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 2. What is a QMS and integrating GDPs
Supply Chain Temp Mgt • ICH Q1A – standard stab testing • Establishing “storage” label claim • Temperature cycles studies • File the “cycling studies” • Develop a stability budget • Excursion management
Supply Chain map • What is it, where did it come from
Are you sure?
4
To have a good QRM program you must have
1. A well designed process (QMS) to demonstrate control
2. Great data (data integrity)
5
What are the GDPs? GDP Dashboard
General
GDPs GIP TCM DCSPort
Handling / Customs
OffloadingGeneral Layout /
Contruction
Loading & Receiving
Bays
Building Cleanliness
General Security
Temperature Monitored
Storage Areas
Product Stability Profiles
Temperature-Controlled Transport
Humidity Control and Monitoring
Shipping Containers & Packing
General Lableling
Relabeling
Packaging, Prcoessing
Qualified Personnel,
Training
Good Documentatio
n Practices
Stock Control
Systems
Exception Management &
Product Compaint
Procedures
Product Return, Recall,
Withdraw, Control and
Disposal
Serialization & ePedigree
GPS and Bulk Security, Counterfeits
GS1 Identification
Traceability / Stock
Tracking
Argentina X X XBrazil X X X X X X X X XMexico x x x x x x x x
Australia X X X X X X X X X X X X X XX X X X X X X XX X X X X X X X X X X X X X X X
Japan X X XMalaysia X X X X X X X X X X X X X X X X X X X X XSingapore X X X X X X X X X X X X X X X X XSouth Africa X X X X X X X X X X X X X X X X XPhillipines X X X X X X X X X X X X X X X X X X X X
Austria X X X X X X XX X X X X X X X X X X X X X X
X X X X X XEMA X X
X X X X X X X X X X X X X X X XX X X X X X X
X X X X X X X X X X X X X X X X X
Ireland X X X X X X X X X X X X X X XSwitzerland X X X X X X X X X X X X X
Canada X X X X X X X X X X
X XX X X X X
Egypt X X X X X XX X X X X X X X X X X XX X X X X X X X X X X X X X X X X X X X
Romania X X X X X X
Saudi Arabia, Saudi Food & Drug Authority
X X X X X X
UAE X X X X X X
XX 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 XX X X X X X X X X X X X X X X X X X X XX X X X X X X X X X X X X X XWHO
Model requirements for the storage and New Guidance for storage and transport of
Directive 2001/83/EC of the European
International Health Organizations
MHRA
Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment StrategyRegulatory Provisions for Quality Controlled
NMA No. 30/24.09.2009
GCC Guidelines for Stability, PP-SPC-9031, TOPA GTS - 6000
Circular No. 246-2011
Middle-Eastern European RegionMinster Decree for Wholesalers - Circular
Israel Pharmacist Regulations - Circular 6Status of Current GDP Regulations in Israel
North American RegionGuidelines for Temperature Control of Drug
United StatesFDA to Revise Component GMPs to Bolster Bar Code Technologies for Drugs and Standards for Securing Drug Supply Chain...
Distribution of Temperature Controlled
xRx-360 Summary of IPEC GDPGuide to Control and Monitoring of Storage
x xx x x xx x xx x x xx x x
European Medicines Agency: " QP
EU
Guidelines on Good Distribution Practice of
The IPEC Good Distribution Practices GuideEurope - Good Distribution Practices Audit
Austrian GDP RegulationsCzech Republic
Guidelines for Correct Distribution of Human Czech GDP Guidelines
Adoption and Implementation of the World Central European Region
Biological Pharma Revision H15.5.15Guidelines on Good Distribution PracticeGuidance Notes on Good Distribution Good Whilesaling Practice for Wholesales,
Code of Good Wholesaling Practice for
India (OPPI)Cold Chain Pharmaeutical ProductsGuideline on Good Distribution Practices for
Guidelines for Imported Biotechnological &
Inventory Procedures
LAA RegionRegulating the Cold Chain of Medicines (Ley Resolution - RDC No. 234
GDP's Quality Systems
Countries
Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling
Just like there are core elements to other GxPs (e.g. cGMPs):
1. PV, Cleaning Validation, E/U/F Validation 2. Test Method Development and TMT 3. Audits (Internal and External), SQA: QTA, QQ and QTA 4. Change Control / Change Mgt 5. Exception Mgmt., CAPA, Complaints, AE / PV 6. QRM
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?
