1. Dave Ulrich, Abbvie HPCLC, Chicago Sept 20th 2016
Global GDPs - A risk based approach to management of distribution Focus – Supply Chain Temp Controls
Dave Ulrich, Abbvie
HPCLC, Chicago
Sept 20th 2016

2. Agenda
What do the regulations say
Pharma / Biopharma companies need a QMS (Quality Management System) that includes QRM (Quality Risk Mgt) system
Where GDPs & GMPs meet
One Big GxP (are you in control of your processes)
ICH Q9 – Quality Risk Management (QRM)
Scientific approach to Risk
Temperature management
Do I have to ship at label claim?

3. What are the GDPs?  GDP Dashboard
There are core elements to all world-wide GDPs
just like there are core elements to other GxPs (e.g. cGMPs):
Quality Management
Process
Validation / Qualification (process, cleaning, E/U/F)
Verification e.g. Audits (Internal and External)
Good Distribution Practices (GDPs)
Good Import Practices (GIPs)
Temperature Control Management (TCM)
Distribution Control Systems (DCS)
Product Protection
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?

4. They are a “Logical” extension of the GMPs
Good Distribution Practices (GDPs)
Security Audits & Supply Chain Controls
Marketing Authorization and License Control
Good Import Practices (GIPs)
Export Controls
Temperature Control Management (TCM)
Cold Chain  End-2-End Supply Chain Management
Distribution Control Systems (DCS)
GS1, Track and Trace, Serial Number Mgmt., Trade Relations
GPP
Global Product Protection

5. Core areas of focus for GDP
General GDPs
Temperature Control
Trade Controls (import/export)
Supply Chain Traceability
Supply Chain Risk Management
Vs. Temp Mgt

6. Structure of EU GDP Guideline
Chapters
Introduction:
Quality Management
Personnel
Premises and Equipment
Documentation
Operations
Complaints, Returns, Falsified Medicinal Products and Recalls
Outsourced Activities
Self-Inspections
Transportation
Specific Provisions for Brokers

7. 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
Control of APIs (Active Pharmaceutical Ingredients) Importation
Good Distribution Practices
Issued March 2013
Re-issued Nov. 2013
Safety Features
Barcodes and TEP (Tamper Evident Packaging)
Internet Sales
Supply Chain Maps
Falsified Medicine
Directive

8. 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.

9. Supply Chain Mapping – Distribution
Same philosophy for distribution:
Routes
Carriers / contractors
Conditions
End-to-end approach = knowledge!

10. EU GMP – Annex 15: Qualification and Validation10

11. 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 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 11

12. 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 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. 12

13. 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)?

14. 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.
products-some-things-to-consider/

15. 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).

16. 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 16

17. Know what use you are developing the data for !
There are 2 main issues with pharma supply chain controls
Temperature controls (how robust)
Security (street value)

18. Know failure points How the product reacts at highs (50C) and lows (-20C)
That will help determine level of control needed during shipping

19. Control the storage label

20. 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

21. So when the inevitable happens…..
Options for CRT shipping
Active shippers
Passive shippers
Blankets
Controlled networks
Risk it

22. Bulk Drug Shipment Temp Monitoring (Stability Budget)
Mean ambient temperature at
O’Hare on 6/22/2014: 21.17°C
Held by Port (CBP, MoH, etc))
Pack out at Mfg’ing site
Transport to packaging site
Mean ambient temperature at
Airport on 6/19/2014: 16.11°C
Belly of plane
Arrival at packaging site

23. Passive Shippers – one origin, multiple destinations
Internal & External Monitoring – Know your product and know your data
Tarmac handling
final unloading
Loading
Example of multiple shipments – same origin and destination
Need to know your supply chain temps and
How your product reacts 23

24. 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