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This presentation describes the complex process of manufacturing clinical trial materials using examples from the InstantGMP manufacturing execution system. InstantGMP is an electronic batch record system for small pharmaceutical operations and is ideal for manufacturing CTM or tracking inventory worldwide.
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InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
GMP MANUFACTURING FOR WORLDWIDE CLINICAL TRIALS
Richard Soltero, Ph.D.
Founder
InstantGMP
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations2
Discussions
Flow of GMP Manufacturing processes Approaches to GMP compliance
throughout the world Impact on clinical trial supplies
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations3
ICH Q7A Good Manufacturing Practice
International Conference on Harmonization
ICH Member Countries –European Union (EU) - 27 countriesJapanUnited StatesAustraliaCanadaNorway
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations4
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations5
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations6
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations7
Manufacturing Facility
Facility and flow designed to minimize potential contamination and mix-ups
Defined areas for:Receipt
Quarantine
Storage
Production
Packaging
Washing
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations8
Small ScaleCTM Manufacturing Facility
Material flow
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations9
GMP Facility Inspections
FDA conducts facility inspections for products to be sold in the USDoesn’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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations10
Typical GMP Facilities in US and UK
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations11
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations12
GMP Facilities in India
Schedule M regulations were harmful to the small players in the pharmaceutical industry
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations13
GMP Facilities in India
So the government is cutting them some
slack
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations14
MaterialsOnly QA approved materials can be used in CTM manufacturing
Excipients Containers/Closures
ComponentsWork in Process
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations15
Getting ready for manufacturing – Control of Materials
No
Vendor Qualification
API , excipients and components
identified
YesPM InitiatesProject
VendorsQualified?
ProjectDefinitionCompleted
QualityManager
ProjectManager
SpecsApproved?
Assign Part #s,tests, methods,
Specs
Select Personnel and Roles
Yes
QualityManager
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations16
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations17
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations18
Vendors
QA shall qualify vendors for materials used in CTM
Phase 1 CTMPaper based quality survey
Phase 2 CTMEither a paper based quality survey or an on-site audit
Phase 3 CTMOn-site audit
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations19
SpecificationsQA 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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations20
Specifications have version control to keep track of changes
Most recent specs apply, but old specs must be kept available for review
Specifications
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations21
Specifications can have Safety, Handling and Sampling instructions
Specifications
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations22
Specifications include Test, Methods and Limits that will go on Certificate of Analysis
Specifications
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations23
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations24
Process Flow – Material Management
Receipt at Warehouse Record into
I nventoryReleased
Quarantine,Test &
Release
No
Available for Bill of Materials &
ProductionYes
QualityManagerFacility
Manager
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations25
Receiving
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations26
Quality Testing and Release
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations27
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
GMP in China
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations28
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
GMP in China
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations29
GMP in China
Only a small % of Chinese factories have FDA inspections
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations30
GMP in China
The rest are inspected locally where corruption remains a possibility
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations31
Process Flow - Production
Master Production
Bill ofMaterials
ManufacturingI nstructions
Batch Production
ApproveBatch Record
QualityManager
FacilityManager
I n ProcessTests
Equipment
Sponsor
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations32
Master Production Record
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations33
Master Production Record - BOM
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations34
Master Production Record –Manufacturing Instructions
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations35
Batch Production Record –Manufacturing Instructions
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations36
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations37
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.
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations38
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations39
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations40
Inventory
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations41
Tracking of CTM Distribution
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations42
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations43
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
InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
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