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Supply Chain Qualification

Rafik H Bishara, Ph.D.

Technical Advisor

Chair, Pharmaceutical Cold Chain Interest Group

(PCCIG)

Parenteral Drug Association (PDA)

Sindusfarma / ANVISA / FIP-IPS

Brasilia, June 24-25, 2013

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Global Regulatory Requirements

Domestic Regulations

Global Regulations

Pharmacopeial Requirements

Industry Best Practices

Public Standards

3

Regulatory and Standards-Based Guidance

Standards

USP <1079>, <1083>, <1118>

<1197>

IATA PCR, Ch. 17, 2009

AFF et SFSTP *. ISTA

Industry Best

Practices

PDA Technical Reports

39, 46, 52, 53, 58

Regulatory Guidance

Argentina

Australia

Austria

Bahrain

Brazil

Canada

China

Czech Rep.

Egypt

EU

FDA

ICH

India

Ireland

Italy

Jordan

Mexico

MHRA

Romania

Singapore

Saudi Arabia

S. Africa

S. Korea

UAE

Syria

Venezuela

WHO

Reference: Rafik H. Bishara, “The Impact of USP <1079> on Cold Chain Management”, March 7, 2006 (Sensitech Sponsored Webinar),

Revised January 17, 2013

* Guide Pratique: Chaine du froid du medicament

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ANVISA

National Sanitary Surveillance Agency

Resolution – RDC # 234, of August 17, 2005

2nd Article: “The importing company is liable for the quality,

efficacy, and safety of the imported lots of biological

products…”

3rd Article: “The importing company (registration owner) of

Finished Biological Products Lots… shall be exempted of

performing quality control tests…when meeting all the

following requirements.”

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ANVISA

National Sanitary Surveillance Agency (cont’d.)

3rd Article: (Paragraphs 1-7)

• 6th Paragraph: “The importing company (registration owner) must

present continuous recordings of the transport chain temperatures

proving that the product has been kept under recommended

storage and transport conditions.“

• “The temperature records shall identify the name of the product, the

number of the lot, time and date in which it was delivered and

received.”

• “The storage and transport conditions must be specified in the

Import License, according to the conditions established in the

registration of the finished biological product to be imported.”

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Increased Focus on End-to-End

Cold Chain Compliance

Republic of Argentina – Law 26,492 - Official Bulletin

• Enacted March 26, 2009 – Enforceable March 26, 2011

• “all medicine for human or animal use containing thermolabile

active principles must have a temperature indicator incorporated

in the individual container … that will provide confirmation that said

product has not lost the cold chain by the time it reaches the

consumer.”

• “The indicator will be installed by the factory and must remain on

the medicine, even on the individual consumer unit.”

• “For multidose packaging, the indicator must remain on the

container, so that the consumer can check to see that the cold

chain was not interrupted…”

Reference: Official Bulletin of the Republic of Argentina, Law 26,492 “Law for Regulating The Cold Chain of Medicine”,

March 26, 2009

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Increased Focus on End-to-End

Cold Chain Compliance (cont’d.)

Mexico Ministry of Health (MOH) – Official Letter

• “The cold chain report must correspond to the temperature of the

product , not to the external one.”

• “The devices that do not keep a punctual record of the temperature

during the whole transportation period will not be accepted as

neither those that activate the alarms for the temperatures above or

under the authorized temperature range in the labeling projects

(for example – Freeze Tag®, Reagent Stripes, etc.).”

• Mexican MOH only allowing use of data loggers not allowing use of

electronic or chemical indicators

Reference: Official Letter, Mexico D.F. , Commission of Sanitary Authorization, December 2007

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Saudi Arabia: Saudi Food and Drug Authority

Decree No. M/6 25/01/1428H, 01/07/1430H, 29/01/1427H

Ministry of Health and Customs General Department –

Placement of Temperature Measuring Gauge on Drug Shipments

“A temperature monitoring device must be placed for measuring

the shipment temperature and it shall be activated from the time

of shipment until the arrival of shipment to the point of entry”

Phase 1 – March 1, 2011 - Refrigerated (2-8 degrees Celsius)

Phase 2 – June 1, 2011 – “All drug shipments”

FAQ (Frequently Asked Questions for Temperature Monitors)

