Global Regulatory

Framework

Presented by Pharmacist
Wefak Mohamed Abd-Elmoneim
GMP, QA and Technical Training Consultant
 Milestones in Europe Drug Law
History

Agenda
Milestones in Europe Drug Law History
The PIC/S GMP Guide
EU Legislation - Eudralex
PIC/S GMP Guide
GMP References
The relevant links to regulatory agencies

15 April 2018 2
 Milestones in Europe Drug Law
History
1518: Royal Charter by Henry VIII to
found Royal College of Physicians:
Appointed inspectors for medical
practitioners and apothecaries in
London.
Destroyed defective stock.
Act of Parliament in 1523 extending
this charter to rest of England
15 April 2018 3
 Milestones in Europe Drug Law
History (cont.)

1618: first editions of the London

Pharmacopoeia
1864: First edition of the British
Pharmacopoeia
1875 Food and Drugs Act
1925 Therapeutic Substances Act

15 April 2018 4
 Milestones in Europe Drug Law
History (cont.)
1925 Therapeutic Substances Act
“control the regulation of the
manufacture, sale, and the importation
of vaccines, sera, and other
therapeutic substances … &
substances of which the purity or
potency cannot be adequately tested
by chemical means”.
15 April 2018 5
 Milestones in Europe Drug Law
History (cont.)
1957: Thalidomide tragedy
1964: Voluntary licensing system
1968: 1968 – The Medicines Act (UK) (an Act
of Parliament) governs the manufacture and
supply of medicines.
It introduced system for:
- product licensing covering old (pre 1968)
and new medicines;
- licensing of manufacturing sites;
- licensing of clinical trials 6
15 April 2018
-The Medicines Act Still in force today…..
 Milestones in Europe Drug Law
History (cont.)
1965 the first directive for GMP
(65/65/EEC) – European legislation:
Each Directive has to be
•Transposed into national laws for each
Member State (MS)
•Implemented directly by each MS who;
- Conduct their own licensing,
inspection and enforcement
- Issue national licenses
15 April 2018 7
 Milestones in Europe Drug Law
History (cont.)

OECD (Organization for the Economic

Co-operation and Development) set up in
late 1970’s
• Global definition of GLP
• To reduce the amount of testing – set up
the “MAD” agreement! (Mutual
Acceptance of Data)

15 April 2018 8
 Milestones in Europe Drug Law
History (cont.)
GMP: 1972
Davenport disaster
•Intravenous fluids were contaminated
& killed 6 people.
•Prompted GMP regulations
Often as a result of a disaster…not just
in the medical world!!!

15 April 2018 9
 Milestones in Europe Drug Law
History (cont.)
GLP Regulations and Guidelines
Organisation for the Economic Co-operation
and Development ( OECD ) Principles of GLP
(as revised in 1997) and Inspection
and Verification procedures
Adopted by European Commission in
2004/9/EC and
2004/10/EC
SI No. 3106 (as amended by SI No. 994)
Implemented above directives within the UK
10
Guide to UK GLP Regulations (blue book!)
15 April 2018
European Regulatory Structure
Treaties Signed by all Member States.

Directives‫توجيهات‬ Defines objectives to be achieved.

Member States have to define
compliance in their own law
Regulations Directly applicable to all Member
States.
Decisions Applicable to a specific case, person,
organization…
Opinions Does not need to be enforced, but
MSs can use them to support national
law
15 April 2018 11
 EMA
1. Manufacturing Authorisations(v1) 2007
2. GMP Certificates(v1) 2007
3. GMP non-compliance(v2) 2009 Search capabilities
4. Inspection plans in 3rd Alert on event capabilities
countries
5. Information on Links to other
“faulty Manufacture” Community
Wholesale distributors, API databases e.g.
manufacturers (v4) 2013 live Eudra CT a
database of all
Clinical Trials

Eudra GMP Database

15 April 2018 12
 The PIC/S GMP Guide
Pharmaceutical Inspection Co-operation
Scheme (PIC/S)
History
• PIC : Pharmaceutical Inspection Convention
• PIC Scheme : Pharmaceutical Inspection
Cooperation Scheme
• Both operate in parallel under the
logo/abbreviation

