key points from eudralex volume 4 part iv and some
TRANSCRIPT
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
3
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
4
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
6
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
7
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
8
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
9
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
10
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
11
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.
12
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
14
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
15
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
17
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
19
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
20
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
21
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
22
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?
24