European GMP/GDP Updates and the Real

Word

Ian Holloway
Senior GMDP Inspector
MHRA, UK
Toronto, March 2016
 Agenda

Recent and future updates to EU GMP and GDPs

New Annex 16 sample shipments, test and release
Risk assessment and mitigation for transportation
 Recent and future changes to EU regulations with
impact on cold-chain and transportation
Annex 15 Qualification and Validation in operation since 1 October
2015
Good distribution practice of active substances for medicinal
products for human use (2015/C 95/01). Effective 21 September
2015

Guidelines on the formalised risk assessment for ascertaining the

appropriate good manufacturing practice for excipients of medicinal
products for human use (2015/C 95/02) . Effective 21 March 2016
Annex 16 Certification by a Qualified Person and Batch Release -
coming into operation on 15 April 2016

Annex 21 Importation - at concept paper stage. Expected to cover

import activities which are not part of other GMP regulations
 Annex 15

A quality risk management approach shall be adopted

throughout the lifecycle of the product

Retrospective validation is no longer considered an

acceptable approach.

Data supporting qualification or validation obtained

from sources away from the manufacturer can be used
..subject to justification and controls
Annex 15
GDP for active substances
GDP for active substances
 GMP for excipients (2015/C 95/02)

Requirement to carry out a risk assessment for

excipients (in human medicines) by 21 March 2016.
To identify the risks presented to the quality, safety
and function of each excipient from its source
through to its incorporation in the finished dose
form
Needs to be done for each manufacturer if multiple
sources each needs their own evaluation
Should consider previous incidents of quality defects
Classify excipient as low, medium or high risk
 GMP for excipients (2015/C 95/02)

Risks to be considered relating to transportation

include:-
1. Environmental control, storage and transport
conditions and cold-chain management
2. Supply-chain complexity
3. Stability of excipients
4. Packaging integrity evidence

Additional consideration is to be given to known

quality defects and fraudulent adulterations both
globally and at a local company level related to the
excipient..
Annex 16
Annex 16
Annex 16
 Annex 16

Also a requirement for details of the entire supply chain to be available for
the QP:-
 Annex 21

Specific guidance for Importers

Deadline for comments on concept paper was

August 2015
Release of new annex draft for public consultation
January 2016 (not out yet.)
 Risk mitigation

Knowledge of transport route and potential failure points

Map the route with all key steps, handover points, timelines,
security risks, document exchange, decisions and
communications
Monitor the performance of the route against KPIs. Take
action for adverse trends
Be aware of cultural differences and monitor the local geo-
political situation
Consider using simulated failure exercises to see if your rescue
plans are valid.
 Risk mitigation

Knowledge of capabilities of participants

Detailed knowledge of their Quality Systems, Procedures,
Vehicles, Monitoring Systems
Comprehensive technical agreements in place
External audit and self-inspection programs in place
Is there a focus on blue-chip Pharma clients
Training programs are well documented and efficacy of
training is challenged
 Risk mitigation

Plan for breakdowns and failures

Contingency arrangements made
Procedures available for situations such as vehicle
breakdown, delays and equipment failure
Local fixers/contacts available to resolve problems
Clear 24/7 contact information available to report
and discuss issues
Human error will occur often no evidence will
remain
 Risk mitigation

2014 Statement from Q&As on GDP

http://ec.europa.eu/health/files/gdp/2014-04_qas_.pdf
 Risk mitigation

Knowledge of the product and pack

Use of a stability budget, mean kinetic temperature,
or any storage outside labelled conditions is not
normally acceptable.
Transportation stability information may still be
useful for science-based discussions with the
Regulator in the event of problems
 Risk mitigation

Data integrity
Applies to all records not just computers!
Audit trails used where possible?
Reliable recovery of data from archives
Suitable password control
Suitable user levels and privileges
Incomplete data
 Risk mitigation - ALCOA in Data Integrity

Attributable Who did it/Link to source data

Legible Can you read it? Permanent record
Contemporaneous Was it completed in real time?
Original An original or true copy?
Accurate No errors
can also add the following
Complete Includes repeats or re-analysis
Consistent Date/Time stamps in expected order
Enduring Controlled and lasting records
Available For the life of the record
 Risk mitigation

https://www.gov.uk/government/uploads/system/uploads/attachment_da
ta/file/412735/Data_integrity_definitions_and_guidance_v2.pdf
 Despite all your risk assessment and mitigation the
humans involved will still make errors
Everyone makes mistakes every day and many of these go undetected.
Task Demands
Time pressure, high workload, unclear goals and responsibilities
Work Environment
Confusing displays, interruptions, unusual situation
Individual Capabilities
Inexperience, fatigue, poor problem-solving ability
Human Nature
Complacency, mental biases, habit patterns, inaccurate risk perception

An international supply-chain is at high risk from human error

due to the number of players, different companies, language
barriers, time pressures, transport and weather variability
etc.
 Additional information sources verified 21 Feb 2016
Good Distribution Practice of active substances for medicinal products for human use
(2015/C 95/01). Effective 21 September 2015
http://eur-lex.europa.eu/legal-
content/EN/TXT/PDF/?uri=CELEX:52015XC0321(01)&from=EN

Annex 15 and Annex 16 all parts of EU GMP Guide

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

Guidelines on the formalised risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use (2015/C
95/02) . Effective 21 March 2016
http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52015XC0321(02)

Annex 21 Concept Paper

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/05/W
C500187398.pdf

EU GDP Guide
http://ec.europa.eu/health/human-use/good_distribution_practice/index_en.htm