PIMS 2013 / 2014 Peter Murray GSK By www.GBX.uk.com

Aseptic Manufacturing
Implications of current technical
expectations for new and existing
facilities
Peter Murray
©Peter Murray – peter.x.murray@btinternet.com PIMS 2013 - 13th-14th Feb 2013 1 of 18

Topics
This is a high level overview – for specific facilities/products, ‘the
devil is in the detail’
What is driving change?
What has changed?
What are the key features of current aseptic standards?
What are the key areas of potential facility design weakness?
What are the implications for existing plants?
Key messages
©Peter Murray –– peter.x.murray@btinternet.com PIMS 2013 - 13th-14th Feb 2013 2 of 18

Why is change important?
What is driving it?
‘We have been making steriles
for years – what is the problem?

‘…Start with the end in mind…’
Aseptically manufactured injections are
a patient-critical dose-form
• Often given to patients who are
seriously ill and/or immuno-compromised
• Bypass the patient’s primary defences
against pathogenic micro-organisms
• Absence of microbial contamination in
every dose unit required
• Testing cannot assure freedom from
microbial contamination
• Process design and skilled operation
critical to success
The regulator’s role is to ensure patient
needs are met
Patient
Regulator

Aseptic filling – state A to state B challenge
State A
Sterile components and API
Vial
Overseal
Stopper
API
State B
Assembled unit –
No microbial
contamination in orange
zone

What has changed?
Standards vs. enforcement

What are the standards – and what has changed?
The current standards for aseptic manufacture have existed implicitly
for some time in the EU and US guidance
WHO 2010 & 2011 guidance on sterile manufacture - WHO Technical
Reports 957( Annex 4) & 961 (Annex 6):
• Closely parallel the previously existing US/EU guidance
• Are explicit that ‘..As far as possible, personnel should be excluded from
grade A zones..’
Historically, the regulators have not been aggressive in interpreting
what is ‘possible’ – but this is changing
• A recent pattern of enforcement actions – warning letters, restrictions on
supply etc indicate this is now a hot topic for EU and US regulators
• Prudent to anticipate rigorous application of WHO standards by all
regulators, rather than play ‘catch up’ - possibly under regulatory sanction.

Standards
What are the key features?

Standards – what is critical?
The key requirement is avoidance of microbial contamination during the
dose-form assembly process
The focus is very much on ‘…design for sterility assurance..’:
• Achieving initial sterility in the materials and components used to manufacture
a aseptic dose form
• Using current available technical solutions to ensure these materials can be
transferred uncontaminated to the filling unit, without introducing
contamination into that unit
• Using ‘clean in place/sterilise in place (CIP/SIP) ’ or equivalent technology to
ensure the filling unit is initially uncontaminated.
• Using optimised workflows, advanced barrier technology and good machine
design to avoid microbial contamination from material transfers or operator
intrusions during routine operation
• Validation/on-going monitoring to monitor design intent continues to be met
None of the above is static – as better solutions emerge, regulatory expectation is
that they will be adopted in a timely manner

‘…Design for sterility assurance…’
For a sterile injection, the patient expectation is that every dose unit is
uncontaminated
Assurance of achievement of this intent is critically dependent on:
• Design which minimises, to the fullest extent possible, potential for
microbial contamination in routine setup, assembly and operation
• Understanding of the potential failure modes of the design
• Consistent working practices, applied by well trained operators, which take
account of the strengths/vulnerabilities of the design
Testing cannot substitute for good design and consistent operation
• Sterility tests, Media Fills and Environmental Monitoring can only measure
gross failure – they cannot detect or control low levels of individual dose units
failing to meet the required standard

Facility design weakness
Key areas typically needing attention

Key areas of typical facility weakness
Facility and workflow
• Overall design incompatible with consistent sterility assurance
Inadequate operator separation from grade A areas
• Lack of suitable barriers
• Regular operator intrusions into grade A filling zone required for
routine operation
Transfers into grade A zone
• Materials & Components
Training and understanding
• Understanding the strengths and potential failure modes of a
design
• Understanding why things should be done in a specific way and
consistently operating in that specific way

Implications for existing plants
Basic design and layout critical
• Fixed items such as HVAC, prep rooms, sterilising units may dictate
sub-optimal workflows
Retrofitting protection
• Facility layout may critically constrain what can be done
• Sub-optimal placing of key, non-moveable equipment, adversely
affects reliable aseptic material transfers
• Filling equipment – particularly its sterilisation, material-transfers
and adjustment during running – can give significant/insoluble
retrofitting issues
Some plants are flawed to an extent that complete rebuild and
re-equipment may be necessary

Change
Buying in to the need for change
Current State
Future State

‘Buying in’ to the reality of the need to change
Necessary change will not happen unless the need to change is
accepted
• ‘…We were approved 2 years ago so we don’t need to change…’ could
be a serious mis-reading of the current/future enforcement climate
The most advanced facilities and equipment in the world can
produce poor product if operated incorrectly
• Clarity required on what issues affecting sterility assurance a particular
design feature or process is attempting to control
• Critical that management understand the protection provided by the
design feature/control and are aware of potential failure modes
• Operator understanding ‘..why you do this in that specific way…’ is
critical

To summarise
Key messages

Key messages
An increase in enforcement, using regulatory sanctions, of
existing standards for aseptic manufacture, is in progress
Manufacturers need to recognise:
• Logic dictates the standards are necessary
• Current enforcement of regulatory standards in a specific market
may not match that regulator’s future expectations
• There is no ‘one size fits all’ solution – many key issues are facility,
manufacturing scale and product specific
• Designs meeting the standards are not new – examples from the mid
1990’s full meet these expectations
Manufacturers need to act to:
• Establish the current state of compliance of facilities, equipment
and processes vs. current standards
• As appropriate, institute a programme to remediate any issues
identified – before action is forced under regulatory sanctions

Thank you for your attention
Questions?

Supplementary slides

References – aseptic manufacture stds.
EU Standards – ‘Orange Guide’ Annex 1
• http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf
US Standards – Guidance for sterile drug products produced by aseptic
processing, section IV (particularly IV E)
• http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf
WHO – Technical reports 957 annex 4 & 961 annex 6
• http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf
• http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf

References - air quality standards
EU - EU Guide to Good Manufacturing Practice – Annex 1
US - Guidance for sterile drug products produced by aseptic processing

Control by testing – the fallacy
Process simulation
• Measures only the interventions you think of
• A significant number of human upper-respiratory organisms will
not reliably grow in the specified media
Air sampling
• Annex 1 only effectively requires 0.0013% of air that has an
influence over product to be tested for microbial content
• Same problem with microbial growth as process simulation
Sterility test
• Batch with ~3.5% contaminated units has 50/50 chance of passing
• ~14% contaminated units needed for 95% chance of failing
• Same problem with microbial growth as process simulation

PIMS 2013 / 2014 Peter Murray GSK By www.GBX.uk.com

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PIMS 2013 / 2014 Peter Murray GSK By www.GBX.uk.com