Pharmaceutical Manufacturing & Quality: Emerging
Regulations and Their Impact
Industry Perspective on Annex 1
Tuesday, 22. September 2020
Gabriele Gori PDA Co-Chair Annex 1
Di Morris PHSS Co-Chair Annex 1
DISCLAIMER: The views and opinions expressed in this presentation are those of the authors and do
not necessarily represent official policy or position of GlaxoSmithKline
2
History of Annex 1
COPYRIGHT © PDA 2018
3
Rationale
COPYRIGHT © PDA 2018
4
Regulatory Stakeholders
COPYRIGHT © PDA 2018
EU – 28 Member States
PICS – 54 Agencies
WHO – 194 members
Annex 1 Working Group – UK; Japan; Germany; Ireland; Poland; Switzerland; Australia; US; Singapore; Canada; Taiwan
5
Industry Stakeholders
COPYRIGHT © PDA 2018
6
Annex 1 Format
COPYRIGHT © PDA 2018
General OverviewSection Number
• Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied1 Scope
• General Principles as applied to the manufacture of medicinal products. Includes requirements for Contamination Control Strategy2 Principles
• Highlights the specific requirements of the PQS when applied to sterile medicinal products3 Pharmaceutical Quality System (PQS)
• Guidance on the requirements for specific training knowledge and skills. Also gives guidance to the qualification of personnel4 Personnel
• General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology5 Premises
• General guidance on the design and operation of equipment6 Equipment
• Guidance with regards to the special requirements of utilities such as water, air and vacuum7 Utilities
7
Annex 1 Format continued
COPYRIGHT © PDA 2018
General OverviewSection Number
• Discuss the approaches to be taken with regards to aseptic and terminal sterilization processes. Also discusses different technologies such as single use, lyophilization and BFS/FFS where specific requirements may be required. Discuss approaches to sterilization
8 Production and specific technologies
• This section differs from guidance given in Section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data
• The section also gives guidance on the requirements of Aseptic Process Simulation
9 Viable and non viable environmental and process monitoring
• Give guidance on some of the specific Quality Control requirements relating to sterile medicinal products10 Quality Control
• Explanation of specific terminology11 Glossary
8
Revision process
COPYRIGHT © PDA 2018
AND THEN – SECOND TARGETED CONSULTATION
9
Targeted Consultation of Annex 1 Version 12 via 12 appointed commenting groups – the final stage of revision!
COPYRIGHT © PDA 2018
2020 Consultation with Targeted commenting groups following the public
stakeholder consultation in 2017.
Targeted Sections and clauses of Annex 1 v12 – encouragement not to repeat
comments from last public consultation (that received 6218 comments).
There are other significant comments both for the targeted clauses and over the
complete document.
EMA extended the commenting deadline to 20 July 2020 providing more time for
comment collation and review before submission.
The PDA have facilitated an ‘All commenting groups’ co-ordination series of Tcon
discussions to promote harmonisation and consensus. Each group individually
provided comments to the EC/ EMA but one combined covering letter was sent to
make clear industry expectations and concerns with version 12.
10
Associations’ Letter
COPYRIGHT © PDA 2018
1. The Annex should be flexible to support the use of appropriate alternative
approaches.
2. There must be clear interpretation of the Annex.
• Avoid use of specific examples
• Clear distinctions between similar but different technologies and approaches
3. More work is needed.
Associations have offered to help with training/education programmes, once the Annex
is approved.
11
PDA commenting process
COPYRIGHT © PDA 2018
• Core Team («Annex 1 Task Force», 2° wave): 12 experts from 10 companies from US, EU, ASIA, in
addition to consultants and PDA
• Solicited comments from 10K plus PDA members
• More than 25 meetings (teleconf), and hundreds of working hours
• Additional effort with BioPhorum (BPOG) to develop studies and generate&analize data on PUPSIT
• Overall, 88 Comments reviewed and endorsed by the PDA Science Advisory Boards (SAB) and then
by the Board
• Coordination of 9 Meetings (teleconf) with the representatives of the other 11 professional and trade
associations invited by EC to provide comments to the Annex (draft v12), with the purpose to verify
alignment and potential areas requiring further discussion
• Other professional and trade associations worked in the same way collating comments
12
Positives from current version
COPYRIGHT © PDA 2018
• Better structure of the annex
• More alignment to Contamination Control Strategy
• Increased principles of Quality Risk Management
• Clarity between ‘hard goods’ and ‘terminally sterilised products’ in that F0 not relevant for hard
goods
• For lyophilizers loaded by automated closed systems or located within systems that exclude
operator intervention, the frequency of sterilization should be justified and documented as part of
the CCS
• Changes in microbial flora type and numbers and predominance of specific organisms. Particular
attention should be given to objectionable organisms or those that can be difficult to control such
as spore-forming microorganisms.
