Integrating the Global GDPs into the · Guidelines for Correct Distribution of Human Czech GDP...

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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?

To have a good QRM program you must have

1. A well designed process (QMS) to demonstrate control

2. Great data (data integrity)

What are the GDPs? GDP Dashboard

General

GDPs GIP TCM DCSPort

Handling / Customs

OffloadingGeneral Layout /

Contruction

Loading & Receiving

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

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

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?

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

Contruction

Loading & Receiving

General Security

Storage Areas

General Lableling

Relabeling

Training

Good Documentatio

n Practices

Stock Control

Systems

Product Compaint

Procedures

Disposal

GS1 Identification

Tracking

X X X X X XEMA X X

X XX X X X X

Romania X X X X X X

X X X X X X

UAE X X X X X X

XX X X X X X X X X

NMA No. 30/24.09.2009

Countries

• 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

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

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 !

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

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

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.

• 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

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

Contruction

Loading & Receiving

General Security

Storage Areas

General Lableling

Relabeling

Training

Good Documentatio

n Practices

Stock Control

Systems

Product Compaint

Procedures

Disposal

GS1 Identification

Tracking

X X X X X XEMA X X

X XX X X X X

Romania X X X X X X

X X X X X X

UAE X X X X X X

XX X X X X X X X X

NMA No. 30/24.09.2009

Countries

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

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

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

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

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

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

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

Procurement and Sales • A list of all qualified suppliers and customers should be in

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

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)

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)

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

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

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 • 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

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)

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

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

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

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

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

MITIGATION CATEGORY

Storage /Temperature System Failure • loss of electrical

power • failure of

temperature control and air circulation systems

• unusual weather event

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

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

Fuel contingencies, in-route; alternative/emergency storage; contingency vehicles; See “Excursions” under Hazard

Training for “exceptions”; Business Continuity Plans

Risk and Mitigation

MITIGATION CATEGORY

Protective Packaging – delivery delays beyond package qualification

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)

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

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

Integrating the Global GDPs into the · Guidelines for Correct Distribution of Human Czech GDP...

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