Drug Pedigree and SerializationDecember 5, 2008

Robert Yocher, M.H.Sc., RAC, FRAPS, CQEVice President, Regulatory Affairs and

Corporate Quality ComplianceGenzyme Corp.

Why Pedigree?

Challenges Presented by Globalization

• Increasing volume of imported products

• Imports coming from countries with less well developed regulatory systems

• More outsourcing of manufacturing

• Greater complexity in supply chains

• Greater opportunities for economic fraud

Challenges*• Number of Foreign Sites Making FDA Regulated Drug

Products More Than Doubled Since 2001 from 1,200 to 2,800

• Number of Drug Products Manufactured at Foreign Sites More Than Doubled Since 2001 (by Registered Sites from 18,000 to 43,000)

• Many Possible “Points of Entry”– International Mail Branches (14 total) – Express Consignment Facilities (29 total)– Number of Ports – in State (312 total)

The existing U.S. supply chain safety system for FDA-regulated products, including drugs, is not adequate to meet the growing challenges presented by globalization

• *from “Supply Chain Safety: Pharmaceutical Electronic Track- and-Trace” by Jeffrey Shuren, M.D., J.D. Associate Commissioner, U.S. Food and Drug Administration presented Nov.17, 2008

Counterfeiting

• FDA warns of two dozen websites selling counterfeit drugs in 2007

• Thai national extradited for Cialis counterfeits and sentenced with two others Feb 2008

• (July 2008) – Defendant arrested sold counterfeit Zyprexa, Casodex, Tamiflu, Aricept & Plavix to undercover agents July 2007

• Guilty Pleas in Counterfeit Toothpaste Investigation: (August 2008) – Imported tubes of counterfeit Colgate toothpaste from China lacked fluoride and some contained microorganisms, such as bacillus spores, and diethylene glycol (DEG)

Legislation

• 1988 Federal Prescription Drug Marketing Act (PDMA)

• As modified by the Prescription Drug Amendments of 1992, Pub. L. No. 102-353, the PDMA is intended to provide legitimate participants in the drug distribution system with a history of the drug’s source—a “pedigree” of the drug to prevent counterfeit, diverted, or adulterated products from reaching consumers.

PDMA

• Implementing regs-final rule in 1999, stayed as the result of a pending lawsuit by secondary prescription drug distributors

• The FDA appealed in April 2007, claiming that congressional intent requiring pedigree be traced back to the original manufacturer is clear in the PDMA.

• Pending a final decision in the court case, FDA has indicated that it will not initiate enforcement actions against any wholesaler for failing to provide a pedigree that goes back to the manufacturer.

FDAAA Section 913• 505D(a) – In general,

– The Secretary shall develop standards and identify and validate effective technologies for the purpose of securing the drug supply chain against counterfeit, diverted, sub-potent, substandard, adulterated, misbranded, and expired drugs.

• 505D(b)(1) - General• Secretary shall prioritize and develop standards

for– Identification• – Tracking and Tracing• – Authentication• – Validation

FDAAA

• 505D(b)(2) – Standard numerical identifier• The Secretary shall develop a standardized

numerical identifier• Harmonize with international consensus

standards, to the extent practical• To be applied to Rx drug at point of

manufacturing and repackaging• Pallet or package level• No later than 30 months after enactment (March

2010)

FDAAA

• Federal register notice standards

• Comments included– uniform, national standards– Step-wise approach preferred for developing

standards---identification number first– Risk-based implementation

Proposed Legislation

– FDA Globalization Act– Under development but pedigree requirement may include drug ingredients

– May include Buyer-Matheson

– Drug and Device Accountability Act– Cannot distribute unless provide an electronic statement of each prior sale, purchase, or trade, including transaction date and the names and addresses of all parties to the transaction. Includes drug ingredients.

State Laws to Fill Fed Void

• At least 29 states, including California and Florida, have adopted their own pedigree laws. (4 more states pending and 1 withdrawn)

• State laws with diverse, potentially conflicting pedigree requirements makes it increasingly difficult for prescription drug manufacturers and distributors to comply the law.

Source: http://www.healthcaredistribution.org/gov_affairs/.state/state_legis-static.aspIndividual companies are strongly encouraged to consult with their company's legal counsel to determine their specific compliance requirements for PDMA and all federal and state regulations. HDMA disclaims any or all liability arising from reliance on any statements or materials.

US State Regulatory Requirements• The California Pedigree Law effective date has been

delayed until 1/1/11– “…based on the effort exhibited thus far by industry, the expectations

of the Board that this effort will continue unabated in the intervening period, the express assurances by industry of full implementation by January 1, 2011,…

– There is the potential for additional modifications to the law in the current or future legislative sessions• SB 1270 (Cedillo) Allows Board to extend to unspecified

date• SB 1307 (Ridley-Thomas) Clarifies unique Identification

number is to be included in the pedigree• TBD (“PHRMA” bill) Allows grandfathering and inference

US State Regulatory Requirements

• There is the potential for other states to implement regulatory requirements prior to 1/1/11– The majority of states are defining regulations

based upon the “Normal Distribution” concept with pedigree starting at the wholesaler

– Oregon and New York are two states where legislation similar to California has been proposed

US Federal Regulatory Requirements• FDA

– Requirements similar to California are expected as a result of the FDAAA 2007• [By March 2010] the Secretary shall develop a standardized numerical identifier (which, to the extent practicable, shall be harmonized with

international consensus standards for such an identifier) to be applied to a prescription drug at the point of manufacturing and repackaging (in which case the numerical identifier shall be linked to the numerical identifier applied at the point of manufacturing) at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug.

• “… [CABOP] to continue its partnership work with the FDA on the development of federal unique identifier standards, to ensure that California and federal standards remain consistent.”

• The FDA has requested comments and information by May 19, 2008 regarding technologies used for the identification, validation, tracking and tracing, and authentication of prescription drugs.

US Federal Regulatory Requirements

–Requirements are expected if re-importation is allowed

• The President -elect has indicated his support for re-importation with product tracking requirements

–Visible issues with sourcing raw materials (i.e., Heparin) and product from outside the US may result in upstream tracking requirements

CA delay until 1/1/2011

• Remaining Drivers:• Turkey has just announced a pedigree law to be

implemented 1/1/2009,• the Florida pedigree law is still in effect and our trading

partners have expressed a strong desire to eliminate paper pedigrees,

• France has a mandate for the vignette to be a 2D barcode which includes lot number and expiration date for 12/31/2010,

• the US FDA has a mandate to implement a national program no later than 4/1/2010,

• the serialization of product at the unit level is a keystone of business process changes to eliminate costly shipping errors

Proposed Legislation

EC Proposed Legislative Changes• Traceability– Unique and centrally accessible record of

all past transactions, accessible by all parties• Mass serialization*• Transparency of Wholesalers– Routine GDP certificates

issued after each inspection• Database of wholesaler compliance with GDPs*• APIs– Mandatory notification of importation*• Mandatory audits by manufacturers and importers*

* public comments generally expressed support

Other Country Regulatory Requirements

• European Requirements– Turkish Ministry of Health

• Item level 2D Datamatrix containing SGTIN, Expiry Date, Batch Number

• Data submitted to TMOH DB• All manufacturers have system integrated 1/01/09• 12 more months for consumption of existing drugs in the market by

1/1/10– Italy

• Today: Bollini label with National ID number and data submission of daily shipment quantities

• Future: Timing TBD for transition to GS1 number and item level serialization data submission

– France• Transition from 7 digit 1D to 14 digit Datamatrix Vignette label• Transition between 1/1/09 and 12/31/2010• No data exchange requirements

Nordisk Varenummer (13 digits)

France CIP code 13 (13 digits)

GS1 EAN Code Structure (13 digits)

Spanish Codigo National (13 digits)

PZN (Germany/Austria)

Italian Bollino (AIC code – 9 digits)

Belgium ABP code (16 digits)

Greek EOF sticker

Portuguese code

KNMP Code (Netherlands)

Identification across Europe : Overview of National Codification Systems

Source: EFPIA

2D Data Matrix

EFPIA’s visions is to have a unique harmonised coding solution throughout European based on the 2D Data matrix bar code.

Identification across Europe: Perspective 2011+

Source: EFPIA

• World Health Organization’s International Medical Products Anti-Counterfeiting Task Force (IMPACT)

• Developing a Toolkit with:– Experience from different countries – Model legislation & regulations– Training materials and methodologies– Tools and manuals to assist national authorities in implementing activities– Tools and methodologies for the assessment of national/regional situations

Largest and most coordinated international public/private public health effort for counterfeit medical products

International Medical Products Anti-Counterfeiting Task (IMPACT)

Summary

• Challenges brought on by globalization have resulted in increased opportunity for economic fraud

• State, Federal and International efforts are underway to slow counterfeiters.

• Pedigrees and serialization are two tools for tracking and tracing drug shipments

• Harmonization and standardization is crucial to success

Summary

• A global problem requires a global solution

• Greater supply chain accountability

• Increased supply chain transparency

• Know and audit your business partners, particularly suppliers/distributors

• Safety is everybody’s responsibility!