13
Contamination Control Strategy (CCS)
COPYRIGHT © PDA 2018
Definition in Annex 1 Glossary*:
Contamination Control Strategy (CCS) – A planned set of controls for microorganisms, pyrogens
and particulates, derived from current product and process understanding that assures process
performance and product quality. The controls can include parameters and attributes related to
active substance, excipient and drug product materials and components, facility and equipment
operating conditions, in process controls, finished product specifications, and the associated
methods and frequency of monitoring and control.
*Also from EU GMP Annex 15 and derived from ICH Q10.
14
COPYRIGHT © PDA 2018
production
Quality systems
deviation, investigation,
CAPA, change control,
complaints, continuous
improvement
equipment
design, qualification,
maintenance, calibration,
cleaning, sterilization
cleaning
validation
SHT,
CCIT,
facilities / utilities
design/clean rooms, water/
gas quality, HVAC, material
flow, maintenance and
calibrationenvironmental
and utilities
monitoring,
smoke studies
incoming /
Starting
materials
pre-assessment, URS,
specification,
agreements, testing
supplier
qualification
personnel
health, gowning, training /
education, behavior,
aseptic techniques,
personnel flow, access
control
material transfer
grade A continuity,
wrapping, autoclave
personnel
qualification
Key process
risk
assessments
e.g. EM
validation
(incl. APS) &
qualificationhouse-
keeping,
cleaning &
disinfection
trending
product
testing,
CQA
trending of
monitoring
data
disinfectant
validation
continuous monitoring /
governance
Management
Review, PQR
Self Inspection
management and
QA oversight,
Quality risk
management
audit,
monitorin
g
monitoring
and
trending of
data
trending
trending
CPV
15
Quality Risk Management
COPYRIGHT © PDA 2018
• There are strict requirements
• Grade A / B and Grade C and D
– Air quality by viable, non-viable particles and
air flow pattern
– Minimum requalification interval
– Smooth surfaces
– No particle shedding materials
– Airlocks
– etc.
Nothing really new
Annex 1 special requirements for cleanroom classes address the critical risks of sterile
manufacturing - no variability by applying QRM
Apply Additional QRM Principles
• Define best clean room design for the process
• Evaluate movement of material and personnel in
the light of contamination and cross
contamination
• Requalify periodically and after changes of
equipment, facility or processes based on the
principles of QRM
BUT
16
Introduction
COPYRIGHT © PDA 2018
17
Clauses requiring comment related to concerns raised by stakeholders during the 2017 Public Stakeholder consultation.
COPYRIGHT © PDA 2018
Qualification and
re-qualification of
Cleanrooms
Integrity testing of large
volume parenteral
containers
Handling of Water
Systems
Sterility Testing
Handling of Sterilizing
filter including Pre-use
Post-use sterilization
integrity testing
(PUPSIT)
Handling of Lyophilizer
18
Clauses requiring comment related to concerns raised by stakeholders – Key Messages
COPYRIGHT © PDA 2018
Qualification and
re-qualification of
Cleanrooms
Integrity testing of
large volume
parenteral
containers
Handling of Water
Systems
• Take a phased approach to
from Classification (particulate
clean-up performance) into
qualification that verifies both
particulate and microbial
contamination levels do not
exceed set limits.
• Add clarity to requalification
requirements.
• Removal of 1µm particle size
• Apply principles of ISO14644*
• Not all water systems require
pyrogen control (e.g. Purified
Water).
