Annex 2 - Manufacture of biological medicinal substances and products for human use & Annex 11 - Computerised systems

1. PIC/S Guide to GMP PE009-13
Key Changes to Annex 2 – Manufacture of Biological Medicinal
Substances and Products for Human Use
June 2018
Francesco Cicirello
GMP Inspector
Manufacturing Quality Branch

2. Key changes to Annex 2:
Major re-write to provide clarification on existing GMPs and new technologies
Guidance for application of GMP to starting materials
Emphasis on controlling adventitious agents, TSE and zoonotic diseases
Part A: General Guidance
Part B: Specific guidance for selected product types
1

3. Scope of Annex 2
Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2
Type and
source of
material
Example
product
Application of this guide to manufacturing steps shown in
grey
1. Animal or
plant sources:
non-
transgenic
Heparins,
insulin,
enzymes,
proteins,
allergen extract,
ATMPs
immunosera
Collection of
plant, organ,
tissue or fluid
3
Cutting,
mixing, and /
or initial
processing
Isolation and
purification
Formulation,
filling
2. Virus or
bacteria /
fermentation /
cell culture
Viral or bacterial
vaccines;
enzymes,
proteins
Establishment &
maintenance of
MCB4, WCB,
MVS, WVS
Cell culture
and/or
fermentation
Inactivation
when
applicable,
isolation and
purification
Formulation,
filling
3.
Biotechnolog
y
fermentation/
cell culture
Recombinant
products, MAb,
allergens,
vaccines Gene
Therapy (viral
and non-viral
vectors,
plasmids)
Establishment &
maintenance of
MCB and WCB,
MSL, WSL
Cell culture
and /or
fermentation
Isolation,
purification,
modification
Formulation,
filling
4. Animal
sources:
transgenic
Recombinant
proteins,
ATMPs
Master and
working
transgenic bank
Collection,
cutting,
mixing, and/or
initial
processing
Isolation,
purification
and
modification
Formulation,
filling
• Clarification of the application of GMP to
biological substances and products
• Master Cell Banks, Working Cell Banks,
etc.
• Collection of plant, tissue or fluid
• GMP applies to all steps in grey
• Sponsors – refer to TGA website for
evidence requirements
• Manufacturers – should hold
evidence of GMP for the materials
you source
2

4. 5. Plant
sources:
transgenic
Recombinant
proteins,
vaccines,
allergen
Master and
working
transgenic bank
Growing,
harvesting
5
Initial
extraction,
isolation,
purification,
modification
Formulation,
filling
6. Human
sources
Urine derived
enzymes,
hormones
Collection of
fluid
6
Mixing, and/or
initial
processing
Isolation and
purification
Formulation,
filling
7. Human
and/or animal
sources
Gene therapy:
genetically
modified cells
Donation,
procurement
and testing of
starting tissue /
cells8
Manufacture
vector
7
and
cell
purification
and
processing,
Ex-vivo
genetic
modification of
cells,
Establish
MCB, WCB or
primary cell lot
Formulation,
filling
Somatic cell
therapy
Donation,
procurement
and testing of
starting tissue /
cells
8
Establish
MCB, WCB or
primary cell lot
or cell pool
Cell isolation,
culture
purification,
combination
with non-
cellular
components
Formulation,
combination,
fill
Tissue
engineered
products
Donation,
procurement
and testing of
starting tissue /
cells
8
Initial
processing,
isolation and
purification,
establish
MCB, WCB,
primary cell lot
or cell pool
Cell isolation,
culture,
purification,
combination
with non-
cellular
components
Formulation,
combination,
fill
3 See section B1 for the extent to which GMP principles apply.
4 See section on ‘Seed lot and cell bank system’ for the extent to which GMP applies.
5 In the EEA: HMPC guideline on Good Agricultural and Collection Practice - EMEA/HMPC/246816/2005 may be applied to growing, harvesting and initial processing in open fields.
6 For principles of GMP apply, see explanatory text in ‘Scope’.
7 Where these are viral vectors, the main controls are as for virus manufacture (row 2).
8 In the EEA, human tissues and cells must comply with Directive
Currently regulated with
the Australian code of
GMP (2013)
3

5. Heads up: PIC/S Annex 2 Revision
• Working Group established to revise the Annex 2 (Manufacture of biological
medicinal products for human use) of the Guide to Good Manufacturing
Practice of Medicinal Products PE 009-13 (Annexes)
• TGA (chair), WHO and EMA amongst participants
• Objectives:
Ø The revision of the requirements for ATMPs will remain an integral part to the existing GMP guidelines and will not
be a standalone guide
Ø The WG will draft a separate Annex specific to ATMP and align the existing Annex 2 to the EU for remaining
products
Ø Efforts will be made, with the aim at maintaining as close harmonisation as possible, to use the language of the
“Guidelines on Good Manufacturing Practice (GMP) specific to Advanced Therapy Medicinal Products (ATMP)”
where possible. PIC/S and WG represented stakeholder’s concerns will guide the final language.
Ø Efforts will be made to accommodate language that address challenges such as “diffuse manufacturing”
Ø Efforts will be made to accommodate language that will permit the standard to facilitate cross border movement
of ATMP. The standard will aim to be bridging across the expectations for these products through all jurisdictions,
even the ones that will not formally adopt it
4

6. PIC/S Guide to GMP PE009-13
Key Changes to Annex 11– Computerised Systems
Francesco Cicirello
GMP Inspector
Manufacturing Quality Branch
June 2018

7. 6
Annex 11: What’s new?
Scope
Applies to all forms of computerized systems (CS) in
GMP environment.
software applications validated and IT infrastructure
qualified.
Focus on QRM CS lifecycle management.
Roles and Responsibilities
Suppliers and Service Providers
Quality/technical Agreements
Audits of service suppliers visible
Review and approval of supplied documentation

8. 7
Annex 11: What’s new?
Validation
Life-cycle approach
System inventory list
URS for each system - traceability matrix
System parameter limits, data limits and error
handling
Periodic Review
Change Control
Data Integrity
Data accuracy, audit trails, and security
Data migration controls
Electronic Signatures
Checks on back-up
IT support
Back-up and archiving
Incident management – RCA & CAPA
Business continuity

9. Validation
Retrospective validation not
permitted
Parallel testing not required
Annex 11: What’s gone?
8
• Retrospective Validation
– Annex 11 originated in 1992
– Retrospective validation allowed manufacturers to
validate existing systems
– All systems in use today should be validated
• Parallel testing
– Not widely adopted
– Allows increased focus of resources on new system