GMP 2023 - Sessions Presentations

1: Welcome and opening remarks
2: Forward vision: regulation and manufacture supply

3: Remote inspections: the past, present and future
4: Data integrity and lab deficiencies
5: Common inspection deficiencies and trends
6: GMP for listed medicines
7: Australian Sponsors and GMP
8: Medicinal Cannabis: Complying with TGO 93
9: PIC/S Annex 1
10: Medicine Shortages
11: Adoption of future PIC/S revisions
12: GMP for ATMP
Welcome and opening remarks
The regulatory landscape – with an
eye to manufacturing issues
Adjunct Professor John Skerritt

Deputy Secretary
Health Products Regulation Group
Department of Heath and Aged Care, TGA
Overview
Manufacturing quality central to all
medicine and vaccine products
• TGA GMP and clearance statistics

• What did we learn from the pandemic
• Evolution of GMP reliance
• Some current GMP issues – nitrosamines, medicinal cannabis, comp meds, sunscreens, MRNA
products
• What else is happening in medicines and vaccines at the TGA ?
• Medicine shortages and manufacturing issues
• Cells and tissues, faecal transplants, leeches and maggots
• TGA’s public good role has significantly increased
Therapeutic Goods Administration – tga.gov.au

Outcomes of inspections of Australian manufacturers
As at 30 June 2022, there were 265 Australian companies holding manufacturing licences
covering 410 sites
2020-21 2021-22
Number (% of Total)
Compliance status (Australia)
Number of inspections conducted 210 139
Satisfactory compliance (of completed inspections) 139 (66%) 99 (71%)
Marginal compliance (of completed inspections) 35 (17%) 25 (18%)

Unacceptable (of completed inspections) 9 (4%) 7 (5%)
Compliance under assessment 27 (13%) 8 (5%)

2020-21 2021-22
Foreign inspection
Number (% of Total)
statistics 2021/22
Number of inspections conducted 54 104
Satisfactory compliance 41 (76%) 80 (77%)
Marginal compliance 4 (7%) 17 (16%)
Unacceptable 1 (2%) 2 (2%)
Compliance under assessment 8 (15%) 5 (0%)
2020-21 2021-22
Number (% of Total completed)
6,778 (93%) 8,103 (91%)

GMP clearances Approved
2021/22 Rejected
524 (7%) 799 (9%)
7,302 (100%) 8,902 (100%)

Total completed
The importance of vaccine GMP during the pandemic
Need for rapid expansion of global manufacturing capacity presented many challenges:
• Increased reliance on Contract Manufacturing Organisations – New

relationships and jurisdictions as well as limitations in the number of CMO’s
available
• Supply chain constraints – Limitations in suppliers of raw materials
• Technology transfer – Several sites around the world are being brought online
together
• Cross contamination – Multiple products manufactured in the same facilities
• Public Scrutiny – increased pressure on manufacturers to deliver
Robust adherence to GMP principles helped mitigate many of these risks

The COVID-19 GMP hangover
GMP Inspections:
• Years of international travel restrictions have
resulted in a large numbers of manufacturers
requiring inspections, affecting all regulators
• Manufacturers blame COVID-19 when poor GMP
compliance identified
GMP Clearance:
• Flexibilities introduced during the pandemic
increased the complexity and risk profile
• Application volumes and work on hand continue to
increase
• Target timeframes increased

Remote and hybrid audits - benefits and challenges
Remote audits = Performed offsite in real time with the audited party using videotelephony
Hybrid audits = One auditor on site for at least part of the audit PLUS remote audit component
Benefits
• Increased efficiency – more audit days, fewer days and costs lost to travel
• Can bring in wider range of technical expertise
• Ability to audit in high-risk travel areas
Challenges
• May not be as effective – hard to review all manufacturing activities, and paper records, detect
nonconformities
• Can be seen as confrontational, language issues, time zone differences, Internet patchy
• Audits can take more time
Can the GMP inspection reliance model evolve ?
Australia has one of the most extensive reliance models
For overseas manufacturing sites, TGA either performs:

• A desktop audit of the overseas site incorporating evidence from “Recognised Regulatory Authorities” (RRA),
OR
• An inspection of the overseas site
The extent to which we rely on inspection outcomes from the RRA is dependent on
• Level of equivalence between TGA and the RRA (not all PIC/S members are equivalent)
• International agreements (e.g. MRAs) and other arrangements in place
But the TGA needs to

• Better document rationale for acceptance of RRA GMP inspections and have a transparent framework for
assessing new and existing partners
• Determine whether third country inspections by RRAs can be in scope for GMP Clearances
• We plan to develop and communicate a “GMP Inspection Reliance Framework” in 2023-24

Nitrosamine contamination of medicines
• Nitrosamine contamination found in a number of
medicines since 2018 globally
o Sartans, ranitidine, metformin, varenicline, rifampicin,
quinapril, sitagliptin, reboxetine
• Levels are small however

o If a patient takes the medicine for 70 years should not
increase cancer risk by more than 1 in 100,000 based
on animal studies
• Generated during manufacturing or storage

o US FDA working with manufacturers on process
changes to determine whether contamination can be
reduced

Medicinal cannabis GMP reforms
Current situation
• All medicinal cannabis products supplied in Australia must
comply with a product standard TGO 93
• Australian manufacturers of medicinal cannabis products must
hold a TGA GMP manufacturing licence
• There is an exemption from holding GMP evidence for starting
materials only if it is further manufactured at a GMP approved
facility
• Compounding of medicinal cannabis products still permitted but
SAS or AP approvals now required before prescribing
After 1 July 2023