15-Apr-18 13
 The PIC/S GMP Guide
History
PIC = Pharmaceutical Inspection
Convention
• Founded by The European Free Trade
Association (EFTA) in October 1970
• PIC is a legal Treaty between countries
• Initially only 10 member countries:
Austria, Denmark, Finland, Iceland,
Liechtenstein, Norway, Portugal, Sweden,
Switzerland and UK.
15-Apr-18 14
46 PIC/S Members (as of 1
July 2014) • EUROPEAN UNION Member
10 PIC/S Applicants & Pre-Applicants States Agencies (29)
Iceland
Canada Norway
Switzerland Liechtenstein
USA Ukraine

Israel
Malaysia

Singapore

Australia
4 Partners
EDQM
European Directorate for the
EMA Quality of Medicines (EDQM)
UNICEF Argentina South Africa
WHO
EUROPEAN UNION Member States
Agencies (29)
1) AUSTRIA 10)GREECE 20)POLAND
2) BELGIUM 11)HUNGARY 21) PORTUGAL
3) CZECH REP. 12) ICELAND 22) ROMANIA
(Human & 13)IRELAND
Vet) 23)SLOVAK
14)ITALY REPUBLIC
4) CYPRUS
15) LATVIA 24) SLOVENIA
5) DENMARK
16) 25)SPAIN
6) ESTONIA LIECHTENST 26)SWEDEN
7) FINLAND EIN
27) SWITZERLAND
8) FRANCE 17)LITHUANIA
(Human & 28)UKRAINE
18)MALTA
Vet) 29)UNITED
19)NETHERLAN KINGDOM
9) GERMANY DS (Human & Vet)
 PIC versus PIC/S

PIC PIC/S
Convention ‫اتفاقية‬ Scheme ‫مخطط‬
Between countries Between agencies
A formal treaty An informal
Has legal status arrangement
Focus on inspection Has no legal status
Mutual recognition of Focus on training &
inspections Developing guidelines
Exchange of
15 April 2018 information 17
 Original Goals

• Harmonised GMP requirements

• Mutual recognition of inspections
• Uniform inspection systems
• Training of Inspectors
• Mutual confidence

15-Apr-18 18
Reason for creating the PIC Scheme
• After 1993, no new members of PIC possible
• Reasons: Under EU law, only European
Commission authorized to sign agreements
with other countries
• Expansion of PIC not possible unless
European Commission became a member of
PIC
• Amendment of Convention difficult & lengthy
• Inspectorates (& industry) favored
maintaining the principles of PIC
15-Apr-18 19
 Main features of PIC Scheme
 Commenced ‫بدأت‬operating on 2 Nov. 1995
 An informal arrangement between Agencies
 Networking and confidence building
 Exchange of information and experience on GMP
 Development of Quality Systems for
Inspectorates
 Training of inspectors
 International harmonization of GMP
 No obligation to accept inspection reports
 PIC & PIC/S operate in parallel - jointly referred
15-Apr-18 to as “PIC/S” 20
 The PIC/S GMP Guide

PIC/S Goal
“To lead the international
development, implementation and
maintenance of harmonized GMP
standards and quality systems of
inspectorates in the field of
medicinal products”.
15-Apr-18 21
 Achievement of PIC/S Goal
PIC/S Goal to be achieved by:
Developing and promoting harmonized
GMP standards and guidance documents.
Training competent authorities, in
particular GMP inspectors.
Assessing (and reassessing) GMP
Inspectorates.
Facilitating the co-operation and
networking for competent authorities and
international organizations.
15-Apr-18 22
 Benefits of PIC/S Membership

1. Accession forces improvements – Discipline, SOPs.

2. Cost savings – more effective use of ressources.
3. Inspector training (Seminars, Joint, coached
inspections).
4. Internationally harmonised GMP & GDP
inspections.
5. Maintaining a consistently high standard of
inspections.
6. Developping international GMPs & GDPs.
7. Sharing of information & experiences.
8. Networking & personal contacts. 23
 Benefits of PIC/S Membership

