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Global GDPs - A risk based
approach to management of
distribution
Focus – Supply Chain Temp
Controls
Dave Ulrich, Abbvie
HPCLC, Chicago
Sept 20th 2016
Agenda
1. What do the regulations say
 Pharma / Biopharma companies need a QMS (Quality
Management System) that includes QRM (Quality Risk
Mgt) system
2. Where GDPs & GMPs meet
 One Big GxP (are you in control of your processes)
3. ICH Q9 – Quality Risk Management (QRM)
 Scientific approach to Risk
4. Temperature management
 Do I have to ship at label claim?
2
What are the GDPs?  GDP Dashboard
GDP's
Regulations
Countries
Argentina
Brazil
Mexico
Australia
General
GDPs
GIP
Quality Systems
Importation
Storage Buildings / Warehousing
Transport, Delivery, Storage
Labeling
Inventory Procedures
Exception Product Return,
Port
General
Loading &
Temperature Product Temperature- Humidity Shipping General
Qualified
Good
Stock Management &
Recall,
GPS and
Traceability /
Building General
Packaging,
Serialization
GS1
Handling / Offloading
Layout /
Receiving
Monitored
Stability Controlled Control and Containers Lableling
Personnel, Documentatio Control
Product
Withdraw,
Bulk Security,
Stock
Cleanliness Security
Prcoessing
& ePedigree
Identification
Customs
Contruction
Bays
Storage Areas Profiles
Transport Monitoring & Packing Relabeling
Training n Practices Systems Compaint
Control and
Counterfeits
Tracking
Procedures
Disposal
There are core elements to all world-wide GDPs
 just like there are core elements to other GxPs (e.g.
cGMPs):
1. Quality Management
2. Process
3. Validation / Qualification (process, cleaning, E/U/F)
4. Verification e.g. Audits (Internal and External)
TCM
DCS
LAA Region
Regulating the Cold Chain of Medicines (Ley
Resolution - RDC No. 234
Guidelines for Imported Biotechnological &
Code of Good Wholesaling Practice for
Cold Chain Pharmaeutical Products
India (OPPI) Guideline on Good Distribution Practices for
Japan
Biological Pharma Revision H15.5.15
Malaysia
Guidelines on Good Distribution Practice
Singapore Guidance Notes on Good Distribution
South Africa Good Whilesaling Practice for Wholesales,
Phillipines
Adoption and Implementation of the World
Central European Region
Austria
Austrian GDP Regulations
Czech
Guidelines for Correct Distribution of Human
Republic
Czech GDP Guidelines
EMA
European Medicines Agency: " QP
Guidelines on Good Distribution Practice of
Directive 2001/83/EC of the European
EU
The IPEC Good Distribution Practices Guide
Europe - Good Distribution Practices Audit
Rx-360 Summary of IPEC GDP
Ireland
Guide to Control and Monitoring of Storage
Switzerland Distribution of Temperature Controlled
North American Region
Canada
Guidelines for Temperature Control of Drug
FDA to Revise Component GMPs to Bolster
United States Bar Code Technologies for Drugs and
Standards for Securing Drug Supply Chain...
Middle-Eastern European Region
Egypt
Minster Decree for Wholesalers - Circular
Pharmacist Regulations - Circular 6
Israel
Status of Current GDP Regulations in Israel
Romania
NMA No. 30/24.09.2009
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Product Protection
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Good Distribution Practices (GDPs)
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Good Import Practices (GIPs)
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Temperature Control Management (TCM) Distribution Control Systems (DCS)
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What is it? Where did it come from? Is it allowed to come into
commerce? Can you prove it is what you say it is?
Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031,
Saudi Food & TOPA GTS - 6000
Drug Authority
UAE
Circular No. 246-2011
International Health Organizations
Updated Policy on Returns of Non-Defective
Guidance on Preventing Breaches in the
MHRA
Cold Chain Distribution GDP Risk
GDP Risk Assessment Strategy
Regulatory Provisions for Quality Controlled
Model requirements for the storage and
WHO
New Guidance for storage and transport of
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They are a “Logical” extension of the GMPs
GDP's
Regulations
Countries
Argentina
Brazil
Mexico
Australia
General
GDPs
GIP
Quality Systems
Importation
TCM
DCS
LAA Region
Regulating the Cold Chain of Medicines (Ley
Resolution - RDC No. 234
Guidelines for Imported Biotechnological &
Storage Buildings / Warehousing
Transport, Delivery, Storage
Labeling
Inventory Procedures
Exception Product Return,
Port
General
Loading &
Temperature Product Temperature- Humidity Shipping General
Qualified
Good
Stock Management &
Recall,
GPS and
Traceability /
Building General
Packaging,
Serialization
GS1
Handling / Offloading
Layout /
Receiving
Monitored
Stability Controlled Control and Containers Lableling
Personnel, Documentatio Control
Product
Withdraw,
Bulk Security,
Stock
Cleanliness Security
Prcoessing
& ePedigree
Identification
Customs
Contruction
Bays
Storage Areas Profiles
Transport Monitoring & Packing Relabeling
Training n Practices Systems
Compaint
Control and
Counterfeits
Tracking
Procedures
Disposal
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• Good Distribution Practices (GDPs)
• Good Import Practices (GIPs)
• Security Audits & Supply Chain
• Export Controls
GPP
Controls
• Marketing Authorization and License
Global
Control
Code of Good Wholesaling Practice for
Cold Chain Pharmaeutical Products
India (OPPI) Guideline on Good Distribution Practices for
Japan
Biological Pharma Revision H15.5.15
Malaysia
Guidelines on Good Distribution Practice
Singapore Guidance Notes on Good Distribution
South Africa Good Whilesaling Practice for Wholesales,
Phillipines
Adoption and Implementation of the World
Central European Region
Austria
Austrian GDP Regulations
Czech
Guidelines for Correct Distribution of Human
Republic
Czech GDP Guidelines
EMA
European Medicines Agency: " QP
Guidelines on Good Distribution Practice of
Directive 2001/83/EC of the European
EU
The IPEC Good Distribution Practices Guide
Europe - Good Distribution Practices Audit
Rx-360 Summary of IPEC GDP
Ireland
Guide to Control and Monitoring of Storage
Switzerland Distribution of Temperature Controlled
North American Region
Canada
Guidelines for Temperature Control of Drug
FDA to Revise Component GMPs to Bolster
United States Bar Code Technologies for Drugs and
Standards for Securing Drug Supply Chain...
Middle-Eastern European Region
Egypt
Minster Decree for Wholesalers - Circular
Pharmacist Regulations - Circular 6
Israel
Status of Current GDP Regulations in Israel
Romania
NMA No. 30/24.09.2009
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Product
Temperature Control Management
• Distribution Control Systems
Protection
(TCM)
(DCS)
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• Cold Chain  End-2-End Supply Chain
Management
Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031,
Saudi Food & TOPA GTS - 6000
Drug Authority
UAE
Circular No. 246-2011
International Health Organizations
Updated Policy on Returns of Non-Defective
Guidance on Preventing Breaches in the
MHRA
Cold Chain Distribution GDP Risk
GDP Risk Assessment Strategy
Regulatory Provisions for Quality Controlled
Model requirements for the storage and
WHO
New Guidance for storage and transport of
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• GS1, Track and Trace, Serial
Number Mgmt., Trade Relations
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4
Core areas of focus for GDP
1. General GDPs
2. Temperature Control
3. Trade Controls (import/export)
4. Supply Chain Traceability
5. Supply Chain Risk Management
 Vs. Temp Mgt
5
Structure of EU GDP Guideline
Chapters
Introduction:
1.
Quality Management
2.
Personnel
3.
Premises and Equipment
4.
Documentation
5.
Operations
6.
Complaints, Returns, Falsified Medicinal Products and Recalls
7.
Outsourced Activities
8.
Self-Inspections
9.
Transportation
10. Specific Provisions for Brokers
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Supply Chain Maps – where do you ship your product from - to
2012 – European Commission: Health and Consumers Directorates Central
EU GDPs (Good Distribution Practices)
•
Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use
 Approval – Dec. 2012, effective June 2013
 Sec. 5.4 “… The supply chain of medicinal products should be known and
documented.”
 Stresses GMP, supply chain security and temp mgt
Supply Chain Maps
Control of APIs (Active
Good Distribution
Pharmaceutical
Practices
Ingredients)
Issued March 2013
Importation
FalsifiedRe-issued Nov. 2013
Medicine
Directive
Safety Features
Barcodes and TEP
(Tamper Evident
Packaging)
Internet Sales
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Supply Chain Mapping – Annex 16 EU GMP
• The entire supply chain of the active substance and medicinal
product up to the stage of certification is documented and available
for the QP.
• This should include the manufacturing sites of the starting materials
and packaging materials for the medicinal product and any other
materials deemed critical through a risk assessment of the
manufacturing process.
• The document should preferably be in the format of a
comprehensive diagram, where each party, including subcontractors
of critical steps such as the sterilisation of components and
equipment for aseptic processing, are included.
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Supply Chain Mapping – Distribution
• Same philosophy for distribution:
• Routes
• Carriers / contractors
• Conditions
• End-to-end approach = knowledge!
