Pharmaceutical Continuous Manufacturing

Michael Levy

VP, Research & Innovation

June 20, 2019

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© 2018 USP

200 Years of building trust

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© 2018 USP

Continuous Manufacturing

A process in which the input materials are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system1,2,3

• 1FDA guidance (draft), “Quality Considerations for Continuous Manufacturing Guidance for Industry”, March 2019.

• 2System: integrated process consisting of two or more unit operations in series.

• 3USP NF 44(6) Stimuli to the revision process: U.S. Pharmacopeialperspective for PCM

Benefits and Challenges

• Faster development

• More process knowledge

• Quality Control, OOS rejection

• Smaller facility size, no size-scale up

• Improved availability of quality medicine

Advantages

• Switchover costs

• Lack of trained personnel, standards, guidances

• Technical challenges (low and high drug loading)

Challenges

State of CM adoption in the US• Janssen: Prezista, 2016: HIV

• Vertex: Two products Orkambi (lumacaftor/ivacaftor, 2015) and Symdeko (tezacaftor/ivacaftor, 2018): Cystic Fibrosis

• Eli Lilly: Verzenio: (2018) Breast Cancer

• Most other companies (including some generics manufacturers) at various stages of development

• Easiest implementation in DP, followed by DS and Biologics

• Six approvals in US so far, several in the pipeline

2016PCM Technology & Quality Road Mapping Roundtable

Attended by 85 of PCM thought leaders from academia, industries, and government agencies, incl. FDA

Provided an open platform to share knowledge about PCM and insights on the future role of quality standards

Identified scientifically sound, novel technologies and control strategies that will enable and grow CM

Helped prepare a technology and quality roadmap for accelerating development, implementation and standardization of CM

Stimuli Article

Standards

Explore opportunities to provide

new standards for quality of

medicine production using PCM

Support capability building of industry through expansion of USP offerings and collaborations

Capability Building Advocacy

PCM at USP

A recognized thought leader in advancing PCM quality standards

• Material characterization

• Helping the industry switch

• New standard materials

• PAT strategy standardization

• PCM PE course: 5-day course under development with Rutgers (C-SOPS)

• Internal expertise building (biologics, data analytics)

• Academic collaborations

• Participation in ICH Q13

• Hosting public events

• Communications pieces

ICH Q13

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Background: ICH Q13• Initiated: September 2018

• Concept Paper and Business Plan Endorsed:

November 14, 2018, Charlotte, NC, U.S.A.

• Organizational Membership:

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

o Rapporteur: Dr. Sau (Larry) Lee (FDA, US)

o Regulatory Chair: Dr. Yoshihiro Matsuda (MHLW/PMDA)

o ANVISA, Brazil

o BIO

o EC, Europe

o EFPIA

o FDA, US

o Health Canada, Canada

o HSA, Singapore

o IGBA

o JPMA

o MFDS, Republic of Korea

o MHLW/PMDA, Japan

o NMPA, China

o PhRMA

o Swissmedic, Switzerland

o TFDA, Chinese Taipei

o IFPMA

o APIC

o IPEC

o National Center,

Kazakhstan

o USP

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Need for New Guideline • The current ICH Guidelines do not sufficiently address technical and regulatory

requirements that are unique to CM.

• A harmonised regulatory guideline can facilitate implementation, regulatory approval,

and lifecycle management, particularly for products intended for commercialization

internationally.

• This approach will benefit industry and regulators, and improve access to medicines.

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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Objectives Capture key technical and regulatory considerations that promote harmonisation, including

certain CGMP elements specific to CM,

Allow drug manufacturers to employ flexible approaches to develop, implement, or

integrate CM for the manufacture of small molecules and therapeutic proteins for new

and existing products, and

Provide guidance to industry and regulatory agencies regarding regulatory expectations on

the development, implementation, and assessment of CM technologies used in the manufacture

of drug substances and drug products.

