EMA regulatory perspective on continuous manufacturing for ... · An agency of the European Union EMA regulatory perspective on continuous manufacturing for Biologicals Dr Veronika

An agency of the European Union

EMA regulatory perspective on continuous manufacturing for Biologicals

Dr Veronika Jekerle (European Medicines Agency, The Netherlands)

CASSS – CMC strategy forum – Seville (13 – 15 May 2019)

Content

Challenges and opportunities

Regulatory considerations

Guidance landscape

Update on ICH Q 13

EMA/BWP experience on continuous manufacturing for Biologicals

1 EMA perspective on continuous manufacturing for Biologicals - Jekerle

Opportunities & Challenges


Opportunities

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• Flexibility to respond to manufacturing needs (shortages, supply chain demands)

• Decreased need for comparability

• Reduced manufacturing footprint (smaller facilities) & possibility for increased proximity to patient

• Single-use technology and reduced media volumes/ simpler cleaning procedures etc.

• Better product understanding (online monitoring & control)

EMA perspective on continuous manufacturing for Biologicals - Jekerle

Challenges

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• Raw material properties and variability• Impurities and removal (degradation products over time)• Viral safety & bioburden• Material traceability• Cell line stability and life span

• Product knowledge and structural/functional relationship• Analytical technology and control strategy• Design spaces and potential interactions between steps• Evaluation of manufacturing changes & impact on

product quality


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New chemical reactions Fast development & screeningScale-up*

Smaller footprint

Shorter production times

Flexibility and agility

Easier to accommodate supply needs

On line monitoring & controlIncreased assurance of product

quality in real time

Enhanced process

understanding & control

Potential benefits to patients, industry & regulators of CM

Slide by Dolores Hernán Pérez de la Ossa, EMA

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Key concepts

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batchraw

material

equipment

processdescription

processcontrol



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Batch! Definition of batch size should be stated prior to manufacture ! ICH Q7 (EU GMP Guide Part II) “A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval”.• in process testing,• specifications• Process validation• GMP compliance

Raw materialEudralex Vol 4. GMP Part II:Raw Material (= general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs).

• Raw material properties (functionality, safety, impurities).

• Batch to batch/lot to lot variability and sources of variability

• Impact on process and control strategy (IPC measurements)

• Continuous drip feeding/hybrid approach

• Stability & traceability of raw materials within the CM process

Process descriptionVolume 2B (Notice to ApplicantsMedicinal products for human usePresentation and format of the dossierCommon Technical Document (CTD)) Differences to a batch process• Time-related parameters as a result of

dynamic process • Flow rates (e.g. volume over time),

mean residence times • Scalability aspects (e.g. running time,

equipment design)• Procedures for start up/shut down and

interruption• Design spaces –address potential

interactions between steps• Alternative processes (?)



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Control strategy= manufacturing process produces product of intended quality in a reproducible way (=batch process)

• Product and process specific• Product knowledge (structural & functional relationship (e.g. mABs),

platform knowledge/prior knowledge• Control systems (automated valves, feed-back & feed-forward controls (?),

feeder controls)• IPCs and sampling potentially different to batch processes• Online measurement (e.g. multi-attribute method: relevant readout /

degradation products)• In perfusion culture: end of production cell characterisation• Procedures for handling deviations, non-conforming material• Real time release testing (for Bio ?) or Hybrid approach realistic

Equipment= discussed during a pre-approval inspection (GMP)

• Design considerations• Larger contact surface area (temperature

control, leaching)• Single use equipment• Location of segregation points• Potential for microbial

growth/contamination• Indicators of equipment failure• Strategy for cleaning validation


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Guidance landscape


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The EU regulatory framework has no specific CM guidelines but…

Current regulations and guidelines are supportive of innovative pharmaceutical development and manufacturing approaches.

Although continuous manufacture is not specifically addressed in guidelines, it fits well into the “enhanced approach”.

Regulatory & guidance landscape

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ICH Q5D

• Derivation and characterisation of cell substrates used for the

production of biotechnological/biological products (Q5D)

• Cell banking

• Characterisation & testing of cell banks

• End of production cells characterisation (genetic stability)

• EU GMP Annex 17: Real Time Release Testing and Parametric Release (results on CoI – online monitoring)

• Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission (i.e. continued process verification)

• Guideline on process validation for finished products -information and data to be provided in regulatory submissions chemical & biological medicinal products

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Guidance landscape


EMA Guideline on process validation for finished products - information and data to be provided in regulatory submissions (main principles)

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process validation after pharmaceutical development / process development, after scale-up and prior to marketing authorisation

• Manufacturing/process performance continuously monitored and evaluated. (ICH Q8)• Science and risk-based real-time approach (in-line, on-line or at-line controls &

monitoring of process performance & product quality on each batch)• Most appropriate method for validating continuous processes

Combination of traditional process validation and continuous process verification approach for different steps within the manufacturing process.


