connuousmanufacturingoftabletsandcapsules …...2 an industry in transition • change drivers –...

Con$nuous manufacturing of tablets and capsules The Emerging Paradigm

By Fernando Muzzio, Dis$nguished Professor, Rutgers University

Director, NSF Engineering Research Center on Structured Organic Par$culate Systems

2

An industry in transition

•  Change drivers –  Patent expirations –  Biologicals and biosimilars –  Emerging markets

•  Game changers in development –  Outsourcing, re-shoring, CROs & CMOs

•  Manufacturing megatrends –  Continuous manufacturing –  Personalized/precision medicine

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Why Continuous Manufacturing? •  Reduced cost

•  Smaller equipment •  No scale up •  Faster development •  Great savings in API and excipients during development •  Lower cost of quality assurance •  Reduced processing @me

•  Increased robustness and reliability, beGer quality •  Flexible batch size (no validated batch size, can adjust to market demand in real @me) •  BeJer quality control •  Meaningful PAT and integrated closed loop control: real @me release •  Enhanced containment and environmental control •  More uniform processing: Prevented segrega@on and agglomera@on •  No wasted batches

Continuous Manufacturing Landscape - today

•  FDA actively promoting it (Advanced controls and enhanced process understanding required)

•  Most brand companies have implemented systems •  Pfizer, GSK, J&J, Vertex, Novartis, Abbvie, Lilly, BMS

•  FDA has multiple filings

•  Generic companies (Teva, Actavis, Dr. Reddy) getting involved •  One domestic manufacturer in China (Hisun) has announced plans to implement

a CM factory in south China

•  Leading contract manufacturer (Patheon) is building a GMP facility

•  Equipment companies demonstrating enormous interest •  GEA, Bosch, Glatt, Bohle, Hosokawa, Fette, Lodige, Gericke, Ktron, Schenk, others

•  Academia actively involved •  Rutgers & ERC – since 2002 – focus on solid dose manufacturing

•  MIT – Novartis project – focus on end to end implementation

•  RCPE (Graz, Austria) – focus on HME

•  Ghent - focus on wet granulation

•  CMAC – UK – focus on API and crystallization

Summary of Rutgers Accomplishments in Continuous Manufacturing

•  Promoted FDA support for CM

•  Demonstrated feasibility – implemented first integrated line (2008) and built first closed-loop control line (Inspire, 2011)

•  Developed approach to minimize feeder variability during refill

•  Developed RTD framework for design of continuous mixers and for traceability of materials in integrated line

•  Developed integrated flowsheet modeling methodology

•  Demonstrated integrated closed loop control of feeders, RC, mixers, TP

•  Integrated PAT approach for continuously moving powder

•  Demonstrated arrested segregation in DC CM

•  Created Integrated Product/Process Development Paradigm

Current State of Solid Dose CM Technology

•  Integrated lines available from multiple vendors •  GEA Consigma line – mechanically integrated, standardized

•  Glatt, Bohle also offering integrated systems

•  Equipment components available from many sources •  Feeders: Ktron, Gericke, Schenk, Brabender, others

•  Mixers: Glatt, Lodige, Hosokawa, Gericke

•  Granulators & driers: Glatt, Lodige

•  Tablet presses, roller compactors, capsule filling, extruders, mills – same as batch processing

•  Control systems: Siemens, Emerson, equip. vendors

•  PAT: mainly NIR and PSD

•  Missing or underdeveloped components – see next slide

Research Needs in Continuous Manufacturing •  We need effective tools to measure ROI and NPV •  Modeling methods to support integrated design, risk assessment,

optimization, and process control need further work •  Distributed control systems not yet standard •  Continuous functional coating not yet available •  PAT instrumentation incomplete

•  Powder density •  Tablet/capsule Content Uniformity •  Tablet dissolution

•  Low flow rate systems unavailable •  Capsule products •  Inhalables •  Hot Melt Extrusion •  Pilot lines for development

•  Role of material properties and process parameters not fully understood •  Regulatory expectations unclear •  Standard filing and review documents unavailable

•  Increased regulatory expectations regarding process understanding and control will drive adoption of CM with advanced controls

•  Research pharma will get increasingly involved via new and existing products

•  Generics will get involved following Teva

•  Chinese and Indian manufacturers will get involved following Hisun

•  CMOs will adopt the technology to supply customers

•  Our prediction: 50% penetration by 2025 – accounting for: •  $300 billion per year worldwide in market value of manufactured products

•  $100 billion in investments required to upgrade manufacturing systems

•  New excipients, new formulation modalities, new technology platforms

Continuous Manufacturing Market: The next 5 years

Process map Three main routes to solids: -‐ direct blending -‐ dry granula$on -‐ wet granula$on

