Philip Dell’orco and Matthias Tix, The State of Continuous Processing

ISCMP 2018

October 3rd, 2018

THE STATE OF CONTINUOUS PROCESSING 13 COMPANIES SHARE THEIR EXPERIENCES PHILIP DELL’ORCO MATTHIAS TIX

SURVEY MOTIVATIONS AND PARTICIPANTS

In Q1 2018, Pharmaceutical Manufacturer’s Forum completed a benchmarking survey of its members for continuous processing in pharma with the following objectives: • Understand the current state • Understand challenges to overcome for accelerating technology adoption The scope included large and small molecules, drug substance and drug product, and common regulatory/control strategy approaches

SURVEY CORE TEAM ACKNOWLEDGEMENTS Thomas Scheidmeir Jon-Paul Sherlock Silke Gotthardt Nancy Barbour Andrew Share Mauricio Futran Bryan Crowley Stephen Conway Jean-Philippe Giraud Maria Soler-Nunez Kevin Nepveux Siddharthya Mujumdar Hubert Scoble Sponsor: Roger Connor (GSK) Project Leader: Phil Dell’Orco (GSK) Survey Administration and Insights: Matthias Tix, Markus Hayex, Vish Joshi (Accenture)

* Further participants not shown due to confidentiality Copyright © 2018 Accenture

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SURVEY METHODOLOGY

SURVEY STRUCTURE AND PRINCIPLES COMPANY REPRESENTATIVES SUBMITTED QUESTIONS

QUESTIONS ASSEMBLED, REVIEWED, SIMPLIFIED AND AGREED

DISTRIBUTION OF SURVEY RESPONDENTS AND INTERVIEW PARTICIPANTS

BY FUNCTIONS AND LEVEL

RESPONSES TO QUESTIONNAIRE RECEIVED AND ANALYZED

2% 6% 4% 43%

10% 4% 11% 18%

R&D

Tech Transfer

Supply Chain C-Level/President

Technical Operations

Quality and Regulatory SVP/VP

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Director

All companies could ask questions they wanted answered; simple pick lists where appropriate (Questionnaires = Qs) • Participant information (Size, scope): 7 Qs • Continuous manufacturing strategy (approach, motivation): 23 Qs • Small molecule drug substance: 51 Qs • Small molecule drug product: 45 Qs • Large molecules: 52 Qs • Quality/Regulatory/Control Strategy: 28 Qs

2%

INTERVIEWS CONDUCTED FOR DISCUSSIONS AND CLARIFICATIONS

SHARED DRAFT FINDINGS FROM QUESTIONNAIRE AND INTERVIEWS

FINAL REPORT PUBLISHED AFTER INCORPORATING FEEDBACK

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Subject Matter Expert 3

ALL COMPANIES HAVE A POSITIVE OUTLOOK TOWARDS CONTINUOUS MANUFACTURING GENERAL SUMMARY

90%

>80%

59%

… see CM as

… consider their

… have an ambitious

… consider their CM

important for the supply of their products in the next 5 to 10 years

C-level to be well aware about the importance of CM

adoption strategy (driving agenda with regulatory bodies, equipment providers, ecosystem partners etc.)

strategy as mature, CM strategy is still at exploratory stage for all others; approximately 1/2 consider themselves early adopters

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ONLY

17%

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AGILITY OF SUPPLY, REDUCED FACTORY FOOT PRINT AND EASIER SCALE-UP ARE THE TOP 3 BENEFITS FROM CM GENERAL SUMMARY FURTHER COMMENTS

6

5

4

3

2

1

0 Agility of Supply Reduced Factory Easier Scale-up Footprint of new entities

Speed of Development

Cost of Manufacture

Improved Quality Process Safety

Worker Safety

Other

• Agility of supply: Being able to adjust campaign length to demand is ranked as top benefit as it will allow to deal with increasing demand volatility and uncertainty • Bringing products to market faster and allowing for easier scale up is considered to be highly important as well • Surprisingly, cost efficiencies and improved quality (in most literature considered to be the top benefits) not ranked at the very top, yet still highly ranked • Other benefits include “localization”, “flexibility with smaller batch sizes”, “simplified control strategy” and “enhanced process understanding”

HIGHEST POSSIBLE RANKING OF 6

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5

CM ADOPTION IS HIGHEST IN SMALL MOLECULES R&D AND FOR DRUG SUBSTANCE DEPLOYMENT The adoption is likely to go up in R&D as the understanding of CM improves.

For commercial products, switching to CM will remain as a business case decision

B

COMMERCIAL

B* C

R&D

E

F

D

G H* I*

*

E G* H*

J

K*

M

I* J K* M

SMALL MOLECULE DRUG SUBSTANCE

A*

B* C*

B*

D

F

E G*

G*

H

I

H

I

J

K

K*

L*

SMALL MOLECULE DRUG PRODUCT

F*

D*

E*

I*

H

J

I*

M

J

K*

M*

LARGE MOLECULE

Of all companies, two consider their CM strategy as mature, all others as exploratory.

