Integrating the Global GDPs into the

Quality Management System (QMS)

Dave Ulrich
• Abbvie QA Director –Global Supply Chain
Agenda: GDP, QMS and QRM

1. What do the regulations say

 What are the GDPs?
 Do we need them?
• Can’t we just use the GMP To have a good QRM
2. What is a QMS and integrating GDPs program you must have
 Supply Chain Temp Mgt 1. A well designed
• ICH Q1A – standard stab testing process (QMS) to
• Establishing “storage” label claim demonstrate
• Temperature cycles studies control
• File the “cycling studies” 2. Great data (data
• Develop a stability budget integrity)
• Excursion management
 Supply Chain map
• What is it, where did it come from
̶ Are you sure?

4
 What are the GDPs?  GDP Dashboard
GDP's Quality Systems
Regulations 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 /
Countries General Building General Packaging, Serialization GS1
GIP TCM DCS Handling / Offloading Layout / Receiving Monitored Stability Controlled Control and Containers Lableling Personnel, Documentatio Control Product Withdraw, Bulk Security, Stock

Just like there are core elements to other GxPs (e.g. cGMPs):
GDPs 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
LAA Region
Argentina Regulating the Cold Chain of Medicines (Ley X X X

1. PV, Cleaning Validation, E/U/F Validation

Brazil Resolution - RDC No. 234 X X X X X X X X X
Mexico Guidelines for Imported Biotechnological & x x x x x x x x

Australia
2. Test Method Development and TMT
Code of Good Wholesaling Practice for
Cold Chain Pharmaeutical Products
India (OPPI) Guideline on Good Distribution Practices for
X
X
X
X
X

X
X
X
X
X

X
X

X
X
X
X
X
X
X
X
X
X
X
X
X X
X

X
X

X
X

X
X

X
X

X
X

X
Japan
Malaysia 3. Audits (Internal and External), SQA: QTA, QQ and QTA
Biological Pharma Revision H15.5.15
Guidelines on Good Distribution Practice
Singapore Guidance Notes on Good Distribution
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Phillipines 4. Change Control / Change Mgt

South Africa Good Whilesaling Practice for Wholesales,
Adoption and Implementation of the World
Central European Region
X
X X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X X X
X
X
X
X
X X X X
X
X

Austria
Czech 5.
Austrian GDP Regulations
Exception Mgmt., CAPA, Complaints, AE / PV
Guidelines for Correct Distribution of Human X X
X
X
X X
X X
X
X
X
X X
X
X X
X
X X X X X

6. QRM
Republic Czech GDP Guidelines X X X X X X
EMA European Medicines Agency: " QP X X
Guidelines on Good Distribution Practice of X X X X X X X X X X X X X X X X
Directive 2001/83/EC of the European X X X X X X X
EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X
Europe - Good Distribution Practices Audit
x x x x x x x x x x x x x x x x x
Rx-360 Summary of IPEC GDP
Ireland Guide to Control and Monitoring of Storage X X X X X X X X X X X X X X X

Good Distribution Practices (GDPs) Good Import Practices (GIPs)

Switzerland Distribution of Temperature Controlled X X X X X X X X X X X X X
North American Region
Canada Guidelines for Temperature Control of Drug X X X X X X X X X X
FDA to Revise Component GMPs to Bolster

Product Protection
Temperature Control Management Distribution Control Systems
United States Bar Code Technologies for Drugs and X X
Standards for Securing Drug Supply Chain... X X X X X
Middle-Eastern European Region
Egypt Minster Decree for Wholesalers - Circular X X X X X X
Israel
Romania
(TCM)
Pharmacist Regulations - Circular 6
Status of Current GDP Regulations in Israel
NMA No. 30/24.09.2009
(DCS)
X
X X X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X

X
X
X X
X
X X X X X

What is it? Where did it come from? Is it allowed to come into commerce?
Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031,
X X X X X X
Saudi Food & TOPA GTS - 6000
Drug Authority

Can you prove it is what you say it is?

UAE Circular No. 246-2011 X X X X X X
International Health Organizations
Updated Policy on Returns of Non-Defective X
Guidance on Preventing Breaches in the X X X X X X X X X
MHRA Cold Chain Distribution GDP Risk X X X X X X X X X X X X X X X
GDP Risk Assessment Strategy
Regulatory Provisions for Quality Controlled X X X X X X X X X X X X X
Model requirements for the storage and X X X X X X X X X X X X X X X X X X X X
WHO New Guidance for storage and transport of X X X X X X X X X X X X X X X

5
From GMPs to GDPs

GDPs cover the whole development process

• Migration of GMPs into the pharma supply chain

• GDPs are the “new kid on the (cGxP) block”
• Theses include clinicals (IND NDA)

6
 GDPs are a “Logical” extension of the GMPs
GDP's Quality Systems
Regulations 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 /
Countries General Building General Packaging, Serialization GS1
GIP TCM DCS Handling / Offloading Layout / Receiving Monitored Stability Controlled Control and Containers Lableling Personnel, Documentatio Control Product Withdraw, Bulk Security, Stock
GDPs 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
LAA Region
Argentina Regulating the Cold Chain of Medicines (Ley X X X
Brazil Resolution - RDC No. 234 X X X X X X X X X
Mexico Guidelines for Imported Biotechnological & x x x x x x x x

Australia
• Good Distribution Practices (GDPs)
Code of Good Wholesaling Practice for
Cold Chain Pharmaeutical Products
India (OPPI) Guideline on Good Distribution Practices for
• Good Import Practices (GIPs)
X
X
X
X
X

X
X
X
X
X

X
X

X
X
X
X
X
X
X
X
X
X
X
X
X X
X

X
X

X
X

X
X

X
X

X
X

X
Japan
Malaysia • Security Audits & Supply Chain Controls • Export Controls
Biological Pharma Revision H15.5.15
Guidelines on Good Distribution Practice
Singapore Guidance Notes on Good Distribution
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

• Marketing Authorization and License • Supply Chain Maps

GPP
South Africa Good Whilesaling Practice for Wholesales, X X X X X X X X X X X X X X X X X
Phillipines Adoption and Implementation of the World X X X X X X X X X X X X X X X X X X X X
Central European Region
Austria
Czech Control
Austrian GDP Regulations
Guidelines for Correct Distribution of Human • What is it – where did it come
X X
X
X
X X
X X
X
X
X
X X
X
X X
X
X X X X X

