API Audits & Inspections: An APIC Point of View Chris Oldenhof DSM / The Netherlands President of...

API Audits & Inspections:API Audits & Inspections:An APIC Point of ViewAn APIC Point of View

Chris OldenhofChris Oldenhof

DSM / The NetherlandsDSM / The Netherlands

President of APICPresident of APIC

1111thth APIC/CEFIC European Conference on APIs APIC/CEFIC European Conference on APIs

Paris, 22 - 24 October 2008Paris, 22 - 24 October 2008

DefinitionsDefinitions

API Audit:API Audit:Formal review of GMP compliance Formal review of GMP compliance and/or Quality status by a and/or Quality status by a customercustomer or by a ( or by a (non-authoritynon-authority)) third partythird party

API Inspection:API Inspection:Formal review of GMP-, Quality- Formal review of GMP-, Quality- and/or Regulatory compliance by and/or Regulatory compliance by an an authorityauthority

APIC: APIC: Active Pharmaceutical Ingredients CommitteeActive Pharmaceutical Ingredients Committee

Sector Group of CEFIC Sector Group of CEFIC (European Chemical Industry Council)(European Chemical Industry Council)

APIC founded in 1992APIC founded in 1992

APIC’s Mission:APIC’s Mission:

- To promote the use of compliant APIs in medicinal - To promote the use of compliant APIs in medicinal products to ensure patient safetyproducts to ensure patient safety

- To represent the interests of pharmaceutical and - To represent the interests of pharmaceutical and chemical companies producing APIs and chemical companies producing APIs and intermediates in Europe by being recognized experts intermediates in Europe by being recognized experts who advance and influence the global GMP and who advance and influence the global GMP and Regulatory environment.Regulatory environment.

General APIC Positions on General APIC Positions on API Audits & InspectionsAPI Audits & Inspections

Neither is needed: Neither is needed: NONOOnly any one of the two is needed: Only any one of the two is needed: NONOOnly Audit = Sufficient: Only Audit = Sufficient: NONOOnly Inspection = Sufficient: Only Inspection = Sufficient: NO / NO / yesyes

Both are always needed: Both are always needed: YES / YES / nono

Agreement on:Agreement on: Inspection is always required!Inspection is always required!

Industry insists upon being inspected…Industry insists upon being inspected…

Which single aspect is of Which single aspect is of paramount importance in paramount importance in

relation to inspections/audits?:relation to inspections/audits?:

Availability of resources Availability of resources Low costsLow costs

No duplication of workNo duplication of work

Patient safety Patient safety WorkableWorkable GuidelinesGuidelinesCompetitiveness of the industryCompetitiveness of the industry

Trade RelationsTrade Relations HarmonizationHarmonizationBetter QualityBetter Quality ProfitsProfits

ComplianceCompliance Legal AspectsLegal Aspects

Clear ResponsibilitiesClear Responsibilities RegulationsRegulations

Which single aspect is of Which single aspect is of paramount importance in paramount importance in

relation to inspections/audits?:relation to inspections/audits?:Availability of resources Availability of resources Low costsLow costs

No duplication of workNo duplication of work

Patient safetyPatient safety Workable GuidelinesWorkable Guidelines

Competitiveness of the industryCompetitiveness of the industry

Trade RelationsTrade Relations HarmonizationHarmonization

Better QualityBetter Quality ProfitsProfits

ComplianceCompliance Legal AspectsLegal Aspects

Clear ResponsibilitiesClear Responsibilities RegulationsRegulations

Proposed Priority #1:Proposed Priority #1:

No compromises No compromises when patient when patient

safety is at stake!safety is at stake!