• Importers of medicinal cannabis products will have to be
“manufactured to a recognised international GMP standard”
• Levels playing field – list of GMP standards on the TGA website
GMP for complementary medicines and sunscreens
GMP inspections required because Australian law classifies both as medicines
Sunscreens
• TGA guidance for demonstrating compliance with PIC/S
• New evaluation pathways for sunscreen actives and excipients
o Mandatory requirements for new ingredient applications, but data
requirements tailored for products for topical use
o Mandatory review timeframes and appeal rights for ingredient
applications
o Use of monographs for certain ingredients
o New sunscreen standard addresses application methods for spray
sunscreens
Complementary medicines
• Reinspection frequency based on risk
• Yet some compliance concerns with certain manufacturers

mRNA vaccines and therapeutics – additional GMP issues
Quality and consistency of the lipid nanoparticles as important as mRNA
mRNA vaccines - encoding a viral protein to elicit a protective immune response for prophylaxis of viral
diseases and immunotherapies for cancer
mRNA therapeutics – for treatment, mitigation or cure of a disease - encoding a protein that is missing
or dysfunctional in the patient to provide functional gene expression
Manufacture of the stabilising and delivery system of the mRNA

(usually lipid nanoparticles) requires close review as part of drug
product manufacturing
Raw material lipids should also be carefully controlled
For the drug product, determine consistency of manufacture:
quantify the amount of mRNA encapsulated
determine the size distribution of particles

mRNA vaccines and therapeutics
Major process points for quality control
Manufacturing controls
• Validation of all processes for consistency and product stability - manufacturer needs to agree release
specification and product characterisation methods with regulator
• Control of starting and raw materials
• In-process control of the manufacturing process critical – bulk mRNA, LNP manufacture, encapsulation
as is characterisation of the drug substance and final filled vaccine (drug product)
Stability testing
• Storage temperature and expiry date based on real-time evidence - consider shelf-life extensions later
• Must be in the final vials used commercially
• Short term stability at refrigerator and room temperatures also important to inform clinical deployment
• Stability and freedom from microbial contamination particularly important for multidose vials

What else is
happening in
medicines and
vaccines at the
TGA ?
Facilitated prescription medicine pathways enable
earlier patient access
But they can put pressure on GMP inspection or clearance requirements
Priority review (max 150 working days)

• 48 have been approved under this pathway since July 2017
• Average decision time 126 working days
Provisional Approval
• 60 have been approved since 2018
• Average decision time 70 working days
Comparable Overseas Regulator pathway

• 58 approved since 2018
ACCESS Worksharing initiative

• 25 NCEs and 8 generics approved since 2018

Generic medicines reforms
Only some relate to manufacturing quality, although it is important to ask sponsors to maintain
up to date manufacturing site information
• Requirement to include Product Information hard copy in injectables being reviewed

• Developing guidance for supplying prescription medicines in shortage that do not have
Australian specific labelling
• Early scientific advice – complex generics, possibly also non-oral dose forms
• Greater use of overseas reference products for bioequivalence
• Complex generic products – review regulatory pathways, strengthen international cooperation
• Reforms to application and evaluation processes – submission of additional data, updating
of Product Information

On the other hand, a period of consolidation following many
recent complementary medicine reforms
• Permitted indications
• Efficacy evidence guidelines
• Listed (Assessed) pathway - data protection and
efficacy claimers
• Permitted ingredients (and an online catalogue)
• Sport supplement reforms
• Market exclusivity for new ingredients
• More comprehensive post-market monitoring
• Compliance review database
• Risk-based GMP reinspection frequencies

Paracetamol and Psychedelic rescheduling –
3 February 2023
Paracetamol – interim decision
Responsive to increasing incidence of intentional self-poisoning - about 50 deaths per year and 250
serious liver injuries
• Reduce size of packs on general sale from 20 to 16 tablets/capsules and require blister packs
• Reduce size of pharmacy only (S2) packs to 32 tablets/capsules and require blister packs
• Other packs of up to 100 tablets/capsules
Psychedelics – final decision

Rescheduling to Schedule 8 (“controlled drugs”) of psilocybin for treatment-resistant depression, and
MDMA for post-traumatic stress disorder
• Authorisation to prescribe the substances for the above conditions restricted to registered
psychiatrists who have obtained approval from a Human Research Ethics Committee and have
also been authorised by the TGA to be an Authorised Prescriber
• TGA Advice on local manufacturing requirements for psilocybin mushrooms to come soon

Pholcodine cancellation and recall
• Pholcodine was used widely in OTC cough syrups and

lozenges
• Shown to cause a significantly increased risk of
serious anaphylaxis if neuromuscular blocking agents
are used in anaesthesia
• Recalled at pharmacy level effective 8 March and
cancelled from ARTG effective 29 March 2023
• Main alternative product is dextromethorphan
• May require GMP inspections / clearances of new
dextromethorphan API and finished product facilities

Medicine shortages – manufacturing issues are
often at the centre
• Often older, low profit generics with only 1-2 API manufacturers globally
• Currently 40-50 critical medicine shortages – shortages of antibiotics, diabetes, warfarin,

steroid medicines high profile
• Some other medicines in shortage difficult to manufacture so rapid scale up not possible
• TGA actions
o Bring sponsors, wholesalers and healthcare professionals together - managing supply
o Approve temporary supply of overseas substitutes
o Allow pharmacists to dispense substitute combinations of different strengths
o Wholesalers to facilitate equitable distribution
o Public and prescriber communications