Global from
Republic Czech GDP Guidelines

• S. Africa GWP
X X X X X X
EMA European Medicines Agency: " QP X X
Guidelines on Good Distribution Practice of X X X X X X X X X X X X X X X X
Directive 2001/83/EC of the European X X X X X X X

Product
EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X
Europe - Good Distribution Practices Audit
x x x x x x x x x x x x x x x x x
Rx-360 Summary of IPEC GDP

Temperature Control Management • Distribution Control Systems (DCS)

Ireland Guide to Control and Monitoring of Storage X X X X X X X X X X X X X X X
•
Switzerland Distribution of Temperature Controlled X X X X X X X X X X X X X

Protection
North American Region

(TCM) • GS1, Track and Trace, Serial

Canada Guidelines for Temperature Control of Drug X X X X X X X X X X
FDA to Revise Component GMPs to Bolster
United States Bar Code Technologies for Drugs and X X

• Cold Chain  End-2-End Supply Chain Number Mgmt., Trade Relations

Standards for Securing Drug Supply Chain... X X X X X
Middle-Eastern European Region
Egypt Minster Decree for Wholesalers - Circular X X X X X X

Management
Pharmacist Regulations - Circular 6 X X X X X X X X X X X X
Israel
Status of Current GDP Regulations in Israel X X X X X X X X X X X X X X X X X X X X
Romania NMA No. 30/24.09.2009 X X X X X X

Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031,

X X X X X X
Saudi Food & TOPA GTS - 6000
Drug Authority
UAE Circular No. 246-2011 X X X X X X
International Health Organizations
Updated Policy on Returns of Non-Defective X
Guidance on Preventing Breaches in the X X X X X X X X X
MHRA Cold Chain Distribution GDP Risk X X X X X X X X X X X X X X X
GDP Risk Assessment Strategy
Regulatory Provisions for Quality Controlled X X X X X X X X X X X X X
Model requirements for the storage and X X X X X X X X X X X X X X X X X X X X
WHO New Guidance for storage and transport of X X X X X X X X X X X X X X X
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 Good Distribution

API importation into the Pharmaceutical Practices
EU listed and non-listed Ingredients) Issued March 2013
countries and SC maps Importation FalsifiedRe-issued Nov. 2013
Medicine
Directive
Safety Features
Barcodes and TEP
(Tamper Evident
Internet Sales
Packaging)

8
Standard Supply Chain Maps
Regulatory Starting Material through Distribution

• Example
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

1
0
“Wholesale and Broker” Regulations (page 1 of 2)
“Wholesale and Broker” Regulations
IMB GDPs (Slide 1 of 3)
IMB’s GDPs (Slide 2 of 3)
IMB’s GDPs (Slide 3 of 3)
Temperature Management (Slide 1 of 2)
Temperature Management (Slide 2 of 2)
Steps to Show Control (QMS and QRM)
1. What do the regulations say
 Know your product
• Failure points high and low
 Demonstrate control (QMS)
2. ICH Q1A – standard stab testing
 Establishing “storage” label claim
• Not good enough
 Temperature cycles studies
• To manage “typical supply chain temp excursions”
 File the “cycling studies”
3. Develop a stability budget (QRM)
 Excursion management
 Shipping outside of “storage” label claim
1
8
Know what use you are developing the data for !

File the data!

1
9
 Know Product Failure Points

How the product reacts at highs (50C) and lows (-20C)

That will help determine level of control needed during shipping
Control the Storage Label Condition
e.g. Controlled Room Temperature Stability Budget
So when the inevitable happens…..

Options for CRT shipping

1. Active shippers
2. Passive shippers
3. Blankets
4. Controlled networks
5. Risk it
Cold Chain  End-End Supply Chain Temp Mgt

Cold Chain has expanded to be

End to End Supply Chain Temp Mgt
Includes mfg’ing lanes to the Rx/POS (point of Sale)

Includes all temperature ranges

– Including CRT – controlled room temperature
EU GMP – Annex 15: Qualification and Validation
Verification of Transportation in the EU GMP
Bulk Drug Shipment Temperature 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

2
7
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

Summary / Conclusion

 GDPs need to be part of (integrated into) the QMS

 GMP and GDPs need to be integrated (not siloed)
 QRM needs to incorporate / use:
• Supply Chain Maps
• Product knowledge vs. temperature control needed
• Appropriate levels of risk management

GMP Crxx Granulator Fluid Bed Dryer Tablet press

2-8 Room temp 60C Room temp

GDP BDS (API) Tableting (BDP) Packaging (BDP) Finishing (market

Singapore Ireland Germany Specific)
2-8 Room Temp Room Temp Netherlands
Global GDP’s - A Risk Based Approach
to Management of Distribution

Dave Ulrich, Ph.D.

• Abbvie QA Director –Global Supply Chain
Patient Safety

Patient health and safety is of the utmost

importance to the pharmaceutical industry.

 Goal
• Maintain product quality, safety and efficacy by
preventing security and temperature incidents*
in our end-to-end supply chain

• (* e.g. counterfeiting, tampering, theft, illegal diversion, and temperature excursions)

GDP Regulations
Risk Management

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©2016 | SUPPLY CHAIN RISK MANAGEMENT

EU Falsified Medicines Directive (FMD) June 2011

Importation of Active
Substances
‘Active Pharmaceutical Ingredients EU Good Distribution Practices
Import Control’ (GDP)
Issued 23 January 2013 Issued March 2013
+ Re-issued Nov. 2013
GDP for Active Substance
Effective 25 May 2015

EU Safety Features Internet Sales

2D-Matrix barcode + Anti-Tampering Devices Common logo
Effective 9th Feb 2016 24 June 2014
EU Falsified Medicines Directive (FMD) June 2011

Good Distribution Practices (GDP)

GDP is that part of quality assurance which ensures that the quality of
medicinal products is maintained throughout all stages of the supply chain
from the site of manufacturer to the pharmacy or person authorized or
entitled to supply medicinal products to the public