All consider CM to be important for the supply of their products in the next five to ten years A

Each letter represents one participating company. Some companies did not want to display their position, which is why this slide is anonymized

Note: Size of bubble indicates number of molecules in consideration * Number of molecules not precisely indicated Copyright © 2018 Accenture

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IMPLEMENTATION APPROACHES ARE DIVERSE ACROSS COMPANIES/APPLICATION DEPLOYMENT SMALL MOLECULE/ DRUG SUBSTANCE • Start development with traditional batch technology, evolving into CM at later stage • Piloting at small scale for early stage DS

LARGE MOLECULE • In parallel with batch for R&D • Piloting on a unit operations basis

SMALL MOLECULE/DRUG PRODUCT • In parallel with traditional batch operations

TECHNOLOGY SELECTION

PRODUCT SELECTION

• Decision based on intended synthesis route, no parallel development • Opportunistic, replacing existing unit operations where there is a positive business case • In parallel with established technologies

• First legacy products then NCEs • NCEs with no parallel option • Small volume products or products prone to stability issues during protein expression in cell culture • For capacity/capability expansion

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RANKING

MOTIVATIONS DIFFER FOR LARGE VS SMALL MOLECULES: EMPHASIS ON COST AND CLINICAL SUPPLY AGILITY DEPLOYMENT SMALL MOLECULE/DRUG SUBSTANCE

SMALL MOLECULE/DRUG PRODUCT

LARGE MOLECULE

1.

2.

3.

4.

5.

1.

2.

3.

4.

5.

1.

2.

3.

4.

5.

Agility of Supply Factory Footprint Cost of Manufacture Improved Quality Easier Scale-up of new entities & Process Safety

SIGNIFICANCE

OBSERVED IMPROVEMENTS COMPARED TO BATCH?

Speed of Development Agility of Supply Process Safety Worker Safety Improved Quality

OBSERVED IMPROVEMENTS COMPARED TO BATCH?

SC Agility Easier Scale-Up Speed of Development

0% Insignificant

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Cost Quality SC Agility Easier Scale-up Speed of Development Wo rker S afety Process Safety

Easier Scale-Up Speed of Development Wo rker S afety Process Safety

Wo rker S afety Process Safety

Wo rse

OBSERVED IMPROVEMENTS COMPARED TO BATCH?

Cost Quality SC Agility

Cost Quality

50% Significant

0%

100% Very significant

Wo rse

Improved Quality Agility of Supply Cost of Manufacture Reduced Factory Footprint Easier Scale-up of new entities

Insignificant

50% Significant

100% Very significant

0% Wo rse

Insignificant

50% Significant

100%

Very significant

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DEPLOYMENT OF CONTINUOUS PROCESSING AT THE UNIT OPERATIONS LEVEL DEPLOYMENT SMALL MOLECULE/DRUG SUBSTANCE

SMALL MOLECULE/DRUG PRODUCT

LARGE MOLECULE Continuous or semi-continuous perfusion reactors

Compression Dispensing/Feeding Blending We t granulation Dire ct compaction Dry g ra nulation Coating Other

Reaction Purification Crystallization Drying Salt Formation 0%

50%

100%

• All respondents apply CM for Reaction stage • Majority respondents also apply CM for purification and crystallization stages

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Continuous/in-line buffering Continuous chromatography Continuous cell lysis and separation Other 0%

50%

100%

• All respondents apply CM for dispensing and compression stages • Blending, direct compaction or wet granulation are done in CM by more than 70% of respondents • Dry granulation (38%) or coating (18%) are less common for the participants

0%

50%

100%

• The majority of respondents are developing continuous or semi-continuous perfusion reactors, closely followed by continuous/in-line buffering and continuous chromatography • Significantly less respondents are developing continuous cell lysis and separation • Ca. 10% of respondents are developing other technologies 9

ANSWERS TO TYPE OF CONTROL STRATEGY HIGHLY HETEROGENEOUS CONTROL STRATEGY WHAT CONTROL STRATEGY DO YOU APPLY?

WHAT PROCESS CONTROL APPROACHES DO YOU APPLY FOR CONTINUOUS? ARE THE APPROACHES DIFFERENT IF YOU HAVE SINGLE CONTINUOUS STAGE OR MULTIPLE STAGES?

Deviation management Start-Up and shut-down processes

Conventional controls (e.g. feed rates)

11%

Divert to waste

Yes

Spectroscopic PAT

Divert to quarantine Setting acceptable duration and frequency of…

No

89% 0%

50%

Mo del based controls

100%

IS IT DIFFERENT TO HOW YOU MANAGE BATCH PROCESS?