Derived Proposed Principle:Derived Proposed Principle:

Putting patient safety at risk by:Putting patient safety at risk by:… … Tampering, cheating, cutting corners, Tampering, cheating, cutting corners, counterfeiting, not adhering to counterfeiting, not adhering to regulations in the manufacture and trade regulations in the manufacture and trade of APIs - all with the aim of earning more of APIs - all with the aim of earning more money - is unacceptablemoney - is unacceptable

… … A lack of API oversight, enforcement A lack of API oversight, enforcement and deterrence is also unacceptableand deterrence is also unacceptable

What does not work:What does not work:

A Paper Tiger:A Paper Tiger: Relying solely on checking Relying solely on checking paperwork => Deterrence: Zero... or worsepaperwork => Deterrence: Zero... or worse

Paper Tiger => Lack of oversight, Paper Tiger => Lack of oversight, inspection, enforcement:inspection, enforcement:

Opens the door to and Opens the door to and even stimulates even stimulates and attractsand attracts the proliferation and the proliferation and

escalation of:escalation of:

Sloppiness =>Sloppiness =>

Cutting corners =>Cutting corners =>

Deliberate non-compliance =>Deliberate non-compliance =>

Cheating =>Cheating =>

Counterfeiting =>Counterfeiting =>

Crime…Crime…

Example of inspectional weakness:Example of inspectional weakness:FDA 2003 + 2004 (including PAIs)FDA 2003 + 2004 (including PAIs)

Example of inspectional weakness:Example of inspectional weakness:FDA 2007 (including PAIs)FDA 2007 (including PAIs)

China: 18 of 714; India: 54 of 410

Example of overdue inspections: CEPsExample of overdue inspections: CEPs

After around 150 inspections worldwide (After around 150 inspections worldwide (++65% in Asia, 65% in Asia, most others in Europe) in most others in Europe) in ++10 years time EDQM has in 10 years time EDQM has in total suspended or withdrawn almost 40 CEPstotal suspended or withdrawn almost 40 CEPs

This implies: Large quantities of at least around 40 very This implies: Large quantities of at least around 40 very unsafe APIs have been administered to patients in the unsafe APIs have been administered to patients in the EU for yearsEU for years

From a patient safety perspective the CEPs should From a patient safety perspective the CEPs should never have been granted in the first placenever have been granted in the first place

AllAll the CEP suspensions and withdrawals by EDQM the CEP suspensions and withdrawals by EDQM related to API manufacture in Asia (so zero to Europe)related to API manufacture in Asia (so zero to Europe)

… … but APIC has always applauded EDQM because until but APIC has always applauded EDQM because until recently it has been the only European entity arranging recently it has been the only European entity arranging for API inspections for API inspections (*) (*) outside Europe…outside Europe…

(*)(*) Centralised procedure APIs are inspected globally through EMEA coordinationCentralised procedure APIs are inspected globally through EMEA coordination

Victims of counterfeited / non-Victims of counterfeited / non-inspected pharmaceutical ingredientsinspected pharmaceutical ingredients

Heparin Haiti

Panama

Gentamicin

Fatal Non-Inspected Ingredients Fatal Non-Inspected Ingredients A worrying pattern emerges:A worrying pattern emerges:

ProductProduct OriginOrigin DeliberateDeliberate Where DeathsWhere Deaths CommentsComments

Heparin/OSCSHeparin/OSCS ChinaChina YesYes US, not in EU - Side effects in GermanyUS, not in EU - Side effects in Germany(Counterfeit)(Counterfeit) - Mimics in analyses- Mimics in analyses

Pet Food/MelaminePet Food/Melamine ChinaChina YesYes US, not in EUUS, not in EU - Mimics in analyses- Mimics in analyses(Counterfeit)(Counterfeit)

Gentamicin sulfateGentamicin sulfate ChinaChina YesYes US, not in EUUS, not in EU - Only seen with- Only seen with(Counterfeit)(Counterfeit) special analyses special analyses

- Germany - Germany reacts: reacts: Würzburg project Würzburg project

Glycerin/DEGGlycerin/DEG ChinaChina YesYes Not inNot in US/ US/EUEU - But found in US/EU:- But found in US/EU:(Counterfeit)(Counterfeit) In toothpaste In toothpaste

L-TryptophanL-Tryptophan JapanJapan NoNo US, not in EUUS, not in EU - Trace impurity- Trace impurity(Not a counterfeit)(Not a counterfeit) - Side effects in Germany- Side effects in Germany