Slide 9

Process map Three main routes to solids: -‐ direct blending -‐ dry granula$on -‐ wet granula$on

Slide 10

M

M

API

M

M

M

M

M

M

EX

Material Proper,es-‐Process Parameters Interrela,on: Rutgers Con,nuous Line

Tablet Press

Blender

Feeders

Mill

Modeling in Pharmaceutical Development

The goal is to model pharmaceu$cal processes in silico and use these tools for op$miza$on

Integrated Process Model “Flowsheets”

Reduced Order Model

Opera,ng Parameters & Design

Material Proper,es

Unit Ops Models

e.g., Flow, Bulk Density, Angle of Repose

y = f (x,a,t,m,n)dydt

= g(x,a,t,m,n)M

M

e.g., Feeders

min f (x)st. h(x) = 0 g(x) ≤ 0

Op,miza,on

Predic,ve Modeling

20

1 1

k k

i i ii i ij i ji i i j

y x x x xβ β β β ε= = <

= + + + +∑ ∑ ∑∑

Interrela,on between Process Parameters and Material Proper,es

Direct Compression

•  More properly termed “direct blending” •  Can go into tablets, capsules, vials, etc.

•  Feeding and blending is the heart of the process

•  Ques$ons: •  Can we achieve homogeneity? •  Does the blend flow? •  S$cking (electrosta$cs?) •  Segrega$on?

Direct Compaction for Segregating Systems

•  Continuous blenders exhibit superior quality to batch blenders

Formulation d50 (µm) Bulk Density (g/cc)

Mustard 1298 0.7103 Microcrystalline Cellulose PH 101

50 0.3

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1 5 10 30 50

Rela,v

e Stan

dard Devia,o

n

Mustard concentra,on (wt %)

Mixing Performance

Batch (experimental)

Batch (sta$s$cal)

Con$nuous (experimental)

Con$nuous (sta$s$cal)

Critical Material Properties

•  Particle size and size distribution (tablet density, porosity, cohesion)

•  Powder Density (flow, weight)

•  Cohesion (flow, weight uniformity)

•  Moisture Content

•  Hydrophobicity (wetting)

•  Electrostatics (flow, sticking, agglomeration)

•  Segregation tendency (composition)

•  Shear sensitivity •  Hydrophobicity (overlubrication)

•  Electrostatics (dynamic charging)

•  Attrition

A Standardized Development Approach:

•  Create a decision tree for DCCM -  Question-driven, supported by

-  Materials characterization -  Models -  Table-top Unit op tests -  Minimum number of confirmation experiments in the

integrated line at desired conditions -  Useful for selecting ingredients -  Enables fast screening of formulations (goal: 1 week turn

around) -  Uses minimum amounts of material -  Framework for accumulating knowledge

Tablet Press

Lubricant

Feeders

M

M

EX

M

M

API

M

M

Mill

Cri,cal ques,ons to process in DC line

Blenders

Q1: Can we feed each ingredient at the required flow rate?

Q3: Can we “delump” all agglomerates?

Q4: Can we achieve blend homogeneity?

Q5: Are blend flow proper$es good enough to support Weight Uniformity?

Q6: Can we get tablets at target hardness and dissolu$on at reasonable high flow rate?

Q2: Can we feed each ingredient with variability below certain threshold?

Q1: Can we feed each ingredient at the required flow rate?

•  Predict feeder performance using the regime map. The feeder performance (op$mal tooling, etc.) of each ingredient can be predicted through the process knowledge of its similar materials.

Q3: Can we delump?

•  Approach: -‐  Observa$ons in feeder -‐  Surface energy of ingredients before feeding -‐  Impedance/Dielectrophoresis tes$ng of materials before and

afer feeders -‐  Sieving/Icon tes$ng afer feeders -‐  PCA/PLS analysis

Observa$ons in feeders

•  S$cking inside bowl •  Bearding •  Changes in flow or density during feeding •  Agglomera$on during feeding

API 2 API 3 APAP

Silicon Dioxide at feeder outlet

Surface Energy: Inverse Gas Chromatography •  Reten$on Time is

associated with Solid-‐Gas Interfacial Energy.

•  Non-‐Polar component with non-‐polar gases.

•  Polar component is the difference obtained with polar gases.

Lactose

Tribo-‐Electrosta,cs •  Feeder jamming •  Par$cle Agglomera$on •  Par$cles s$cking to walls of

container •  Flow problems •  Tablet weight variability •  Segrega$on

Problems arising form par,cle charging

•  Material flows from a hopper, feeder, mill, or blender into a faraday cup

•  Charge is monitored versus mass

LaMarche, Keirnan R., et al. "Electrosta$c charging during the flow of grains from a cylinder." Powder Technology 195.2 (2009): 158-‐165.