Purpose
Maintain quality and integrity of medicinal products across complex global
supply chains
 safeguard product quality and integrity (patient impact)
 prevent unnecessary product loss, scrap (availability to patients)
Risk Management as per the EU GDP

1. Quality Management 6.3 Returns

‘Wholesale distributors must maintain a ‘Returned products must be handled
quality system setting out responsibilities, according to a written, risk based
processes and risk management process’
principles in relation to their activities’
9. Transportation
1.5 Quality Risk Management  Refers ‘A risk based approach should be
to ICH Q9 (2005) utilized when planning transportation’
‘The level of effort, formality and
documentation of the process should be ‘Risk assessment of delivery routes
commensurate with the level of risk.’ should be used to determine where
temperature controls are required’
3. Premises and Equipment
‘qualification activities should be
determined using a documented risk Also reference:
assessment approach’ PDA Technical Report 58
Risk Management for Temperature
Controlled Distribution
GDP’s Around the World

GDP's Quality Systems

Regulations 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 /
Countries General Building General Packaging, Serialization GS1
GIP TCM DCS Handling / Offloading Layout / Receiving Monitored Stability Controlled Control and Containers Lableling Personnel, Documentatio Control Product Withdraw, Bulk Security, Stock
GDPs 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
LAA Region
Argentina Regulating the Cold Chain of Medicines (Ley X X X
Brazil Resolution - RDC No. 234 X X X X X X X X X
Mexico Guidelines for Imported Biotechnological & x x x x x x x x

Australia Code of Good Wholesaling Practice for X X X X X X X X X X X X X X

Cold Chain Pharmaeutical Products X X X X X X X X
India (OPPI) Guideline on Good Distribution Practices for X X X X X X X X X X X X X X X X
Japan Biological Pharma Revision H15.5.15 X X X
Malaysia Guidelines on Good Distribution Practice X X X X X X X X X X X X X X X X X X X X X
Singapore Guidance Notes on Good Distribution X X X X X X X X X X X X X X X X X
South Africa Good Whilesaling Practice for Wholesales, X X X X X X X X X X X X X X X X X
Phillipines Adoption and Implementation of the World X X X X X X X X X X X X X X X X X X X X
Central European Region

There are core elements to all world-wide GDPs, just like there
Austria Austrian GDP Regulations X X X X X X X
Czech Guidelines for Correct Distribution of Human X X X X X X X X X X X X X X X
Republic Czech GDP Guidelines X X X X X X

are core elements to other GxPs (e.g. GMP)

EMA European Medicines Agency: " QP X X
Guidelines on Good Distribution Practice of X X X X X X X X X X X X X X X X
Directive 2001/83/EC of the European X X X X X X X
EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X
Europe - Good Distribution Practices Audit
x x x x x x x x x x x x x x x x x
Rx-360 Summary of IPEC GDP
Ireland Guide to Control and Monitoring of Storage X X X X X X X X X X X X X X X
Switzerland Distribution of Temperature Controlled
North American Region
Canada Guidelines for Temperature Control of Drug
X
The EU GDP is the basis of our Quality Management
X X
X X

X
X

X
X

X
X

X
X

X
X

X
X X

X
X

X
X X

System (QMS) on Supply Chain Controls.

FDA to Revise Component GMPs to Bolster
United States Bar Code Technologies for Drugs and X X
Standards for Securing Drug Supply Chain... X X X X X
Middle-Eastern European Region
Egypt Minster Decree for Wholesalers - Circular X X X X X X
Pharmacist Regulations - Circular 6 X X X X X X X X X X X X
Israel
Status of Current GDP Regulations in Israel X X X X X X X X X X X X X X X X X X X X
Romania NMA No. 30/24.09.2009 X X X X X X

Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031,

X X X X X X
Saudi Food & TOPA GTS - 6000
Drug Authority
UAE Circular No. 246-2011 X X X X X X
International Health Organizations
Updated Policy on Returns of Non-Defective X
Guidance on Preventing Breaches in the X X X X X X X X X
MHRA Cold Chain Distribution GDP Risk X X X X X X X X X X X X X X X
GDP Risk Assessment Strategy
Regulatory Provisions for Quality Controlled X X X X X X X X X X X X X
Model requirements for the storage and X X X X X X X X X X X X X X X X X X X X
WHO New Guidance for storage and transport of X X X X X X X X X X X X X X X
Temperature Controlled Management (TCM)

Temperature Controlled Product Management Process

2. Define
1. Define 3. Monitor
Temperature
Product Temperatures 4. Manage
Controls
Temperature (Storage) Exceptions
(Storage)
Requirements (Transport)
(Transport)

Stability Budget, Temp. Cycle

Studies, Product Stability
Testing
Know Your Product (Failure Points, High and Low)

Identify your product failure points will help determine level of control required
during shipping
Know what use you are developing the data for!
Supply Chain Security, Risk Control

8. Lab Test Product Authenticity

Supply Chain Risk Assessment - Process
Supply Chain Risk Assessment - Process

 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

Same philosophy for Distribution

The supply chain of medicinal products
should be known and documented
• Routes
• Carriers / contractors
• Conditions
 End-To-End approach
 = knowledge!
GDP Risk
Assessment
Process

45

©2016 | SUPPLY CHAIN RISK MANAGEMENT

GDP Risk Assessment - Process

 A cross-functional team approach must be utilized to

perform the task.
 Utilize the knowledge and experience of relevant staff
 A structured group discussion exercise can be an effective
forum
 Risk assessment does not need to be a complicated
process and should be appropriate to your
company/processes
 Communication of assessment outcome and follow up
actions

46

©2016 | SUPPLY CHAIN RISK MANAGEMENT

GDP Risk Assessment - Objectives

 The objective is to identify, understand and

prioritize current risks, evaluate the robustness of
current controls and develop remediation plans
when required to further strengthen the integrity
of the product supply chain.
 This risk assessment utilized quantitative
evaluation tools which detailed the risk involved in
the supply chain.
 The risk control strategy highlights the
quantitative evaluation results.
GDP Risk Assessment - Rating Risk

Severity Rating Scale (Process Impact) Severity Rating Scale (Patient Impact)
# Description Criteria
# Description Criteria
Stock out: DC shutdown; Regulatory
Death or Life-
5 Severe impact-- warning letter; 5 Death or Life-Threatening
Threatening
Restock/return

