GMP Updates

Dearbhla Cullen, GMP Inspector

QP Forum

25 April 2017

Content

MRA between the EU and the US

Safety features

Annex 17 revision

Draft Q&A on setting health based limits for manufacture of medicines in shared facilities

Reflection paper on Good Manufacturing Practice and Marketing Authorisation Holders

Annex 1 revision

78th Meeting of Pharmaceutical Committee for Human Medicines

24/04/2017 2

MRA between EU and US

• Annex to the EU-US Mutual Recognition Agreement (MRA)

which was signed in 1998 but not yet implemented.

• All human and veterinary API and finished product medicines

with the exception of veterinary immunological medicines.

What

• Teams from the European Commission, EU national competent

authorities, EMA and the US FDA have been auditing and

assessing the respective supervisory systems since May 2014. How

• November 1, 2017

• Initially, 8 EU member states

• Gradually extend to other member states When

24/04/2017 3

Safety feature requirements

4

Commission Delegated Regulation (EU) 2016/161 sets out detailed requirements

for unique identifiers, including the repository system where they will be stored

New requirements will apply to in-scope medicines released to the EU market from

9th February 2019

Batch document review: Print quality ok? Reconciliation ok? Tamper evidence ok?

Production order serial number data set uploaded to company database?

Data upload to EU Hub upon QP certification of batch

Confirmation of data upload to EU / national Hub

Visit EMVO website https://www.emvo-medicines.eu/

Annex 17 – Real time release testing

Parametric

release

Advances in

PAT, QbD &

QRM

Process

control,

continuous

monitoring,

verification

24/04/2017 5

Annex 17 – Real time release

Public

consultation

phase

complete

Working

group

progressing

through

comments

Planned for

publication

in 2017

07-02-17 6

Q&A on implementation of risk based

prevention of cross contamination in production

24/04/2017 7

‘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)

Public consultation started in Jan 2017.

Deadline for comments is 30 April 2017.

Health based exposure limits (HBELs) for highly hazardous

products are expected to be completed in full as per the

EMA guide (EMA/CHMP/CVMP/SWP/169430/2012)

Reflection paper on Good Manufacturing

Practice and Marketing Authorisation Holders

• Lack of clarity on the responsibilities of MAHs Why

• Concept Paper EMA/582064/2016 published 01 September

2016 (public consultation ended Dec 2016).

• Reflection paper to be prepared by drafting group Q3 2017. What

• Review of the reflection paper at the GMP/GDP Inspectors

Working Group: May 2017.

• Agreement of the reflection paper: June 2017. When

24/04/2017 8

Annex 1 - Rationale for Revision

Needed “Tidying up”

Introducing principles of Quality Risk Management

New technologies:

• Reinforcing the need of manufacturers to keep up with current technologies

• Single use closed systems

• Disposable systems

• Innovative technologies

• Some ambiguities

Micro data averages

9

Annex 1 – what’s changing?

24/04/2017 10

Additional guidance in each of the sections to

incorporate QRM and new technologies, in addition

to general clarifications e.g. Airlocks for personnel

and materials should typically be separate

Personnel: requirement for personnel to wear

goggles in grade A/B.

Premises: Requirement to measure 5.0µm particles

has been removed.

Annex 1 - revision timelines

Public Consultation phase – Estimated – Q3 2017

IWG & PICs review – Feb 2017

Container closure integrity & Pre-use post sterilisation integrity

Comments received back

Two rounds of review - circulated to PIC/S and IWG Mid 2016 & November 2016

Subgroups – tasked with drafting various sections

Joint working group between PIC/S and EMA

07/02/2017 11

78th meeting of the Pharmaceutical Committee

for Human Medicines, 27 March 2017

In March 2017, the European Parliament adopted some

recommendations on shortages of medicines. the Commission and

Council are to establish a mechanism whereby medicine shortages

across the EU can be reported upon on an annual basis

Proposal to examine Article 81 of the pharmaceutical legislation

which is difficult to implement and enforce.

Agenda and documents at

https://ec.europa.eu/health/documents/pharmaceutical-

committee/human-meeting_en

24/04/2017 12

Thank you

Additional information

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

07-02-17 15

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

07-02-17 16

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 ?

07-02-17 17

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

07-02-17 18

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.

07-02-17 19

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

07-02-17 20

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_leadin

g_service=All&page=1

07-02-17 21

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

07-02-17 22

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

07-02-17 23