Note: Ketek® affair includes similar discrepancies between EU and US casualties dataNote: Ketek® affair includes similar discrepancies between EU and US casualties data

Rogue APIs in EuropeRogue APIs in EuropeQuotes from a presentation by French/Chinese trading Quotes from a presentation by French/Chinese trading

company on frequently occurring trade situations with APIs company on frequently occurring trade situations with APIs from China as a result of lack of oversight from China as a result of lack of oversight (*)(*)

““COS/DMF is disconnected with reality of GMP level, even of existing of COS/DMF is disconnected with reality of GMP level, even of existing of sitesite

““Producers submit false documents and refuse any audits, visits to Producers submit false documents and refuse any audits, visits to site”site” (If Audit or Inspection announced => Immediate close-down)(If Audit or Inspection announced => Immediate close-down)

““Competition mainly focused on price, bring the sector going down -Competition mainly focused on price, bring the sector going down - destroying pharmaceutical European industry in generics”destroying pharmaceutical European industry in generics”

““In fact, no respect of European laws and regulations”In fact, no respect of European laws and regulations”

““Europe becoming the last served market after USA / Japan and the restEurope becoming the last served market after USA / Japan and the rest of the world”of the world”

Bad news for the safety of patients in Europe…Bad news for the safety of patients in Europe…

(*) Charles Hu (Bim Sifram Group), EFCG Conference Lisbon, 29-30 May 2008(*) Charles Hu (Bim Sifram Group), EFCG Conference Lisbon, 29-30 May 2008

Rogue APIs in EuropeRogue APIs in EuropeContrast of Mr. Hu’s view with the recent Contrast of Mr. Hu’s view with the recent EMEA report:EMEA report:

““Community project on the practical Community project on the practical implementation of the new obligations for implementation of the new obligations for manufacturing authorisation holders (Art. manufacturing authorisation holders (Art. 46f/50f Directive 2001/83(2)/EC)” (14 July 46f/50f Directive 2001/83(2)/EC)” (14 July 2008)2008)

on MA holder inspection outcomes on EU on MA holder inspection outcomes on EU API complianceAPI compliance in 2005 - 2006in 2005 - 2006 is difficult to is difficult to understand. understand. Note:Note: Recent trader statement at same Lisbon Conference that Recent trader statement at same Lisbon Conference that ““++90% of APIs entering EU via traders and brokers (about 40% 90% of APIs entering EU via traders and brokers (about 40% of total API volume) does not comply with ICH Q7” confirms the of total API volume) does not comply with ICH Q7” confirms the concerns as expressed by Mr. Hu.concerns as expressed by Mr. Hu.

Rogue APIs in EuropeRogue APIs in Europe

Quote from the Executive Summary Quote from the Executive Summary of the EMEA Report:of the EMEA Report:

Rogue APIs in EuropeRogue APIs in EuropeQuote from the EMEA Report’s conclusions:Quote from the EMEA Report’s conclusions:

Is the word “although” suggesting that the Is the word “although” suggesting that the legal initiative may not be necessary because legal initiative may not be necessary because everything is under control?everything is under control?With patient safety being at stake serious With patient safety being at stake serious concern and zero tolerance should prevailconcern and zero tolerance should prevail

Rogue APIs in EuropeRogue APIs in EuropeBut also coming from EMEA:But also coming from EMEA:(Press Conference, 5 June 2008)(Press Conference, 5 June 2008)

““EMEA urges more collaboration after EMEA urges more collaboration after heparin scandal”heparin scandal”

……EMEA Head Thomas Lonngren said: EMEA Head Thomas Lonngren said:

""This is a new scenario for us as regulators on both This is a new scenario for us as regulators on both sides of the Atlantic. Suddenly we discover that we sides of the Atlantic. Suddenly we discover that we have important manufacturing far away that we don't have important manufacturing far away that we don't have any control ofhave any control of."."

