Pharmaceutical Standardization Division Drug Evaluation Department

NIFDS

Strategies to Implement Continuous Pharmaceutical Manufacturing

in Korea

Hyunkyung Kang

Continous manufacturing (CM)

• In continuous manufacturing, the input

material(s) is continuously fed into and

transformed within the process, and the

processed output material(s) is continuously

removed from the system.

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Comparison of conventional vs continuous Manufacturing

Require various equipments by batch size

different process variable by batch size

PV for each batch size

Low quality reproducibility

Research Scale-up commercial: long time

and high cost

Open system

One equipment regardless of scale

Equivalent product quality regardless of batch

size

Closed system

Lab scale commercial (Scale-up)

minimized process development research /

time and cost saving

Real time process monitoring / unattended

automation

Continuous ManufacturingBatch-based Manufacturing

1Kg

1Kg HSM

10Kg

10Kg HSM 100Kg HSM

100Kg1Kg

10Kg 100Kg

Needs for CM

Manufacturer

• Rise in facilities utilization rate

• Reduce process development time

• Shorten time to market

• flexibility

• Cost reduction

• Reduced GMP management caused by manual inter-process operation

Regulatory body

• Quality improvement by QbD design

• Reduced preparation time for commercialization of new drug

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Implementation of Continuous Manufacturing by VertexTM

• World’s first approved drug by CM (2015, Orkambi®)

* ConsiGma™ - A platform for Continuous Solid Dosage manufacturing enabling Quality by Design and Lean Manufacturing, CONTINUOUS MANUFACTURING IN THE PHARMACEUTICAL INDUSTRY DANISH

PHARMACEUTICAL SOCIETY 26TH OF APRIL, 2017

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Wet granulation

Dry granulation

Direct compression

Approved product with CM

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Path CM platform USA EU Japan Korea

NDA

Wet granulation

Vertex’s Orkambi

2015 2015

Directcompression

Lily’s Verzenio

2017 2018 2018 2019

Roller compaction

Vertex’s Symdeko

2018

NDAsupplement(switch from batch to CM for an approved product)

Direct compression

Janssen’s Prezista

2016 2017

Regulatory trends_USA

• 2004. 09 “Guidance for industry PAT”

* Guidance for Industry PAT – A framework for innovative pharmaceutical development, manufacturing, and quality assurance (2004) 7

• 2017.09 “Guidance for industry – Advancement of Emerging Technology Applications for pharmaceutical Innovation and Modernization”

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Regulatory trends_USA

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• 2019.02 “Quality consideration for Continous Manufacturing –Guidance for Industry

1. Key concept of CM

• Process dynamic

• Batch definition

2. Control strategy

• Input material control

• Process monitoring and control

• Material diversion

• RTRT

• Specification

• Equipment

• System integration, data processing and management

3. Process validation

4. Additional pharmaceutical quality

system consideration

5. Scale-up

6. Stability

7. Bridging existing batches to CM

Regulatory trends_USA

• Emerging Technology Team (ETT)• Emerging Technology program in Center for Drug Evaluation and Research (CDER)

• Laison between Pharmaceutical company and quality evaluation departments to introduce new

technology

• Publication of guidelines on new technology

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Regulatory trends_USA

• 2016.11 “Guideline on process validation for finished products -information and data to be provided in regulatory submissions”

*EMA “Guideline on process validation for finished products - information and data to be provided in regulatory submissions”, 2016.11

Verification of CM- Continous process verification (CQA, CPP)- Needs sufficient understanding of the process- Process control by Available PAT such as NIR, Multivariate Statistical

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Regulatory trends_Europe

• EMA support to innovation

• The Committee for Medicinal Products for Human Use (CHMP)

Adivise in development strategies that do not have sufficient guidelines or out of

guidelines

• PAT team

To support PAT and QbD in EU

• Innovation Task Force (ITF)

Overall coordination of the regulatory body to introduce innovative drug

development method

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Regulatory trends_Europe

• Japan Agency for Medical Research and Development (AMED)

• Supporting Division of Drugs _ National Institute of Health Sciences (NIHS)

Points to Consider Regarding Continuous Manufacturing (May. 2017)

