How the European Pharmacopoeia Provides the Framework to Implement QbD Principles Dr Emmanuelle Charton Deputy Head, European Pharmacopoeia Department, EDQM, Council of Europe
Structure of the Presentation Ph. Eur. General notices and flexibility QBD examples in the field of Chemicals QBD-like approaches in the field of Biologicals QBD and Public Standards
PH. EUR. GENERAL NOTICES & FLEXIBILITY
Flexibility in the Ph.Eur. -Alternative methods The Ph. tests Eur. tests and assays are reference described methods, are the essential official methods in cases upon of dispute. which the standards of the Pharmacopoeia are based. Compliance With the is required, agreement but of alternative the competent methods authority, may be alternative used as long methods as they of analysis lead to the may same be used pass/fail for control result. purposes, It is the provided responsibility that of the the methods user to used demonstrate enable an their unequivocal suitability. decision Approval to of be the made competent as to whether authority is compliance necessary with in many the standards cases. of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.
Flexibility in the Ph.Eur. Waiving of tests Compliance to the Ph. Eur. is a prerequisite Testing might be omitted based on Demonstration of compliance with the Pharmacopoeia (1) An article is not of Pharmacopoeia quality unless it complies with all the product requirements design stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite control for strategy a manufacturer in assessing compliance with the Pharmacopoeia process before validation release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process. As a consequence: Tests for process-specific impurities may be omitted if it is demonstrated that they will not occur with the particular process used. New (Suppl. 8.2.)
Flexibility in the Ph.Eur. PAT/RTR As a consequence of the publication of the EMA Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 The Ph. Eur. provides a framework for the use of PAT/RTR Demonstration of compliance with the Pharmacopoeia (2) An enhanced approach to quality control could utilise process analytical technology (PAT) and/or real-time release testing (including parametric release) strategies as alternatives to end-product testing alone. Real-time release testing in circumstances deemed appropriate by the competent authority is thus not precluded by the need to comply with the Pharmacopoeia. NEW (Suppl. 8.2.)
Flexibility in the Ph.Eur. Animal welfare Reference to the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes of the Council of Europe Demonstration of compliance with the Pharmacopoeia (3) All new. Reduction of animal testing: the European Pharmacopoeia is dedicated to phasing out the use of animals for test (1986) purposes, in accordance with the 3Rs (Replacement, Reduction, Refinement) set out in the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. In demonstrating compliance with the Pharmacopoeia as indicated above (1), manufacturers may consider establishing additional systems to monitor consistency of production. With the agreement of the competent authority, the choice of tests performed to assess compliance with the Pharmacopoeia when animal tests are prescribed is established in such a way that animal usage is minimised as much as possible Consistency of production Minimise the use of animals NEW (Suppl. 8.2.)
QBD EXAMPLES IN THE FIELD OF CHEMICALS
Excipients functionality testing EDQM International Symposium, Brussels, 4-5 April 2002 Separate section in excipient monographs: «Functionality related characteristics» (FRCs) Section is non-mandatory Tests are linked to use (lubricant, tablet compression, etc..) Section provides information on important parameters and may include test methods, limits, tolerance on label claim General Chapter 5.15: Functionality related charctaristics of excipients (Supplement 6.1, 04/2008). From quality to functionality Reference to ICH Q8 Knowledge of FRCs may facilitate the application of process analytical technology (PAT).