6
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)
GDPs are a “Logical” extension of the GMPs General
GDPs GIP TCM DCSPort
Handling / Customs
OffloadingGeneral Layout /
Contruction
Loading & Receiving
Bays
Building Cleanliness
General Security
Temperature Monitored
Storage Areas
Product Stability Profiles
Temperature-Controlled Transport
Humidity Control and Monitoring
Shipping Containers & Packing
General Lableling
Relabeling
Packaging, Prcoessing
Qualified Personnel,
Training
Good Documentatio
n Practices
Stock Control
Systems
Exception Management &
Product Compaint
Procedures
Product Return, Recall,
Withdraw, Control and
Disposal
Serialization & ePedigree
GPS and Bulk Security, Counterfeits
GS1 Identification
Traceability / Stock
Tracking
Argentina X X XBrazil X X X X X X X X XMexico x x x x x x x x
Australia X X X X X X X X X X X X X XX X X X X X X XX X X X X X X X X X X X X X X X
Japan X X XMalaysia X X X X X X X X X X X X X X X X X X X X XSingapore X X X X X X X X X X X X X X X X XSouth Africa X X X X X X X X X X X X X X X X XPhillipines X X X X X X X X X X X X X X X X X X X X
Austria X X X X X X XX X X X X X X X X X X X X X X
X X X X X XEMA X X
X X X X X X X X X X X X X X X XX X X X X X X
X X X X X X X X X X X X X X X X X
Ireland X X X X X X X X X X X X X X XSwitzerland X X X X X X X X X X X X X
Canada X X X X X X X X X X
X XX X X X X
Egypt X X X X X XX X X X X X X X X X X XX X X X X X X X X X X X X X X X X X X X
Romania X X X X X X
Saudi Arabia, Saudi Food & Drug Authority
X X X X X X
UAE X X X X X X
XX 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 XX X X X X X X X X X X X X X X X X X X XX X X X X X X X X X X X X X XWHO
Model requirements for the storage and New Guidance for storage and transport of
Directive 2001/83/EC of the European
International Health Organizations
MHRA
Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment StrategyRegulatory Provisions for Quality Controlled
NMA No. 30/24.09.2009
GCC Guidelines for Stability, PP-SPC-9031, TOPA GTS - 6000
Circular No. 246-2011
Middle-Eastern European RegionMinster Decree for Wholesalers - Circular
Israel Pharmacist Regulations - Circular 6Status of Current GDP Regulations in Israel
North American RegionGuidelines for Temperature Control of Drug
United StatesFDA to Revise Component GMPs to Bolster Bar Code Technologies for Drugs and Standards for Securing Drug Supply Chain...
Distribution of Temperature Controlled
xRx-360 Summary of IPEC GDPGuide to Control and Monitoring of Storage
x xx x x xx x xx x x xx x x
European Medicines Agency: " QP
EU
Guidelines on Good Distribution Practice of
The IPEC Good Distribution Practices GuideEurope - Good Distribution Practices Audit
Austrian GDP RegulationsCzech Republic
Guidelines for Correct Distribution of Human Czech GDP Guidelines
Adoption and Implementation of the World Central European Region
Biological Pharma Revision H15.5.15Guidelines on Good Distribution PracticeGuidance Notes on Good Distribution Good Whilesaling Practice for Wholesales,
Code of Good Wholesaling Practice for
India (OPPI)Cold Chain Pharmaeutical ProductsGuideline on Good Distribution Practices for
Guidelines for Imported Biotechnological &
Inventory Procedures
LAA RegionRegulating the Cold Chain of Medicines (Ley Resolution - RDC No. 234
GDP's Quality Systems
Countries
Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling
• Good Distribution Practices (GDPs) • Security Audits & Supply Chain Controls • Marketing Authorization and License
Control • S. Africa GWP
• Good Import Practices (GIPs) • Export Controls • Supply Chain Maps
• What is it – where did it come from
• 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
8
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
Falsified Medicine Directive
API importation into the EU listed and non-listed countries and SC maps
Standard Supply Chain Maps Regulatory Starting Material through Distribution
• Example
10
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
“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 18
Know what use you are developing the data for !
19
File the data!