Supply chain excursion; failed Harm (injury) with residual (non-

4 Significant 4 High
batch/MDO (Investigation) reversible) pathology

Supply chain velocity slowdown Harm (injury) with reversible

3 Moderate 3 Moderate
(product or paperwork) pathology

2 2 Minor Minimal effect or injury

Minimal/Non-
1 Minor No impact 1 Non-safety Related
safety Related

• Regardless of the scale numbers (e.g. the above

scale), you need to define corresponding criteria
GDP Risk Assessment - Scope

During transportation the product attributes that need to be

assessed for potential impact to product quality are:
1. Transportation Security
 Typically involves the supplier status of the transportation
carrier (approved, audited, etc.), the certification status of the
transportation carrier and the physical security methods
employed by the transportation carrier.
2. Temperature Control Management
 Is the temperature adequately maintained throughout the
entire supply chain under evaluation. This incorporates
qualitative testing as applicable, stability data, the stage of
production and anticipated time in transit.
Manufacturing Supply
Chain
Risk Assessment & Risk
Control Strategy

©2016 | SUPPLY CHAIN RISK MANAGEMENT

Manufacturing Supply Chain Risk Assessment

(1) Supply Chain Security and (2) Temperature Control Management

main focus during Transportation Risk Assessment because of
potential direct product quality impact.
• The following information is showing an example of performing a
manufacturing supply chain risk assessment using a basic risk
ranking tool
• Various security attributes were assessed and assigned
numerical risk values.
• By multiplying those risk values an overall risk associated was
generated.
• Based on that overall value action is or is not then required to be
taken per the criteria identified
Transportation Security Criteria (3x)
Transportation Security Risk Ranking

By multiplying the determined rankings A, B & C an

overall supply chain security risk is determined.

Per the result:

• < 2: Security is adequate
• 2: Security is adequate however the ASL requires
updating
• > 2: Security may be adequate however the carrier needs
to be assessed, certified and added to the ASL
Transportation Security Criteria (3x)
Temperature Control Risk Ranking

By multiplying the determined rankings A, B, C & D an overall

temperature control risk is determined.

Per the result:

• >47: Transportation temperature control, temperature monitoring
and lane qualification are required
• 17-47: Transportation temperature control required, no temperature
monitoring required however lane qualification recommended
• 5-16: No temperature monitoring, temperature controls or lane
qualification required. For risk control ranking verification, periodic
monitoring may be implemented
• ≤ 4: No temperature control or monitoring requirements, no further
action required
Internal & External Monitoring

Know your product and analyze your data

Example of multiple shipments – same origin and destination, using a passive shipper
Need to know your supply chain temperature profiles and how your product reacts
Risk Control Strategy & Risk Assessment Summary

- example -

 This risk control strategy concludes that the supply

chain does maintain adequate product security and
temperature.
 As the security and temperature risk is minimal,
qualification of the lanes at this time is not required.
 Temperature monitoring will be performed for each
shipping lane in the manufacturing supply chain.
 Verification of the transportation security and
temperature requirements performed each time product
is received at the manufacturing site.
Conclusion

 Supply Chain Risk Assessments are important to prevent

drug shortages
 Supply Chain Mapping is a key element in the supply
chain risk management process
 Supplier Management program must be in place to
ensure supplier controls (e.g. audit program)
 Cross-functional team approach
 Warehouse operator training, driver awareness training to
include security aspects
 Do not underestimate the risk of data flows
 Quality Management as a Foundation
for Good Distribution Practices
Compliance

Glaucia Karime Braga, Ph.D.

•USP Packaging and Distribution Expert Committee Member
•USP <1079> Sub-Committee Co-Chair
•PPP Auditor, Quality Assurance, FURP - Sao Paulo State Government (BR)
Agenda

Quality Management System – QMS

 Understand the concept of a Quality System
 Know the key elements of a QMS for the storage and distribution
processes
 Key point: Having a Quality System that is build based on risks
and their mitigation strategies
Pharmaceutical Supply Chain - Overview
Risks and Mitigation Strategies

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Environmental Product Warehouse, Qualification /
storage or quality, Vehicle and Validation
shipping integrity and Packaging
conditions out patient safety Qualification
of specification (e.g. freezing of Documentation
(Temperature vaccine or Operations
out of biologic) SOP (storage,
specification) transportation)
Product loss
(e.g. money)
Risks and Mitigation Strategies

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Personnel Mishandling Appropriate
mistakes due anywhere number of
to excessive along the personnel in Organizational
duties and or supply chain order to avoid
lack of training excessive Training
duties being
placed to one
individual

Evaluate the
efficacy of
training
GDP: Key Point

Quality Management System

Documentation Training Qualification/Validation

Instructions, Schedules and Competence Development and Ensure suitability of the purpose
Records Instructions Understanding Warehouse/Packaging
System/Transportation and ERP
INFORMATION COMPREHENSION ASSURANCE

Mitigation Strategies

Process Knowledge & Risk Identification

The central idea is having a Quality System that is build based on risk. Generally, mitigation strategies are
related to instructions (SOPs), training (ensure instructions understanding) and Qualification/Validation
(warehouse temp map, packaging system, ERP software, process validation (in case of distribution, is the
transport mode/route validation).
And all of this are GDP requirements!
Quality Management Systems

 A Quality Management System (QMS) is defined as a set of interrelated

or interacting elements, such as policies, objectives, procedures,
processes, resources which individually or collectively, established to
guide an organization

 Risk-based approach
 QMS framework for all supply chain partners
 Can be integrated into other management

QMS systems:
– Quality (ISO 9001 and GMP)
– Environmental (ISO 14001)
– Occupational Health and Safety (OHSAS 18000)
Key Elements

Management
Responsibility

Regulatory
Documentation
Affairs

Validation/
Resources
Change
Control
QMS Management

Monitoring
Operations
Improvement
Complaints
Returns
Recalls
Documentation
Documentation

