ingredients & sourcing: a voluntary supplier qualification ... · pdf fileingredients...

Ingredients & Sourcing: A Voluntary Supplier Qualification Guideline

Andrew Shao, PhDVice President, Global Product Science & SafetyHerbalife InternationalMay 31, 2012

Wednesday, June 6, 12

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Why qualify?

• Required by regulation– DS GMPs– FSMA

• Good business practice– Supply chain is global and more complex– Increased need for supply chain controls

• Protect consumers– Prevent tainted products from getting to market– FDA is increasing focus on preventive controls


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Supplier Qualification and GMP Compliance

• In order to rely on the component COA to determine that established specifications have been met, the component user must verify the minimum required information (test results, specification limits, and methods) on the COA.

21 C.F. R. §111.75(a)(2)(ii): • (A) You first qualify the supplier by establishing the reliability of the

supplier’s certificate of analysis through confirmation of the results of the supplier’s tests or examinations [§111.75(a)(2)(ii)(A)].

• (B) The certificate of analysis includes a description of the test or examination method(s) used, limits of the test or examinations, and actual results of the tests or examinations [§111.75(a)(2)(ii)(B)].


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FDA Food Safety Modernization Act of 2011

Title One – Prevention:• Inspection of records• Registration of facilities• Hazard analysis• Performance standards• Produce safety• Intentional adulteration• Re-inspection fees• NDI agreementTitle Two – Response:• Risk-based inspection • Accreditation of Labs• Traceback and record keeping• Mandatory recall authority

Title Three – Import Safety:• Foreign supplier verification• Voluntary qualified importer• Inspection of foreign facilities• 3rd party accreditation • FDA foreign officesTitle Four – Misc. Provisions: • Funding for food safety • Jurisdiction


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FSMA – Supplier Qualification-Related

• SEC. 106. PROTECTION AGAINST INTENTIONAL ADULTERATION.– Not later than 18 months after the date of enactment of the FDA Food

Safety Modernization Act, the Secretary, in coordination with the Secretary of Homeland Security and in consultation with the Secretary of Agriculture, shall promulgate regulations to protect against the intentional adulteration of food subject to this Act

– (1) specify how a person shall assess whether the person is required to implement mitigation strategies or measures intended to protect against the intentional adulteration of food; and(2) specify appropriate science-based mitigation strategies or measures to prepare and protect the food supply chain at specific vulnerable points, as appropriate.


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FSMA – Supplier Qualification Related

• TITLE III--IMPROVING THE SAFETY OF IMPORTED FOOD SEC. 301. FOREIGN SUPPLIER VERIFICATION PROGRAM.

– Verification requirement.--Except as provided under subsections (e) and (f), each importer shall perform risk-based foreign supplier verification activities for the purpose of verifying that the food imported by the importer or agent of an importer is--"(A) produced in compliance with the requirements of section 418 or section 419, as appropriate; and"(B) is not adulterated under section 402 or misbranded under section 403(w).

– "(1) In general.--Not later than 1 year after the date of enactment of the FDA Food Safety Modernization Act, the Secretary shall promulgate regulations to provide for the content of the foreign supplier verification program established under subsection (a).


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The Foods and Veterinary Medicine (FVM) Program


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FDA On Supplier Qualification

“A strong program of qualifying your suppliers, testing incoming ingredients, and verifying the contents of finished products – all of which are required by the CGMP regulations – can help minimize those risks.” Margaret A. Hamburg, M.D., Commissioner of FDA, Joint FDA-trade association letter to DS manufacturers, December 15, 2010


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Why need for Industry Guidance?

