrit Paudel (RCPE)
• Richard Storey (AZ)
• Mike Tobyn (BMS)
• Gregor Toschkoff (RCPE)
• Kiren Vyas (GSK)
• Morten Allesø (Lundbeck)