Quality Manual

Brief information on the

Identification of the processes and
organization
Activities as licensed by their sequences, linkages, and
the competence interdependences
Types of material, authorities Organizational Chart
products, services Matrix of key personnel
handled Scope and Overview of responsibilities
QMS
Reference to supporting procedures
and documents, such as Validation
Quality Police and Objectives
Master Plan and a list of SOPs
Operations

 Core Operations for Distribution:

• Procurement
• Receiving
• Sampling
• Storage
• Sales
• Picking
• Packing
• Shipping
• Transportation
• Outsourcing and service agreements
 For each one a SOP should be written!
Operations

 Procurement and Sales

• A list of all qualified suppliers and customers should be in
place
 Receiving and Shipping
• A checklist should be utilized as a reminder of what to
inspect and what to record when receiving goods
• Deliveries should be verified at receipt in order to check that
containers were not damaged and the consignment
corresponds to the order
Operations

 Storage
• The organization should have:
̶ A written procedure should be established for storage and inventory
control
̶ Each product and material should have a storage specification regarding
Temperature, Relative Humidity, and other Special Requirements
̶ Storage areas should be qualified and a temperature mapping and
monitoring program should be in place
 Storage: holding at production area is storage!
• Tablets or capsules waiting for packaging
 Picking & Packaging
• A written procedure should be established ensuring that the correct
product was selected, property packaged and dispatched
• Package should be appropriated and its qualification tests should be
performed according to approved protocols
Operations: Transportation

 Transportation
• A written procedure should be established, including at least:
– Responsibilities
– Approvals for subcontracting
– Methods for defining transportation routes
– Capacities and limitations of transportation systems
– Loading patterns (First-out, Last-in)

Transportation modes:
Choice criteria is related to:
scale of transportation (national or international),
nature of product,
level of service
Generally is used intermodal transportation

73
Resources Management

 Organization should have

• Organizational chart: responsibilities
• Job descriptions: tasks, competences, authorities
• Training: initial and ongoing, training needs, schedule, records and
effectiveness assessment
– Training SOP, should describe:
• Who can be a trainer (competences of a trainer)
• How training needs are identified and linked to job description
• Types of training needs
Resources Management

 Premises should be designed taking into account

• Security and safety
• Product characteristics
• Ease of cleaning and maintenance
• Logical flow of personnel and material
• Means of preventing mix-ups and cross contamination
• Ergonomic measures
Validation and Change Control
 Commissioning:
• Factory Acceptance Test (FAT)
• Site Acceptance Test (SAT)
 Qualification: The documented verification that the facilities, systems, and
equipment, as installed:
• Installation Qualification (IQ): comply with the approved design and
recommendations of the manufacturer
• Operation Qualification (OQ): operate within the ranges established by the
manufacturer
• Performance Qualification (PQ): operate for a long time with robusteness and
reproducibility within the specification established by the organization
 Validation
• Includes:
– Analytical Method
– Process
– Cleaning
– Computerized System
• Should have a Validation Master Plan (VMP), containing the strategy and the
rationale for the validation efforts
Validation and Change Control

 Core for packaging, storing and transportation is

ensuring the control of environmental conditions
 Two approaches:
• By controlling the environmental conditions in equipment, storage rooms and
transportation vehicles (e.g. heating, ventilation and air-conditioning HVAC,
refrigerator, (de)humidifier)
• By using packaging materials that allow the control of environmental conditions
(e.g. thermal blankets, temperature stabilizers, desiccants, light resistant
material)
Validation and Change Control

 Environmental controlled facilities, equipment and vehicles:

• Should have a validated SOP for storage and in-transit storage considering:
̶ Product category (prescription pharmaceuticals, narcotic, medical devices)
̶ Storage layout (floor-standing pallet, pallet racking, boxes inside the refrigerator)
̶ Volume of Storage (including peaks of storage)
̶ Environmental conditions and air circulation
̶ Contingency Plan for outages and breakdowns
 Should have a validated SOP for shipping package, considering:
• Environmental conditions during shipping
• Package system selection
• Product-package configuration for shipping
• Monitoring device necessity
• Temper evident closure system
• Forms and Records (during shipping and temporary storage)
• Documentation necessary for shipping (including labeling, courier documents)
78
Validation and Change Control

 Should be carried out to evaluate if the equipment,

warehouse facility, shipping container and temperature-
controlled vehicles perform as required. Can be any of
the following:
• Prospective (lab simulation):
̶ When documented evidence for PQ is generated before the
start-up of the operation or system
• Concurrent (cargo monitoring):
̶ When documented evidence for PQ is generated during the
actual operation of the system
• Retrospective (historical data):
̶ When documented evidence for PQ is generated using
historical data for systems
Validation and Change Control

 Performance Qualification Protocols:

• Should be approved prior to execution and should have:
̶ Responsibilities including third parties
̶ Material or product storage requirements as established by means of stability
studies (T and RH ranges allowed during storage and transportation)
̶ Description of the storage room or payload compartment, including dimensions,
layout, active environmental controls (coolers, heaters, etc.), power systems
̶ Location and volume of the material or product inside the storage room or
shipping container
̶ Packaging material
̶ Environmental conditions during storage and transportation
̶ Transportation mode, route, and duration
̶ Monitoring devices and alarms (warning systems) in place
̶ Temperature mapping to show whether temperatures are evenly distributed or if
there are hot or cold spots in storage areas and dedicated vehicles
̶ Acceptance criteria and approvals
̶ Audible or visible alarms or both should be in place if temperature or relative
humidity or both are out of specification:
̶ These alarms should be qualified and also periodically changed
Validation and Change Control
 Computerized Systems
• Extent of validation depends on the risk to/impact of the software on product
quality
• An inventory of computerized systems should be done periodically, including at
least:
̶ Software identification (name, version, supplier)
̶ Processes where software is used
̶ Process owner
̶ Risk assessment
̶ Status (validated, not validated, in progress, not applicable)
• A multidisciplinary team should be in charge of protocols and report approvals
• Software validation tests should cover:
̶ Security (e.g., access levels, profiles, responsibilities inclusion, exclusion, changing profiles)
̶ Data validity (e.g., challenge the software with entries above and below specification and with entry value
errors)
̶ Documentation (e.g., software design in accordance with user requirements and other documents)
̶ Functionality (e.g., calculations, operations)
̶ Note: Most of these tests for embedded software are covered during equipment qualification (installation,
operation, and performance qualifications)
̶ Data integrity (e.g.; changes, traceability, backup, recovery, protection)
• Records should be kept
Validation and Change Control