Renewed interest in domestic manufacturing
• Commonwealth and State/Territory funding of initiatives

• Not easy for existing manufacturers to pivot to new products
• Some medicines are very complex and difficult to step up
manufacture of
• Australian market may not be sufficient for Return on
Investment for local manufacture – so local manufacturers will
need a regulatory strategy to support export
• TGA will be ready to support the companies as needed – as
we did during COVID

$15 billion National Reconstruction Fund – announced
in Oct 2022 budget
To diversify and transform Australia's industry and economy and drive sustainable economic growth
• “Medical science” one of 7 priorities - including supporting essential supplies
• Government has earmarked $1.5 billion investment in medical manufacturing
• Other areas include
o renewables and low emissions technologies; transport
o value-add in the agriculture, forestry and fisheries sectors; value-add in resources
o defence capability; enabling capabilities
• It will provide finance (including loans, guarantees and equity) to drive investments and look for co-
investment to add value and develop capability
• NRF will operate commercially and its board will make independent investment decisions

Essential supplies vs industry transformation ?

Australian Medtech Manufacturing Centre
$ 20 m Victorian Government initiative aims to:
• Grow medtech manufacturing in Victoria

- Mapping capability in supply chain and local procurement
opportunities
• Increase local content in procurement of health products

- Grants to local companies for medtech manufacturing
- Clinical researcher – medtech partnerships
• Improve collaboration between government, indudtry and

health sectors
- In medtech, cell and gene therapies, medical software

Cell and tissue manufacturing
GMP quality and scale up an increasing issue
Especially an issue for clinical trials – scale up from clinical

trial scale to commercial scale can be challenging
Autologous human cell and tissue (stem cell) reforms 2018
- Non-minimally manipulated products and products for non-homologous
use now within TGA regulatory framework
- CART cells pose particular challenges as cells collected and infused
locally but processed offshore – class 4 biologicals
- Three products approved – Kymriah, Yescarta, Tecartus – certain
leukaemia and lymphomas

TGA regulation of faecal microbial transplants
• First regulatory approval globally was by TGA
- Currently approved only for treatment of Clostridioides
difficile infection - trials underway for use in other
conditions
• New faecal microbial transplant regulatory framework

commenced on 1 July 2021
- Commercial products are class 2 biologicals and require
GMP, TGA review and ARTG registration
- In-house hospital products are class 1 biologicals with
lower regulatory oversight
• Medical and leeches and maggots will be next, and
commercial provision will require GMP
- Regulated differently overseas – medicines (Canada,
EU) versus medical devices (US)

TGA’s public good role has significantly increased - 1
Many activities cannot be directly attributed to a particular

sponsor or may not be appropriate to cost recover
• Orphan drug scheme for rare diseases and less
common cancers – 28 designations /yr
• 222,000 Special Access Scheme and 14,000
Authorised Prescriber Scheme approvals for patient
access to unapproved products where registered ones
have not succeed
• Management of Medicines shortages – 12,000
reports annually
• Emergency access to products

TGA’s public good role has significantly increased - 2
• Compliance and enforcement – 33,000 investigations

annually
• Access to prescription medicinal cannabis and nicotine

vaping products
• Responding to enquiries – 87,500 phone calls and emails

annually
• Assistance to small business and research developers of

emerging therapies and devices – 60,000 enquiries /yr
• Public communication and education – 20 million reaches

on social media/yr

So finally, we do have teeth – but we will not be reckless
• TGA’s Compliance and Enforcement Powers were significantly increased following Act changes
in 2018
• Graded range of powers – warning, enforceable undertaking, fines, civil and criminal action
• Infringement notices are a rapid and effective tool
- If issued to a company they are named in the media
- Recipient is entitled to dispute the notice
• TGA has issued $ 3.82 m in fines in last 19 months
(we don’t get to keep the money !)
- Mainly for alleged advertising and import breaches
- But $ 100 k in fines were issued to companies for
products allegedly not conforming to applicable
standards or failing to observe manufacturing principles

Therapeutic Goods Administration –
Forward vision: regulation of
manufacture and supply
Jenny Burnett
Assistant Secretary
Manufacturing Quality Branch
Australian Government Department of Health, TGA
Setting the scene
The way we do things is changing!
• Outline some factors that may affect Australia’s regulation of medicines and
biologicals
• Suggest why we think TGA, Australian sponsors and manufacturers should be

aware of these and make changes
• Open discussion – this is not a lecture!

Disruptors to our current
1 Increased transparency and public
accountability on medicine supply
approach to regulation
3 themes and an assessment
2 Fast-paced technological innovations
• Patient and consumer expectations
• Manufacturing/technology advances
• Changes for the TGA
3 New and varied approaches being taken by
regulatory agencies • What does this mean for me (when applying to
the TGA)?
4 But for the audience – how does this affect

my business interactions with TGA?

Patient and consumer expectations
We all want more …
• Access to more information about each

medicine
• Location of manufacturer(s)
• All ingredients and their source
• Reliable supply
• Management of shortages
• Efficient, effective recall actions
• Environmental concerns

New manufacturing approaches and technologies
Affecting both industry and the regulator
• Site-based technology vs product specific

manufacture
• Manufacturing by the bedside
• Product knowledge management
• Tech-driven GMP inspections: remote and
hybrid

TGA is changing …
… because the world is changing around us

• COVID19 pandemic – required flexible
approaches
• Increasing rate of change … new regulation
and guidance/educational materials
• Transition from emergency use/provisional
approvals
• Non-traditional access pathways: medicinal
cannabis supply in Australia
• Increasing use of
• IT /electronic data
• data-sharing approaches – security!
• reliance mechanisms

What does this mean for you?