Guidance on real-time release testing

• Specifications are required for

active substance & finished product

• Specific tests: “Complies if tested”

when RTR testing is applied

• Release Tests can be moved into Process Controls, however specifications must be adequate.


Guidance landscape

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ICH Q8-12• Product and process understanding and process control (ICH Q8R2)

• Quality risk management (ICH Q9)

• Quality Systems (ICH Q10)

• Development and manufacture of drug substances (ICH Q11)

• Quality-by-Design

• Lifecycle approach to process control/validation (ICH Q12)

principles apply to enhanced development, manufacturing and control

strategy approaches including CM flexibility, agility & product

understanding


ICH Q 13



Business Plan for ICH Q13:

• Step 1: Initiated November 2018

• Step 2a/Step 2b: June 2020

• Step 3: June 2020 – November 2021

• Step 4: November 2021

• Step 5: Initiate after November 2021

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

Initiated: September 2018Concept paper & Business plan endorsed: November 2018, Charlotte, NC, U.S.A.

o Rapporteur: Dr. Sau (Larry) Lee (FDA, US)o Regulatory Chair: Dr. Yoshihiro Matsuda (MHLW/PMDA)o EMA team: Dolores Hernan (EMA) & Nick Lee (HPRA)

Status of ICH Q13 Guideline Development: https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

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Objectives

Capture key technical and regulatory considerations that promoteharmonisation, 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 andtherapeutic proteins for new and existing products, and

Provide guidance to industry and regulatory agencies regardingregulatory expectations on the development, implementation, andassessment of CM technologies used in the manufacture of drug substancesand drug products.



ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products

Concept paper

Definitions & regulatory concepts

• definition of CM

• startup/shutdown

• state of control

• process validation

• continuous process verification

Key scientific approaches

• Concepts of system dynamics

• monitoring frequency,

• detection and removal of non-conforming material

• material traceability

• process models

• advanced process controls

Regulatory aspects initial marketing authorisation and post-authorisation phase

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EMA/BWP experience on continuous manufacturingfor Biologicals


Additional considerations (BWP)

Definition of ‘continuous’ manufacture

• direct formulation from active substance to finished product (ATMPs) (?)

Continuous manufacturing process where the active substance is directly formulated into the finished product, a drug substance shelf life is not required to be registered.

Alternative processing in case the direct formulation becomes optional(vs. a holding step – shelf life etc.) – acceptability (?)

Single use equipment (i.e. extractables & leachables)

Experience at PAT team is monitored (2 BWP members in the PAT team)


EMA/BWP experience on continuous manufacturing

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• PAT team

• Scientific advice requests (small molecules): active substance and finished product

• 3 MAAs (1 in EMA-FDA QbD pilot program: e. g. Orkambi) and 1 variation in the centralised procedure: all relate to the finished product

• Very limited experience on CM approaches with Biologicals

• Discussion topic at the BWP interested parties meeting (June 2017)

Few examples:

• Perfusion cell culture

• (partial) continuous downstream purification process without holding steps

• Cell therapy products (continuous process without holding step at level of active substance)


chem

ical

exp

erie

nce

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EMA Support for Continuous Manufacturepoints of contact

CHMP Scientific Advice - official advice from the CHMP on appropriate tests and studies

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000049.jsp&mid=WC0b01ac05800229b9

PAT team - supports PAT and QbD activities in the EU (including CM)http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000162.jsp&mid=WC0b01ac058076ed73

Contact [email protected] for orientation

Innovation task force – can also support innovative approaches to the development of MPs through informal ITF meetings

https://www.ema.europa.eu/en/human-regulatory/research-development/innovation-medicines


Regulator’s conclusions Commercial implementation is underway - Regulators & Industry are building

experience.

Current regulatory framework is adequate & existing GLs are supportive. ICH Q13 is welcome and will provide further specific support

EU regulators support novel pharmaceutical technologies and offer an increased exchange/dialogue on this topic (stakeholder interaction, ICH, product specific)

Some technical aspects can be very specific & different (i.e. process description, control strategy etc.) – technical detail & consideration by the Company need to be shared with Regulators (pre-authorisation & in the dossier (e.g. QOS))

Applicants are highly recommended to establishing an early dialogue with EU Regulators


Acknowledgements

• Dolores Hernan

• Peter Richardson

• Steffen Gross

• Nino Mihokovic


Thank you for your attention

Dr Veronika Jekerle, BWP Scientific secretariat, Quality Office, Specialist Scientific Disciplines Department, EMA

European Medicines Agency

Domenico Scarlattilaan 6, 1083 HS Amsterdam, The NetherlandsTelephone ++31 (0)88 781 6000Send a question via our website www.ema.europa.eu/contact

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EMA regulatory perspective on continuous manufacturing for ... · An agency of the European Union EMA regulatory perspective on continuous manufacturing for Biologicals Dr Veronika