Process Analytical Technologies EDQM International Symposium, Cannes, 3-4 May 2004 Concurrent to Q8 finalisation Recognition of the dilemma faced by the European Pharmacopoeia: Provides legal requirement for the quality of medicinal products and their components: methodologies and acceptance criteria Provides flexibility, keeps pace with current thinkings and concepts, allows for the use of modern technologies
PAT Working Party (1/2) 2.9.47 Demonstration of Uniformity of Dosage Units Using Large Sample Sizes (New: Supplement 7.7, 04/2013) intended for, but not limited to the evaluation of medicinal products that are manufactured using PAT Designed as an alternative to demonstrate compliance with 2.9.40 Criteria described for large sample sizes 2.2.40 Near Infrared Spectroscopy (Revised: 8th edition, 01/22014) Revision to introduce PAT concepts published accommodates changes from bench-top to in/on-line measurements elaborated in parallel with the current revision of the EMA Guideline on the use of Near Infrared Spectroscopy (NIR) 2.2.37 X-Ray fluorescence spectrometry 2.2.48 Raman spectrometry Revisions to introduce PAT concepts in progress specification differences between bench-top an in-process instruments
PAT Working Party (2/2) Additional Ph.Eur. activities to enable implementation of QbD Development on an information chapter concerning Chemometric techniques applied to analytical data: Multivariate statistical methods Extract relevant information by data analysis Continuous reflection on the need for new texts: Chemical imaging Tera hertz spectroscopy Acoustics
QBD-LIKE APPROACHES IN THE FIELD OF BIOLOGICALS
0153 General provisions Consistency of production process: batches must be The production method for a given product must have comparable to batches of proven safety and efficacy been shown to yield consistently batches comparable with the batch of proven clinical efficacy, immunogenicity Omission and safety of in tests man. is Product possible specifications when consistency including is inprocess testing should be set. Specific requirements for demonstrated - production validation including in-process testing are included in - individual agreement monographs. by the competent Where justified authority and authorised, certain tests may be omitted where it can be demonstrated, for example by validation studies, that the production process consistently ensures compliance with the test. 14
0153 General provisions Consistency of production is an important feature of vaccine production. Monographs on vaccines for human use give limits for various tests carried out during production and on the final lot. These (during limits production may be in the or form on the of maximum final lot) values, are not minimum sufficient values, to ensure or minimum consistency and maximum of production tolerances around a given value. While compliance with these limits is required, it is not necessarily sufficient to ensure consistency of production for a given vaccine. For (statistical relevant tests, process the manufacturer control) must therefore define for each product a suitable action or release limit or limits to be applied in view of the results found for batches tested clinically and those used to demonstrate consistency of production. These limits may subsequently be refined on a statistical basis in light of production data. Consistency of production important feature Compliance to the Tests described in monographs The manufacturer must define suitable additional tools 15
Influenza vaccine (surface antigen, inactivated, prepared in cell cultures) (2149) Extraneous Acknowledgement agents of (2.6.16). time constraint The working seed lots comply with the requirements for seed lots. It is Alternative recognised to that 2.6.16 due is to possible a seasonal (e.g. change PCR) in one or more of the influenza vaccine strains, timely testing of a - risk assessment virus seed for extraneous agents according to general - chapter validation 2.6.16 may be problematic (e.g. duration of in - vivo agreement tests, timely by the competent availability authority of specific neutralising antisera). In agreement with the competent authority, and in light of a risk assessment, rapid assays (e.g. multiplex PCR) may be applied as alternatives to general chapter 2.6.16 following validation. 16
QBD AND PUBLIC STANDARDS
Acceptance criteria/specifications: Conventional specifications are needed! (see Q6A and Q6B) Correlation to be made between the prediction (RTR) and the conventional specifications. Conventional expression of specifications will always be needed for Product development Independent controls (OMCL) Stability studies Applicants that decide to apply the conventional approach
Acceptance criteria/specifications: Independent of the way they have been set - should not be evaluated in isolation but in connection with pharmaceutical development, process controls, involving risk management, within an appropriate quality system, but also based on batch results. Need to closely watch further developments, e.g. re. paradigm in setting specifications: predictability concept; need for additional specification Need for a tiered system, providing conventional specifications, but enabling the implementation of new approaches, e.g. PAT
QbD and Public Standards (Pharmacopoeias) Where is the problem? Public standards reflect quality, safety and efficacy. Industry has to comply with these specifications. Industry responsible how to comply and is free in their way how to comply. Similar philosophy: CEP procedure for APIs: assessed in relation to the monograph taking into account the manufacturing process.
Acknowledgements Dr. J.-L. Robert, Chair of Ph. Eur. Commission Dr. Susanne Keitel, Director of EDQM
Thank you very much for your attention!