How to ask questions
Verbal questions:
Raise your hand to ask a verbal question. A member of Scan the QR code below or click the link in your calendar
the GMP Forum staff will provide a roaming to access Slido via your mobile device. You can submit
microphone. your question, and vote on other questions submitted.

Jenny Hantzinikolas
Director
GMP Inspection Section
Manufacturing Quality Branch, TGA
Remote Inspections: the past, present and future

Remote Inspections:
past, present and future
Jenny Hantzinikolas
Director
Department of Health and Aged Care, TGA
Overview
• The past
• The present
• Process issues
• Deficiencies
• Some statistics
• The future

The Past
Remote inspections performed in 2020
Regulators had to find alternatives to on-site

inspections for assessing GMP compliance
of pharmaceutical companies.
Many had implemented distant assessment
processes using communication and
information technology including real-time
video streaming of facilities and activities
The remote inspection process was
introduced in March 2020 for domestic
inspections and August 2020 for overseas
inspections performed by TGA.

The Past
Remote inspections performed in 2020
Domestic sites – PIC/S data in 2020
69% of responders were able to conduct on-site
inspections
57% were using distant assessment with virtual
components
57% were using hybrid inspections
Foreign sites – PIC/S data in 2020

Only 14% of responders were performing on-site
inspections
38% were using Distant Assessment with virtual
components

The Past
Remote Inspections
GMP clearances were extended Future Plans When Pandemic Has Ended- future
gazing in 2020- PIC/S data
Some agencies used distant assessment to justify
extensions and postponing inspections 28% of responders will continue to use distant
assessment process for some activities
Developed reflection paper on experiences
49% had not decided their post-pandemic plans yet
Strong support for the development of guidelines and

tools to harmonise procedures for distant
assessments to facilitate continued reliance between
international partners

The Past
Inspection/assessment terminology
Distant assessment , distant
inspection, virtual inspection,
Remote or desktop inspection,
inspections remote assessment
Each jurisdiction used a different term for
inspections and assessments and this led to
confusion and some impact on sharing of
information.
A common approach (including shared All agree on the same term Hybrid
inspections
definitions) on remote assessment was part
of a mandate with a PICS working group to
align terminology and foster some
harmonisation in 2021.
On site All agree on the same term
The agreed approach was to define the inspections
types of remote inspections and align terms
and show where terms could be used
interchangeably.

The Present
Agreed terminology
• Fully interactive distant or remote
assessment
Developed definitions of remote, hybrid Remote • Partially interactive distant or remote
inspections assessment
Inspection • Remote inspections is also called distant,
Guidance on remote inspections remote assessment , virtual inspection, or
developed to harmonise terms by PIC/S desktop inspection
with TGA chair on the PIC/S Working
Group on Remote Assessments.
Hybrid • Combination of on-site inspection and
A best practice approach to conducting Inspection remote assessment
remote inspections that covers logistics,
feasibility, documentation
On site
• No change
inspection

Remote Inspections past and present
The mechanics for a remote inspection performed by TGA
• Meeting apps: MS Teams and WebEx only (secured document repository)

Meeting • Phone if no other options
• Meeting apps for sharing of documents uploaded and documents on company’s

Document review database
• Emails
• Live streaming using meeting apps, phone, tablet

Facility review • Uploaded photos and pre-recorded videos

Remote Inspections past and present
Overview of the remote inspection process
Notify company Inspector: Request

Determine type of
and agree type for
inspection
and methodology documents/records
Company: prepare
Close out Inspection and upload
documents
This the overall process used from 2020 until now

TGA decision making process for type of inspection
Criticality
• Manufacturing type (risk)

• Manufacturer’s compliance history
On-site Remote
Protection of products and personnel
• Manufacturer’s internal restriction requirements for protection of

staff and products
• Manufacturer’s corporate restriction requirements for protection
of staff and products
• Manufacturer’s procedures for protection of inspectors
Hybrid
Technology
• Manufacturer’s technological capability to support remote

inspection

Remote inspections
Common issues with remote overseas inspections
Resources, time zone, inspection duration, translation, documents requested, soft skills,
Logistics facility review limitation
Technology Connection issues, document sharing, data privacy, file size
Regulatory Flexibility with inspection, travel costs, useful for follow up inspections

Remote Inspections
The benefits of the remote inspection for Industry as mentioned by Industry
The flexibility of remote inspections as it was less rigid and pressured than onsite.
Reduces/eliminates the travel costs associated with onsite inspections for the industry.
A remote evaluation may also warrant delaying an on-site inspection, or justifying a reduction in
depth and scope of an on-site inspections

The present - Common Deficiencies from TGA inspections
Remote On site
Poor Investigations Poor investigations
Validation Validation
Documentation Data Integrity
Data Integrity Training
Domestic Inspections
Contributing causes
The present - Common Deficiencies from TGA inspections
Remote On site
Poor Investigations, CAPA and
Poor investigations
deviation handling
Validation and qualification Validation
Documentation Quality Risk Management
Data Integrity Training
International Inspections
Contributing causes
Compliance outcomes from all inspections performed
Domestic inspections performed by TGA
Inspection outcome
90
Compliance rating
80 for inspections
performed in 2019
70
to 2022.
60
50
A1 and A2-
40
Satisfactory
compliance
30
A3- Basic
20 compliance
10
U- unacceptable
1 2 3 4 5 6
Series1 Series2 Series3