 Validation and Change Control

• The organization should have a written procedure describing
the steps for change control, including at least:
– Responsibilities
– Impact assessment of the change based on risk
– Necessary validation
– Documentation review
– Regulatory impact
– Necessity to have planned activities for the change.
• Customers and regulatory bodies should be notified of any
changes in packaging, handling, storage, transportation, or
documentation
Complaints, Deviations, Returns, Recalls

 Complaints
 Deviations
 Recalls
 Returns
• RECALLS: Quality/safety/efficacy issue (GMP) recall is
necessary to avoid the product from being used.
̶ Challenge: Send back what was shipped. However, product will be
destroyed
• RETURNS: There is NO quality/safety/efficacy issue. It´s a
logistic issue (GDP)
̶ Challenge: the core question is deciding if the returned product is
acceptable for restocking and resale or whether it should be destroyed.
̶ The product could be restocked for new selling (Risk)
Complaints, Deviations, Returns, Recalls
 Returns
• CRITICAL!!!! backward flow.
• A written procedure for handling returns should be in place
• A risk-based evaluation should be performed to determine if the product will be
accepted for restocking and resale or if it will be destroyed
• During the evaluation, returned products should be kept in a segregated area.
Restocking should be accepted only once
• The organization should inform customers if there is a returned product included
in their order, prior to shipment
• The evaluation should take into account at least the following:
– Reasons for return
– Appearance and integrity of the original packaging
– Evidence of conditions in which the cargo was transported and stored throughout the
entire time
– Duration of time between the original shipment and its return
– Authenticity of product
– Representative sampling for quality control analysis
– Expiry date and batch number
– Information from any track-and-trace system in place
Complaints, Deviations, Returns, Recalls

 Corrective Action and Preventive Action (CAPA) and

Continuous Improvement
 CAPA is a system established to perform actions to
eliminate the cause of a detected nonconformity or other
untoward situation in order to prevent reoccurrence
(corrective action) and actions to eliminate the cause of a
potential nonconformity or other untoward potential situation
to prevent occurrence (preventive action)
Complaints, Deviations, Returns, Recalls

 Monitoring and Improvement:

• Audit
• Product or Service Quality Reviews ~Annual Product Review:
• Management Reviews
• Corrective action and Preventive Action (CAPA)
• Continuous Improvement
 Management Reviews:
• QMS should be reviewed periodically
• Review by senior management of the suitability and effectiveness of
the QMS at defined intervals and with sufficient frequency according
to established procedures to ensure that the system satisfies the
requirements of the FDA and the manufactures established quality
policy and objectives
Complaints, Deviations, Returns, Recalls

 Some inputs for management reviews:

• Previous management reviews reports
• Audit and regulatory inspection reports and actions in place
• Complaints, deviations, returns and recalls
• Detected or potential counterfeiting
• Status and effectiveness of the CAPA system
• New or updated regulatory requirements
• Quality policy
• Quality objectives metrics as Key Performance Indicators
• Quality Manual and Change control reports
 Some outputs of the management reviews:
• Recommendations for improvement of the system, processes, products
or services
• Demand for resources
 The Importance of Temperature
Control and Best Practices for
Products Moving Through the Supply
Chain: Risks and Migration Strategies

Chris J. Anderson

• USP Packaging and Distribution Expert Committee Member

• USP <1079> Sub-Committee Co-Chair
• Director, Quality Systems, Cardinal Health
Temperature Control Risks and Mitigation Strategies

Storage, Packaging, and Transportation

 Maintaining manufacturer’s labeled temperatures for
storage and transportation is important to maintaining
product integrity to include efficacy and expiry
 Contingency storage and temperature excursion response
plans are (risk evaluation and mitigation) an important part
of operational management
 Responding to exceptions/excursions is important to
preventing product loss
 Documentation of temperatures and time is important to
obtaining dispositions from manufacturers
Temperature Control Risks and Mitigation Strategies

Storage, Packaging, and Transportation

 Storage Conditions
• Freezer: typically thermostatically between -25º and -10ºC (-13º and
14ºF)
• Refrigerator (Controlled Cold): between 2º and 8ºC (36º and 46ºF)
• Cold: Not exceeding 8ºC (46ºF)
• Cool: Between 8º and 15ºC (46º and 59ºF)
• Room Temperature: the temperature prevailing in a work area
• Controlled Room Temperature (CRT) product: Thermostatically
maintained between 20º and 25ºC (68º and 77ºF). Warm: Any
temperature between 30º and 40ºC (86º and 104ºF)
• Excessive Heat: any temperature above 40ºC (104ºF)
• Dry Place: does not exceed 40% average relative humidity at 20ºC (69ºF)
• Protect From Freezing
• Protect From Light
Today we are going to focus on Controlled Cold and Controlled Room Temperature
Product
Temperature Control Risks and Mitigation Strategies

Storage, Packaging, and Transportation

 Refrigerated (Controlled Cold) Product: 2-8ºC (36º
and 46ºF)
• Typically the most costly products
• Biologics, biosimilars, vaccines
• For packaging, colder is not better
̶ Dangers of freezing
• Shipping options:
̶ Active shippers
̶ Active temperature controlled vehicles
̶ Passive/qualified shippers
Temperature Control Risks and Mitigation Strategies

Storage, Packaging, and Transportation

 Controlled Room Temperature (CRT) Product: 20-
25ºC
• Excursions between 15º and 30ºC (59º and 86ºF) that are
experienced in pharmacies, hospitals, and warehouses,
and during shipment are allowed
• Maintain Mean Kinetic Temperature (MKT) ≤25ºC
• Provided the mean kinetic temperature does not exceed
25ºC, transient spikes up to 40ºC (104ºF) are permitted as
long as the do not exceed 24 hours.
• Biologics (think fever or hypothermia), injectables and oral
liquids and liquid suspension particulates
• The most challenging temperature range to maintain
Risk and Mitigation