Know Product Failure Points
That will help determine level of control needed during shipping How the product reacts at highs (50C) and lows (-20C)
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
27
Bulk Drug Shipment Temperature Monitoring
Pack out at Mfg’ing site
Belly of plane
Transport to packaging site
Arrival at packaging site
Mean ambient temperature at Airport on 6/19/2014: 16.11°C
Mean ambient temperature at O’Hare on 6/22/2014: 21.17°C
Held by Port (CBP, MoH, etc))
Stability Budget
Passive Shippers: one origin, multiple destinations
• Internal & External Monitoring – Know your product and know your data
Loading
Tarmac handling
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 2-8
Granulator Room temp
Fluid Bed Dryer 60C
Tablet press Room temp
GDP
BDS (API) Singapore 2-8
Tableting (BDP) Ireland Room Temp
Packaging (BDP) Germany Room Temp
Finishing (market Specific) 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)
34
©2016 | SUPPLY CHAIN RISK MANAGEMENT
GDP Regulations Risk Management
EU Falsified Medicines Directive (FMD) June 2011
Importation of Active Substances
‘Active Pharmaceutical Ingredients Import Control’
Issued 23 January 2013 +
GDP for Active Substance Effective 25 May 2015
EU Good Distribution Practices (GDP)
Issued March 2013 Re-issued Nov. 2013
EU Safety Features 2D-Matrix barcode + Anti-Tampering Devices
Effective 9th Feb 2016
Internet Sales Common logo 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 ‘Wholesale distributors must maintain a quality system setting out responsibilities, processes and risk management principles in relation to their activities’ 1.5 Quality Risk Management Refers to ICH Q9 (2005) ‘The level of effort, formality and documentation of the process should be commensurate with the level of risk.’ 3. Premises and Equipment ‘qualification activities should be determined using a documented risk assessment approach’
6.3 Returns ‘Returned products must be handled according to a written, risk based process’ 9. Transportation ‘A risk based approach should be utilized when planning transportation’ ‘Risk assessment of delivery routes should be used to determine where temperature controls are required’ Also reference: PDA Technical Report 58 Risk Management for Temperature Controlled Distribution
GDP’s Around the World
General GDPs GIP TCM DCS
Port Handling / Customs
OffloadingGeneral Layout /
Contruction
Loading & Receiving
Bays
Building Cleanliness
General Security
Temperature Monitored
Storage Areas
Product Stability Profiles
Temperature-Controlled Transport
Humidity Control and Monitoring
Shipping Containers & Packing
General Lableling
Relabeling
Packaging, Prcoessing
Qualified Personnel,
Training
Good Documentatio
n Practices
Stock Control
Systems
Exception Management &
Product Compaint
Procedures
Product Return, Recall,
Withdraw, Control and
Disposal
Serialization & ePedigree
GPS and Bulk Security, Counterfeits
GS1 Identification
Traceability / Stock
Tracking
Argentina X X XBrazil X X X X X X X X XMexico x x x x x x x x
Australia X X X X X X X X X X X X X XX X X X X X X XX X X X X X X X X X X X X X X X
Japan X X XMalaysia X X X X X X X X X X X X X X X X X X X X XSingapore X X X X X X X X X X X X X X X X XSouth Africa X X X X X X X X X X X X X X X X XPhillipines X X X X X X X X X X X X X X X X X X X X
Austria X X X X X X XX X X X X X X X X X X X X X X
X X X X X XEMA X X
X X X X X X X X X X X X X X X XX X X X X X X
X X X X X X X X X X X X X X X X X
Ireland X X X X X X X X X X X X X X XSwitzerland X X X X X X X X X X X X X
Canada X X X X X X X X X X
X XX X X X X
Egypt X X X X X XX X X X X X X X X X X XX X X X X X X X X X X X X X X X X X X X
Romania X X X X X X
Saudi Arabia, Saudi Food & Drug Authority
X X X X X X
UAE X X X X X X
XX 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 XX X X X X X X X X X X X X X X X X X X XX X X X X X X X X X X X X X XWHO
Model requirements for the storage and New Guidance for storage and transport of
Directive 2001/83/EC of the European
International Health Organizations
MHRA
Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment StrategyRegulatory Provisions for Quality Controlled
NMA No. 30/24.09.2009
GCC Guidelines for Stability, PP-SPC-9031, TOPA GTS - 6000
Circular No. 246-2011
Middle-Eastern European RegionMinster Decree for Wholesalers - Circular
Israel Pharmacist Regulations - Circular 6Status of Current GDP Regulations in Israel
North American RegionGuidelines for Temperature Control of Drug
United StatesFDA to Revise Component GMPs to Bolster Bar Code Technologies for Drugs and Standards for Securing Drug Supply Chain...