• Lack of guidance and clarity in GMP Regulation 21 CFR Part 111

• Lack of clarity from regulators concerning expectations– USFDA 483 Observations– USFDA Warning letters

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm234131.htm













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Supplier Qualification: Major Issues

• Lack of justification for reliance on component supplier’s Certificate of Analysis

• Lack of specifications for key parameters, e.g. contaminants

• Lack of verification that components are manufactured to applicable cGMPs

• Lack of corrective action plans


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Proactive Precedent from Other Industries

http://www.rx-360.org/Default.aspx

http://www.gma-safe.org

www.ipecamericas.org

http://www.mygfsi.com/


http://www.qmi-saiglobal.com/Default.asp?language=english

http://www.qmi-saiglobal.com/Default.asp?language=english






http://www.gma-safe.org/

http://www.gma-safe.org/

http://www.ipecamericas.org/

http://www.ipecamericas.org/



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• A joint US trade association initiative

– Consumer Healthcare Products Association (CHPA)

– Council for Responsible Nutrition (CRN)

– United Natural Products Alliance (UNPA)

• Member companies: manufacturers, suppliers, testing labs, consultants, etc…

• Active since 2006

www.sidiworkgroup.com

Comments due June 18, 2012


http://www.sidiworkgroup.com/


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Guidance for Industry

• Voluntary Guideline: Dietary Supplement Component Supplier Qualification Assist with GMP compliance

Assist component users in development of supplier qualification programs. Establish the reliability of the component supplier’s certificate of

analysis (21 CFR Part 111.75, Subpart E)

Assist regulators with establishing guidance or requirements

Draft released on April 17, open for a 60-day comment period Available on www.sidiworkgroup.com




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Voluntary Dietary Supplement Component Supplier Qualification Guideline

Section Title

1. INTRODUCTION

2. PRE-ASSESSMENT CRITERIA

3. SUPPLIER CAPABILITY/AUDIT ASSESSMENT

4. CERTIFICATE OF ANALYSIS CONFIRMATION RECOMMENDATIONS

5. SUPPLIER/COMPONENT REQUALIFICATION CONSIDERATIONS6. SUPPLIER/COMPONENT DISQUALIFICATION

7. COMPONENT AND SUPPLIER DEFINITIONS8. SUPPLIER AND COMPONENT RISK FACTORS

9. EXAMPLES


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Section 1: Introduction

• Primary Goal: Guideline to assist dietary supplement component users in qualifying suppliers to allow reliance on certificate of analysis

• Voluntary guideline

• GMP compliance – basis for relying on supplier’s COA

• Based on risk management principles (ICH) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdf


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdf






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Risk-Based Supplier QualificationSupplier/Component Risk Pyramid


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Risk-Based Supplier Qualification

Routine C of A Verification

Supplier/Component Risk Pyramid


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More Frequent C of A Monitoring




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Testing, Auditing, On-site corrective actions





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Special Cause Testing






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Special Cause Testing





Resource Allocation

High

Low


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Risk Management Approach

• Maximize finite resources • Allocate more resources to components or suppliers

that pose the greatest risk.

• Allows for greater flexibility


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Supplier qualification: Defining risk

• Risk of a quality event (e.g., out of specification resulting in adulteration or misbranding)

• Safety risk to the component user or consumer

• Risk of disruption of service or supply


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• Preliminary risk assessment for a particular component or supplier. Documentation

Standardized Information on Dietary Ingredients (SIDITM) Protocol

User’s self-generated product or audit questionnaire Enforcement history, third-party certifications, COAs


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Section 3: Supplier Capability/Audit Assessment

• Recommendations for assessing component supplier’s QMS and compliance with applicable GMPs and other standards

• Information that cannot be assessed through documentation alone

• Audit recommendations Direct audits, third-party certifications and audits Frequency


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Section 4: Certificate of Analysis

• Recommendations on the confirmation of the Certificate of Analysis– SIDI Work Group’s COA Guideline

• Risk-based COA testing confirmation: pre-commercial and commercial– Pre-commercial (Phase I) – testing COA against supplier’s own

specifications; performed early in qualification process to help assess risk

– Commercial (Phase II) – testing COA against agreed upon specifications for product intended for commerce

– The number of component batches commensurate with component/supplier risk


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Section 5: Supplier/Component