See: See: http://www.reuters.com/article/governmentFilingsNews/idUSL0658807820080606http://www.reuters.com/article/governmentFilingsNews/idUSL0658807820080606

and: and: http://www.reuters.com/article/governmentFilingsNews/idUSL0658807820080606http://www.reuters.com/article/governmentFilingsNews/idUSL0658807820080606

Why Inspect?Why Inspect?

To protect patient safety by:To protect patient safety by:

Not onlyNot only Detecting GMP non-complianceDetecting GMP non-compliance Detecting RA non-complianceDetecting RA non-compliance

But also byBut also by Detecting Fraud Detecting Fraud Detecting CounterfeitingDetecting Counterfeiting

Note:Note: And as has now been proven by the outcomes of And as has now been proven by the outcomes of EDQM’s inspection program: A system based on EDQM’s inspection program: A system based on trusting on MA holder audits only does not trusting on MA holder audits only does not work!work!

A recent example of what may be found during API-A recent example of what may be found during API-focused inspectionsfocused inspections

February 2006: FDA inspection at an Indian top-of-the-bill generics February 2006: FDA inspection at an Indian top-of-the-bill generics company’s company’s (*)(*) API plant in India resulted in severe Warning Letter API plant in India resulted in severe Warning Letter in June 2006in June 2006

February 2007: US Federal Agents’ raids at the company’s US February 2007: US Federal Agents’ raids at the company’s US headquarters and headquarters and manufacturing facilitiesmanufacturing facilities

July 2008: US Government court filings make reference to “a July 2008: US Government court filings make reference to “a pattern of systemic fraudulent conduct” at the company (including pattern of systemic fraudulent conduct” at the company (including sourcing of APIs from unapproved sources, fraudulent API stability sourcing of APIs from unapproved sources, fraudulent API stability testing, use of rapidly degrading APIs)testing, use of rapidly degrading APIs)

July 2008: US Congress Subcommittee on Oversight and July 2008: US Congress Subcommittee on Oversight and Investigations launching investigation on possible FDA failures to Investigations launching investigation on possible FDA failures to stop involved unsafe products from entering the USA.stop involved unsafe products from entering the USA.

September 2008: FDA bans 33 of the company’s generic drug September 2008: FDA bans 33 of the company’s generic drug products and 6 of its APIs from the US market. products and 6 of its APIs from the US market. Impact on Europe…?Impact on Europe…?

(*) The company exports >25% of its drug products(*) The company exports >25% of its drug products output to the USA and ca. 17% to Europeoutput to the USA and ca. 17% to Europe

How to inspect / audit for API fraud?How to inspect / audit for API fraud?

Tips and tricks: At the API manufacturer (1)Tips and tricks: At the API manufacturer (1)

Check location and details of site up front on Google EarthCheck location and details of site up front on Google Earth

Check for large discrepancies between annual output and Check for large discrepancies between annual output and sales (Indicates purchase API elsewhere and re-labeling)sales (Indicates purchase API elsewhere and re-labeling)

Check the label book for labels from other manufacturersCheck the label book for labels from other manufacturers

(Indicates labeling own API as if produced by others)(Indicates labeling own API as if produced by others)

Check if any API is shipped in neutrally labeled packagingCheck if any API is shipped in neutrally labeled packaging

(Indicates illegitimate re-labeling at receiving end)(Indicates illegitimate re-labeling at receiving end)

Check if API warehouse inventory is lower than theoretically Check if API warehouse inventory is lower than theoretically (Indicates hidden API may be stored in other warehouses)(Indicates hidden API may be stored in other warehouses)


Tips and tricks: At the API manufacturer (2)Tips and tricks: At the API manufacturer (2) Do not only check first rows of drums (Other rows may be Do not only check first rows of drums (Other rows may be

unlabeled)unlabeled)

Do not follow the company’s agenda; ask to see things that Do not follow the company’s agenda; ask to see things that were not expected by the companywere not expected by the company

Only inspect when manufacture of the API is runningOnly inspect when manufacture of the API is running

Check for compliance of all data included within the API Check for compliance of all data included within the API registration documents (e.g. CEP dossier or DMF)registration documents (e.g. CEP dossier or DMF)