Distribution of Temperature Controlled
xRx-360 Summary of IPEC GDPGuide to Control and Monitoring of Storage
x xx x x xx x xx x x xx x x
European Medicines Agency: " QP
EU
Guidelines on Good Distribution Practice of
The IPEC Good Distribution Practices GuideEurope - Good Distribution Practices Audit
Austrian GDP RegulationsCzech Republic
Guidelines for Correct Distribution of Human Czech GDP Guidelines
Adoption and Implementation of the World Central European Region
Biological Pharma Revision H15.5.15Guidelines on Good Distribution PracticeGuidance Notes on Good Distribution Good Whilesaling Practice for Wholesales,
Code of Good Wholesaling Practice for
India (OPPI)Cold Chain Pharmaeutical ProductsGuideline on Good Distribution Practices for
Guidelines for Imported Biotechnological &
Inventory Procedures
LAA RegionRegulating the Cold Chain of Medicines (Ley Resolution - RDC No. 234
GDP's Quality Systems
Countries
Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling
There are core elements to all world-wide GDPs, just like there
are core elements to other GxPs (e.g. GMP)
The EU GDP is the basis of our Quality Management System (QMS) on Supply Chain Controls.
Temperature Controlled Management (TCM)
1. DefineProduct
Temperature Requirements
Temperature Controlled Product Management Process
2. Define Temperature
Controls(Storage)
(Transport)
3. Monitor Temperatures
(Storage)(Transport)
4. Manage Exceptions
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!
45
GDP Risk Assessment Process
©2016 | SUPPLY CHAIN RISK MANAGEMENT
©2016 | SUPPLY CHAIN RISK MANAGEMENT
GDP Risk Assessment - Process
46
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
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
• Regardless of the scale numbers (e.g. the above scale), you need to define corresponding criteria
Severity Rating Scale (Process Impact) Severity Rating Scale (Patient Impact)
# Description Criteria # Description Criteria
5 Severe Stock out: DC shutdown; Regulatory impact-- warning letter; Restock/return
5 Death or Life-Threatening Death or Life-Threatening
4 Significant Supply chain excursion; failed batch/MDO (Investigation) 4 High Harm (injury) with residual (non-
reversible) pathology
3 Moderate Supply chain velocity slowdown (product or paperwork) 3 Moderate Harm (injury) with reversible
pathology
2 2 Minor Minimal effect or injury
1 Minor No impact 1 Minimal/Non-safety Related Non-safety Related
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)
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
Agenda
Pharmaceutical Supply Chain - Overview
Risks and Mitigation Strategies
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Environmental storage or shipping conditions out of specification (Temperature out of specification)
Product quality, integrity and patient safety (e.g. freezing of vaccine or biologic) Product loss (e.g. money)
Warehouse, Vehicle and Packaging Qualification Operations SOP (storage, transportation)
Qualification / Validation Documentation
Risks and Mitigation Strategies
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Personnel mistakes due to excessive duties and or lack of training
Mishandling anywhere along the supply chain
Appropriate number of personnel in order to avoid excessive duties being placed to one individual Evaluate the efficacy of training
Organizational Training
GDP: Key Point
Quality Management System
Process Knowledge & Risk Identification
Mitigation Strategies
Documentation Training Qualification/Validation Instructions, Schedules and
Records
INFORMATION
Competence Development and Instructions Understanding
COMPREHENSION
Ensure suitability of the purpose Warehouse/Packaging
System/Transportation and ERP ASSURANCE
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!
