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CONTINUOUS MANUFACTURING A qualitative analysis of challenges and opportunities for introducing

continuous manufacturing in pharmaceutical companies

p. 01

5 May 2017

Vibeke Jessen, LEO Pharma

Agenda

5 May, 2017

p. 02

• Regulatory actions to support Quality by Design (QbD), Process Analytical Technology (PAT) and Continuous Manufacturing (CM)

• A qualitative analysis of challenges and opportunities for

introducing continuous manufacturing in pharmaceutical companies

• Commercial drug products manufactured by CM

Continuous Manufacturing 5 May 2017

p. 03

Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. Sau L. Lee et al. J. Pharm. Innov. DOI 10.1007/s12247-015-9215-8. March 2015.

Batch, Hybrid and CM (end to end) 5 May 2017

p. 04

Presented from FDA on the 2015 PDA Manufacturing Science Workshop. September 30 – October 1, 2015 in Washington, DC

Batch

End to end

Hybrid

Regulatory actions to support QbD, PAT and CM

5 May, 2017

p. 05

EMA and FDA parallel assessment of applications with QbD • A pilot programme expected to run for 3 years was started in

March 2011 • The pilot programme was extended for 2 additional years

from April 2014

• Program concluded in April 2016. Results:16 requests (one rejected, one not reviewed, two MAA/NDA applications, three variations and 9 scientific advice)

2015 PDA Manufacturing Science Workshop. September 30 – October 1, 2015 in Washington DC

Regulatory actions to support QbD, PAT and CM

5 May 2017

p. 06

EMA: • A PAT team was set up in 2003 to support activities with

PAT and QbD in EU FDA: • A PAT team was also established in US. This PAT team is

however replaced with the Emerging Technology Team (ETT) in 2015

PMDA: • An innovative manufacturing technology working group

(IMT-WG) was established in July 2016

Regulatory actions to support QbD, PAT and CM

5 May, 2017

p. 07

• FDA blogs (FDA Voice) with e.g. encouragement for

implementation of CM

• FDA training of employees

• “White papers” posted in 2014 from symposium regarding continuous manufacturing. 2nd international symposium September 2016

International symposium on CM of Pharmaceuticals (ISCMP)

5 May 2017

p. 08

Participants: • Drug manufactures • Suppliers • Research institutions • Regulatory agencies Sponsors: • Novartis – MIT center for continuous

manufacturing • Centre for Continuous Manufacturing and

Crystallisation (CMAC)

ISCMP - Results

5 May 2017

p. 09

May 2014: • Discussion of existing knowledge, opportunities,

challenges, gaps and regulatory aspects • Result: 8 “white papers” September 2016: • Real case studies and identify remaining gaps

• Step by step approach is recommended – many

hybrid approaches. Two examples of full end-to-end

• Small molecules both API synthesis and drug product (wet granulation, direct compression, coating)

• Result: One “white paper”

A qualitative analysis of challenges and opportunities for introducing continuous manufacturing in pharmaceutical companies.

p. 010

“Will continuous manufacturing be the future concept in Denmark and Europe for pharmaceutical companies when manufacturing medicinal products?”

5 May, 2017

Qualitative research

p. 011

• Literature studies and interviews with

selected representatives from pharmaceutical companies, authorities and an alternative industry

• In total 9 interviews (four pharmaceutical

companies, two from authorities, one alternative industry)

5 May, 2017

Results - Pro and Cons Continuous Manufacturing

p. 012

PRO • Simple scale- up • Increased quality • Small equipment/footprint • Cost savings • Increased safety CONS • Technology is not mature. • Investment in new equipment for CM is needed and the

companies have already equipment for batch manufacturing

5 May, 2017

Quality challenges/opportunites

5 May, 2017

p. 013

• Out Of Specification (OOS) results • Guideline needed to address the following:

- Control strategy - Process validation

- Def. batch

- Residence Time Distribution (RTD)

Business/culture challenges/opportunities

5 May, 2017

p. 014

• Already investment in batch manufacturing

• Culture, skills and training. Upgrade knowledge of statistic

• Mind-set of the formulation and process

development scientists • Dedicated group with focus on CM - R&D and commercial process development - Control systems engineer - PAT specialists - Statistician

• Cooperation with universities and other

companies

Regulatory

challenges/opportunities

5 May, 2017

p. 015

• New concept to regulators/training of regulators

• Regulatory approval worldwide

• Seek scientific advice

• “White paper symposium”

• ETT and EU PAT team

Technology challenges/opportunities

5 May, 2017

p. 016

• Available equipment for CM (e.g. “Plug and Play” equipment)

