Update on Falsified Zidolam-N®

(Lamivudine, Zidovudine and Nevirapine Tablets)

found on Kenya market

Deusdedit K. Mubangizi

Technical Officer

Inspector

World Health Organisation

EMP/QSM/PQM

mubangizid@who.int

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In this presentation

• PQ process and monitoring activities.

• Source of information - complaint.

• Investigations.

• Findings.

• Actions taken.

• Lessons and recommendations.

• WHO-PQ contributing to Universal Access.

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WHO Prequalification: Inspection activitiesExpression of Interest

(EOI)

WHO route SRA* route

Dossier Q/E GMP/GCP Innovators Generics

Simplified procedure

PQ

*Stringent Regulatory Authority

APIs,FPPs,

BE/CROs,QCLs

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Expressionof Interest

Compliance

Additional informationand data

Correctiveactions

Compliance

Assessment Inspections

Medicines Prequalification Process

Prequalification

Monitoring

Product dossierSMF

Dossier maintenance(variations)

Handling of

complaints

Zidolam-NZidovudine 300mg, Lamivudine 150mg

and Nevirapine 200mg tablets

• Prequalified on 23 May 2006 with reference number HA275

• Manufactured by Hetero at its Unit III, Andhra Pradesh, India

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Source of Information: MSF12th September 2011

PHOTO by MSF Alert from CHMP to MSF

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Immediate Investigation13th September 2011

• Alerted Kenya Pharmacy and Poisons Board

– Had not been notified by CHMP (Kenya) or MSF (Kenya)

• Special Inspection of Hetero Unit 3:

– Retention samples

– Manufacturing records

– Analysis records

– Distribution records

– Observed re-analysis of retention samples

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Findings (1)

Genuine Zidolam-N

Batch No. E10076

Falsified Zidolam-N

Batch No. E10076

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Findings (2)ZIDOLAM-N Batch No. E100766

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GENUINE FALSEFIED

• Font style of zero the batch

number; is printed as 0.

• Font style of zero the batch

number; is printed as Ø.

• The spacing between licence

number and the batch

number on the bottle label is

constant in all samples.

• The spacing between licence

number and the batch number

on the bottle label varies from

one bottle to another.

• The samples of the genuine

Hetero batch do not carry a

COIP logo.

• Falsified samples bear the

COIP logo. (The logo is that of

a Canadian nongovernmental

organization.)

Findings (3)

• Affected batches;

– E100766, E110467, A9351, A9357, A9366

• the genuine batches E100766 and E110467 were never supplied to the Kenyan market

• the quantities of Zidolam-N with a reference to “batch number

A9351, A9357 or A9366”, found in Kenya, exceed the quantities

manufactured, packed and dispatched by Hetero as batches A9351, A9357 and A9366 to Kenya.

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Findings (4)• Results of analysis by Kenya’s NQCL and Hetero:

– Intact samples comply with the manufacturers’ and with international pharmacopoeia specifications.

– Open samples discoloured with high friability, low assay, fungal growth

• Nature of falsification:

– Relabeling and repackaging of donated batches (whose

expiry dates are unknown) in order to divert them to the commercial market.

– Extent and conditions under which the falsification (re-labelling) was undertaken is unknown and thus the quality of the products cannot be fully ascertained

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Actions taken• Collaborated with Kenya authorities in conducting

investigation and taking necessary actions.

• Special inspection of the manufacturing site.

• Analysis of complaint and retention samples.

• KPPB ordered a recall of the batches.

• Issued public notices which were updated as more information became available – careful not to cause anxiety and fear.

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Lessons for the future• Inadequate market controls and procurement

procedures:

– Diversion of donations, relabeling and repackaging.

– Purchase from middlemen at very low prices without question.

– NMRA not informed promptly.

• PQ prompt reaction and coordination facilitated quick investigation.

• Collaboration between PQ, MSF, KPPB, KNQCL and Hetero was crucial for the success of investigations.

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Recommendation

• Supply chain should be fully known and actions should be taken to shorten it wherever possible

• A supply chain is no stronger than its weakest link

WHO-PQ contributing to Universal Access• International norms, standards and guidelines are used in inspection activities

to ensure wide applicability• Collaborative and Risk management principles are applied to ensure

efficient use of available resources:– By a team of qualified and experienced inspectors

�WHO representative (qualified inspector)

�Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S)

�National inspector/s invited to be part and observe the inspection

�Observer from recipient/developing countries (nominated by DRA of the country)

– Use of Inspection reports from other NMRAs– WHO-PQ Collaborative Procedure in Inspections

• nominated inspectors from NMRAs of selected member states are invited to participate in WHO-PQ organized inspections and in turn, the NMRAs is given appropriate access to outcomes of these inspections.

– Capacity building of NMRAs inspectors.– Facilitating use of WHO-PQ inspection results in national regulatory environment for

information and decision making.– Facilitation of harmonization through joint inspections and sharing of outcomes.– Share the workload and promote avoiding duplicative inspections.

• Reduces inspection burden:• Information put in public domain - for use by NMRAs, procurement agents:

WHOPIRs and NOCs

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Prequalification Programme: Use of Inspection reports from other NMRAs

� Inspectorates whose reports are recognized:√ PICS member inspectorates√ EU (EDQM + EMA)√ USFDA – new member of PICS

� What GMP evidence to submit:– SMF – Up-to-date– Inspection report - conducted NMT 2 years

• + CAPAs to deficiencies + final conclusion

– Product Quality Review – not more than 1 year old� Review of the report:

� scope covered the specific block, products, BE study, API� Is comprehensive and supports the final outcome.

� PQP reserves the right to inspect the API manufacturer – as long as product is active in WHO-PQP.

� on-going GMP compliance will be confirmed by WHO√ Desk review may only be use once in every 5 years.

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What manufacturers can do to facilitate this collaboration

• Use same standards and policies– Regulated markets versus Unregulated markets/rest of the world

• Separate blocks, sources of APIs, production procedures (use and control of recovered solvents and materials, QC procedures/specification/OOS.

• Allow joint inspections and observers from user countries.

• Information put in public domain - available for use by NMRAs: WHOPIRs and NOCs

• Inspection results show that there are still a lot of poor manufacturing practices out there. Collaborative effort and skills are needed to ensure access to medicines of assured quality. Results show that WHO-PQP has made tremendous contribution in this respect.

• The support of NRAs in providing co-inspectors and observers is appreciated. This is good for:

– Tapping into international skills

– Ensuring transparency

– Facilitating ownership

– Contributing to capacity building

– Reduces duplication and inspection burden

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