Check any reports of inspections of the site performed by Check any reports of inspections of the site performed by other reputed authoritiesother reputed authorities


Tips and tricks: At the API manufacturer (3)Tips and tricks: At the API manufacturer (3)

Check on EDQM’s website if the manufacturer holds any Check on EDQM’s website if the manufacturer holds any CEPs that have been suspended or withdrawn by EDQMCEPs that have been suspended or withdrawn by EDQM

• Check purchasing records and sales records for illicit Check purchasing records and sales records for illicit transactionstransactions

• Take API samples and have them analytically fingerprinted Take API samples and have them analytically fingerprinted vs. an original sample from the company and/or compare vs. an original sample from the company and/or compare with registered API quality in CEP dossier or DMFwith registered API quality in CEP dossier or DMF

• Obtain a list of shipped batches, dates and clients and later Obtain a list of shipped batches, dates and clients and later cross-check these during inspections of clients’ sitescross-check these during inspections of clients’ sites


Tips and tricks: At the Exporting API traderTips and tricks: At the Exporting API trader

• Check for discrepancies between volumes of API purchased Check for discrepancies between volumes of API purchased from companies vs. volumes sold under the labels of those from companies vs. volumes sold under the labels of those companiescompanies

• Check for traces of activities of replacing original labels by Check for traces of activities of replacing original labels by different labels (e.g. equipment to remove labels: e.g. a different labels (e.g. equipment to remove labels: e.g. a burner)burner)

• Check for the presence of API in warehouses with labels Check for the presence of API in warehouses with labels from producers not included in official documentationfrom producers not included in official documentation

• Scrutinize entire labels production, management and Scrutinize entire labels production, management and reconciliation system for irregularitiesreconciliation system for irregularities

• Take API samples for analytical fingerprinting as aboveTake API samples for analytical fingerprinting as above


Tips and tricks: At the Importing API traderTips and tricks: At the Importing API trader

• Same points as for Exporting API traderSame points as for Exporting API trader

• Check information on the origin of the API material at Check information on the origin of the API material at customs vs. data on file at the importing tradercustoms vs. data on file at the importing trader


Tips and tricks: At the API user / Dosage Form Tips and tricks: At the API user / Dosage Form manufacturer (1)manufacturer (1)

• Check for fraudulent actions with documentation aimed at Check for fraudulent actions with documentation aimed at hiding the true origin of the materialhiding the true origin of the material

• Check the purchasing records on sourced APIs from specific Check the purchasing records on sourced APIs from specific companies vs. the volumes of API from these specific companies vs. the volumes of API from these specific companies actually used in production of the dosage formscompanies actually used in production of the dosage forms

• Check if API with labels from producers not included in official Check if API with labels from producers not included in official documentation is present in warehousesdocumentation is present in warehouses


Tips and tricks: At the API user / Dosage Form Tips and tricks: At the API user / Dosage Form manufacturer (2)manufacturer (2)

Take API samples for analytical fingerprinting vs. authentic Take API samples for analytical fingerprinting vs. authentic samples of the approved API supplier and check fingerprint vs. samples of the approved API supplier and check fingerprint vs. registered API qualityregistered API quality

• Compare information obtained from the approved API supplier Compare information obtained from the approved API supplier on the API volume sold annually to the inspected dosage form on the API volume sold annually to the inspected dosage form manufacturer and compare vs. volume used annually in manufacturer and compare vs. volume used annually in production of the dosage formsproduction of the dosage forms

• Verify also that batch numbers and dates match those of the Verify also that batch numbers and dates match those of the ones obtained from the API manufacturerones obtained from the API manufacturer

What is needed to solve Europe’s What is needed to solve Europe’s Rogue API Problem?:Rogue API Problem?:

CEFIC’s submitted 10 Points to the CEFIC’s submitted 10 Points to the European CommissionEuropean Commission

1.1. Mandatory API GMP Certification from Mandatory API GMP Certification from European inspectorateEuropean inspectorate

