how the european pharmacopoeia provides the framework to ... · the european pharmacopoeia provides...

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

E. Charton, CMC Strategy Forum, 6 May 2014 ©2014 EDQM, Council of Europe. All rights reserved.

PH. EUR. GENERAL NOTICES & FLEXIBILITY


Flexibility in the Ph.Eur. -Alternative methods

“The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards 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.”

Ph. Eur. tests are reference methods, essential in cases of dispute.

Compliance is required, but alternative methods may be used as long as they lead to the same pass/fail result.

It is the responsibility of the user to demonstrate their suitability. Approval of the competent authority is necessary in many cases.


Flexibility in the Ph.Eur. – Waiving of tests

“Demonstration of compliance with the Pharmacopoeia (1) An article is not of Pharmacopoeia quality unless it complies with

all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before 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.”

New (Suppl. 8.2.)

Compliance to the Ph. Eur. is a prerequisite Testing might be omitted based on product design control strategy process validation

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.


Flexibility in the Ph.Eur. – 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.)

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


Flexibility in the Ph.Eur. – Animal welfare

“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 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”

NEW (Suppl. 8.2.)

Reference to the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes of the Council of Europe (1986)

Consistency of production Minimise the use of animals


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

The production method for a given product must have been shown to yield consistently batches comparable with the batch of proven clinical efficacy, immunogenicity and safety in man. Product specifications including in-process testing should be set. Specific requirements for production including in-process testing are included in individual monographs. Where justified 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.

Consistency of production process: batches must be comparable to batches of proven safety and efficacy

Omission of tests is possible when consistency is demonstrated

- validation

- agreement by the competent authority

14 E. Charton, CMC Strategy Forum, 6 May 2014 ©2014 EDQM, Council of Europe. All rights reserved.

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 limits may be in the form of maximum values, minimum values, or minimum and maximum 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 relevant tests, the manufacturer 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 (during production or on the final lot) are not sufficient to ensure consistency of production

The manufacturer must define suitable additional tools (statistical process control)


Influenza vaccine (surface antigen, inactivated, prepared in cell cultures) (2149)

Extraneous agents (2.6.16). The working seed lots comply with the requirements for seed lots. It is recognised that due to a seasonal change in one or more of the influenza vaccine strains, timely testing of a virus seed for extraneous agents according to general chapter 2.6.16 may be problematic (e.g. duration of in vivo tests, timely availability 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.

Acknowledgement of time constraint

Alternative to 2.6.16 is possible (e.g. PCR)

- risk assessment

- validation

- agreement by the competent authority


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!


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