QP Current Practices, Challenges and Mysteries

Caitriona Lenagh16 March 2012

• QP Roles and Responsibilities• QP Current Practices

– Supply Chain Verification

– Study Specific Information– Lot Specific Information

– QP Release

• Mysteries– What happens when things go wrong?

Agenda

• Qualified Person must:– Ensure product has been manufactured in

accordance with»GMP»Product Specification File»Clinical Trial Application

– Certify in a register or equivalent document that product satisfies provisions of Article 13, 2001/20/EC.

QP Roles and Responsibilities

• IMPs manufactured in a third country to standards at least equivalent to EU GMP

• How does the QP ensure these requirements are met in practice?

QP Roles and Responsibilities

QP RELEASE PROCESS

1. Supply Chain

Verification

2. Study Specific

Information

3. Lot Specific

Information

QP RELEASE PROCESS

1. Supply Chain

Verification

Supply Chain Verification

• Why is the supply chain so important?– Regulators place significant emphasis on

verification• BSE/TSE• Heparin Incident

– Need to be aware of the origin- may not be what it seems!

– Provides confidence in sites involved in the supply chain

– Assurance that any risks are managed• QP must

– Have knowledge of the COMPLETE supply chain involved in manufacturing

Supply Chain Verification

• ‘Manufacturing’ includes

– Process of formulating Drug Product– Packaging (Primary and Secondary)

– Labelling– Analytical Testing sites (Release and

Stability)

– Storage including cell bank storage for biological

Sites to be verified

• Chemical Drug Substance– Confirmation of compliance with at least

Local or National GMP for• Manufacturing• Analytical Testing• Storage

– No requirement for QP assessment to EU GMP compliance

Sites to be verified

• Biological Drug Substance– QP assessment for compliance with EU or

equivalent EU GMP • Working Cell Bank (preparation,

maintenance and storage)• Manufacturing• Analytical Testing (release and stability)• Storage

Sites to be verified

• Why

– Essentially the same as the DP– Difficult to be an Established Process

– Greater variation– Higher risk

– Member States requirements vary

Sites to be verified

• Drug product

– QP assessment for compliance with EU or equivalent EU GMP

• Manufacturing• Analytical Testing (release and stability)• Storage

Sites to be verified

What does the process involve?

• Risk Assessments to formally document the process of verification

• Identify each site involved

• Determine if on-site audit is required• Justification provided if on-site audit is not

required

Continued…

• Who can confirm EU GMP / equivalent EU GMP compliance– European Medicines Agency– EEA member state Competent Authority

e.g MHRA– Competent Authority within a country with

a Mutual Recognition Agreement in place

– QP– Under the supervision of a QP

Criteria

• Scope of the audit appropriate

• Outcome satisfactory• Certificate confirming EU/equivalent EU GMP

compliance

• Documentation remains valid

• Copy of

– audit report, audit summary or supporting documentation

– QP resume or evidence of QP eligibility

QP Declaration

• May be confused with the lot specific QP Statement of Release

• Signed by QP, confirming…manufacturing sites to be used outside of the EEA operate to equivalent EU GMP standards

• Protocol and Product specific• Submitted as part of the CTA to the relevant

Competent Authority• QP is taking personal responsibility for

certifying the sites

QP Declaration

• All sites verified- only sites of manufacture, packaging and labelling detailed– Czech Republic- QP Declaration to also

included sites of release and stability testing

– Sweden- Details of site verification to be provided in an additional memo

• May be issued at client risk pending favourable outcome of inspection/audit

• Determined as part of Risk Assessment

Common Pitfalls

• All sites used in the supply chain (e.g. analytical testing labs) not identified to QP– Can occur at various stages in the study

– Sub contracted sites forgotten– Assessment not performed– Possible delays

Common Pitfalls

• Scope of GMP certification does not cover scope of work performed (e.g. manufacturing line or dosage form)– Inspection report covers Buildings 1,2 and

3; product manufactured in Building 4

– Inspection report covers solid dose- sterile injectable in the study

Common Pitfalls

• Site address or location incorrect (e.g. postal address vs building address)– Inspection report details postal address

– Building Address different– Sites of actual manufacture at a separate

location

– Queries could be raised

QP RELEASE PROCESS

2. Study Specific

Information

Study Specific Documentation

• Remember QP Legal Duties

– Each batch of product has been manufactured…..according to GMP, Product Specification File (PSF) and Clinical Trial Application (CTA)

• QP must have knowledge of – CTA which should be consistent with PSF

Continued…

• Study Specific Documentation– Clinical Trial Application Form (Annex 1)– Protocol– IMPD / sIMPD / SmPC / Commercial

Specifications– IMPD Summary of Changes Document (if

applicable)– Master English Label Text and Country

Specific Text (as submitted)– Almac CTA Questionnaire

Continued…

• Document of greatest relevance to the QP ….IMPD – Contains the quality data that has been

submitted to the Competent Authorities• Data provided on

– Drug Substance – Drug Products

• IMP, Comparator, NIMPs, e.g. Rescue medication

– Placebo

Continued…

What is the Product Specification File?• Responsibility of the Sponsor

• A ‘changing’ reference document • May consist of a number of ‘files’ in different

locations

• QP MUST have access to any information if required

• Assessed by Inspectors

Continued…

Contains or makes reference to:– Specifications / Analytical Methods

• Starting materials, packaging, intermediate, bulk and finished

– Manufacturing Methods– In-process testing & methods– Approved Label Text– Randomisation Codes– Technical Agreements– Stability Data– Storage & Shipment information

Common Pitfalls

• Changes to the IMPD need to be communicated immediately

• Why?