2.2. Global prioritization of API inspectionsGlobal prioritization of API inspections3.3. Central European Unit to coordinate API Central European Unit to coordinate API

inspections worldwideinspections worldwide4.4. Including focus on fraud and Including focus on fraud and

counterfeiting within GMP inspectionscounterfeiting within GMP inspections5.5. Resolve resource problems for Resolve resource problems for

inspections through user feesinspections through user fees

What is needed to solve Europe’s What is needed to solve Europe’s Rogue API Problem:Rogue API Problem:

CEFIC submitted 10 Points to the CEFIC submitted 10 Points to the European CommissionEuropean Commission

6.6. Use of analytical technologies by Use of analytical technologies by authorities and industry to detect authorities and industry to detect counterfeit APIs (e.g. NIRS)counterfeit APIs (e.g. NIRS)

7.7. IT system to help customs to stop IT system to help customs to stop importation of Rogue APIsimportation of Rogue APIs

8.8. Introduction of tough sanctions and Introduction of tough sanctions and penalties for API counterfeitingpenalties for API counterfeiting

9.9. Introduction of licensing system for Introduction of licensing system for traders and brokerstraders and brokers

10.10. Clarify legal liability of Qualified PersonsClarify legal liability of Qualified Persons

A Fatal Example: HeparinA Fatal Example: Heparin• Heparin use: Heart surgery, kidney Heparin use: Heart surgery, kidney dialysis, angioplasty: millions of patients dialysis, angioplasty: millions of patients per yearper year

• Q1 2008: In USA 149 patients reported Q1 2008: In USA 149 patients reported dead and ca. 800 adverse reactions (partly dead and ca. 800 adverse reactions (partly life-threatening) due to contaminated life-threatening) due to contaminated heparinheparin

• The involved heparin manufacturer in The involved heparin manufacturer in China was never inspectedChina was never inspected

• Contaminated heparin detected in 11 Contaminated heparin detected in 11 countries but no casualties in Europe…countries but no casualties in Europe…

• Europe: Only in Germany 80 adverse Europe: Only in Germany 80 adverse reactionsreactions

• Massive recalls but we appear to be Massive recalls but we appear to be trapped: availability vs. risk! trapped: availability vs. risk! (vide infra)(vide infra)

HeparinHeparin

FDA identifies contaminant: 5% - 45%FDA identifies contaminant: 5% - 45%Oversulfated chondroitin sulfate (OSCS)Oversulfated chondroitin sulfate (OSCS)OSCS molecular structure closely resembles heparinOSCS molecular structure closely resembles heparinOSCS mimics heparin in standard testingOSCS mimics heparin in standard testingOSCS is not a natural compound => synthesized!OSCS is not a natural compound => synthesized!Chondroitin sulfate origin: animal cartilageChondroitin sulfate origin: animal cartilageOSCS is cheap (< $80 vs. heparin $500-1500)OSCS is cheap (< $80 vs. heparin $500-1500)OSCS most likely added OSCS most likely added deliberatelydeliberatelyContaminated heparin comes from 12 different sources located Contaminated heparin comes from 12 different sources located all throughout Chinaall throughout ChinaProfit: $ 1 - 3 millionProfit: $ 1 - 3 millionProof obtained that OSCS caused the toxic effectsProof obtained that OSCS caused the toxic effectsHeparin API price > tripled by end of 2007 Heparin API price > tripled by end of 2007 (blue ear pig disease)(blue ear pig disease)

Heparin & EuropeHeparin & EuropeDue to:Due to:The very high incidence of OSCS contaminationThe very high incidence of OSCS contaminationOur high dependency upon Chinese supply of Our high dependency upon Chinese supply of heparin API resulting in shortage of uncontaminated heparin API resulting in shortage of uncontaminated heparinheparinThe life-saving aspects of heparin use…The life-saving aspects of heparin use…