Compliance outcomes for all inspections performed
International Inspections performed by TGA
Inspection Outcome
90
80
Compliance rating for
70 inspections performed
60
in 2019 to 2022.
50
40
A1 and A2- Satisfactory
30 compliance
20
A3- Basic compliance
10
U- unacceptable
0
1 2 3 4 5 6
Series1 Series2 Series3

Inspection mode –Remote vs Onsite/hybrid
Domestic Inspections performed by TGA
Domestic inspection mode (%)

120
100 The data shows

the proportion of
80
remote to onsite
inspections for
the periods 2020
60
to 2022 in
Australia
40
20
1 2 3 4 5 6
Series1 Series2

Inspection mode
International Inspections performed by TGA
International inspection mode (%) The data shows the

proportion of remote to
120
onsite inspections for
100
the periods 2020 to
2022 internationally
80
60
40
20
1 2 3 4 5 6
Series1 Series2

The Future
Remote Inspections- settings – Feedback internationally
Will perform under these settings

Travel difficulties
Certain close out inspections
Will not be performing under these settings

For cause inspections
Initial inspections
Poorly compliant sites

Participate in the Q&A
Verbal questions: Written questions:

Emmett Broderick
GMP Inspector
Common Inspection deficiencies and trends

Data integrity & related
laboratory deficiencies
Gaye Camm
Senior GMP Inspector – Technical Specialist
What is Data Integrity?
The degree to which data are:
• Complete
• Consistent
• Accurate
• Trustworthy
• Reliable
…and these characteristics of the data
are maintained through the data life
cycle.

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ALCOA+ Principles
• Clearly • It must be • Data, or • The original • Data must • Complete
Plus
Attributable
Legible
Contemporaneous
Original
Accurate
identify who possible to evidence of record is the truthfully • Consistent
performed a read or actions, first-capture represent
recorded interpret the events or of the action / • Enduring
task and data after it decisions information observation • Available
when the is recorded should be • Data must made
task was • Permanent recorded as be • Data
performed they take preserved in checked
• Software place
• Applies to available to its unaltered where
changes, interpret state necessary
corrections data if in • Supported
& deletions dynamic by robust
format PQS

Creating the right environment
• Data management controls embedded in PQS

• System design to ensure good DI practices
• QRM approach to data integrity
• Ongoing risk review of data criticality vs. risk
• Robust self inspection program
• Clear understanding of importance of data integrity
at all
levels of the organisation
Rationalisation
• Internal reporting encouraged & supported by
Management
• Mature, open management approach to data
integrity
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Risk management approach to Data Integrity
Data Criticality
Data
Data Risk • Batch release data > cleaning records
Criticality
• Data relating to product quality/safety
Data Risk
• Vulnerability of data to alteration, deletion,
recreation, loss or deliberate falsification
Desired outcome = effective control

strategy to manage identified risks

Where does it go wrong?
Data integrity issues seen during TGA
inspections
• Deficiencies relating to data integrity failure may have varying

impact to product quality. Prevalence of the failure may also
vary between the actions of a single employee to an endemic
failure throughout the inspected organisation.
• - PIC/S guidance - PIC/S Good Practices for Data

Management and Integrity PI 041

Data integrity in microbiological laboratories
Manipulation of data Incomplete Testing Poor test records

Samples not taken or “lost” in Not recording all key test data
No testing conducted
transit
Worksheets ripped up and
Not counting all colonies No reconciliation of samples replaced
No reconciliation of forms used

OOS data not being investigated Incubation conditions incorrect Lack of proper computerised
system security
Resampling/retesting without Colony morphology not matching
Using unvalidated test methods
justification identification results
Computerised system Organisational Culture /

Competence/supervision Effective controls Secondary Checks
configuration resources
71
Data integrity controls for manual test methods
Sampling Procedures
Sampling schedule/plans
Test methods
Training of technicians
Sample forms Test volumes/weights recorded Incubation
Detailed collection Calibrated equipment used
methods Reference to all reagents Incubation records maintained
Reading results
Identity of sampler Reference to validated
recorded Min/max incubation time defined
methods/dilution factors and validated
Technicians trained in detection, enumeration and
Samples processed under All transfers/sub-culturing morphology – clear SOPs, photos
clean conditions, e.g. LAF recorded
Controlled environment for reading, light,
Negative controls for All incubated samples tagged magnification
processed samples and identified
Counting device used for colonies
Identity of tester/equipment
Clear acceptance criteria/limits
recorded
OOS & ID policy for manual recording
All samples reconciled
Results recorded
Calculations applied correctly
Second checks and verification in accordance with
quality risk management
Computerised Systems
Annex 11 §4.3 An up-to-date listing of all relevant systems and their GMP functionality
(inventory) should be available. For critical systems, an up-to-date system description
detailing the physical and logical arrangements, data flows and interfaces with other
systems or processes, any hardware and software pre-requisites, and security measures
should be available.
No consolidated listing available

Missing information e.g. PLC controlled
equipment, simple testing instruments such as
auto titrators
Interfaces with other systems or processes not
documented
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Questions to consider when determining GMP criticality
• Does the system control the purchasing and/or status of products and
materials?
• Is it used for control and/or data acquisition for critical manufacturing
processes or testing activities?
• Does the system generate, store or process data that are used to determine
batch quality?
• Will the system generate data that are included in the batch processing or
packaging records?
• Is the system used in the decision process for the release of products?
• Do you have simple systems that generate initial records in electronic
format?