Cellulose adhered to the end of a rod

Oscilloscope

Amplifier

Frequency generator

Faraday Cup

Impedance Mesaurement

0

5000000

10000000

15000000

20000000

1 10 100 1000 10000 100000

Frequency (Hz)

Impe

danc

e (o

hms)

Display on Oscilloscope

Impedance Measurement

Amplifier ElectrodeTeflon

Isolation

Powder

Grounded Cup

TriaxConnector

Oscilloscope

1 kΩ

Amplifier ElectrodeTeflon

Isolation

Powder

Grounded Cup

TriaxConnector

Oscilloscope

1 kΩ

API Excipient

0 5 10 15 20 25 30 35 40 45 500

0.2

0.4

0.6

0.8

1

Time (Sec)

E(t)

(1/s

) Pulse

0 50 100 1500

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

Time (Sec)

E(t)

(1/s

)

Axial motion and dispersion

Q4: can we achieve blend homogeneity?

Q5: Are blend flow proper,es good enough to support Weight Uniformity??

Change formula$on

Characteriza,on Techniques: Flow Proper,es

•  FT4 Shear Cell: cohesion, UYS, MPS, and flow function

•  FT4 Stability/ Variable Flow Rate

•  Basic Flowability Energy, Stability Index, Flow rate index, SE

•  FT4 Compressibility: bed density as a function of applied normal stress, compressibility index

Material Proper,es-‐Process Parameters Interrela,on Lubricated Blend

Raw Material Proper,es (RMP)

Cohesion1. Compressibility Electrosta,cs Surface Energy

PSD

Process Parameters

RPM1a

RPM1b

Process Parameters

RPM2 (Mill)

Screen Size

Process Parameters

RPM3 (Blender)

Intermediate Material Proper,es (IMP)

Lubricity4 Compactability4.

Cohesion4 Agglomera,on4

Blend Homogeneity4 Bulk Density4

M

M

API

M

M

M

M

EX

Lubricant

Feeders

Mill

Process Parameters

RPM5 (Feed Frame)

RPM6 (flow Rate)

Chute Height (CH)

Thickness Gap (ThG)

Pre Compac$on (PC)

Fill Cam [FC]

Product Material Proper,es (RMP)

Thickness Weight Variability Density (porosity) Content Uniformity

Hardness Dissolu,on

Product

3/2/16

Tablet Press

Blender

Feeders

mill

API

M

M

M

M

M

M

M

M

RTR Sensing Approach

Content/Density Blend Uniformity

NIR, Raman

LT

Thickness

Density

US

Hardness

NIR

Dissolu,on (check)

Feed forward control

Force

Weight

Compression Gap

Cross-‐check

Content (check)

Moving Forward

•  C-SOPS focusing even strongly on continuous manufacturing

•  International Institute for Advanced Pharmaceutical Manufacturing (C-SOPS+RCPE+CMAC) has been launched

•  Major Partnership between Rutgers and Janssen ($6 million in 2015) open for participation to other companies

•  Integra Manufacturing Systems - a new company that provides support to the industry in implementing CM

•  Major grant from FDA to Rutgers ($4 million) to develop science-based regulation for continuous manufacturing (Materials, RTR, Sensing and Control)

•  At J. Woodcock’s request, C-SOPS has organized a regulatory working group that is developing a proposed CM guidance

Proposed new FDA/BARDA Standardiza$on Project:

•  Accelerate product and process development by: -  Create a “Integrated development pathway” -  Decompose manufacturing trains into smaller standard

modules -  Standardize the equipment, the formulations, the control

requirements, and the development process

Goals •  Create Integrated CM plaoorms that enable:

–  Easy adop$on of CM –  Fast development of products and processes –  Low cost, high quality manufacturing

•  Create knowledge based needed for: –  Fast and reliable implementa$on of CM plaoorm –  Equipment transla$on –  Science-‐based regula$on –  Ability to respond quickly to medical emergencies

•  Conduct case studies to: –  Demonstrate effec$veness of the technology –  Provide implementa$on examples demonstra$ng that products and processes

can be developed in parallel in less than 8 weeks.

A Comprehensive plaoorm includes:

•  A Standard Pathway for development and approval: Integrated Pharmaceu$cal Product and Process Development template that enables rapid product development and rapid regulatory assessment

•  Standardized equipment that is fully understood and easily and flexibly configured (modular approach) and integrated with standard communica$on protocol (OPC)

•  Standard formula$ons that can be applied to a wide range of APIs within a known range of material proper$es

•  Standardized modular sensing and control infrastructure that enable effec$ve process control

•  Performance standards and methods for specifying and modifying material proper$es of APIs and excipients to enable desired product CQAs and required process performance

Developing the Standard Pathway

•  Define a generic template for integrated product/process development (i.e., “what needs to be done”)