• Cooperation's between pharmaceutical companies, the academia and government:

- F3 (Flexible, Fast and Future), 2009-2013 - CMAC (Centre for Continuous Manufacturing and Crystallisation), 2011

• Publication of specific examples and challenges

together with business cases

Results - Implementation

p. 017

• CM needs to start up in development, preferable after PoC • Obvious to start up in API manufacturing • Timeframe for widely implementation of CM is estimated to

be between 5 to 10 years in EU

• In the future CM is expected to be in the range 10% to 50 % of the manufacturing processes in the companies

5 May, 2017

Alternative industry – Food industry 5 May, 2017

p. 018

• CM implemented since 2002

• End-to-end for e.g. baby food and milk powder. 3 weeks without stop – one cleaning day

• 30 % of the processes are CM

• Solutions are not CM due to formation of

microfilms on the equipment and analytical tools

• PAT in-line for e.g. humidity, density and particle size

Conclusions

p. 019

• Top management should support the implementation strategy

• Select the right product or process for CM in the

company with a beneficial business case preferable from phase 2 b

• Establish a dedicated cross-functional team with

the right competences and mind set within chemistry, engineering, quality, regulatory, statistical and process development from development and commercial manufacturing

5 May, 2017

Conclusions (continued)

p. 020

• Partner up with other pharmaceutical companies, academia and suppliers of equipment e.g. with regard to technical challenges and share successful cases as well as failures

• Seek regulatory advice during the implementation

phase

5 May, 2017

Commercial drug products manufactured by CM

5 May 2017

p. 021

April 8, 2016 FDA approval of an update in the

manufacturing of PREZISTA (darunavir) 600 mg tablets,

Janssen Supply Chain (JSC) can now produce tablets

on a continuous manufacturing production line at its

manufacturing facility in Gurabo, Puerto Rico

Severin – nimesulide tablets by Chinoin has been

licensed, and is available in the Mexican market

Vertex continuous facility 5 May 2017

p. 022

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Vertex - Orkambi p. 023

5 May 2017

• Orkambi ((lumacaftor/ivacaftor) is a drug product for

relatively few patients (cystic fibrosis) in the world,

approximately 75.000 patients

• Manufacturing of Orkambi consists of feeding,

blending, wet granulation, compression and finally

coating. Definition of batch: range max 150 kg

• The CM facility at Vertex was built in an empty facility

from scratch

• Vertex has also similar facilities at CMO’s (Aesica

pharmaceuticals and Hovione)

Janssen continuous facility 5 May 2017

p. 024

http://www.in-pharmatechnologist.com/Processing/Continuous-manufacturing-gets-broad-support

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Janssen - Prezista p. 025

5 May 2017

• Prezista (Darunavir) is a high volume product (HIV

medication)

• Manufacturing of Prezista is based on direct

compression and consists of weighing, milling,

blending, compression, and coating

• Already approved batch manufactured product.

Change from batch to CM

• Cooperation with Rutgers University

Novartis, Continuous Manufacturing Pilot Facility

5 May 2017

p. 026

Novartis and MIT initiated a 10 year collaboration project in 2007

2015 PDA Manufacturing Science Workshop. September 30 – October 1, 2015 in Washington DC

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Novartis - Aliskiren p. 027

5 May 2017

• Aliskiren hemifumarate coated tablets (hypertension)

• End to end process

• Upstream: Intermediate reactions, separations,

crystallisation and drying

• Downstream: Mixing, granulation, drying and

compression replaced by extrusion and molding

• Novartis expect to have an “end to end” CM

procedure ready in 2017

• Cooperation with MIT

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Implementation of CM p. 028

5 May, 2017

• Eli Lilly and Merck is working on regulatory files with CM products

• Several companies have implemented CM lines for solid dosage forms e.g. GSK, AstraZeneca, Chinoin, Sanofi, Pfizer, Ghent and J&J

• Also companies in Korea, Japan and east

EU have implemented ConsiGma models

• CMO’s have implemented CM: e.g. Aesica Pharmaceuticals and Hovione

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Modul based CM p. 029

5 May, 2017

• Pfizer is working together with GSK and GEA with implementation of a module based CM set up

• “If you going to sell here, you are going to

manufacturing here” • This setup will make it possible to set up a

continuous line where ever needed in the world within a week

Lawrence Yu from the FDA:

5 May 2017

p. 030

“I can see it is changing, a lot of companies talk with us” “CM is a reality and FDA is not the problem” “You need to think about it now”

2015 PDA Manufacturing Science Workshop. September 30 – October 1, 2015 in Washington DC

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Thank you 5 May 2017

p. 031