– Newly imported lots (including new imports from bulk lots previously released) need to comply with the currently approved version of the CTA i.e. IMPD in the intended country for release

– May result in delay of release

QP RELEASE PROCESS

3. Lot Specific

Information

Lot Specific Information

• Remember QP Legal Duties….

– Each batch of product has been manufactured and assembled according to GMP, PSF and Clinical Trial Application

• QP must therefore have knowledge of the specific lot of – Drug Substance – Drug Product – Placebo

Documentation required

For Drug Substance, Drug Product, Placebo• Certificate of Analysis

– To verify compliance with the specification in the IMPD / sIMPD

• Lot specific GMP Statement for the manufacture, testing & packaging / labelling

– To verify manufacture in accordance with GMP

Continued…

• Critical or major deviations / Out of Specification investigations for manufacture / storage / testing

– Drug Product

– Placebo• Why?

– To identify any possible impact on • Product quality • Patient Safety

Continued…

• Biological Drug Substance – Critical or major deviations / OOS for API

manufacture /storage / testing

• Why?

– GMP starts from maintenance of the Working Cell Bank

– QP must assess to identify possible impact on • Product quality• Patient safety

Continued…

• Stability Memo and supporting stability data– In support of extension plan– Must be comprehensive– Substantial Amendment may need to be filed later

• Why?

– QP must confirm shelf life for Drug Product complies with available stability data.

Continued…

• Memo to confirm the Manufacturing and testing sites as applicable

• Why?

– To confirm supply chain remains in accordance with • IMPD/sIMPD• QP Declaration (if applicable)

Continued

• Documentation required for EU Licensed Drug Products

– Commercial pack direct from manufacturer• QP Certification

– Wholesale dealer• Statement of Authenticity / ‘Pedigree

document’– Manufacturer supplied Brite Stock

• Memo from QP to confirm product compliance with MA with any exceptions identified (e.g. labelling)

Continued

• Non- EU Licensed Drug Products

– Difficulties when establishing supply chain– Confirm EU GMP / EU GMP equivalency of

supply chain

– Preference is to use EU licensed Drug Products where possible

– The specific documents required are assessed on a case by case basis

• QP involved during submission• Advise on exact means of verification

– Recent Almac experience- MHRA acceptance

Common Pitfalls

• Finished Goods Lot– Is the entire supply chain for product to be

released consistent with IMPD / QP Declaration?

– Are the languages on the labels consistent with the destination countries?

– Cold chain product – Any temperature excursions justified?

Continued

Licensed Drug Products – Does the CTA take into account any

modification in relation to the MA or equivalent?– Are NIMPs in the study truly NIMPs?– Is the Drug Product the same as that detailed in

the CTA?– Is the expiry date the same or less than the

expiry date of the licensed lot?

– Be wary of counterfeit material?

Common pitfalls

- Shelf life detailed in IMPD not reflected in drug product labelling

- Regulatory Authorities or QP not informed of changes

- Critical path- may result in delay in QP Release!

QP release

• Remember QP Legal Duties…QP is to certify batches prior to use in a Clinical Trial– Study Specific and Lot specific information

in place– QP release

• Lots specific Checklist– Details checks to verify compliance

• CTA Questionnaire– Provides details of regulatory status in

country for release

– Blinded QP Statement of Release

Updates

• Annex 13 compliant– Manufacturer’s Authorisation Number– Expiry date

• IVR controlled– Strongly controlled within inventory when

label does not detail expiry date– Challenges to sponsor when product leaves

QP inventory system– Is there adequate control at patient level?– Enhanced regulatory scrutiny in QP’s

involvement in IVRS design

Updates

• QP Facilitation Programme at site

– Aimed to remove QP release from the critical path

– Quality Compliance Manager placed on-site

– Information gathering

– Establishing relationships– Educating

– Beneficial to both Sponsor and Almac

Mysteries

• What happens when things go wrong?

– Controls in place have not been ‘effective’?• Manufacturing sites – inspections

indicate critical findings• Lot specific non conformities identified

post release

• Recall– Panic- not an option

Continued…

• Common goal for both Sponsor and QP

– Patient Safety– Maintain Drug Supply

– Minimal study impact• Communication of paramount importance

– Sponsor and QP– QP and Regulators

Continued

• Additional information required

• Sponsor supplied Risk Assessment• Almac Risk Assessment

– Impact Assessment• Discussions with Regulator as required

• Outcome determined; Product to– Remain at site– Be recalled– Be released

• QP Roles and Responsibilities• QP Current Practices

– Supply Chain Verification

– Study Specific Information– Lot Specific Information

– QP Release

• Mysteries– What happens when things go wrong?

Summary