1. Reduced duplication of inspections (cost

savings).
2. Export facilitation (including to non-PIC/S
countries).
3. Enhanced market access.
4. Reputation of industry enhanced.
5. Transparent inspection standards.
6. Consistency of inspections.
7. Reliable quality of medicines available locally &
internationally. 24
 Applicants being
assessed for PIC/S membership

The GMP Regulatory Authorities of:

Brazil / ANVISA
Hong-Kong SAR / PPBHK
Iran / MoH
Philippines / PFDA
Thailand / Thai FDA
Turkey / TMMDA

15 April 2018 25
 Applicants for Pre-Accession

Armenia / SCDMTE
Belarus / MoH
Chile / ISP
Kazakhstan / CCMPA
Mexico / COFEPRIS

15 April 2018 26
 Agencies showing interest
in joining PIC/S
China / CFDA
Croatia / HALMED
Nigeria / NAFDAC
Russia / Roszdravnadzor
Saudi Arabia / SFDA
Thailand / Thai FDA
Zimbabwe / MCAZ
15 April 2018 27
 Accession+ Pre-accession
procedure
Useful Documents
1) Pharmaceutical Inspection Cooperation Scheme
(PIC/S 1/95)
2) Guidelines for Accession to PIC/S (PS/W
14/2011)
3) Questionnaire for Competent Authorities (PS/W
1/2011)
4) Audit Checklist (PS/W 1/2005)
5) Recommendations on quality system
requirements for pharmaceutical inspectorates
15 April(PI
2018 002) 28
 PIC/S GMP Guide
Virtually identical to EC GMP Guide (main
difference = “Qualified Person” vs. “authorized
person”)
1) Basic GMP Guide (Part I)
2) GMP Guide for APIs (Part II)
3) Plus Annexes, covering:
Sterile Medicinal Products
Sampling of Starting Materials & Packaging
Materials
Pressurised Metered Dose Aerosols
Liquids, Creams & Ointments
15 April 2018 Computerised Systems 29
 PIC/S GMP Guide (2)
Plus Annexes, covering:
Biologicals
Herbals
Medicinal gases
Use of Ionising Radiation
Investigational Medicinal Products
Products Derived from Human Blood &
Plasma
Qualification and Validation
Parametric release
15 April 2018
Reference and Retention Samples 30
Useful PIC/S : Aide Memoires
Aide Memoires
Whilst PIC/S Aide Memoires are written for GMP
inspectors, they can be very useful for a company’s
internal audits.
1) GMP INSPECTION RELATED TO PACKAGING
PI 028-1 13 January 2009
2) INSPECTION OF ACTIVE PHARMACEUTICAL
INGREDIENTS
PI 030-1 13 January 2009
3) INSPECTION OF UTILITIES
PI 009-3 25 September 2007
4) GMP PARTICULARITIES IN THE MANUFACTURE OF
MEDICINAL PRODUCTS
TO BE USED IN CLINICAL TRIALS ON HUMAN SUBJECTS
15 April 2018
PI 021-2 25 September 2007 31
Useful PIC/S : Aide Memoires (cont.)
5) INSPECTION OF PHARMACEUTICAL QUALITY CONTROL
Aide Memoires LABORATORIES
PI 023–2 25 September 2007

6) INSPECTION OF BIOTECHNOLOGY MANUFACTURES

PI 024-2 25 September 2007

7) INSPECTION OF MEDICINAL GASES

PI 025-2 25 September 2007

8) ASSESSMENT OF QUALITY RISK MANAGEMENT

IMPLEMENTATION
PI 038-1 26 March 2012
15 April 2018 32
Useful PIC/S : Guidance Documents
Aide Memoires
Validation (Master Plan, IQ, OQ, Process &
Cleaning) Sept’07
Site Master File Preparation (Explanatory Notes)
PE 008-4 1 Annex 1 January 2011

Recommendations on Sterility Testing

Sept’07
Isolators for Aseptic Processing and Sterility
Testing Sept’07

Validation of Aseptic Processing

January 2011
15 April 2018 33
 KEY GMP DRIVERS
1. United States
2. Canada
3. European Union
4. Pharmaceutical Inspection Convention /Scheme
EU +
Australia,
Canada,
Malaysia,
Switzerland,
Singapore,
South Africa