Excel spreadsheets and ALCOA requirements
• Permit multiple users without providing ability to

attribute entries to a specific person (Attributable)
• Data can be accidently or maliciously over-written
and/or replaced (Legible)
• Does not record when data entries have been made
(Contemporaneous)
• Multiple copies can be made of an Excel
spreadsheet outside of the documentation system
(Original)
• Formulae and other functions have potential to be
corrupted without being detected (Accurate)

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Laboratory Electronic systems

Validation Configuration User Access Data management
SOPs for user

Software validation Audit Trails Data review SOPs
access control
Hardware Individual user Raw data

OS security
qualification access verification
Configuration Data back- Defined user External calculation

management up/archiving privileges tools
Change Test method System

Audit trail review
management configuration administrator
Periodic system
E-signatures
review
Computerised system should be verified for intended use
• No URS available for newly installed computerised

systems
• Documentation supplied with commercial off-the-
shelf products not reviewed to ensure user
requirements are fulfilled
• Validation reports for critical system contained
inadequate system descriptions:
- data flows and interfaces with other systems or
processes
- hardware and software pre-requisites
- security measures required for DI
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Control of standalone systems
• Back up of electronic data poorly administered
• Time & date on computer can be modified by user
• Unique user logins not implemented for all staff
• Inappropriate use of ‘Administrator’ login
• Data can be deleted directly from hard drives without detection
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Annex 11 §9: Consideration should be given, based on a risk assessment, to
building into the system the creation of a record of all GMP-relevant changes and
deletions (a system generated "audit trail"). For change or deletion of GMP-
relevant data the reason should be documented.
Audit trails need to be available and convertible to a generally intelligible form
and regularly reviewed.
• Audit trail not regularly reviewed

• Audit trail review conducted on select data only
• Review requirements not formalised in procedures
• Orphan data not captured in analysis
• Reconciliation of electronic data with associated logbooks
not considered
Audit trail review
 Considerations
1. Periodic review of system wide changes e.g. users, system settings
2. Routinely review for potentially damaging user behaviours
• Unauthorised changes to test methods or instrument settings
• Undocumented manual manipulation of data e.g. integration, calibration,
calculated values
• Explanation for ALL data on the system, including data that is not reported
 Procedure for audit trail review, including frequency
 Process for recording the results of audit trail review
 Deviations from standard procedures or atypical results should be investigated
79
Third party suppliers of cloud services (IaaS, PaaS, SaaS)
• No risk assessment conducted to identify risk

associated with using third parties who are creating,
processing or storing regulated data
• No supplier assessment of cloud service providers
conducted
• No formal agreement in place between the
manufacturer and cloud service provider outlining
GMP responsibilities
Search for ‘SOC 2 Assessment of GxP Suppliers of IT Services’
80
Regulatory expectations
• Design systems to prevent data integrity issues

• Ensure the data is authentic and retrievable
• Train staff and encourage correct behaviours and practices
• Open communication
Incentive/Pressure
• Encourage feedback
• Build a system for ongoing review
FRAUD RISK
Opportunity Attitude/Rationalisation
81
Verbal questions:

Paul Stephney
Senior Inspector and Technical Specialist
GMP for listed Medicines

Common inspection
deficiencies and trends
Emmett Broderick
GMP Inspector
Australian Government Department of Health, TGA
GMP Inspections
Deficiency review
• Overseas & domestic inspections conducted from

Jan - Dec 2022
• Critical, Major & Other deficiencies
• Manufacturers of API and finished dosage form
• Manufacturers of all categories excluding Biologicals
• PIC/S Guide to GMP PE009-15 (1 May 2021)

Previous Trends
Deficiency Category
Deviation & Complaint Investigations
(Part I Clause 1.4 xiv)
Quality Risk Management (Part I
Clause 1.12 & 1.13)
Computerised Systems (Annex 11)
Qualification & Validation (Annex 15)
Therapeutic Goods
Administration –
2022
1 Qualification & Validation
Most cited deficiencies

2 Investigation Management
• Similar trend observed for
Validation & Investigation
deficiencies from previous years
3 Training
• Re-emergence of Training and
Documentation into most
Documentation Systems common deficiencies
4 Including Data Integrity
Therapeutic Goods
Administration –
Qualification & Validation
Annex 15 Principle Part II section 12

Applicable to the facilities, The company's overall policy,
equipment, utilities and processes intentions, and approach to
used for the manufacture of medicinal validation, including the validation
products of production processes, cleaning
It is a GMP requirement that procedures, analytical methods, in-
manufacturers control the critical process control test procedures,
aspects….over the life cycle of the computerized systems, and
product and process. persons responsible for design,
review, approval and
Any planned changes…..should be documentation of each validation
formally documented and the impact phase, should be documented.
on the validated status or control
strategy assessed. Therapeutic Goods
Administration –
All qualification and validation activities
Annex 15 should be planned and take the life cycle
§1.1 of facilities, equipment, utilities, process and
product into consideration.
Validation studies should reinforce

Good Manufacturing Practice and be
conducted in accordance with defined Part 1 Clause
5.23
procedures. Results and conclusions
should be recorded.
Part 1 Clause When any new manufacturing formula or

5.24 method of preparation is adopted, steps should
be taken to demonstrate its suitability for
routine processing. The defined process,
using the materials and equipment specified,
should be shown to yield a product
consistently of the required quality.
Therapeutic Goods
Administration –
Validation Deficiency Themes
Overview
• Poor risk assessment &
determination of validation
requirements
• Incomplete or inaccurate validation
documentation
• Failed validation criteria not
adequately addressed
• Insufficient periodic review of
validation