• Suppliers and/or components must be requalified on a periodic basis– Reconfirmation of CoA, auditing– Frequency is risk-based and dependent on

• Supplier performance over time• Change control/notification• Ability to mitigate risk


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Relationship between COA reconfirmation and supplier/component risk: time model


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Section 6: Supplier/Component Disqualification

• Considerations for disqualification balanced against considerations for risk mitigation

• Potential disqualification criteria– Supplier performance (existing qualified suppliers)– Legal/regulatory action (new suppliers/qualified suppliers)– Special cause event (new suppliers/qualified suppliers)

• Failure to notify for critical change• Falsification of data• Economically motivated adulteration

• Risk Mitigation


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• High-Risk Component and Supplier • Medium-Risk Component and Supplier

• Low-Risk Component and Supplier


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Section 8: Component and Supplier Risk Factors

• List of component and supplier characteristics that may be used in a risk assessment

• Not all-inclusive; intended use important • Some component characteristics:


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Low Risk Medium Risk High RiskComprehensive COA Minor gaps identified in COA that require

consistent follow-up with supplierCOA based on historical data and/or input values or missing key information (e.g., values for agreed-upon specifications)

Compendial grade material No compendial monograph, but identity, strength, purity, and composition well characterized and consistent with material complexity

No compendial monograph or established specifications

Stability studies conducted on component

Some stability due diligence performed No stability data

Limits of storage studies conducted on component

Some limits of storage studies performed No limits of storage studies performed

Component is a single, purified substance

Component has simple composition with only incidental use of processing aids

Component is of complex mixture consisting of many different ingredients

Component is in powder form in a simple matrix with visual confirmation of particle size self-evident

Component is granulated into a complex matrix in which particle size distribution can be critical to performance

Component is composed of a complex matrix or mixture (i.e., proprietary dietary ingredient blends)

Supply chain is fully traceable to original starting materials and/or agriculture commodities

Supply chain is somewhat traceable to original starting materials or agriculture commodities

Supply chain is not traceable and origin of manufacture of the component and its starting materials is unknown

Well-substantiated claims for product performance

Claims may be substantiated, but the evidence is weak

Performance claims lack substantiation

Component is produced by a simple product synthesis that is well established

Component is produced by a more recently developed synthesis that is somewhat well established

Component is produced by a complex synthesis that is relatively new

Comprehensive component production flow chart available

Component production flow chart lacks detail No component production flow chart


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Low Risk Medium Risk High RiskStrong technical dossier (i.e., SIDI protocol)

Technical dossier with gaps in key basic information

No technical dossier

Mature company with many years experience producing target component

Experienced company with some experience producing target component

Start-up company with limited or no production experience with target component

Company manufactures in well-developed country with mature regulatory oversight system

Company manufactures in country with intermediate regulatory oversight system

Company manufactures in country with an immature regulatory oversight system

Strong regulatory history with record of corrective actions

No regulatory history or minor regulatory citations

Significant regulatory citations and weak corrective action execution

Well-documented specifications for identity, strength, purity, composition, and limits on contaminants

Minor gaps identified in specifications Major gaps identified in specifications

Comprehensive change control system Documented change control system with minor gaps

Lack of and/or poorly documented change control system

Formal process capability studies on file Some formal process capability on file, but no formal analysis of data

No process capability data

Low incidence of customer complaints with formal corrective actions program

Intermediate incidence of customer complaints with no formal corrective actions program

High incidence of customer complaints or undocumented program with no formal corrective actions

Component is not known or suspected to be subject to EMA

Component has limited potential for EMA Component is known or suspected to be subject to EMA

Direct purchasing/sourcing relationship with manufacturer of the component

Indirect purchasing/sourcing relationship with respected broker or distributor of the component

Indirect purchasing/sourcing relationship with broker/distributor with unknown or poor compliance/service history Favorable audit results by third party Minor deficiencies noted by third-party

audit firmMajor deficiencies noted by third-party audit firm

Favorable direct audit results Minor deficiencies noted by direct audit Major deficiencies noted by direct auditStrong technical services support personnel with comprehensive knowledge of component and process