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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Concept Paper

• An ICH guideline would facilitate international harmonisation and could

reduce barriers to the adoption of Continuous Manufacturing technology

• Guideline will describe CM-related:

o Definitions and Regulatory Concepts

o Key Scientific Approaches

o Regulatory Expectations

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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Concept Paper: Issues to be Resolved• Definitions and regulatory concepts

o Unique characteristics of CM; different modes of CM operation; state of

control; batch considerations

• Key scientific approaches

o State of control; control strategy; batch size and output; use of data-rich

environments; continuous process verification

• Regulatory expectations

o Process descriptions and operational strategies for commercial CM; process

models; stability; process conversion; process validation; pharmaceutical

quality systems; lifecycle management; CTD

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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ICH Guideline Development Milestones• Step 1: Consensus Building – Develop Technical Document

o Initiated November, 2018

• Step 2a: Confirmation of ICH Parties consensus on the Technical Document/Step 2b:

Adoption of Technical Document as draft Guideline by Regulatory Members

o Planned June, 2020

• Step 3: Regulatory consultation and discussion (3 stage process)

o Planned June, 2020 – November, 2021

• Step 4: Adoption of an ICH Harmonised Guideline

o Planned November, 2021

• Step 5: Implementation

o Planned to be initiated after November, 2021

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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Updates from the 3-6 June F2F meeting

• Finalized the outline for drafting the guideline and the structure.

• Drafting teams were formed to address the different sections of the guideline

• Key topics that will be addressed such as scientific approaches, regulatory

expectations were discussed to gain better understanding of the impact of

these on continuous manufacturing and to have the EWG on the same page on

the level of understanding.

• The progress made on the finalization of the outline framework, content

structure and format, formation of drafting teams and the timelines to next step

from the last F2F meeting in November 2018 to now was presented to the ICH

Assembly/Management Committee on 6 June 2019.

• Focus moving forward: Drafting of the guideline

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

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Keep up with ICH Q13 Online

• ICH Website: http://www.ich.org/

• Status of ICH Q13 Guideline Development:

https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

USP Education

A 5-day long training program in collaboration with C-SOPS1 at Rutgers University

Both laboratory and classroom components

Topics include

– PCM: differences and similarities with batch manufacturing

– Equipment: Loss-in-weight feeders, mixers, granulation, tableting, etc.

–Modeling & Simulation

– Control strategy, systems, technologies

– Facility design, economics

– Regulatory and safety aspects

1Centre for Structured Organic Particulate Systems

• CM has emerged as a revolutionary paradigm

• Challenges persist – beyond early adopters, Gx

• USP has taken steps to help ensure quality of medicines made using CM

• These include providing training, convening meetings and advocacy

• Going forward, USP is working with academic and industrial stakeholders to develop new standards, provide education to manufacturers

Summary and Outlook

APPENDIX

Typical CM Line for OSD Drug Product

Tablet Press, Coater

Mixer Granulator

Mill

Loss-in-weight feeders

More than one feeder, mixer, granulator or mill may be employed In an end-to-end implementation, drug substance can be made upstream of the

drug producto Some equipment such as mixers may not be requiredo Different technologies such as hot melt extrusion can be employed

Core Concepts for CM

• Start-up/shutdown, RTDs, Material traceability, Sampling plans

Understanding of the Process Dynamics

• Time based, Input material based

Batch Definition

• Expected/unexpected variations: risk mitigation

• Materials, monitoring, diversion, RTRT

• Equipment/systems integration

• Data collection, processing, management and archival

Control Strategy under PQS framework

Process Validation

Challenges

• Investment

• Skilled workforce

• Bespoke processes, lot of trial and error during development

• Lines typically cannot be used for multiple products

• Generics: How to produce a product approved using CM?

• Tighter quality window

• Quality perception

USP’s Continuous Manufacturing Strategy

• Standards only where required

• Material testing procedures, RTD tracers, Data collection..

Understanding the need for standards

• A 5-day hands-on training in the works

Bridging the skill-demand gap

• Meetings, conferences

Convening

• Research fellowships

• Academic collaborations

Catalyzing