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Regulatory Oversight – World Health

Organization (WHO)

Technical Report No. 961, 2011

“Model guidance for the storage and transport of time- and

temperature–sensitive pharmaceutical products”

Table of Contents

Importation Warehousing Sites Storage Buildings Temperature-controlled storage Materials Handling Transport and Delivery

Labeling Stock Management General Procedures and Record Keeping Environmental Management Quality Management Personnel/Training

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IATA Label Revised October, 2009

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Regulatory Guidance Pushing Cold Chain

Visibility

Expanding In-Transit Monitoring Market

Manufacturing plant Raw materials Healthcare facility Wholesaler Distribution center Filling & packaging

Last Mile Distribution Raw Material / Manufacturing

Events

Traditional In-Transit Monitoring Market

Events

Revised USP General Chapter <1079>, Published 2012

“Good storage and distribution practices apply to all organizations and individuals

involved in any aspect of the storage and distribution of all drug products”.

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Product Attributes

Identity

Potency

Degradation Profile

Stability

• Accelerated

• Shelf Life

• Annual

• Cycling

• Freeze Thaw

Protein Denaturation

Sterility

Clarity & Color

pH Shift

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Packaging Development and Qualification

Types

• Primary Packaging

• Secondary Packaging

• Distribution Packaging

• Devices

Qualifications

• Component/Installation (CQ/IQ)

• Operational Qualification (OQ)

• Performance Qualification (PQ)

Requirements

• Temperature

• Time

• Payload

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Lane Qualification

• Lane Definition

• Study Protocol in Triplicates

• Verification

‒ Time in Transit

‒ Temperature

‒ Shock/Vibration

‒ Atmospheric Pressure

‒ Humidity

• Hot and Cold Profiles

• Modes of Transportation

‒ Air

‒ Truck

‒ Ocean Vessel

‒ Rail

• Testing

‒ Potency

‒ Degradation

‒ Sterility

‒ Clarity/Color

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Temperature Monitoring and Data Analysis

Monitoring

Data Collection

Analysis

Reporting

Excursions Evaluation

Corrective Action Preventive Action (CAPA)

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Good Distribution Practices (GDP)

Controlled Environment Logistics

• First Mile

• Last Mile

Examples of Supply chain Partners

• Manufacturers

• Distributors

• Importers/Exporters

• Hospitals

• Clinics

• Physician’s Office

• Pharmacies

• Patients

New EU GDP Guidelines

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Good Distribution Practices (GDP)

General

GDPs

Good Import

Practices

(GIPs)

Good Import

Practices

(GIPs)

Distribution

Control

Systems (DCS)

Distribution

Control

Systems (DCS)

Temperature

Control

Management

(TCM)

Temperature

Control

Management

(TCM)

GDP

Global Product

Protection

• Supply Chain Control and

Temperature Monitoring

• Cold Chain to

Temperature-Sensitive

• >30 GDPs

• Shipping Best Practices

• Inventory Management

• LSP/TSP Quality

Agreements

• CTPAT and Customs

• Certified Cargo Screening

Facilities

• Country of Origin Marking

• FDA Division of Import

Operations and Policy (DIOP)

member of Cargo Theft

Response Team (CTRT)

• GS1 Standards (GLN/GTIN)

• Track and Trace, Authentication,

Pedigree,

• Serialization,

• Cargo Security – In-Transit

Monitoring

• FDA SOP for Cargo Theft

• FDA Secure Supply Chain Pilot

Program (SSCPP)

• Pharmaceutical Cargo Security

Coalition (PCSC)

• TAPA (Transported Asset Protection

Association)

• Rx 360

Reference: David Ulrich, Distribution QA Director, Abbott – GDPs for an Ever Increasingly Complex Global Pharma Supply

Chain – GDP Overview MoH Regulations Discussion – Purdue University, April 14, 2012

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Supply Chain Integrity

Track & Trace

Pedigree

• Paper

• Electronic

Numerical Identifier

Authentication

Factors Affecting the Integrity

• Importation

• Anti-Counterfeiting

• Anti-Diversion and Theft

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Global Concern

There are world wide efforts to help protect the integrity of

medicine supply systems and ensure the safety of the

patient.

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Global Effort

Minimize risks that arise anywhere along the supply chain

which include:

• Sourcing of the pharmaceutical raw materials

• Manufacturing of the medicinal ingredients

• Finished dosage form

• Packaging

• Distribution to patient

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Good Supply Chain Integrity

•Encourage sound business practices

•Deter inference and manipulation by bad actors and illicit

people

•Provide effective means to detect adulterated drug

components and drug products

•Prevent adulterated materials from entering the complex

global pharmaceuticals and medical devices supply chain

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Supply System Integrity

•Challenge of drug diversion in the wholesale distribution

system

•Drug paper pedigree to identify prior sales, purchases, or

trades of drugs by anyone other than an authorized

distributor of record

•Electronic track-and-trace pedigree

•Standardized numerical identifier for prescription drugs

•Standards for identification, validation, authentication

tracking/tracing

•Quality systems

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Threats to the Supply Chain Integrity

•Insertion of counterfeit and adulterated medicines into

distribution channel

•Economic gain

•Purposes of terrorism

•Cargo theft of regulated products and their diversion for

illegal activities

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Factors Affecting the Supply Chain Integrity

I. Importation

II. Anti-Counterfeiting

III. Diversion and Theft

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Effective Supplier Partnerships

•Investigate supplier’s reputation

•Research supplier’s certification (e.g. ISO, Customs-Trade

Partnership Against Terrorism (C-TPAT), WHO)

•Determine supplier’s experience as a vendor in the

pharmaceutical industry

•Evaluate supplier’s Regulatory Compliance

•Invest in an early due diligence audit

•Establish Corrective Action Prevention Action (CAPA) Plan

•Quality Agreement

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Supply Chain Security Standards and

Measures

Risks of Logistics Security

Security Management

• Facilities

• In-transit

• Business Partners

• Data Management

• Human Resources

Standards

• Government (C-TPAT & AEO)

• ISO 28000:2007

• TAPA

• RX 360

Secured Shipments

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Global Cargo Theft Threats

Reference: FreightWatch International Supply Chain Intelligence Center, 2013 Global Cargo Theft Threat Assessment

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Brazil

One of the most violent

countries in regards to cargo

crime.

84% of incidents occur in Sao

Paulo and Rio de Janeiro

Cargo theft gangs are

becoming increasingly

specialized and are using

technology to carry out crimes

Most targeted products are

Food / Drinks, Electronics,

Tobacco and Pharmaceuticals

Reference: FreightWatch International Supply Chain Intelligence Center, 2013 Global Cargo Theft Threat Assessment

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Cargo Thefts in Brazil – Top Ten States

Some states do not report or

keep accurate crime statistics

State of Parana, for example, is

known in Brazil to have high

cargo crime incidents, but no

official statistics are published.

Reference: FreightWatch International Supply Chain Intelligence Center, 2013 Global Cargo Theft Threat Assessment

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Trends and Modi Operandi – Brazil

Hijacking continues to be primary method

• Notoriously violent

• Thieves sometimes carry better weapons than police and / or armed escorts

• Not uncommon to see armed confrontation

GPs jammers being used in an attempt to circumvent electronic

monitoring devices.

Criminals use internal information, mainly from transportation

companies’ employees, to obtain details of vehicles carrying high value

goods, the security measures in place, and the details of the escort

cars.

Warehouse thefts have been on the rise, although there are no official

statistics for this type of crime.

Reference: FreightWatch International Supply Chain Intelligence Center, 2013 Global Cargo Theft Threat Assessment

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Logistics Security Challenges

Smuggling of Contraband

Hijacking

Theft

Fire

Natural disaster

Accidents

Brand Integrity and Reputation

Government / Industry Compliance

Compliance audits for multiple programs

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Qualification Master Plan (QMP)

Test Profiles

Lane Qualification

Packaging Qualification

Operation Qualification

Performance Qualification

Evaluate Results

• Assay Tests

• Temperature Data

• Packaging Integrity

• Procedural Completion

Report

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Supply Chain Qualification

QMP

Supply Chain Security

Supply Chain Integrity

Good Distribution Practices

Temperature Monitoring and Data Analysis

Lane Qualification

Packaging Development and Qualification

Product Attributes

Global Regulations

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Questions?

Rafik H. Bishara, Ph.D. rafikbishara2@yahoo.com