EMEA and EU Member States’ Health Authorities EMEA and EU Member States’ Health Authorities issued declarations stating that issued declarations stating that low molecular low molecular weight heparin contaminated with OSCS should weight heparin contaminated with OSCS should continue to be used until the shortage will be continue to be used until the shortage will be resolved.resolved. But the pharmacological properties of OSCS are But the pharmacological properties of OSCS are completely unknown…completely unknown…

See e.g.:See e.g.:http://www.emea.europa.eu/humandocs/PDFs/EPAR/heparin/27196708en.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/heparin/27196708en.pdf http://www.emea.europa.eu/humandocs/PDFs/EPAR/heparin/27772208en.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/heparin/27772208en.pdf http://agmed.sante.gouv.fr/pdf/1/fiche-presse-heparines.pdfhttp://agmed.sante.gouv.fr/pdf/1/fiche-presse-heparines.pdfhttp://www.mhra.gov.uk/Publications/Safetywarnings/Drugalerts/CON017989http://www.mhra.gov.uk/Publications/Safetywarnings/Drugalerts/CON017989

A reaction to the Heparin disasterA reaction to the Heparin disaster

William Hubbard, former Deputy Commissioner William Hubbard, former Deputy Commissioner of the US / FDA:of the US / FDA:

(US Congress Hearing, May 2008)(US Congress Hearing, May 2008)

““These APIs are a string of ticking time bombs. These APIs are a string of ticking time bombs. Heparin has gone off Heparin has gone off and there will be more until we and there will be more until we

fix the problemfix the problem””

““We’re inspecting where the drugs aren’t being made We’re inspecting where the drugs aren’t being made and not where the drugs are being made”and not where the drugs are being made”

InspectionsInspectionsDo not give guarantees for safe APIsDo not give guarantees for safe APIsDo not give guarantees against counterfeit & Do not give guarantees against counterfeit & fraudfraudBut the more frequent and the more deterrent But the more frequent and the more deterrent they are the smaller the chance for health they are the smaller the chance for health catastrophescatastrophesWithout them the doors are wide open to… Without them the doors are wide open to… anythinganything

““FDA inspections at Changzhou SPL would not FDA inspections at Changzhou SPL would not have prevented the heparin disaster”have prevented the heparin disaster”

Hmm, probably an incorrect conclusion…?Hmm, probably an incorrect conclusion…?

Is it “impossible to inspect all Is it “impossible to inspect all API manufacturers”?API manufacturers”?

A rough calculation:A rough calculation: China:China:

Ca. 1% of ca. 5,000 API producers operate at EUCa. 1% of ca. 5,000 API producers operate at EU

standards = standards = ++5050 (Includes the 3,000 illegal manufacturers not (Includes the 3,000 illegal manufacturers not

licensed by SFDA. If excluded: only licensed by SFDA. If excluded: only ++2020))

India:India:

Ca. 1% of ca. 10,000 API manufacturers operate at EU standards =Ca. 1% of ca. 10,000 API manufacturers operate at EU standards =

++100100

Many other manufacturers in China / India will refuse inspectionMany other manufacturers in China / India will refuse inspection

and/or will close down upon announcement of inspection (cf. Hu)and/or will close down upon announcement of inspection (cf. Hu)

Is it “impossible to inspect all Is it “impossible to inspect all API manufacturers”?API manufacturers”?

The number of inspections will be feasible to The number of inspections will be feasible to do, especially when also global priorities will do, especially when also global priorities will be set in a risk-based manner and be set in a risk-based manner and coordination between US, EU, Australia etc. coordination between US, EU, Australia etc. will be in placewill be in place

Very strong deterrent effect!Very strong deterrent effect!

To protect patients:To protect patients: Consider not “to inspect Consider not “to inspect those who supply APIs for EU medicines” those who supply APIs for EU medicines” but “to only allow API in EU medicine from but “to only allow API in EU medicine from inspected and certified API manufacturers”inspected and certified API manufacturers”

Does deterrence really Does deterrence really work?work?

Deterrence works !Deterrence works !

Thank you for your Thank you for your attention!attention!

API Audits & Inspections: An APIC Point of View Chris Oldenhof DSM / The Netherlands President of...

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