15 April 2018 34
 Drug GMPs World-wide
1) Codes Directives Guidelines Industry
practices world-wide voluntary
2) Regulations world-wide compulsory
Example
 WHO
 EU
 United states
 Australia
 Japan
 Canada
15 April 2018 35
 GOOD PRACTICES

GCP GVP GLP GSP

GAMP GXP GQCP

GMP GIP GAP GDP

15 April 2018 36
 EU Legislation -
Eudralex

15 April 2018 37
 GMP – structure

EU Legislation - Eudralex
The body of European Union legislation in the
pharmaceutical sector is compiled in Volume 1 and Volume
5 of the publication "The rules governing medicinal products
in the European Union“:
Volume 1 - EU pharmaceutical legislation for medicinal
products for human use
Volume 5 - EU pharmaceutical legislation for medicinal
products for veterinary use
The basic legislation is supported by a series of guidelines
that are also published in the following volumes of "The
rules governing medicinal products in the European Union":
Volume 2 - Notice to applicants and regulatory guidelines for
medicinal products for human use
Volume 3 - Scientific guidelines for medicinal products for
human use
 GMP – structure (cont.)
EU Legislation – Eudralex
Volume 4 - Guidelines for good manufacturing
practices for medicinal products for human and
veterinary use
Volume 6 - Notice to applicants and regulatory
guidelines for medicinal products for veterinary use
Volume 7 - Scientific guidelines for medicinal products
for veterinary use
Volume 8 - Maximum residue limits
Volume 9 - Guidelines for pharmacovigilance for
medicinal products for human and veterinary use
Volume 10 - Guidelines for clinical trial
Medicinal products for paediatric use, orphan, herbal
medicinal products and advanced therapies are
governed by specific rules.
 GMP – structure (cont.)

• Part I - Basic Requirements for

Medicinal Products
Chapter 1 - Quality Management
Chapter 2 - Personnel
Chapter 3 - Premise and Equipment
Chapter 4 - Documentation
Chapter 5 - Production
Chapter 6 - Quality Control
2011: new structure Chapter 7 - Contract Manufacture and
(three parts) Analysis
Chapter 8 - Complaints and Product
Recall
Chapter 9 - Self Inspection
 GMP – structure (cont.)

• Part II - Basic Requirements for

Active Substances used as
Starting Materials

• Note: GMP part II is the former

annex 18 on API manufacture.
2011: new structure
(three parts)
 GMP – structure (cont.)

• Part III - GMP related

documents
Site Master File
Q9 Quality Risk Management
Q10 Note for Guidance on
2011: new structure
Pharmaceutical Quality System
(three parts) Mutual Recognition Agreements,
(MRA) Batch Certificate
• Annexes
• Glossary
 GMP – structure (cont.)
• Annex 1 Manufacture of Sterile Medicinal
Products
• Annex 2 Manufacture of Biological Medicinal
Products for Human Use
• Annex 3 Manufacture of
Radiopharmaceuticals
• Annex 4 Manufacture of Veterinary Medicinal
Products other than Immunological
Veterinary Medicinal Products
• Annex 5 Manufacture of Immunological
Veterinary Medicinal Products
2011: new
structure
• Annex 6 Manufacture of Medicinal Gases
(18 annexes) • Annex 7 Manufacture of Herbal Medicinal
Products
• Annex 8 Sampling of Starting and Packaging
Materials
• Annex 9 Manufacture of Liquids, Creams and
Ointments
 GMP – structure (cont.)