• Text should be more line with
PhEur 10.0
• Containers closed by fusion,
e.g. Blow-fill-seal (BFS), Form-
Fill-Seal (FFS), Small and
Large Volume Parenteral
(SVP & LVP) bags, glass or
plastic ampoules, should be
subject to 100% integrity
testing.
• This is not feasible for all
presentations – should allow
other validated methodology.
19
Clauses requiring comment related to concerns raised by stakeholders – Key Messages
COPYRIGHT © PDA 2018
Handling of Sterilizing
filter including Pre-use
Post-use sterilization
integrity testing
(PUPSIT)
Handling of Lyophilizer Sterility Testing
• Until capped, product removed from the
lyophilizer should remain under Grade
A conditions air supply
• Cf. 8.25 Finishing of sterile products
where grade A is required until capped?
• Sterility test: suggested to be taken
beginning, middle and end of the
batch and after any significant
intervention (e.g. open barrier door).
It is suggested that sampling
frequency should be justified and
documented in a CCS.
• Filtration - From the text in
section 8.82 it is difficult to
understand what the requirement
is and what the recommendation
is and what is good to have.
• Clarification is really needed to
prevent mis-interpretation. The
filtration of very small volumes of
solution is not the only case
where PUPSIT can add more
risks than benefits.
20
COPYRIGHT © PDA 2018
PUPSIT – Not a new requirement, but new Regulatory Enforcement*
Historically, there are different positions
- Industry: Flaw masking is uncommon; PUPSIT adds risk,
may disrupt aseptic pathway, adds complexity and
interventions, stresses filter
- Regulators*: Flaw masking is a relevant risk. PUPSIT is
easy to implement, industry just does not want to do it.
Risk assessments can be biased
• NEED OF DATA & FACTS* Not all regulators have the same position
21
COPYRIGHT © PDA 2018
PDA – BioPhorum:Sterile Filtration Quality Risk Management (SFQRM) consortium
Recommendations:
Masking
Trials
BCT* Data
Mining
Best
Practice
Risk
Assessment
* BCT: Bacterial Challenge Test
22
Clauses that were substantially changed following 2017 Public Stakeholder consultation.
COPYRIGHT © PDA 2018
Definition and Handling of
Barrier systems including
disinfection/
decontamination
Personal qualification and
gowningHandling of Gas Filters
Aseptic Process
Simulation (APS)
Aseptic production Personal Monitoring
Quality Control
Moist Heat
23
Clauses that were substantially changed – Key Comments
COPYRIGHT © PDA 2018
Definition and Handling of
Barrier systems including
disinfection/
decontamination
Personal qualification
and gowningHandling of Gas Filters
• Requirements state that personnel
working in grade C and D should go
through gowning qualification. Gowning
qualification of personnel working with
non critical activities in lower grade
cleanrooms should include training but
not full qualification based on the lower
risks.
• To restrict people entering – facilities
need to be better designed.
• Add clarity to differentiation
between RABs and Isolators
• Make clear differences between
RABs and Isolators and the
sterility assurance of in-direct
product contact parts
• Glove testing physical vs visual
inspection/campaign or batch
• Gases should be of
appropriate quality
• Should be tested as part of
campaign manufacture
24
Clauses that were substantially changed – Key Comments
COPYRIGHT © PDA 2018
Aseptic production Moist heat
• Suggested the use of the principles and
measures taken shall be documented in the
CCS.
• Should reference the processes already
mentioned – use of barrier systems,
sterilisation-in-place, robotics etc and defined
in CCS
• The required Intervention list should in APS
section and not in aseptic production
• Needed differentiation between porous
loads, terminal sterilisation of
products/fluid cycles and steam-in-place
• Validation needs both minimum and
maximum temperatures attained
• Need a validated air detector with
periodic Bowie Dick for verification
25
Clauses that were substantially changed – Key Comments
COPYRIGHT © PDA 2018
Personal Monitoring
• It is unclear what is intended by the
statement that “Particular
consideration should be given”.
Unclear whether the intent is to
include exit monitoring for all
personnel regardless of activity
• A requirement to monitor all
personnel entering the aseptic area
and in exit also introduces risk by
requiring additional presence of
personnel / sampling media.