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Storage Area Out-of-range cold or Qualification and Training for
Temperature Stability hot areas; product temperature “exceptions”;
storage temperature evaluation; storage Documentation ;
excursion; product temperature Validation;
loss; financial loss; monitoring program; Planning
patient product homogenous airflow;
availability monitoring, alarms;
and response plan
See “Excursions”
under Hazard
Temperature Out-of-range cold or Back-up monitoring Training for
Monitoring Device hot areas; product devices with “exceptions”;
Failure storage temperature independent power Documentation;
excursion; product source Maintenance
loss
See “Excursions”
under Hazard
Risk and Mitigation

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Storage /Temperature Out-of-range cold or Temperature and Training for
System Failure hot areas; product power alarms, back- “exceptions”;
• loss of electrical storage temperature up power and coolant Documentation;
power excursion; product systems (redundant) Maintenance;
• failure of loss and/or contingency Business Continuity
temperature control
storage; Plans
and air circulation
systems
• unusual weather See “Excursions”
event under Hazard

Product Stored in the Product storage System storage Training;

Wrong Environment temperature coding; product Documentation;
excursion; product storage notification; Communication
loss understanding
storage labels
Risk and Mitigation

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Fear of Reporting Product integrity and Independent quality Organizational;
Non- patient safety, reporting structure; Training;
conformance/Excepti serious conditions education on product Policy
on conditions not communicated integrity and the
impact to patients
and the supply chain
if discovered
Transportation – Out-of-range cold or Fuel contingencies, Training for
Delivery Delays hot areas; product in-route; “exceptions”;
storage temperature alternative/emergen Business Continuity
excursion; product cy storage; Plans
loss contingency vehicles;

See “Excursions”
under Hazard
Risk and Mitigation

HAZARD EFFECT MITIGATION MITIGATION

STRATEGY CATEGORY
Protective Packaging – Out-of-range cold or hot Qualify to account for Training for exceptions;
delivery delays beyond areas; product storage delays; Weather monitoring
package qualification temperature excursion; alternative/emergency (don’t assume that all is
product loss storage; conduct well just because a
extended testing (you carrier / transportation
can’t do anything company picked up your
without data); delivery); Contingency
reconditioning communication and
contingency; decision making plan
temperature monitors
Excursions – Out-of-range cold or hot Response plan; data Training for exceptions;
temperature or time areas; product storage gathering plan Documentation;
excursion exception temperature excursion; (template); Communication
response: mitigation of product loss Product quarantine
out-of-range process; customer,
temperature and/or trading partner and
time excursions (effect service vendor
of all Hazards listed communication
above)
Risk Mitigation Decision Map: Transportation Delay
of Controlled Cold Product
Risk Mitigation Decision Map: CRT Product Storage
Area Excursion
Risk Mitigation Decision Map: Product Temperature
Excursion Management Process
 Good Distribution Practices (GDPs):
Other Topics and Considerations

Matin L. Jeiven, MS, BPharm, RPh

• USP Clinical Trials Expert Panel Member
• President, Jeiven Pharmaceutical Consulting
Agenda

 How much is distribution (commercial and

clinical) considered by a company?
 How often is distribution an issue for
clinical trials?
 What do the GMPs say regarding proper
distribution?
Commercial and Investigational Drug Products

 Both must comply with GMPs (Good

Manufacturing Practices) for manufacture,
testing and packaging and labeling.
 Both most comply with the same warehousing
(storage) and distribution practices.
The Phases of Clinical Trials
Phase I
 Follow animal testing to help ensure the safety of the first human doses
 Typically at one or two sites, limited number of subjects
 Short duration
 Safety and perhaps some efficacy as the goal
 IDP (investigational drug product) limited in quantity
 Closely monitored
 Unusual to have robust stability profile
 Limited expiration date
Phase II (a and b)
 Multi-site, larger subject population
 Larger quantities of IDP
 Longer trial duration
 Domestic and international (?) sites
 Goals: establish efficacy, determine dosing regimen and identify potential
adverse events
 Usually include comparators
The Phases of Clinical Trials
Phase III
 Increasing larger trials
 Additional international sites
 Almost always include comparators
 Similar goals as for Phase II
 Will include pivotal trial(s)

Phase IV
 After-market trials
 Study additional indications and patient populations
 May or may not require large quantities of IDP
 Companies may have to commit to regulatory authorities that trials
will have to be conducted as a condition for product approval
Controlled Temperatures

Storage and Distribution Temperatures (USP):

 Liquid Nitrogen (submerged): -196°C
 Liquid Nitrogen (vapor phase): -150°C
 Dry Ice: -80°C
 Frozen: -25°C to -10°C
 Cold/Refrigerated: 2-8°C
 Cool: 8-15°C
 Controlled Room Temperature (CRT): 20-25°C
Global Temperature Challenges
External Temperature Influences

24 Hour Shipping Profile Example

Good Distribution Practices

 Global initiatives to apply Quality principles to the

distribution process:
• Guideline 2013/C 68/01: EU 2013
̶ Good Distribution Practice of Medicinal Products for Human Use

• GUI-0069: Health Canada 2011

̶ Guidelines for Temperature Control of Drug Products during Storage and
Transportation

• <1079>: USP
̶ Good Storage and Distribution and Practices for Drug Products

 Many others, including WHO, multiple individual countries,

IATA (International Air Transport Association), IPEC
(International Pharmaceutical Excipients Council), etc.
Quality Systems for Distribution

 Implement Basic Quality Systems:

• Oversight and responsibility
• Management review
• Deviation investigation and CAPA
• Complaint handling; recall process
• EU: designate Responsible (Qualified) Person
 Expectations for Control of Storage Areas in line with GMPs
• Calibration and qualification
• Mapping
• Monitoring
• Recordkeeping
 Control of environmental conditions during transportation
• EU: transport conditions = labeled conditions
• US: MKT (mean kinetic temperature) concept allows for excursions
What is Mean Kinetic Temperature?

Mean Kinetic Temperature (MKT) is a simplified way of expressing the overall

effect of temperature fluctuations during storage or shipment of perishable
goods.

