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 : MCS@apsgb.org

• 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)