Sistema de classificação de fabricação e seus impactos nas

alterações pós-registro

APS Manufacturing Classification System Working Group

Kendal Pitt, GlaxoSmithKline Michael Leane, BMS Gavin Reynolds, AZ

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Novas fronteiras farmacêuticas nas ciências, tecnologia, regulamentação

e sistema da qualidade, Brasilia. 22 de junho 2015

Manufacturing classification system and its impact on post-registration changes

APS Manufacturing Classification System Working Group

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New frontiers in manufacturing technology, regulatory sciences and

pharmaceutical quality system, Brasilia June 22nd 2015

Kendal Pitt, GlaxoSmithKline Michael Leane, BMS Gavin Reynolds, AZ

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

Permeability

• BCS is a scientific framework for classifying drugs based on their solubility and permeability. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account: solubility, intestinal permeability, (and dissolution rate), all of which govern the rate and extent of oral drug absorption from IR solid oral-dosage forms.

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.

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.

‘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

. .

• Class I Direct compression. • Class II: Dry Granulation, • Class III: Wet Granulation, • Class IV: Other Technologies.

• Assumes there is a preference for simpler

manufacturing routes. • Builds on prior knowledge e.g. Hancock’s direct

compression criteria could form the foundation of MCS Class I.

• Ultimate aim of prediction from previous experience.

MCS Based on Processing Route

MCS Based on Processing Route

Direct compression

Dry Granulation

Wet granulation

White Paper

• Industry and academic collaboration • International contributions • Feedback questionnaire rolled out http://informahealthcare.com/doi/abs/10.3109/10837450.2014.954728

Parallel Co-ordinates Charts

Visualisation: Radar Charts Example representation; Best is nearest the bulls eye!

Capping and in-filling No issues

Powder flow, variable density and dissolution Capping in film coater

Abstract in Paper: 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.”

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AAPS 2014 + Webinar (San Diego) Global input

IFPAC 2015 (Washington DC) 25-28 Jan 2015: Regulatory Input

SSPC meeting 14 April15: Particle formation

ANVISA, Brasilia, 22nd -23rd June 2015 Sistema de classificação de fabricação e seus impactos nas alterações pós-registro

UK Pharm Sci 2015 (Nottingham UK): EU input

FIP 2015 (Dusseldorf) 28 Sept -3rd Oct 2015 Summary

Events for Input

Survey Questions • What next steps do you think the MCS

working group should take: – Pre-competitive sharing of API properties – Setting up boundaries for DC, RC, WG, OT – Identifying surrogate materials to represent

the different zones – Using modelling tools to link API properties to

manufacturing performance – Others?

Survey

What kind of things could we find out from this data?

• What processes are being used to manufacture currently approved products?

• How important are company and geographical factors in choosing processes?

• Have preferences changed over time? e.g. has there been a move away from wet granulation to dry granulation over time?

• How many products are made by non-traditional processes?

• Can we plot drug loadings / therapeutic area vs process choice?

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EMA review; initial observations

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Example Results

Therapeutic area

Commercial name

Active Ingredient

Dose Dosage form Route of

administration

Strength

Manufacturing process of Final Medicinal

Product

Manufacturer responsible for batch release

Marketing Authorization

Holder

Classification

Date of Approved/ Submited

Breast Neoplasms

Colonic Neoplasms Colorectal Neoplasms

Stomach Neoplasms

Ecansya (previously

Capecitabine Krka)

capecitabine

625 - 1250

mg/m2

body surface

area

tablet, film-coated

oral use 150 mg, 300 mg, and 500

mg

GW = Wet granulation (GW), sieving, mixing, granulation, drying,

sizing and lubrication prior to compression to

tablets and film coating.

Accord Healthcare Ltd., United Kingdom;

Pharmacare Premium Ltd.,

Malta; KRKA, d.d., Novo mesto,

Slovenia

Krka, d.d., Novo mesto,

Slovenia Generic

20/04/2012

Prostatic Neoplasms

Xofigo radium Ra223

dichloride

50 kBq/kg body

weight

solution for injection

intravenous use

1000 kBq/mL

SS = Dilution and mixing (to obtain target

radioactivity concentration), filling

and sterilization by autoclaving (SS).

Bayer, Norway Bayer Pharma AG, Germany

Reference 13/11/201

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Carcinoma, Non-Small-Cell

Lung Xalkori crizotinib

200 - 250 mg

capsule, hard oral use 200 and 250

mg Process not specified.

Pfizer Manufacturing

Deutschland GmbH, Germany

Pfizer Ltd., United

Kingdom Reference

23/10/2012

Prostatic Neoplasms

Firmagon degarelix 80 and 240 mg

powder and solvent for solution for

injection

subcutaneous use

80 and 120 mg powder and solvent for solution for injection

AP = Sterile filtration of the formulated bulk,

aseptic filling and freeze-drying under aseptic process (AP).