Investigation of deviations, suspected
product defects…
Part I Clause 1.4 (xiv) PIC/S Part II
An appropriate level of root cause analysis Clause 2.16 - Any deviation from
should be applied during the investigation of established procedures should be
deviations, suspected product defects and documented and explained. Critical
other problems deviations should be investigated, and the
investigation and its conclusions
This can be determined using Quality Risk should be documented.
Management principles.
Clause 6.53 - Written procedures should
Appropriate corrective actions and/or be established and followed for
preventive actions (CAPAs) should be investigating critical deviations or the
identified and taken in response to failure of a batch of intermediate or API
investigations. The effectiveness of such to meet specifications. The investigation
actions should be monitored and assessed should extend to other batches that may
have been associated with the specific
failure or deviation.
Investigation Deficiency Themes
Overview
• True root cause not identified
• Insufficient scope or detail of the issue
• Lack of Quality Risk Management
• Ineffective Corrective/
Preventative Actions
(CAPAs)

Training Part I Clause
2.10
‘The manufacturer should provide training for all the
personnel whose duties take them into production
and storage areas or into control laboratories
(including the technical, maintenance and cleaning
personnel), and for other personnel whose
activities could affect the quality of the product’
‘newly recruited personnel should receive

training appropriate to the duties
assigned to them. Continuing training
should also be given, and its practical Part I Clause
effectiveness should be periodically 2.11
assessed….. Training records should be
kept’
‘Training should be regularly conducted by qualified

Part II Clause individuals and should cover, at a minimum, the
3.12 particular operations that the employee performs
and GMP as it relates to the employee's functions.
Records of training should be maintained. Training
should be periodically assessed’

Improvements needed to…
Training effectiveness not demonstrated
• Provide an appropriate level of

Training programs not defined competency
• Ensure operator error is minimised
• Identify operational risks &
Records not available or up-to-date knowledge gaps
• Standardise work practice
• Maintain validated processes &
Training failures not managed product quality

Documentation Systems
Part I Chapter 4 Principle Part II section 6

Good documentation…..is key to operating in Clause 6.10 - All documents related to the
compliance with GMP requirements manufacture of intermediates or APIs should be
The various types of documents and media used prepared, reviewed, approved and distributed
should be fully defined in the manufacturer's according to written procedures
Quality Management System Clause 6.11 - The issuance, revision, superseding
Documentation may exist in a variety of forms, and withdrawal of all documents should be
including paper-based, electronic or controlled with maintenance of revision histories
photographic media Clause 6.14 - When entries are made in records,
The Quality Management System should include these should be made indelibly….and should
sufficient instructional detail to facilitate a common identify the person making the entry.
understanding of the requirements….so that Corrections to entries should be dated and signed
ongoing application of the requirements may and leave the original entry still readable
be demonstrated

Documentation Deficiencies
Overview
• Uncontrolled Document Systems -
adoption of hybrid and digital formats
during pandemic
• Good Documentation Practice not
consistently applied
• Data Integrity issues throughout
document lifecycle
• Procedures not accurate or sufficiently
detailed

Document
Management
Part I Clause 4.1
• All types of document should be defined and adhered to

• Requirements apply equally to all forms of document media
• Complex systems need to be understood, well documented,
validated, and adequate controls should be in place
• Relationships and control measures….need to be stated for
both hybrid and homogenous systems
• Appropriate controls...throughout the retention period

ElecDocumentationtronic
System
User Access & Controls
Data Storage & Security
System Validation &

Governance
Training requirements
E-signatures
Therapeutic Goods
Administration –
Changes to Document Management
• Change Control
• Risk Assessment
• Data Integrity & Compliance Review
• Vendor Qualification
• Validation Review & Plan
• Implementation Plan - include SOP
updates
• System Failure Management/Business
Continuity Plan
• Post Change Review
Therapeutic
100 Goods Administration – tga.gov.au
Critical Deficiency
• A practice or process has produced, or
may result in, a significant risk of
producing a product that is harmful to
the user
• The manufacturer has engaged in fraud,

misrepresentation or falsification of
products or data

Additional Guidance
Documentation & Data Management

PIC/S Guidance PI041-1
ISPE
ISPE GAMP® Guide: Records and Data Integrity
ISPE GAMP® 5: A Risk-Based Approach to Compliant
GxP Computerized Systems
ISPE GAMP® RDI Good Practice Guide: Data
Integrity by Design
PDA Technical Reports
TR84. Integrating Data Integrity Requirements into
Manufacturing & Packing Operations
TR80. Data Integrity Management System for
Pharmaceutical Laboratories Therapeutic Goods
Administration –
Additional common
deficiencies
Cross Contamination Risks • Part I Clause 5.17 - 5.22
• Part I Clause 1.4 (vi) & Clause 5.27

- 5.29
Supplier Qualification & Management
• Part I Chapter 7
Outsourced Activities

Recurring Deficiencies
Possible Reasons
Misinterpretation and poor
understanding of GMP requirements
Focus of inspection and GMP clauses
Hybrid or e-systems not adequately
assessed for compliance
Insufficient planning & resourcing

Raise your hand to ask a verbal Scan the QR code below or click the link in
question. A member of the GMP Forum your calendar to access Slido via your
staff will provide a roaming microphone. mobile device. You can submit your question,
and vote on other questions submitted.
Therapeutic Goods
Administration –
Stephen Farrell
Director, GMP Clearance section
Australian Sponsors & GMP

GMP for Listed Medicines
Paul Stephney
Senior GMP Inspector & Technical Specialist
Manufacturing and Quality Branch
Overview
• Optional ‘onsite’ audits of listed medicine active material suppliers

and manufacturers
• Control of impurities and allergens in listed medicines:
• Elemental impurities (OSDs)
• Residual solvents (OSDs)
• Allergens

