Regulatory Update

Greg McGurk, GMP Manager (acting)

GMP Conference

7 February 2017

Dublin

GMP Update

Chapter 3 - Premises and Equipment (into operation since 1

March 2015)

Chapter 5 - Production (into operation since 1 March 2015)

Chapter 8 – Complaints, Quality Defects and Product Recall

(into operation since 1 March 2015)

Annex 1 – under revision

Annex 2 – Removal of References to ATMPs

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GMP Update

Annex 13 – Investigational Medicinal Products

Annex 15 (October 2015) – Qualification & Validation

Annex 17 – Real Time Release

Annex 21 – GMP for Importers of Medicinal

Products

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Revisions to Legislation and other relevant changes

• Clinical Trials Regulation – delegated acts / directives

related to GMP for IMP

• Risk assessment of excipients

• Safety Features

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Implementation of Chapters 3 & 5

Expectations for application of toxicological guidance

Applicable for all new products (H+V) introduced from 1st June 2015

Applicable for legacy human medicines from 1st December

2015 (including assessment of vet products where vet and

human medicines are manufactured in same facility)

Applicable for legacy veterinary medicines from 1st June 2016

(manufacturers where only veterinary medicines are involved)

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Implementation of Chapters 3 & 5 (continued)

- Programme in place to deal with existing products

- Risk based approach

- Toxicological basis to justify approach taken

- Select worst case products initially for tox evaluation

Cleaning validation is only one aspect to be considered for cross contamination

risk.

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Implementation of Toxicological Approach

Questions and answers on implementation of risk

based prevention of cross contamination in production

and ‘Guideline on setting health based exposure limits

for use in risk identification in the manufacture of

different medicinal products in shared facilities’

• EMA/CHMP/CVMP/SWP/169430/2012

• Consultation – deadline for comments April 2017

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Revision of Annex 1

Parallel session 1A

Revision of Annex 2

Remove references to ATMP

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Annex 15 revision

Effective since October 2015

Take account of changes to other sections of the EudraLex, Volume

4, Part I, relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11

QWP guidance on process validation

Changes in manufacturing technology

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Annex 15 revision

Traditional Process Validation

Concept - Continuous Process Verification

Hybrid approach

Verification of Transportation

Utilities

Packaging

Plenary session 4

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Annex 17 – Real time release testing

Parametric release – Real Time Release Testing

Advances in the application of process analytical technology (PAT)

Advances in the application of quality by design (QbD)

Advances in the application of quality risk management (QRM) principles

Combination of process controls, timely monitoring and verification of pre-established material

attributes provides greater assurance of product quality than finished product testing alone.

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Annex 17 – Real time release

Public

consultation

phase

complete

Working

group

progressing

through

comments

Planned for

publication

in 2017

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Annex 21 – Importation of Medicinal Products

Concept paper & Draft developed

GMDP IWG review phase

Consideration for Definitions

• site for batch certification

• site for importation testing

• site of physical importation

Aspects of importation process

When is a product deemed to have been imported ?

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ATMPs --New GMP Guidance

ATMP Regulation, (EC) No 1394/2007, provides for development of GMP guidance for these

products.

Summary of feedback on consultation document published on EU Commission website along

with details of the output from public consultation phase

Intent of the document is to recognise that manufacture of ATMPs and ATIMPs is different to

other products, (e.g. variable starting materials, small batches, short shelf life).

Synopsises – derogation from existing GMP guidance with some additional changes particularly

for early stage development. Some cross reference to existing GMPs

Applicable to Investigational and Commercial ATMPs

Working group involving GMP inspectors and members of CAT

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GMP for Investigational Medicinal Products

Clinical Trials Regulation No. 536/2014

New Clinical Trials Regulation - Repeals Directive 2001/20/EC

Published 16th April 2014 (effective 2018)

Article 63 – GMP for Manufacture and Import

New GMP Guidance for Manufacture / Importation of IMPs issued for consultation from 28th

August 2015 to 24th November 2015.

Feedback from public consultation now published on the EU Commission website.

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New GMP Guidance for IMPs

Commission Delegated Regulation on GMP for IMPs issued on

13th January 2017 – deadline for comment 10th February 2017

Based largely on Directive 2003/94/EC (GMP Directive)

Cross references to sections of the GMP Guide are included in

the new guidance.

Annex 13 to be deleted from the GMP Guide and some

changes from current requirements

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New GMP Guidance for Human Medicinal Products

Commission Implementing Directive on GMP for Human Medicinal Products

To replace existing Directive 2003/94/EC (GMP Directive)

Feedback Period 13th January 2017 – 10th February 2017

Commission better regulation portal

https://ec.europa.eu/info/law/better-

regulation/initiatives_en?field_brp_inve_resource_type=All&field_brp_inve_leading_service=All&page=1

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Excipients – Risk Assessment

Guidelines for Risk Assessment for ascertaining appropriate GMP for Excipients for

Human Medicines

Published 19th March 2015

Excipient risk assessment to have been completed for authorised medicinal

products by 21st March 2016

Principles of ICH Q9

Considerations: Source; Use of the excipient

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Excipients – Risk Assessment

Identify relevant parts of Eudralex Vol IV which would be applicable based on the risk

assessment

Determine risk profile for the excipient manufacturer

Confirmation of application of appropriate GMP in manufacture of the excipient

Parallel session 1B

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Safety Features

Unique Identifier (2D Barcode)

Harmonised EU format including: Product Code, Serialisation Number, National Reimbursement

No (if applicable), batch number & Expiry Date

Repository set up by stakeholders (supervision by CAs)

Verification at Pharmacy Level

Checks at Wholesale level based on risk

Anti Tampering Device

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Delegated Regulation on Safety Features

Delegated Regulation (2016/161) published 9th Feb 2016 and

mandatory implementation by 9th Feb 2019

New challenges for packaging of prescription products

Interactions with Stakeholders in Ireland

HPRA has written to stakeholders

HPRA hosted workshops in Athlone, Cork and Dublin

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Delegated Regulation on Safety Features

• Will start asking about on-site plans for implementation of

requirements for safety features

• Manufacturer’s status regarding implementation of

requirements will be documented in the inspection report

as a Point to Note

• Controls and procedures for safety features to be reviewed

in detail after implementation

• Parallel Session 2B

Inspections:

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Thank you