ATMP GMP Guidelines

Key Points from Eudralex Volume 4 Part IV and Some Inspection and

Audit Findings

By

Robert Smith

1

ATMP GMP Guidelines

Introduction to ATMPs

Development of the ATMP GMP Guidelines

Key Differences Between Part 1 and Part IV

Audit and Inspection Findings

2

Differences between “Small” Molecules, Biological / Biotechnology Products and Cells

• Size• Chemical elements vs molecular

chains• Limited isomerism vs many isomers• Structure

• Secondary• Tertiary

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EU LegislationDirective

2002/98/ECSetting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC

Directive 2004/23/EC

On setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

Directive 2006/17/EC

Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells.

Directive 2006/86/EC

Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.

Regulation (EC) No 1394/2007

On advanced therapy medicinal products and amending Directive 2001/83/ECand Regulation (EC) No 726/2004

Directive 2015/565.

Amending Directive 2006/86/EC as regards certain technical requirements for the coding of human tissues and cells

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Development of the ATMP GMP Guide

Initial Draft of the GMP Guide Lot of discussion and feedback

General pushback from all parties that the guide

was not workable

Industry did not think that it was robust enough

and in line with the other GMP guidances

Academia and small hospital units thought it too

strict in its requirements5

Development of the ATMP GMP Guide

Initial Draft of the GMP Guide General consensus that guide should focus just

on the specific areas where ATMPs differed from

the other GMPs

Concerns expressed that ATMP guide would

diverge from GMPs for other product types

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Development of the ATMP GMP Guide

Final Draft of the GMP Guide EU Commission confirmation that would be

standalone guidance

Eudralex Vol. 4 Part IV

There was some significant changes in some

parts of the guide which met some of the

concerns raised by interested parties

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Key Parts of the Guidance for QP

Lot of sections that overlap between Part I and Part IV Pharmaceutical Quality System; Personnel; Premises;

Text between Part I and Part IV very similar. More emphasis on a risk-based approach Highly variable starting materials Complex manufacturing processes

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Key Parts of the Guidance for QP

Investigational ATMPs Patient safety Product quality Generate supporting data for later phase clinical

trials Personnel QP can be responsible for either Production or

Quality Control Individuals can perform both QC and production

roles Can’t test product they have made

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Key Parts of the Guidance for QP

Documentation Full traceability ” Arm to Arm” Data to be kept for 30 years

Production Big focus on aseptic processing Key patient safety requirement

Short shelf life Manufacturing in the operating room

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Key Parts of the Guidance for QP

Qualification and Validation Guide recognises starting materials may be in

short supply Use of surrogate materials Concurrent validation, where justified

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Key Parts of the Guidance for QP

QP and Batch Release Section 11.10 allows for QPs to work for two or

more sites Provided the QP services to each site are continuous

Waiver for ATMPs to be tested on import Limited ATMP Short shelf life Key patient safety requirement

De-centralised manufacturing ATMP needs “fresh cells” so manufacturing takes place

close to the patient Central site oversight of decentralised site.

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Key Parts of the Guidance for QPs

Starting and Raw Materials Guide clearly sees that final product

quality is linked to quality of the starting materials Antibiotics in the raw or starting materials must

not be in finished product Guidance on importation of materials Cells Xenogenic cells and tissues that could transmit

human pathogens13

Key Parts of the Guidance for QPs

Seed Lots and Cell Banks Comply with GMP Must be established under appropriate conditions Traceability requirements Safety testing Free from adventitious agents

Storage requirements Continual temperature monitoring with alarms Splitting of cell banks to store is different locations

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Key Parts of the Guidance for QPs

Environmental control measures for GMOs Risk management strategy Appropriate controls to prevent release into the environment

Emergency plans to deal with accidental release

Automated manufacturing of ATMP Qualified equipment Suitable equipment operating instructions Regular calibration and maintenance Training of personnel Defined start and end of the process Monitoring of critical process parameters

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INSPECTION AND AUDIT FINDINGS

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INSPECTION AND AUDIT FINDINGS

Based on 2 MHRA inspections and 5 audits of ATMP manufacturers Majority of findings are general GMP

issues that could be cited against Part I, Part II or the current Annexes PQS Qualification and Validation Personnel Documentation Issues Data integrity

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INSPECTION AND AUDIT FINDINGS

Types of Issues Identified Data Integrity Completion of records in a non-

contemporaneous manner Times and dates could be changed on host

systems Qualification Test not meeting acceptance criteria not

captured so no corrective actions taken Not monitoring hot spots and cold spots

identified by temperature mapping18

INSPECTION AND AUDIT FINDINGS

Types of Issues Identified PQS Complaints and recalls procedures

deficient No mock recall performed Risk assessment process did not

consider patient risk Failure to manage change appropriately Failure to audit key suppliers

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INSPECTION AND AUDIT FINDINGS

Types of Issues Identified Documentation Procedures that had not been issued Procedures that were inaccurate

Premises and Equipment Facility had exterior doors where pests could

enter the facility

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INSPECTION AND AUDIT FINDINGS

Types of Issues Identified Aseptic Processing Process simulation studies not representative

of the manufacturing process Operator constantly removing hands in and out

of the Grade A environment when performing aseptic manipulations

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INSPECTION AND AUDIT FINDINGS

Types of Issues Identified Sterility Assurance No growth promotion performed on

environmental monitoring plates No risk assessments for environmental

monitoring locations Isokinetic heads in not aligned to the laminar

air flow in Grade A biosafety cabinet No qualification of disinfectants against “in-

house” isolates

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ATMP GMP Guidelines

Introduction to ATMPs

Development of the ATMP GMP Guidelines

Key Differences Between Part 1 and Part IV

Audit and Inspection Findings

23

Thank you for your attention

Questions?

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