• Annex 10 Manufacture of Pressurised

Metered Dose Aerosol Preparations for
Inhalation
• Annex 11 Computerised Systems (revision
January 2011)
• Annex 12 Use of Ionising Radiation in the
Manufacture of Medicinal Products
• Annex 13 Manufacture of Investigational
Medicinal Products
2011: new structure
• Annex 14 Manufacture of Products derived
(18 annexes)
from Human Blood or Human Plasma
• Annex 15 Qualification and validation
• Annex 16 Certification by a Qualified person
and Batch Release
• Annex 17 Parametric Release
• Annex 19 Reference and Retention Samples
 Current Differences in Content
of EU & PIC/S GMP Guides

PIC/S GMP Guide (1 Jan.2013) EU GMP Guide (Feb’11)

Part I Basic Requirements for Med. Part I Basic Requirements for Med.
Products Products
Part II Part II
Basic Requirements for APIs Basic Requirements for APIs
No Part III Part III
Site Master File
Q9 - Quality Risk Management
Q10 - Pharmaceutical Quality
Systems
MRA Batch Certificate

Annexes : 1-20 QRM Annexes : 1-19

45

15 April 2018
 PIC/S GMP Guide
• PIC/S GMP Guide to GMP for Medicinal
Products (PIC/S document PE 009-12, 1
October 2015 ).
 Since not all Participating Authorities
under the PIC Scheme are parties to the
European Pharmacopoeia Convention, the
mention of “European Pharmacopoeia”
in the Guide has been amended to read
“European or other relevant
Pharmacopoeia”.
15 April 2018 46
 There are some difference as mentioned
below

PIC/S + EUROPE :main difference = “Qualified

Person” vs “authorised person”.
AUSTRALIA : building must be air-conditioned
FRANCE: pharmacists must be employed in
production areas and in laboratories (1 for 7 staff)
INDIA: Production and laboratory supervisors must
be pharmacists
Production and laboratory supervisors must GMP
Examination

15 April 2018 47
 The Australian Therapeutic
Goods Administration (TGA

• Australia has Codes of GMP and Quality

System requirements for
 the manufacture of medicinal products,
sunscreen products,
human blood and tissues,
 active pharmaceutical ingredients (APIs)
and medical devices.

15 April 2018 48
 The Australian Therapeutic Goods
Administration (TGA
• Each Code/Quality System sets out
requirements relating to
1) quality management,
2)personnel,
3)premises and equipment,
4)documentation,
5)production,
6)quality control,
7)contract manufacture and analysis,
8)complaints and product recall
49
15 April 2018
9) and self inspection.
 The Australian Therapeutic
Goods Administration (TGA

• The observance of these requirements is

necessary through all stages of
manufacture to consistently provide a
high level of assurance of
 the quality,
safety,
efficacy of therapeutic goods.

15 April 2018 50
 The Australian Therapeutic
Goods Administration (TGA

• The current Code of GMP for medicinal

products adopts the international
standard entitled Guide to Good
Manufacturing Practices for Medicinal
Products Annexes,
PE 009-12 (Annexes) 1 October 2015,
published by the Pharmaceutical
Inspection Cooperation Scheme (PIC/S).

15 April 2018 51
 Canadian GMP

GMP Categories
1. Sale C.02.003
2. Premises C.02.004
3. Equipment C.02.005
4. Personnel C.02.006
5. Sanitation C.02.007 - .008
6. Raw Material Testing C.02.009 - .010
7. Manufacturing Control C.02.011
 GMP Categories
8. Quality Control Department C.02.013 -
C.02.015
9. Packaging Material TestingC.02.016 -
C.02.017
10.Finished Product TestingC.02.018-C.02.019
11.Records C.02.020 - C.02.024
12.Samples C.02.025 - C.02.026
13.Stability C.02.027 - C.02.028
14.Sterile Products C.02.029
15.Medical Gases C.02.030
 GMP – definition
Maintaining GMP is everyone’s responsible (Regulatory
Authorities & manufacturers).
Maintaining GMP is a continuous (cyclic) process:
Doing now what patients
need next
 GMP References
World Health Organization
www.who.int/medicines/organization/qsm
/activities/qualityassurance
Australia
www.tga.gov.au/docs/html/gmpcodau.htm
Canada
www.hc-
sc.gc.ca/hpfbdgpsa/inspectorate/gmp_e.h
tml
15 April 2018 56
 GMP References (cont.)
European Union
pharmacos.eudra.org/F2/eudralex/vol-
4/home.htm
Japan
www.yakuji.co.jp/e/publications/index.html
United States of America
www.accessdata.fda.gov/scripts/cdrh/cfdo
cs/cfcfr/ cfrsearch.cfm