Some technical services support, but lacking in experience and component and process knowledge

No technical service support personnel available


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Supplier Qualification Process


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Section 9: Examples

• Section 9: Examples– Scenarios of how risk-based approach to supplier

qualification can be applied

• Other sections: References, Glossary, Abbrev. list


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Examples

• Intended to provide guidance Supplier/Component Risk Classification Supplier/Component Requalification Supplier Disqualification Inform decision-making pertaining to the use of Suppliers and

Components in dietary supplements

Not all-inclusive and not legal advice

• Structure First: Due Diligence Overview Second: Supplier/Component Risk Assessment and decision Each example is unique - due diligence elements carry different risk

levels


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Example 1: Low Risk Component/Supplier Due Diligence Overview:

• Supplier A sells Chondroitin sulfate Manufactured from the trachea of domestic cattle

• Supplier A has a strong compliance program Documented evidence provided showing: Cattle health is monitored closely Traceability and compliance to international regulations Potential for BSE contamination minimized at the time of slaughter


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Example 1: Low Risk Component/Supplier

• > 15 years in Chondroitin sulfate manufacturing business No regulatory enforcement actions

• Facilities located in a country with a mature regulatory oversight system, with low rate of consumer food/dietary supplement safety incidents


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• User determines material is susceptible to EMA onsite audit is warranted

• Audit confirms Supplier A: Is in compliance with applicable GMPs Has excellent traceability Appropriate documentation and recordkeeping

• Reliability of COA confirmed User fully tests the first 5 component batches received from

Supplier A


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Supplier/Component Risk Assessment and decision:

• Supplier A and component are low risk

• Reduced testing on incoming shipments ID testing only

• Based on potential for EMA COA reconfirmation performed 1X/3 mos

• Re-audit period established 1X /3 yrs

• Acceptance of independent 3rd party audit


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Example 2: Medium Risk Component/SupplierDue Diligence Overview:• Supplier F manufactures an Aqueous/ethanolic botanical

extract standardized to specific marker compounds• Supplier F has a:

Solid reputation Large portfolio of other products sold to DS Industry DI has been in use > 50 yrs with no reports of adverse events

• However….• Supplier F has been manufacturing botanical extract ~ 10

mos and has limited production experience with this DI• Limited internal testing capabilities


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Example 2: Medium Risk Component/Supplier

• Component susceptible to high microbial bio-burdens if not properly extracted, packaged and stored

• No independent 3rd party audit report available to share with its customers

• Specifications are established based on: Literature searches Limited production runs of the extraction process but, without

regard for seasonal variation of the botanical DI• Supplier F agrees to develop process capability to address

potential seasonal variation in starting material


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Example 2: Medium Risk Component/Supplier

• User performs GMP Audit No critical deficiencies but, several major and minor deficiencies

• User approves Supplier F’s submitted corrective action plan

• User tests the first 3 commercial batches received which confirm COA is reliable


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Example 2: Medium Risk Component/SupplierSupplier/Component Risk Assessment and decision:

• Supplier F and the component are medium risk • User fully test add’l 3 batches • Re-audit of Supplier F after corrective action plan

implementation • Frequency of COA reconfirmation

3X/yr based on number of lots expected to be purchased annually.

• Supplier F may be reassessed as low risk pending confirmation of completed corrective action plans


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Example 3: High Risk Component/Supplier

Due Diligence Overview:

• Supplier K purchases commonly consumed berries from Chinese suppliers in the spot market

• Berries are: Processed in China as dehydrated fruit Shipped to customers globally

• Subject to FDA automatic detention procedures specific to the presence of pesticides and sulfiting agents.


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Example 3: High Risk Component/Supplier

• User intends to develop a standardized extract from the berries for sale in U.S as a finished dosage form dietary supplement

• User receives small samples of berries for extraction trials; Sends to an independent 3rd party lab for contaminant testing

• Test results: Presence of several pesticide residues with no established U.S.