Aseptic Process
Simulation (APS)
• Not a catch all - part of the sterility
assurance measures
• Frequency of interventions based upon
risk to process that cannot be detected
by other means
Quality Control
• 10.6 Point i. indicates in addition to
pulling sterility samples at the beginning,
middle, and end of a batch, to also pull
samples at a significant intervention (e.g.
interventions where the integrity of the
barrier is breached (open door)) or an
operator intervention into critical zones.
• Clarify lyo load Samples for sterility
testing.
26
Other Significant comments on Annex 1 sections together with update of Glossary
COPYRIGHT © PDA 2018
Disinfection EquipmentPremises
Dry HeatFinishing Sterilisation
Ethylene Oxide FFS & BFSEnvironmental Monitoring
EM
27
Other Significant comments on Annex 1 sections together with update of Glossary
COPYRIGHT © PDA 2018
Disinfection EquipmentPremises
• The requirement to have
different modes of action of
disinfectant is still included
• 4.11 The section describes that
transfer into an aseptic processing
area should be carried out via a
unidirectional process.
• The term 'unidirectional' used in this
context is confusing as it may be
interpreted as UDAF.
• 4.16 "A warning system should be in
place to instantly indicate and warn
operators of any failure in the air
supply or reduction of pressure
differentials…"
• Not all indirect contact parts can be
sterilised – needs have flexibility e.g.
when heat sterilization is not possible
(e.g. large built in stopper bowls in
isolators), surface disinfected with
automated processes based on low
bioburden and spore reduction to the
sterility assurance level.
• Direct contact parts are those that the
product passes through, such as filling
needles or pumps. Indirect product
contact parts are equipment parts that
come into contact with sterilized critical
items and components.“
28
Other Significant comments on Annex 1 sections together with update of Glossary
COPYRIGHT © PDA 2018
Dry HeatFinishing Sterilisation
• It is not clear if IPC testing for
products not closed by fusion
(e.g. vials, syringes) should be
performed per batch. If this is the
requirement, then it should be
clearly stated.
• Lacks clarity as most refers to terminal
sterilisation – but not clear
• Cycle review now part of batch
certification
• 8.34 All parameters should be defined,
and where critical controlled, monitored
and recorded.
• Need to understand what is critical
• 8.66 The description of dry
heat sterilisation is not accurate
and confusing.
• "8.67 Dry heat sterilizing/
depyrogenation tunnels should
be configured to ensure that air
flow protects the integrity and
performance of the Grade A
sterilizing zone by maintaining
pressure differentials and air
flow through the tunnel from
the higher grade area to the
lower grade area."
29
Other Significant comments on Annex 1 sections together with update of Glossary
COPYRIGHT © PDA 2018
FFS & BFSGaseous sterilisation
e.g. Ethylene Oxide
Environmental Monitoring
EM
• Requirements and guidance for
VHP decontamination are missing.
It is understood that this is not a
sterilization method (fully
penetrative) but a decontamination
method and that should be clear in
the Annex.
• But since VHP is a widely used bio-
decontamination method
requirements and guidance is
needed for this process to add
clarity on expectations. The MHRA
Blog ‘Fragility of VHP’ indicated the
need for Clarity.
• Form Fill Seal - There is a mix-
up between the Form-Fill-Seal
process and the Blow-Fill-Seal
process. They are two separate
techniques that should be
addressed separately. Most of
the requirement under the
heading "Form-Fill-Seal" does
not apply to Blow-Fill-Seal.
• Update section specifically for
VFFS to provide more clarity.
• BFS Grade A air conditions
should be Grade A air quality
• Viable and non-viable environmental and
process monitoring - (9.29) "Sampling
methods and equipment used should be fully
understood. The recovery efficiency of the
sampling methods chosen should be
qualified.“
• Location and type of media chosen
determined at facility PQ based upon design
and process knowledge and confirmed with
EMPQ
• Where processes have materials that
contact the product contact surfaces but are
then discarded, the discarded material
should be simulated with nutrient media and
be incubated as part of the APS.
30
COPYRIGHT © PDA 2018
Thank You
Any Questions?
.
Industry Perspective on Annex 1