Consider the following example:

EXAMPLE:
A dozen eggs sat:

In a 20°C room for 2 hours

In a 2°C refrigerator for 4 hours
And on a 25°C loading dock for 1 hour

Using MKT we can calculate that the temperature profile of the eggs
was “thermally equivalent” to storing them at 10.096°C for 7 hours.
How Mean Kinetic Temperature is Calculated

MKT is an expression of cumulative thermal stress experienced by a

product at varying temperatures during storage and distribution. MKT
is a calculated, single temperature that is analogous to the effects of
temperature variations over a period of time.

MKT is not a simple weighted average. The calculation of MKT gives the
higher temperatures a greater weight when computing the average
than would a simple numerical average or an arithmetic mean. This
weighting is determined by a geometric transformation— the natural
logarithm of the absolute temperature.
Packaging Solutions

 Active Systems:
• Internal energy source
̶ Engine, battery, etc.
• Actively heat or cool the shipper contents
• Examples:
̶ Envirotainer/Unicooler
̶ Temperature-controlled Trucks
Packaging Solutions

Thermo Chill Insulated Carton

with Foam Shipper, Small, 6"
Length x 5" Width x 6-1/2" Depth
Packaging Solutions

Non Reversible
Temperature Labels
29°C to 290°C / 84°F - 554°F

Time Temperature
Indicators Relative Humidity Sensing
-18°C to 37°C / 0°F to 98°F Humidity Range 0%-100% RH
Packaging Solutions

Single Use Strip Chart Temperature Recorder

Low Cost Recording of Temperature for HACCP

and Quality Control documentation.

Introducing the TempCheck3, a reliable and

cost-effective strip chart temperature recorder.
The TempCheck3 is driven by a high-torque
quartz motor and displays the time and
temperature on strip chart paper in both
Celsius and Fahrenheit.
Sample of strip chart recording
Packaging Solutions
Multi-Use Temperature Data Loggers
Electronic data loggers have been designed to offer different models for varying
applications. They range from the most exacting requirements such as laboratories
who require NIST certification and calibration, to everyday use such as a temperature
monitoring for refrigeration of perishable products. All data loggers use an internal
thermistor for measuring temperature and share the same basic palm-sized or smaller
design.
RF Wireless Recorders Ethernet & WiFi Recorders
Collect, monitor and
Our WiFi products let you leverage
manage temperature data
your existing WiFi network with the
via wireless
built-in WiFi b/g/n connectivity and
communication in real
avoid expensive installation costs
time. -40°C to +72°C or -
for managing temperature data.
80°C to +30°C.
Temperature range options of -
40°C to +72°C (-40°F to +160°F)
or -80°C to +30°C (-112°F to
+86°F).
Cold Chain Packout for IMP

Temperature Control
Packout Example Clinical
Supplies
Insulation
PCMs
Packaging Solutions

 Passive Systems
• Rely on Phase Change Materials
• Insulated Shipper
Phase Change Materials

 Many companies have developed suitable

PCMs of different (proprietary) composition
• Composition of PCM and construction of shipper
allow temperature-controlled shipments at different
temperature points and of varying durations
GDP for Controlled Room Temperature

 Evolution of established controls from

refrigerated products to controlled room
temperature products
• Storage conditions specified on label
• Conditions must be met during shipping and
distribution
Qualification vs. Validation

 What is the difference when considering Distribution?

• Qualification:
̶ Quality of the equipment (i.e., container)
̶ Tested under standard highly controlled conditions
̶ (“Pre-Qualified” Shippers)
• Validation:
̶ Quality of the process (i.e., combination container and
environment)
̶ Tested by simulating/mimicking actual payloads and actual
transport temperature profiles
̶ (“Validated” Shippers)
Examples of Pre-Qualified Shippers

Cryopak

Credo

Cold Chain Technologies

Temperature Monitoring

 Single use/Multiple use

 Level of information
• Full curve
• Yes/no indicator
 Electronic/Paper
 Temperature range
 Readable at destination vs. Return to sender

Most important: evaluate excursions to assess

suitability of product
Temperature Monitoring

Monitor Report
 Alarm status
 Alarm set points
 Duration of excursion
 Highest/lowest
temperature
 Calculation of MKT
• Mean kinetic temperature
 Documentation of
temperature conditions
during entire transit
Temperature Excursions

 Evaluation of temperature excursions must be

grounded in stability data—consider the effect of
the excursion on the physical and chemical
characteristics of the drug product
 Problem: in early development, stability data may
be limited
• Shipping and storage conditions are restrictive
• Excursions outside of available data may force decision
that product is unusable
 Consider limited stability data to support excursions
Assessing and Mitigating Supply Chain Risk

Whether our supply chain is for commercial products or IDPs, performing a

risk assessment will identify those procedures and equipment that could
put our shipments in jeopardy. There are a number of methods used to
evaluate risk, any of which (including HAZOP=Hazard and Operability
Study) should comply with ICH Q9. To be most effective, the assessment
includes a review of the qualification for containers (passive and active)
that will protect our products from transport hazards.

If HAZOP is the chosen method, the key components include:

• potential deviations from the supply chain design
• causes of these deviations
• consequences of these deviations
• determination if the existing safeguards are adequate
• actions necessary if additional safeguards are required
Guideline for Calculating Shipments Risk
Product Storage External Storage Environmental Overall Duration Vehicle Overall
Conditions Environmental Risk Risk Rating Product Of Shipment
Conditions Rating Risk Journey Risk Rating
Rating
Example 2°-8° 28° 3 3 9 2 3 54

Can’t change these

Can manage these
Storage condition risk rating is defined as:

0°-30° =1
15°-25° =2 Overall risk rating:
2°-8° =3
0-10 = very low risk
External environment risk rating is defined as: 11-25 = low risk
26-40= medium risk
Winter (2°-10°) =1
Spring/autumn (10°-20°) =2 41-65= high risk
Summer (>20°) =3 66-75= very high risk

Duration of journey risk rating is defined as:

Vehicle: 1 = temperature-controlled/validated container
1-5 h =1 2 = insulated truck
5-15h =2
3 = no specific controls
>15h =3
Importation Considerations

 Registration (CTA=Clinical Trial Application,

MAA=Marketing Authorization Application, in
the EU+), if required
 Import License, if required
 Valuation for Customs
 Harmonized Tariff Schedule (HTS) code
 COA, if available
 Country specific documentation requirements