The document discusses GMP compliance for clinical trial manufacturing on a global scale. It notes that while ICH guidelines provide standards, approaches to compliance vary significantly between countries depending on factors like a nation's development level. Oversight and enforcement are also inconsistent internationally. For clinical trials, understanding both local regulations and real-world enforcement is important when manufacturing, packaging, or distributing investigational products worldwide.

1. GMP Manufacturing for
Worldwide Clinical Trials
Richard Soltero, Ph.D.
Founder
InstantGMP
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations

2. Discussions
 Flow of GMP Manufacturing processes
 Approaches to GMP compliance
throughout the world
 Impact on clinical trial supplies
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3. ICH Q7A Good Manufacturing
Practice
 International Conference on
Harmonization
 ICH Member Countries –
 European Union (EU) - 27 countries
 Japan
 United States
 Australia
 Canada
 Norway
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4. Basic of GMPs according to ICH
 Instructions and procedures are clear and
unambiguous
 Manufacturing processes are clearly defined and
controlled
 Facilities designed to minimize cross-
contamination and mix-ups
 Operators are trained
 Records demonstrate that all required steps
were taken
 Distribution minimizes any risk
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5. Different approaches to GMPs
compliance depending on country
 There is a global disequilibrium – quality
and compliance are different
 A nation’s relative development dictates
the level of compliance they can afford
 ICH signatories have the best quality
 BRIC nations generally are struggling with
the cost of compliance, even while they
recognize the value for international
commerce
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6. GMP starts with the Quality System
Structure
First step of compliance is
the quality system
structure
Next is facility design that
prevents cross
contamination and mix-
ups
Then control of materials
Finally documentation of
manufacturing
information
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7. Manufacturing Facility
 Facility and flow designed to minimize
potential contamination and mix-ups
 Defined areas for:
 Receipt
 Quarantine
 Storage
 Production
 Packaging
 Washing
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8. Small Scale
CTM Manufacturing Facility
Material flow
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9. GMP Facility Inspections
 FDA conducts facility inspections for
products to be sold in the US
 Doesn’t include CTM facilities
 Doesn’t include clinical stage products
 UK and EU use UK’s “Orange Guide” to
check compliance
 China, Japan, India et al rely on local
inspectors
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10. Typical GMP Facilities in US and UK
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11. GMP in India
Pharma companies in
India don’t pay taxes for
their first ten years
They don’t go through
complex certification
procedures
Over 20,000 pharma
companies in India
Only 100 have been FDA
inspected
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12. GMP Facilities in India
Schedule M regulations were harmful to the small
players in the pharmaceutical industry
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13. GMP Facilities in India
So the government is
cutting them some slack
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14. Materials
Only QA approved materials can be used
in CTM manufacturing
Excipients Containers/Closures
Components
Work in Process
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15. Getting ready for manufacturing –
Control of Materials
API, excipients Assign Part #s,
and components tests, methods,
identified Specs
PM Initiates Vendors Specs
Yes Yes
Project Qualified? Approved?
Quality Quality
No Manager Manager
Project
Vendor Project
Manager Select Personnel
Qualification Definition
and Roles
Completed
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16. GMP in Russia
 90% of materials used in Russia are from unknown
origins
 Only one out of every five drugs purchased in
Russia is produced domestically
 19 of the top 20 producers of drugs sold in Russia
are foreign owned
 Only 50 of Russia’s 528 drug factories meet
international GMP standards
 Before 1991 the state was the only
supplier, customer and authority to create
standards
 Compliance to plan was more important than
compliance with GMP standards
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17. GMP in Russia
 In 2004 the EU GMP Guideline was approved as
Russian national standard GOST R 52249-2004
 National standards are not mandatory
documents according to Russian Law
 There are multiple challenges to meeting GMP
in Russia including bureaucracy and corruption
 Pharma 2020 is the government's intended fix
 $6 billion in industry-wide investment in training and
infrastructure development, GMP practice
development and R&D
 In the meantime, producing or distributing CTM
through CMOs in Russia carries some risk
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18. Vendors
QA shall qualify vendors for materials
used in CTM
 Phase 1 CTM
 Paper based quality survey
 Phase 2 CTM
 Either a paper based quality survey or an on-site audit
 Phase 3 CTM
 On-site audit
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19. Specifications
QA shall approve specifications of
materials and components
 Test - A measurement of a quality attribute such as
potency or water content
 Method - The procedure by which the quality
attribute is measured
 Limit - The acceptable range for the attribute
 Other Requirements
 Sampling Instructions
 Safety and Handling
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20. Specifications
Specifications have
version control to
keep track of
changes
Most recent specs
apply, but old specs
must be kept
available for review
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21. Specifications