EPA Tolerances. Presence of sulfiting agents at 200 ppm


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Example 3: High Risk Component/Supplier Supplier/Component Risk Assessment and decision:

• Supplier K and the component are high risk

• Risk mitigation not possible Down stream processing of dehydrated berries into an extract will

not address violative pesticide residues All activities pertaining to qualification of Supplier K discontinued

• Seeks alternative supplier


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Example 4: Supplier Disqualification/COA Data Integrity

Due Diligence Overview:• Supplier E manufacturers a Pomegranate Powder supplied

to both DS & Food Industries• User performs COA pre-commercial testing on Supplier E• Determines material suitable for intended use in DS• 3 marker compounds w/ assigned specification values to

support labeling claims; indicative of high quality, pure dehydrated Pomegranate Total Punicalagins A & B > 5% Ellagic Acid < 15%.


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• User tests first 3 batches of material received Results well within pre-established specifications Values for Total Punicalagins and Ellagic Acid listed as discrete

values on the COA User determines No GMP audit required

• User tells Supplier E it will accept material based on the COA

• Next batch of material received accompanied by incomplete COA Test results for Punicalagin and the Ellagic Acid assays reported as

“Complies to Standard” No quantitative values


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• User determines material must be tested• Results from independent 3rd party lab

Total Punicalagins A&B = 4.8% ( > 5%) Ellagic Acid = 15.2% (< 15%)

• Supplier E has no explanation for results• User rejects material; tests next 3 batches received;• All results show same level of consistency with the Total

Punicalagins and Ellagic Acid values that failed to meet specification limits.

• Supplier E offers no rational explanation for sudden change in values


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Supplier Disposition:

• User determines Supplier E is high risk based on un-notified change control events

• Disqualifies Supplier E • Moves to an alternate supplier

• User informs Supplier E it is no longer an approved supplier for this or any other component Reason: Supplier was unable to identify a root cause of the failure

to meet specifications


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Example 5: Supplier Disqualification/Single Sourced Component

Due Diligence Overview:

• Supplier B approved, qualified supplier of a component for ~ 3 yrs

• User performs an audit of Supplier B and discovers falsified data during COA reconciliation

• User informs Supplier B that this is a critical observation and requests an explanation in writing


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Example 5: Supplier Disqualification/Single Sourced Component

Supplier Disposition:• User receives and reviews letter of explaining data

falsification event from Supplier B Determines QMS of Supplier B has failed Only course of action - mitigate the risk from Supplier B by fully

testing each component batch received.• User is single-sourced for this component • Qualification of a new supplier will take 4-6 months. • User performs full testing on all current inventory of

component in stock • Immediately begins process for qualifying a new supplier • Disqualify Supplier B as soon as new supplier is approved


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Other areas to be considered• Supplier management recommendations

– Supply Agreements / Quality Agreements– Continuous Improvement– Claims Substantiation

• Best business practices recommendations– Business Continuity and Capability– Corporate Accountability/Financial Stability– Environmental Stewardship– Labor and Safety– Crisis Management– Recall Capability– Liability Coverage


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Supplier Qualification Guideline – Next Steps

• 60-day comment period on initial draft• Seeking comments from industry and FDA• Intent is to globalize via IADSA

SIDI WORKING GROUPWWW.SIDIWORKGROUP.COM

COMMENTS, [email protected]




mailto:[email protected]


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Global Emphasis• Intent is to globalize via IADSA

– Presented to the IADSA Technical WG on April 23

• IADSA Global Guide to Good Manufacturing Practice for Supplements

• Tool for industry and governments worldwide

• Compliments IADSA’s other Guidelines– Global guideline to Good Manufacturing Practices

– Global guideline for Adverse Event Collection


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Andrew Shao, Ph.D.V.P. Global Product Science & Safety

Herbalife [email protected]




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Thank you!

Andrew Shao, Ph.D.V.P. Global Product Science & Safety

Herbalife [email protected]




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