EMA perspective on Continuous Manufacturing

EMA perspective on Continuous Manufacturing ISCMP Oct 2018 London, 04 October 2018 Presented by Peter Richardson Head of Quality, European Medicines Agency

An agency of the European Union

Overview I.

Continuous Manufacturing (CM) A. Potential advantages of CM B. Current EU Regulatory Environment C. Enablers for CM D. EU experience to date E. Regulatory considerations and Scientific Challenges F. Models and application G. Conclusions & recommendations

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A. Potential Advantages of CM

New chemical reactions

Shorter production times

Fast development & screening Scale-up*

Easier to accommodate supply needs

Flexibility and agility

Enhanced process understanding & control

Benefits to patients, industry & regulators 2

Smaller footprint

On line monitoring & control Increased assurance of product quality in real time

B. Current EU Regulatory Environment No specific EU guidance on CM currently available (case-by-case evaluation) but compatible and supportive: §

ICH Q8, Q9, Q10 and Q11, and PtC: principles apply to enhanced development, manufacturing and control strategy approaches including CM. (Initiated: ICH Q13: CM)

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EU Guidelines, e.g.: Process Validation, RTRT, Manufacture of drug product , Chemistry of new active substances, Use of NIR

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PhEur: chapter on Chemometrics (5.21), NIR (2.2.40), Raman (2.2.48), Large sample sizes (UDU 2.9.47), PAT …

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Q&A on QbD: Lessons learnt from the pilot, Level of details, DSp verification, NORs/PARs/DSp

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GMP Annex 15 (qualification/validation) & Annex 17 (RTRT)

Other information sources: §

Interactions with Regulators / Stakeholders: FDA, PMDA, Academic ..

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ISCMP White papers, ASTM E2629 – 11 (PAT), E2968 – 14 (CM)

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C. Enablers for CM •

Quality by Design / Enhanced approaches

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DOE & Design Space

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Risk Management

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Prior Knowledge

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PAT, RTRT,

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Modelling

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Continuous Process Verification

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Change Management (comparability) Protocols

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D. EU experience - overview ü A number of MAA and variation applications approved in the centralised procedure. Used in single / multiple process unit operations ü Several scientific advice requests (API, FP) ü Discussions with companies at QWP / PAT Group ü Experience relatively limited (particularly biotech) → establish dialogue with regulators e.g. via EMA PAT Group

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D. EU experience - examples ü Mainly tablets (wet, dry granulation, Direct Compression) ü API manufacture – DOE & Design Space (reaction conditions) ü PAT Tools: LIW, NIR, Raman, Light Scattering - Probe placement / robustness, redundancy

ü Continuous Validation ü Models / RTRT - NIR: ID / UDU, Dissolution

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E. Regulatory considerations and Scientific Challenges

A selection of Important factors

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E. Regulatory considerations and Scientific Challenges •

The definition of a batch should be stated prior to manufacture ICH Q7 (EU GMP Guide Part II)

Batch definition

“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”.

Raw Materials

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Process Description

Process Dynamics

Why it is important? It is linked to

Control -Control StrategyRelease Strategy-Validation Testing -Traceability (timestamping) -cGMP compliance, defects, recall, etc.

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Equipment

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EU legislation: 2001/83/EC

Process Changes

”units manufactured in a given period of time”

F. Models and CM applications

EU Regulators aligned with concept of High – Medium – Low Impact Models: Assessor training September 2018 Other risk factors considered e.g. Mechanistic v Empirical Model, statistical tools / robustness

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RTR Guideline Specifications

Specifications are required for Active Substance & Finished Product.

Specific tests: “Complies if tested� when RTR applied.

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

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Performance based approach – deliver consistent quality outputs Draft ICH Q12:

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Current EMA perspective for Continuous Manufacturing

G. Conclusions and recommendations §

Commercial implementation of CM is demonstrated. Regulators and industry gaining experience.

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Current regulatory framework is adequate to allow CM. No specific guideline currently available, but existing GL are supportive . ICH Q13 being developed.

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CM offers some advantages over batch manufacture. The process description, control strategy etc. may look significantly different. Additional considerations may need to be explored.

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EU regulators support the advancement of pharmaceutical technologies, including CM.

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Regulators need to understand the product and process development, manufacturing and process control strategy (and decision making). NOT all of the details - utilise Quality Overall Summary !

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Ensure early dialogue with regulators to ensure there is a mutual understanding.

Acknowledgements Dolores Hernan, EMA Quality Office EU PAT team

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Current EMA perspective for Continuous Manufacturing

Thank you Further information Contact: Peter.Richardson@ema.europa.eu Quality Office European Medicines Agency

30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

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