Web site: www.picscheme.org

15 April 2018 57
 The relevant links to regulatory
agencies.
USA Food and Drug Association (FDA)
www.fda.gov

Europe European Union Drug Regulatory Agency (Eudra)

dg3.eudra.org

EMEA
www.emea.europa.eu

Heads of Agencies for the European Union

heads.medagencies.org

UK Medicines and Healthcare products Regulatory

Agency (MHRA)
15 April 2018 58
www.mhra.gov.uk
 The relevant links to regulatory agencies.

Germany BfArM
heads.medagencies.org/germany.html

Portugal Instituto Nacional da Farmácia e do Medicamento

www.infarmed.pt/index2.html

France French Health Products Safety Agency

agmed.sante.gouv.fr

Spain Agencia Española del Medicamento

www.msc.es/agemed

Belgium http://www.afigp.fgov.be/

Norway Norway Medicines Board

www.legemiddelverket.no
15 April 2018 59
 The relevant links to regulatory
agencies.
Sweden Medical Products Agency
www.mpa.se/eng/index.shtml

Finland National Agency for Medicines

www.nam.fi/english/index.html

Italy Ministero della Salute

www.ministerosalute.it/medicinali

Netherlands CBG
www.cbg-meb.nl

Australia Therapeutic Goods Administration (TGA)

15 April 2018 www.tga.gov.au 60
 The relevant links to regulatory agencies

Bulgaria Bulgarian Drug Agency

www.bda.bg/web_engl/main.htm

Canada Therapeutic Products Directorate (TPD)

www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng

Chile Chile Regulatory Agency

www.minsal.cl

Russia Czech Republic

www.sukl.cz/enindex.htm

Denmark The Danish Medicines Agency

www.laegemiddelstyrelsen.dk/index_en.htm
15 April 2018 61
 The relevant links to regulatory agencies

Estonia State Agency of Medicines

www.sam.ee

Greece EOD
www.eof.gr

Hong Hong Kong Department of Health Welfare and Food

Kong www.fwfb.gov.hk/eindex.html

India Ministry of health and family welfare

mohfw.nic.in

15 April 2018 62
 The relevant links to regulatory agencies

Ireland Irish Medicine Board

www.imb.ie

Japan Ministry of Health, Labour and Welfare (MHLW)

www.mhlw.go.jp/english

Russia Ministry of Health of the Russian Federation

www.minsalud.gov.com

Switzerland Swiss Medic

www.swissmedic.ch

15 April 2018 63
 The Goal

Keep the company in business!

Keep your job!
Keep your boss out of jail!
Keep your family and neighbors safe
with good products because we are
the consumer!
Sunday, April 15, 2018 64
 REFERENCES
1- ISPE International GMP Trends By
Bob Tribe Canberra, Australia
2- REVISION OF EUDRALEX VOL. 4 – GMP By Luisa Stoppa, Ph.D.
Inspection and Certification Department Italian Medicines Agency
Swedish Academy of Pharmaceutical Sciences SAPS
Stockholm, November 8th, 2011
3- 21 CFR Parts 211& 820 US Guidelines.
4- PE 009-10 (Part I)& PE 009-10 (Part II) 1 January 2013
5- Global Drug Development International Collaboration: Overview: PIC/S June 23, 23,
2014 By CARMELO ROSA, M.S., Psy.D. Director, Division International Drug Quality
Organisation: US FDA, CDER-OC,OMPQ
6- GMPs for the 21st Century
By Michael H. Anisfeld Globepharm Consulting

7- Significant Dates in U.S. Food and Drug Law History

8- Regulatory World by Mary Baynes Inspector January 2008

9-Good Manufacturing Practice Trends – Industry side of view in European Union and in
Pharmaceutical Inspections Cooperation Scheme (PIC/S) by Dr.Vee Revithi
ROCHE, PTQG – External Relations Europe August 2014
 ‫شكرا على حسن االستماع‬

Thank
You

Sunday, April 15, 2018 66