Ferring GmbH, Germany

Ferring Pharmaceuticals A/S, Denmark

Reference 17/02/200

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Cancer Area

Table 1. Examples of data collected from EMA documents of products approved for use in Cancer area in the EEA.

Example Results Cancer Area

Graph 2. Types of tablets approved for human use in Cancer Area in EEA.

74%

20%

6% tablets, film-coated

tablets

tablets,dispersible/tablet,buccal

43%

23%

17%

8% 9%

wet granulation

direct compression

dry granulation

Granulation process notspecified

Entire process notspecified

Graph 3. Manufacturing procedures applied in the production of tablets approved for human use in Cancer area in EEA.

Total of 35 products.

Total of 35 products.

Examples of information in public domain Sources: EPAR, NIH, Dictionnaire Vidal

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. Drug Therapy Area Tradename Dose (mg) BCS Drug Load (%) Drug Product Process Launch date Company MCSRanitidine Ulcers 150 3 >50 DC 1981 GSKZidovudine HIV 300 1 >50 Wet granulated 1986 GSKAbacavir HIV 300 3 60 Direct Compression 1998 GSKFosamprenavir HIV 700 2 60 Wet granulated 2004 GSKRetigabine Epilepsy 50 to 400 1 63 Common Granulation 2010 GSKDolutegravir HIV 50 2 17 Wet Granulation 2012 GSKDaclatasvir HCV Dalkinza 30, 60 Dry Granulation 2014 BMSEfavirenz HIV Sustiva 600 Wet granulation 2002 BMSAripiprazole Anti-psychoticAbilify 5, 10, 20, 30 Fluid bed Wet Granula 2005 BMSEfavirenz/emtricHIV Atripla 600+200+300 Bilayer: Wet granulatio 2007 BMS/GileadEntecavir HCV Baraclude 0.5, 1 Wet granulation 2006 BMSWarfarin CV CoumadinHydroxyurea DroxiaApixaban CV Eliquis 2.5, 5 Roller compaction 2012 BMSATV/Cobi HIV EvotazMetformin Diabetes GlucophageMegestrol Megace 20, 40Clopidrogrel CV Plavix 75, 300Pravastatin CV PravacholAtazanavir HIV Reyataz 100, 150, 200 Low shear wet granula 2005 BMSDasatinib Anti-cancer Sprycel 20, 50, 70 25% Wet granulation 2006 BMSDidanosine HIV Videx 200 BMSStavudine HIV Zerit 5, 10, 20, 40 Dry granulation (sluggi 2005 BMSMitotane Anti-cancer Lysodren 500gefitinib Oncology (NSCIressa 250 2 >50 Wet Granulation 2009 AZdapagliflozen Diabetes Forxiga 5/10 3 low Roller Compaction 2012 BMS/AZvandetanib Oncology (MTCcaprelsa 100, 300 2 ~40 Wet Granulation 2012 AZ

Data interrogation:

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Dose (mg)BCS Drug Load (%) Launch date Process MCS Mod150 3 >50 1981 DC YES300 1 >50 1986 WG NO300 3 60 1998 DC YES

50 to 400 1 63 2010 WG NO50 2 17 2012 WG NO

Table 2: Properties of an Ideal Direct-Compression Material Would this be applicable to Continuous Manufacture?

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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

MCS: Applying DC to Continuous

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.

Table 2 Properties of an Ideal direct-compression materialOriginal Source A Source B Source C

D50 >80micrond10 >30micronD90 <100micron

Blend RSD <2%

Internal Friction <41degree ? ? ? ?True Density 1-2.5g/mlBulk Density >0.5g/ml

Dwell time sensitivity LowPre Compression force LowPressure at 0.85 SF 20-125

TS at 0.85SF >1MPaBFI <0.2 ? ? ? ?Indent Hardness 75-250 MPa ? ? ? ?Flow Function >10 ?Continuous Processing ?

Follow-up Paper 2: Data gathered

Continuous, Fluid bed and Hot melt

Digital Data Initiative: Data housing and analysis

Paper 3: Modelling and Prediction?

Future plans

The MCS as part of a Regulatory System? .

Resolve

Identify differences

Discuss impact of differences

Framework for assessment

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Parallel Co-ordinates Charts

Acknowledgements

• APS • Michael Leane (BMS) • Gavin Reynolds (AZ) • Members of the MCS working group

• Federal University of Rio de Janeiro (Faculty of Pharmacy):

Prof. Dr. Bianca Aloise Maneira Corrêa Santos Prof.Dr. Flávia Almada do Carmo

Comments / Questions

Obrigado !