Specifications can have Safety, Handling
and Sampling instructions
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22. Specifications
Specifications include Test, Methods and
Limits that will go on Certificate of Analysis
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23. GMP in Japan
 Japan has meticulous, detailed and strategic local GMP
rules
 You may not know if a Japanese supplier or distributer is
in compliance; you just have to trust them
 Most GMP texts are in Japanese, rare to see local
pharmaceutical guidelines in English
 Japan is a signatory of ICH, but there are differences
between Japan’s and International GMP
 Japan applies a more thorough interpretation of GMPs
than ICH requires
 The Local Government and Certification Bodies
administer GMP in Japan
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24. Process Flow – Material Management
Receipt at Available for Bill
Warehouse Record into
Released Yes of Materials &
Inventory
Production
No
Quarantine, Quality
Facility Test & Manager
Manager Release
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25. Receiving
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26. Quality Testing and Release
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27. GMP in China
 Regulations issued in the 1980’s and
1990’s were supposed to strengthen
China’s pharmaceutical manufacturing
 GMP 2010 has become law
 Nearly 4,000 pharmaceutical companies
in China are small to medium size who
will need significant capital to meet new
standards
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28. GMP in China
 Nearly impossible to verify if Chinese
produced product is in compliance
 GMP guidelines in Chinese
 Locally inspected
 One standard for export and another for
local
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29. GMP in China
Only a small % of Chinese factories
have FDA inspections
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30. GMP in China
The rest are inspected locally where
corruption remains a possibility
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31. Process Flow - Production
Manufacturing
Instructions
Bill of Master Batch Approve
Materials Production Production Batch Record
In Process
Equipment
Tests
Quality Facility Sponsor
Manager Manager
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32. Master Production Record
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33. Master Production Record - BOM
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34. Master Production Record –
Manufacturing Instructions
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35. Batch Production Record –
Manufacturing Instructions
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36. Testing and Release
 Samples pulled from production batch
 QC will test according to methods in
specifications
 In US, QA will disposition batch after
final product in made in the US
 in the UK and Europe, QP (Qualified
Person) is used for batch release
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37. GMP in the UK
 GMP in the UK is based on is the 1968 Medicines Act
 “Guide to Good Pharmaceutical Manufacturing
Practice” issued in 1971
 Basis for US GMP regulations
 Now known as the “Orange Guide”
 Essential reference for all pharmaceutical
manufacturing and distributing in the European
continent.
 GMP Inspectorate uses this document as their
reference for checking the compliance of companies
to EU GMP/GDP standards.
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38. GMP in Brazil
 In the 70s and 80s, steep price control, high
inflation, weak intellectual property rights and
absence of quality assurance affected drugs
 ANIVSA (National Health Surveillance Agency like
our FDA) started regulating generics in the 90s
 ANIVSA revised its GMP in 2000s to be in line with
WHO GMP standards
 Now RDC 25 requires quality control and
compliance of pharmaceuticals made or imported
into Brazil
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39. GMP in Brazil
 Despite the benefits of RDC 25 some manufacturers
opposed it due to the cost of compliance
 RDC eventually was narrowed down and bases the
certification or approval to “risks” of the product
 Risk levels 1 and 2 are considered low level while levels
3 and 4 are high
 The determination of the product risks will be made by
ANIVSA
 Only high risks pharmaceutical products require
certifications
 Level 1 and 2 products are not subjected for registration
procedures
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40. Inventory
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41. Tracking of CTM Distribution
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42. GMP in Taiwan
 Regulated by Taiwan’s DOH (Department of Health)
 1988, DOH’s required manufacturing plant to provide
PMFs (Plant Master File) as mandated by the
international GMP
 1998, Taiwan applied for PIC/S Pharmaceutical
Inspection Co-Operation Scheme membership
 In 2001, it expanded and updated its guidelines to
include product distribution and recall, plant
inspection, auditing and complaints.
 Focused on export and international acceptance
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43. GMP Inspections World Wide
 PIC/S (Pharmaceutical Inspection Cooperation
Scheme)
 PIC/S references “Good Manufacturing
Practice Guide for Active Pharmaceutical
Ingredients” (ICH Q7A)
 Participants include
Australia, Canada, Eastern
Europe, EU, Malaysia, SA, Singapore, UK, US
, Taiwan
 Not participating: Brazil, Russia, India, China
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44. Messages
 No one GMP compliance system exists even
in countries that are signatories to ICH
 BRIC countries want to become compliant, but
they have a long way to go
 Most countries outside of Europe, Japan and
US have little control over quality or
compliance
 If you are manufacturing, packaging or
distributing CTM world wide, you have to
understand both local regulations and how
they are (or are not) enforced
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations