Promoting Supply Chain Security and Integrity to Assure Patient Safety

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Promoting Supply Chain

Security and Integrity to Assure

Patient Safety

Steven Wolfgang, Ph.D.

Acting Associate Director, Risk Science, Intelligence and Prioritization

Office of Compliance

Center for Drug Evaluation and Research U.S. Food and Drug Administration

PDA/FDA Conference Washington, DC September 20, 2011

Problem Statement

• Patients depend on us to assure that products

are safe, of high quality and perform to

expectations

• The landscape of drug manufacturing continues

to expand outside of our borders

• As supply chains grow in complexity new risks

are apparent

THESE RISKS DEMAND OUR UTMOST

ATTENTION!

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Magnitude of What FDA Faces

• Up to 40% of drugs Americans take are manufactured outside US

• Up to 80% of APIs in those drugs are manufactured outside US

• In 2011 we expect nearly 24 million shipments of FDA regulated products to arrive at ports (vs. 6 million a decade ago)

• More than 130,000 importers of FDA-regulated products from more than 300,000 foreign sites in 150 countries

Source: April 13, 2011, FDA Commissioner testimony before US House Energy and Commerce subcommittee on Oversight and Investigations

http://www.fda.gov/NewsEvents/Testimony/ucm250710.htm

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Level of Staffing Dedicated to Managing Importation of All FDA-regulated Commodities Not Keeping Pace with Growth

Source: FDA Strategic Plan Item 2.2

Strengthen the Safety and Integrity of the Global Supply Chain

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Greater Potential for Illicit Activity

• Counterfeit drugs

• Dietary supplements with APIs

• Opaque or fuzzy supply chains and

questionable legitimacy, security and

authenticity of drug components

– CoA laundering

– Show and shadow factories

– Falsification, fabrication

– Substitution motivated by increased profit

margins

Recurring Covert Substitution Upstream in

Supply Chain Leading to Fatalities

• DEG for Polyols

– Glycerin, Propylene Glycol

• Melamine for Protein

– Wheat Gluten

– Milk

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Risks Downstream from

Finished Drug Manufacturing

• Diversion of legitimate product through illicit

channels back into legitimate supply chain

– Cargo theft

– Devious distributors (dilution) or poor distribution practice (improper storage cond.)

– Unsuspecting legitimate wholesalers and pharmacies

• Fake medicines made by criminals

– Illegal rogue pharmacy websites that appear legitimate

– Customers lured by price

– Infiltration into legitimate supply chain through unsuspecting or complicit wholesalers

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June 2011

FDA Commissioner Unveils

“Pathway to Global Product Safety and Quality”

“Global production of FDA-regulated goods has

exploded over the past ten years... making the distinction between domestic and imported products obsolete,” said Commissioner of Food and Drugs Margaret A. Hamburg, M.D. "There has been a perfect storm - more products, more manufacturers, more countries and more access.

A dramatic change in strategy must be

implemented."

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OC/Globa lProductPathway/UCM262528.pdf

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“Pathway to Global Product Safety and Quality”

1) FDA, in close partnership with its foreign counterparts, will assemble global coalitions of regulatorsdedicated to building and strengthening the product safety net around the world.

2) With these coalitions, FDA intends to develop a global data information system and networkin which regulators worldwide can regularly and proactively share real-time information and resourcesacross markets.

3) FDA will continue to expand its capabilities in

intelligencegathering and use, with an increased focus on risk analyticsand thoroughly modernized IT

capabilities.

4) FDA will effectively allocate agency resources based on risk, leveragingthe combined efforts ofgovernment, industry, and public- and private-sector third parties.

June 2011 CDER Office of Compliance unveils

its new “super-office” structure

• OC creates Office of Drug Security Integrity and

Recalls (ODSIR) to implement FDA strategy

across entire pharmaceutical supply chain

– Drug Component Supply Chain – Finished Drug Product Supply Chain – Drug Importation/Exportation

– Policy and Communication – Recalls

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Manufacturers are Responsible for

Managing Vast Global Supply Chain

• API supply chains

– Suppliers of starting materials, reagents, solvents, catalysts, etc.

• Inactive ingredient supply chains

– Suppliers of bulk commodities

• Packaging material supply chains

– Glass, polymer and cellulosic material and associated chemical additive supply chains

• Contract manufacturers

• Service providers, e.g., pest control

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Drug Defects Can Be Traced to Supply Chains

• Glass containers for injectable drug products

shed glass lamellae

• Product odor traced to lumber used to fabricate

wooden pallets upon which HDPE containers for

the products were stored

• Excipients caused recalls of several modified

release drugs due to dissolution failures

• Contamination traced to excipients

– Chemical – Particulate – Microbiological

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FDA Detects High Levels of Peroxide in Crospovidone Issuing a Drug Safety Advisory on 10/21/2010

http://www.fda.gov/drugs/drugsafety/ucm230492.htm • Peroxide levels found (1700 ppm) in imported

Crospovidone were 30-40x typical levels

• Peroxides can degrade APIs resulting in sub-potent drug • Impurity levels were not being monitored by the

manufacturer of Crospovidone

• USP revising all monographs to add limit of peroxide

Responsible parties

• Drug manufacturer

– Responsible for release of product into commercial distribution

• Non-manufacturing entity whose name appears

on product

– Can be held responsible for causing an adulterated product to enter interstate commerce

• Other responsibilities might be delegated

– Contract manufacturers including testing labs – Upstream supply chain

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Regulatory Requirements

Pertaining to Contract Manufacturing Relationships

• Primary manufacturer is responsible – 21 CFR 200.10(b)

• The Food and Drug Administration ….. regards extramural facilities as an extension of the manufacturer’s own facility.

– 21 CFR 211.22(a)

• Quality Control Unit (QCU) is ultimately responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company

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Contractor and Contract Giver

are Liable for Adulterated Product

• The Federal FD&C Act (the Act) states that a drug is considered to be adulterated if the drug is not

manufactured in conformance with CGMP [21 U.S.C. 351(a)(2)(B) ]

– Applies to finished drug products, drug components and all sites under contract to manufacture or supply drugs and drug components

• Manufacturer and private label distributor can both be held liable

– Introducing or causing the introduction of adulterated drugs into interstate commerce is prohibited. [21 U.S.C. 301]

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ICH Q9 - Quality Risk Management

Provides Guidance Regarding Outsourcing

• Members of the supply chain are partners

– play a role in determining success

• Q9 recommends a comprehensive evaluation of

suppliers and contract manufacturers

– including auditing and implementing supplier

quality agreements

• A manufacturer's quality system will drive the

management of outsourced processes and

entities (risk and quality management)

ICH Q9 - Application of Quality Risk Management

to Making Sourcing Decisions

• How does one quantify the true cost of ownership in in a sourcing relationship?

– What are the worst case scenarios?

– Will there be some learning curve that dictates a need to be present at contractor?

• How well do the supplier’s quality systems assure product quality?

– Systems often look good on paper – Trust and confidence are built gradually

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ICH Q10 - Pharmaceutical Quality Systems

Guidance Regarding Purchased Goods and Services

• Control and review of all outsourcing activities is an element of a manufacturer’s pharmaceutical quality system.

• Manufacturer is ultimately responsible to ensure processes are in place to assure the control of

outsourced activities and quality of purchased materials. • A manufacturer should have adequate procedures for

auditing and qualifying facilities prior to outsourcing and throughout the process and for contract management and supervision.

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Quality and the Drug Component Supply Chain

• Upstream Supply Chain

– Agricultural commodities – brokers and traders involved – Crude chemicals – many are commodities

• Manufacturers of APIs, excipients and intermediates – Fine chemicals often produced for multiple markets – Finishing steps affording no purification – milling, etc. – Subdivision for pharmaceutical customer – repackaging • Distribution of Ingredients

– Transportation – Warehousing

– Multiple transfers of ownership – Importation

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Factors Enabling Tragic Events

• There was a lack of transparency in

upstream supply chain

• Members of supply chain were willing and

able to falsify test data and label claim

• Shipments were accepted without any

testing or testing was deficient

Opportunities

• More robust supplier qualification and

maintenance programs

– Audits (knowing who you deal with and quality of their practices)

– Assurance of suitability of excipients for intended use

• Better ability to trace and authenticate

throughout the entire supply chain

– Photo and spectral libraries for ingredients – Identifying characteristics for products – System to track pedigree

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FDA Pharmaceutical Screening Program

• Deployment of portable instrumentation in field

– IMS, X-ray, NIR, Raman

– Increased capacity to screen for abnormality and to focus on highest risk articles

• Development of spectral methods

– for known adulterants in drug components – spectral libraries for drug authentication

• FDA and IPEC published a position paper in American Pharmaceutical Review (July 2011) requesting participation by manufacturers and distributors of excipients to secure supply chain

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Compendial Modernization

• FDA role is to establish USP priorities to

address methodology gaps placing drugs

at risk and inconsistencies within

monograph families

– Acetaminophen containing products (PAP,

inconsistency)

– Povidone (assay, inconsistency)

– Talc (asbestos)

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FDA Builds Networks for Global Regulatory

Cooperation and Establishes Global Presence

• Sharing of Information from Inspections

Under Confidentiality Agreements

– EMA

– TGA

– Joined PIC/S

• Established Foreign Offices

– Outreach to Developing Foreign Regulatory

Agencies

• ICH Guidance Development

Leveraging of Industry Efforts

• Initiative by Consortia and Trade Associations

– Guidance Development – GMP, GDP, importation practice, agricultural practice

• experts can best establish standards

• standards improve industry compliance and consistency

• tool for building quality within supply chain – Third Party Auditing

• potential for certification

– Sharing of Information About Emerging Risk

• provides timely communication to all stakeholders • can stave off a major global quality catastrophe