State of Control in Continuous Pharmaceutical Manufacturing (May. 2018)

• Innovation Manufacturing Technology Working Group (IMT-WG)

• Affiliated with PMDA (2016. 7)

• Primary target : Implementing CM

PMDA Views on Applying Continuous Manufacturing to Pharmaceutical Products for Industry

(provisional draft) (Mar. 30, 2018)

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Regulatory trends_Japan

• 2017. 5. “Points to Consider Regarding Continuous Manufacturing”

• 2018.3. “PMDA Views on Applying Continuous Manufacturing to Pharmaceutical Products for Industry”

1. Control Strategy

• Beneficial control strategy

• Understanding process dynamics

2. Batch Definition

• Run time and the processing speed

• Volume

• Feed amount of raw materials

3. Validation – State of control

• Batch size and the number of batches for process validation

• Validation on changes for an approved productfrom batch to continuous manufacturing

4. Stability Testing

• Size of the primary batch

• Number of primary batch

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Regulatory trends_Japan

• To publish harmonized guideline on CM, a formal working group was established(2018.11) and doing their best.

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Regulatory trends_ICH

Preparation for CM implementation of Korea

• Regulatory body• No domestic manufacturing drugs approved for CM

• Lily’s Verzenio was approved (2019.5)

• Innovative T/F in MFDS: for coordinating the regulatory body for introducing advanced technology, Supporting development of new tech drugs coorperating with regulatory body and manufacturers

• Manufacturers• DGMIF: ConsiGmaTM-25, ConsiGmaTM-1

• Hanmi: ConsiGmaTM-1

• Many domestic pharmaceutical companies are researching PAT (NIR, Raman etc) and application case study to be reflected to drug licensing

• Academy• SKK: GEA-PPRC: ConsiGmaTM-1

• Researching process changing research from batch to CM

• Performing evaluation studies on prescription and process validation in CM equipment

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CM introduction strategy

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Government

UniversityPharma

Regulatory body

manufacturer

Academy

• Establish harmonized standards in accordance with international standard

• Increase process understanding through joint research with manufacturers

• Provide incentives to industry

• Needs expansion of quality control based on risk assessment

• Reduce the risk of CM introduction through cooperation with regulatory body

• Needs conduction of various collaborative research

• Recruiting case study on process transfer

• Educational environment on CM

Considerations for review drug products produced by CM

• Understanding of process

• Needs provision of datas to understand the CM process (QbD based)

• PAT

• Ensuring quality control by PAT based on statistical datas

• Setting criterion and test method

• Real Time Release Testing (RTRT)

• Sample size(sampling frequency)

• Process validation

• Automation program for in-Process Control

• Feasibility of Process variables

• Provision of datas on robustness of program and validation

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• Securing research case on CM

Until now, there is no organization which has entire CM equipment(from blending to

coating) in korea

Many researches on unit processing such as granulation, drying , tableting are under way

Datas on process changing from batch to CM are available

From now, it is required to expand from case research of CM in unit process to entire

manufacturing process

Manufacturers has to cooperate with regulatory body based on their know-how and

needs from CM development not from approval step

Knowledge and experience of CM development should be published and shared as a case

reports

• Policy for encouraging CM introduction

Needs to secure real case of drug approval manufactured by CM

Needs to make new department for supporting approval for pharmaceutical products

by advanced tech such as CM in MFDS

Needs to improve understanding of CM by reviewers in MFDS

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Considerations for review drug products produced by CM

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- Being Efficient comparing batch manufacturing in many aspects (time, space, flexibility, cost, quality control)

- Process control by real time monitoring by PAT

- Improving ensuring quality by QbDdesign

NEEDS

Obstacles

Encouraging policy

Continousmanufacturing

- A lot of investment needed for introducing CM

- Regulatory bodies are not enough prepared

- Lack of PAT for real time monitoring

- lack of automation program for process control

- Establish design space, process parameter range, in-process control studies based on QbD

- Verification of automation program, PAT application studies

- Enhance understanding and knowledge

- Regulatory body’s implementation strategy

expectations

- Acceleration of CM mplementation

- Improve drug quality

- Promoting new drug introduction to market

CM introduction strategy_summary