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EU GMP – Annex 15: Qualification and Validation
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Verification of Transportation in the EU GMP
6. VERIFICATION OF TRANSPORTATION
6.1. Finished medicinal products, investigational medicinal products, bulk
product and samples should be transported from manufacturing sites in
accordance with the conditions defined in the marketing authorisation, the
approved label, product specification file or as justified by the manufacturer.
6.2. It is recognised that verification of transportation may be challenging due
to the variable factors involved however, transportation routes should be
clearly defined. Seasonal and other variations should also be considered
during verification of transport
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Verification of Transportation in the EU GMP
6. VERIFICATION OF TRANSPORTATION
6.3. A risk assessment should be performed to consider the impact of variables
in the transportation process other than those conditions which are
continuously controlled or monitored, e.g. delays during transportation, failure
of monitoring devices, topping up liquid nitrogen, product susceptibility and
any other relevant factors.
6.3. Due to the variable condition expected during transportation, continuous
monitoring and recording of any critical environmental conditions to which the
product may be subjected should be performed, unless otherwise justified.
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Scenario (Real issue)
• A short-term temperature excursion during the transport of a
product from a third country to the EU.
• The label claim for the product is ‘store below 25°C’, and the
excursion was up to 29°C for 3 days.
• Existing stability data demonstrated no issues when stored at 30°C
for up to 3 months.
• Is this an ‘unexpected’ or ‘expected’ deviation (in terms of
definitions within Annex 16)?
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Scenario (continued)
• This situation would fall within the scope of ‘unexpected deviations’,
provided that the shipment process was designed to comply with
the registered conditions (i.e. that the excursion could be reasonably
described as ‘unexpected’).
• However if there were no controls over shipment conditions, then
the use of stability data as a ‘routine’ means to justify such an
excursion would not be acceptable.
• Understand the risks and address with the appropriate risk control
strategy.
•
https://mhrainspectorate.blog.gov.uk/2015/12/07/transportation-of-medicinalproducts-some-things-to-consider/
14
ICH Q9 – Quality Risk Management
Storage, logistics and distribution conditions
• To assess the adequacy of arrangements to ensure maintenance of
appropriate storage and transport conditions (e.g., temperature,
humidity, container design);
• To determine the effect on product quality of discrepancies in
storage or transport conditions (e.g., cold chain management) in
conjunction with other ICH guidelines;
• To maintain infrastructure (e.g., capacity to ensure proper shipping
conditions, interim storage, handling of hazardous materials and
controlled substances, customs clearance);
• To provide information for ensuring the availability of
pharmaceuticals (e.g., ranking risks to the supply chain).
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Definition: Risk Management
Identify, characterize, and
assess threats
Assess the vulnerability of
critical assets to specific threats
Determine the risk (i.e. the
expected consequences of
specific types of attacks on
specific assets)
Identify ways to reduce those
risks
Prioritize risk reduction
measures based on a strategy
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Know what use you are developing the data for !
There are 2 main issues with pharma supply
chain controls
1. Temperature controls (how robust)
2. Security (street value)
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Know failure points
How the product reacts at highs (50C) and lows (-20C)
That will help determine level of control needed during shipping
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Control the storage label
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E.g. CRT Stability Budget (Knowledge)
Can I ship this product outside of the filed temperature range
15-30C (30C is 86F)
We ship it 2-40C with excursions to 50C based off the stab budget
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So when the inevitable happens…..
Options for CRT shipping
1. Active shippers
2. Passive shippers
3. Blankets
4. Controlled networks
5. Risk it
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Bulk Drug Shipment Temp Monitoring (Stability Budget)
Mean ambient temperature at
O’Hare on 6/22/2014: 21.17°C
Pack out at Mfg’ing site
Held by Port (CBP, MoH,
etc))
Transport to packaging site
Mean ambient temperature at
Airport on 6/19/2014: 16.11°C
Belly of plane
Arrival at packaging
site
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Passive Shippers – one origin, multiple destinations
Internal & External Monitoring – Know your product and know your data
Tarmac
handling
Loading
final
unloading
Example of multiple shipments – same origin and destination
Need to know your supply chain temps and
How your product reacts
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Summary / Conclusion
• Global expectation surrounding GDPs are increasing
• Have & maintain the knowledge
• Supply chain map
• Risks (intrinsic & extrinsic)
• Storage Temperature Label claim (filed data)
• Stability data / stability budget
• Embrace risk management & mitigation
• Audit  have a documented risk assessment that shows:
• Stability budget
• Supply Chain
• Controls needed
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