Mu ltivariate analysis/MSPC

Real Time Release testing

• 88% of respondents apply deviation management control strategy followed by start-up and shut-down processes and divert to waste • The approach is different for majority of respondents Copyright © 2018 Accenture

44%

Yes Golden Batch Traceability

56%

No 0%

50%

100%

VARIED RESPONSE FOR USE OF PAT METHODS AS PART OF CONTROL STRATEGY CONTROL STRATEGY DO YOU ALWAYS REGISTER SPECTROSCOPIC PAT METHODS AS PART OF YOUR CONTROL STRATEGY FOR CONTINUOUS PROCESSES?

11%

89%

Always

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Situational

Never

• The approach used by the companies depend on the risks within the unit operations and the holistic control strategy, including if RTRT is utilized. After assessing, it is determined if a particular control (may happen to be PAT) is required to be registered • Residence time distribution (RTD) models and related monitoring should only be used when traceability is important; they should not be needed for a continuous flow unit (e.g. reactor) followed by a batch unit (e.g. crystallizer) • Only one of the participating companies has used real-time release 11

DEVELOPMENT APPROACHES, ‘BATCH’ DEFINITION, AND SPECIFICATION IMPACTS REGULATORY WHAT REGULATORY STRATEGY HAVE YOU ADOPTED WHEN LAUNCHING CONTINUOUS PROCESSES?

WHAT IS YOUR APPROACH TO BATCH IDENTIFICATION FOR CONTINUOUS PROCESSES?

27%

Register continuous processes only

Pre-defined quantity Run duration

18%

Parallel registration of batch and continuous processes

No experience

55%

… NEGATIVE IMPACT ON SPECIFICATION SETTING?

Different approaches for US/EMA than rest of world

36%

… NEGATIVE IMPACT ON BREADTH OF CLINICAL COVERAGE?

30%

Yes

No

No

0%

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50%

100%

64%

Yes

70%

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OVERALL EXPERIENCE WITH EQUIPMENT VENDORS HAS BEEN FAIR EQUIPMENT SMALL MOLECULE/DRUG SUBSTANCE 0%

Excellent

SMALL MOLECULE/DRUG PRODUCT 8%

Excellent

8%

33%

LARGE MOLECULE Excellent

Fair

Fair

Fair

Poor

Poor

Poor

9% N/A

58%

CHALLENGES • Lack of standardization • Major challenges with PAT and hardware system integration • After-sales experience has been poor

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N/A

20%

25%

58%

WHAT HAS WORKED WELL • Working closely with the vendors from the beginning to meet needs on both sides • Use contractual obligations to minimize vendor risks • In-house skills for system integration

N/A

10%

0%

70%

WHAT CAN BE DONE IN FUTURE • Standardization of equipment or platform based equipment trains • Industry consortia level non-proprietary work with vendors for developing standard set of equipment – both hardware and PAT

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CLEANING IN CM - SOLID ORAL DOSE CAN BE MORE DIFFICULT THAN BATCH EQUIPMENT SMALL MOLECULE/DRUG SUBSTANCE

SMALL MOLECULE/DRUG PRODUCT

LARGE MOLECULE

Much better than batch processing.

Much better than batch processing.

Much better than batch processing.

Moderately better than batch processing

Moderately better than batch processing

Moderately better than batch processing

About the same as batch processing

About the same as batch processing

About the same as batch processing

Worse than batch processing

Worse than batch processing

Worse than batch processing

0%

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50%

100%

0%

50%

100%

0%

50%

100%

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CM REQUIRES DIFFERENT SKILLS HUMAN RESOURCES INHOUSE SKILLS REQUIRED Quality organization Process control engineers Process analytical skills Engineers with CM backgrounds Operations staff with enhanced skills Data sciences Chemists / Biologists with CM backgrounds Personnel with enhanced modeling skills Other 0%

20%

40%

60%

80%

100%

% Number of responses (multiple answers possible) Copyright © 2018 Accenture

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ADDITIONAL AREAS ADDRESSED IN SURVEY Openness of sharing manufacturing sites with other companies: majority No Experience in filing across different markets: US, EU, Japan Yes; limited experience outside of these Do you use new facilities or existing to implement: mostly existing facilities Do you use CM equipment for multiple products or dedicated to single products: mostly multiple products Validation: limited experience with continuous process verification Handling of CPPs vs PPs: similar to batch Use of mathematical models for control strategy: used frequently; especially for continuous drug product Resources relative to batch to implement: different resource required; more at commissioning/initial implementation Copyright Š 2018 Accenture

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BUSINESS CASE COMPLEXITY, REGULATORY & CHANGE MGMT. HAVE BEEN THE MAIN CHALLENGES KEY TAKEAWAYS It’s a strategic decision! Look beyond the short term business case, embed CM into long term manufacturing strategy

The approach to CM is companyspecific. Seek a first success in more mature areas (e.g. SM DP) but also start exploring high-value portfolio areas (e.g. LM)

Regulatory guidelines are not harmonized globally. Account for extra effort for regulatory filing with CM process to overcome the limited experience with non-ICH regulatory bodies

Be aware that change management efforts are more driven by technology development than by management endorsement

Engage in non-proprietary knowledge exchanges

Leverage the broader ecosystem

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