•  Define DOE methods, supported by predic$ve models and materials databases, for simultaneous development of product, process, and analy$cal/control methodology (i.e., “how does it get accomplished”)

•  Specify standard, model/sta$s$cally-‐based tes$ng requirement needed to demonstrate product quality, process performance, and real-‐$me quality assurance (i.e., “how do we know that it works”)

•  Implement well defined, shared expecta$ons and standards between industry and regulators (i.e., “if it works, it should be approvable”)

Current Batch Development Paradigm

Formula$on batches ~ 1 kg Formula$on

Process Dev. Batches ~ 5 kg Process

Analyt. Dev. batches ~ 5 kg Analy$cal Method

Scaled up batches – 30 Kg to 1000 kg Scaled up Process

Robustness batches ~ 5 kg Robust/stable Form/Method/process

Valida$on batches – 30 Kg to 1000 kg

Validated/verified Process

Takes 2-‐3 years and uses thousands of Kg of materials Each step is performed at risk – Formula$on is “op$mized” without knowledge of manufacturability, process is “op$mized” without knowledge of scaleability, etc. Does not use DOE for analy$cal development – subop$mal accuracy and robustness Does not support RTR

Integrated development paradigm

•  Performs product, process, and analy$cal development simultaneously and at scale, thus achieving robust product and process design with lower risk

•  Takes <2 months, uses much less material (order of magnitude decrease) •  Uses DOE for Analy$cal Method development (more reliable)

Master DOE at manufacturing scale – formula$on variables, Process variables, robustness

Formula$on Dev. Process Dev.

Process Analy$cal Method, including RTR: non-‐destruc$ve

transmission spectroscopy, followed by dissolu$on and hardness tes$ng OF THE

SAME TABLETS

Analy$cal Method Dev.

Formula$on

Standardized Equipment •  Organized into four (4) connectable/exchangeable modules with

specified inputs and outputs •  Supported by predic$ve models for module performance as a

func$on of input material proper$es and process parameters •  Equipped with standard sensing and control capabili$es •  Can be “plugged” into supervisory control infrastructure through

OPC

Feeder/mill/blender module

Feed frame/

tablet press module

Direct Compac$on


Feed frame/tablet press module


Roller compactor/mill module

Wet Granula$on


Feed frame/

tablet press module


Wet granulator/drier/mill module

Designing for flexibility: Standardized Modules •  Line always start with a feeder/blender module and always end

with a table$ng module •  Tablet press is always fed by a feeder/blender module •  Addi$onal modules are always “sandwiched” between feeder/

blender modules

39


Feed frame/

tablet press module

Direct Compac$on Roller Compac$on


Feed frame/

tablet press module


Roller compactor/mill module

Wet Granula$on


Feed frame/

tablet press module


Wet granulator/drier/mill module

Standard Formula$ons •  Collec$on of master formulas, developed for different “product families”, based

on achieving blend and finished product proper$es •  Within each standard formula$on, establish a database of material proper$es

for ingredients and blends •  For each standard formula$on and each standard equipment design, establish

predic$ve models rela$ng material proper$es and process parameters to intermediate blend proper$es and product performance

•  For each master formula, defined an “opera$onal envelope” in terms of API material proper$es and API content

•  Once the opera$onal envelope is determined in terms of API and excipient proper$es, materials can be systema$cally modified to “fit within the envelope”

•  This knowledge enables: –  Defini$on of meaningful acceptance specifica$ons for raw materials –  Determina$on of sensing and measurement required for quality assurance –  Design of an effec$ve control architecture –  Determina$on of required performance standards for control system

Standardized Sensing and Control Infrastructure •  Overall sensing and control requirements are specified, based on mul$-‐$er risk-‐

based framework •  Each module has standard sensing and local-‐level control, what is needed is to

connect them into an integrated network capable of complying with overall performance requirements

•  Control plaoorm and measurement requirements can be specified and integrated based on models and verified experimentally

•  Sensing and control requirements need to match risk level –  Low risk $er (known product with history of successful manufacture, high dose

product, low toxicity, no risk of dose dumping, known materials, simple process, simple formula$on)

–  Medium risk $er (new product with low risk factors, or exis$ng product with known risk and manageable factors such as high dose with risk of dose dumping, medium level of complexity in process and/or formula$on)

–  High risk $er (highly potent low dose compounds, new product with unknown or high risk factors, high risk of dose dumping, high risk of agglomera$on, highly complex formula$on and/or process)

Opportuni$es for USP

•  Standardize ingredient characteriza$on methods •  Standardize product characteriza$on methods •  Standardize equipment performance requirements •  Standardize sensing methodologies •  Standardize control capabili$es •  Standardize the product/process development methodology

connuousmanufacturingoftabletsandcapsules …...2 an industry in transition • change drivers –...

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