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
Quality Management Systems
QMS Risk-based approach QMS framework for all supply chain partners Can be integrated into other management
systems: – Quality (ISO 9001 and GMP) – Environmental (ISO 14001) – Occupational Health and Safety (OHSAS 18000)
Key Elements
Regulatory Affairs
Validation/ Change Control
Monitoring Improvement
Complaints Returns Recalls
Operations
Resources
Management
Documentation
Management Responsibility
QMS
Documentation
Quality Manual
Brief information on the organization
Activities as licensed by the competence
authorities Types of material, products, services
handled Scope and Overview of QMS
Quality Police and Objectives
Identification of the processes and their sequences, linkages, and
interdependences Organizational Chart
Matrix of key personnel responsibilities
Reference to supporting procedures and documents, such as Validation
Master Plan and a list of SOPs
Documentation
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
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
73
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
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
Resources Management
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
78
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)
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
Validation and Change Control
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
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
Temperature Control Risks and Mitigation Strategies
Risk and Mitigation
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Storage Area Temperature Stability
Out-of-range cold or hot areas; product storage temperature excursion; product loss; financial loss; patient product availability
Qualification and temperature evaluation; storage temperature monitoring program; homogenous airflow; monitoring, alarms; and response plan See “Excursions” under Hazard
Training for “exceptions”; Documentation ; Validation; Planning
Temperature Monitoring Device Failure
Out-of-range cold or hot areas; product storage temperature excursion; product loss
Back-up monitoring devices with independent power source
See “Excursions” under Hazard
Training for “exceptions”; Documentation; Maintenance
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Storage /Temperature System Failure • loss of electrical
power • failure of
temperature control and air circulation systems
• unusual weather event
Out-of-range cold or hot areas; product storage temperature excursion; product loss
Temperature and power alarms, back-up power and coolant systems (redundant) and/or contingency storage; See “Excursions” under Hazard
Training for “exceptions”; Documentation; Maintenance; Business Continuity Plans
Product Stored in the Wrong Environment
Product storage temperature excursion; product loss
System storage coding; product storage notification; understanding storage labels
Training; Documentation; Communication
Risk and Mitigation
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Fear of Reporting Non-conformance/Exception conditions
Product integrity and patient safety, serious conditions not communicated
Independent quality reporting structure; education on product integrity and the impact to patients and the supply chain if discovered
Organizational; Training; Policy
Transportation – Delivery Delays
Out-of-range cold or hot areas; product storage temperature excursion; product loss
Fuel contingencies, in-route; alternative/emergency storage; contingency vehicles; See “Excursions” under Hazard
Training for “exceptions”; Business Continuity Plans
Risk and Mitigation
HAZARD EFFECT MITIGATION STRATEGY
MITIGATION CATEGORY
Protective Packaging – delivery delays beyond package qualification
Out-of-range cold or hot areas; product storage temperature excursion; product loss
Qualify to account for delays; alternative/emergency storage; conduct extended testing (you can’t do anything without data); reconditioning contingency; temperature monitors
Training for exceptions; Weather monitoring (don’t assume that all is well just because a carrier / transportation company picked up your delivery); Contingency communication and decision making plan
Excursions – temperature or time excursion exception response: mitigation of out-of-range temperature and/or time excursions (effect of all Hazards listed above)
Out-of-range cold or hot areas; product storage temperature excursion; product loss
Response plan; data gathering plan (template); Product quarantine process; customer, trading partner and service vendor communication
Training for exceptions; Documentation; Communication
Risk and Mitigation
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
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?
Agenda
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
Relative Humidity Sensing Humidity Range 0%-100% RH
Time Temperature Indicators
-18°C to 37°C / 0°F to 98°F
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
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.
Multi-Use Temperature Data Loggers
RF Wireless Recorders
Collect, monitor and manage temperature data via wireless communication in real time. -40°C to +72°C or -80°C to +30°C.
Ethernet & WiFi Recorders
Our WiFi products let you leverage your existing WiFi network with the built-in WiFi b/g/n connectivity and avoid expensive installation costs for managing temperature data. 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
PCMs Insulation
Clinical Supplies
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
Credo
Cold Chain Technologies
Cryopak
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 Conditions
External Environmental
Conditions
Storage Risk
Rating
Environmental Risk Rating
Overall Product
Risk Rating
Duration Of
Journey
Vehicle Overall Shipment
Risk Rating
Example 2°-8° 28° 3 3 9 2 3 54
Can manage these Can’t change these
Storage condition risk rating is defined as: 0°-30° =1 15°-25° =2 2°-8° =3 External environment risk rating is defined as: Winter (2°-10°) =1 Spring/autumn (10°-20°) =2 Summer (>20°) =3 Duration of journey risk rating is defined as: 1-5 h =1 5-15h =2 >15h =3
Overall risk rating:
0-10 = very low risk
11-25 = low risk
26-40= medium risk
41-65= high risk
66-75= very high risk
Vehicle: 1 = temperature-controlled/validated container
2 = insulated truck
3 = no specific controls
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