Strategies to Implement Continuous Pharmaceutical Manufacturing in … · 2019. 7. 22. · •...
Transcript of Strategies to Implement Continuous Pharmaceutical Manufacturing in … · 2019. 7. 22. · •...
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