Onsite Audits of Listed API suppliers & manufacturers and/or
QC laboratories (not mandatory for listed medicines)
New requirements introduced in PE-009-14 (1 July 2018)
‘...Audits should be carried out at the ‘The medicinal product manufacturer

manufacturers and distributors of active should perform audits, either itself or via
substances to confirm that they comply third parties, at appropriate intervals based
with the relevant good manufacturing on risk at the site(s) carrying out the
practice and good distribution practice testing (including sampling) of the starting
requirements...’ materials...’
– Clause 5.29 PE-009-15 – Clause 5.36 (ii) PE-009-15

Current acceptable approach for Supplier
Approval and Material Qualification for
Listed Medicines
 Appropriately completed and reviewed supplier questionnaire
 Establishment and agreement of relevant specifications
 Risk based period of re-evaluation
 No requirement for GMP/Technical Agreements
 System of material qualification, e.g., full testing of the first three

batches, followed by ongoing rotational testing
 Once qualified, reduced sampling available on incoming listed

medicine active ingredients
Now, if 5.29 and/or 5.36 are followed there is scope for even further
reductions in sampling and testing programs.

Sampling requirements for API pre/post qualification
Pre-qualification Post qualification PQ* including

onsite audit
Sample all Apply
containers √n + 1 *or 1 x sample
reduced
sampling
*Starting materials coming
from a single product
manufacturer or plant

Testing requirements for API pre/post qualification
Pre-qualification Post qualification PQ* including

onsite audit
Full testing Rotational Definitive ID
Testing testing
+ C of A review
against
specification

Pre-requisites and supplier maintenance requirements for ID
only testing of Raw Materials (Annex 8 § 2)
 History of reliable test results (in house QC)
 If agents/brokers are used they must be audited also.
 Material comes directly from the manufacturer or in the manufacturer’s sealed
container
Ongoing maintenance
• Periodic full testing of the raw material and comparison against the suppler CoA
• Any discrepancies with supplier/lab CoA must be investigated!
• Re-audits with the periodicity based on risk

Additional considerations/Exemptions
Herbal raw materials Intermediate & Bulk product

Minimum sampling requirements prior to • Exempt from the supplier approval
qualification, must meet the requirements process
of the default standards: • Manufacturer/sponsor must hold a
• Ph. Eur. Method 2.8.20 TGA GMP licence/certificate, or
clearance respectively
• British Pharmacopoeia Appendix XI T
• Technical/GMP Agreement required
• USP <561>
• Container integrity checks
Annex 7 (PE-009) requirements also apply
• Sample a minimum of one container

What areas should the audit/inspection cover?
Raw material manufacturers:
• Confirm information on the questionnaire is
accurate!
• Quality Management System
• Manufacturing areas (inc. risk of cross
contamination)
• QC Laboratories
• Supply chain traceability
3rd Party QC Laboratories: Audits must be satisfactorily

• Distribution controls completed!
3rd party contractors can be used
• Applicable test methods/validation (see clause 2.23)
• Issuance and authorisation relating to Effective remote inspections allowed
Certificates of Analysis

Summary/ Key points
• Audits of active material suppliers is optional for

manufacturers of listed medicines
• In addition to an onsite audit, the justification for
reducing sampling and testing of incoming raw
materials must be based on an established history of
use with the supplier, with acceptable test results.
• Audits should be comprehensive, relevant to the
material(s) supplied and ongoing.
• Effective remote inspections are permitted but must Updated guidance documents to
be equivalent to an onsite audit be published later on this year!
• ‘Full testing’ must be performed periodically –
frequency should be based on risk.

Control of impurities and allergens in Listed Medicines
Elemental impurities
 Sources
 Application of Quality Risk management
 Methods of calculation
 Case study
Residual solvents
 Overview
 Requirements for testing/methods of calculation
Allergens
 Overview
 Materials of concern
 Control strategy
 Example deficiency

Elemental Impurities – Overview
Elemental impurities include catalysts and environmental contaminants that may be
present in drug substances, excipients, or drug products USP <232>
ICH Q3D adopted by TGA in 2019 as an 80 200.59 82 207.2 33 74.92 48 112.41
‘international scientific guideline’.

Hg Pb As Cd
S6, TGO 101 introduced in 2021 (tablets
capsules and pills) allows:
• ICH Q3D
…human toxicants that have limited or no
• USP <2232> use in the manufacture of pharmaceuticals.
Their presence in drug products typically
General chapters include: comes from commonly used materials (e.g.,
• BP and EP (general chapter 5.20) effectively mined excipients)…. ICH Q3D
defer to ICH Q3D
• USP<232> is the equivalent for non-dietary
supplements Other elements H3C-Hg+ X-
may also apply!
Any specific monograph with heavy metal limits
takes precedence over a general chapter
Sources of Heavy metals in complementary medicine ingredients
All mined excipients and plant/marine/animal based
materials are at risk from potential heavy metal uptake
Sources of contamination
from the environment
• Drug substance/excipient
• Water Mined excipients
Fish oils
RISK (complementary
• Manufacturing equipment
(wear and tear)
medicines)
• Container closure system Cellulose
Other sources include:

• Traditional medicines (TCM, Ayurvedic)
Seeds/oils Lactose
Levels of elemental
contamination found in
natural materials are
inherently variable!
Herbs/Plants
Risk Assessments for Elemental Impurities
• Risk assessment must be wholistic but for Listed Medicines the focus of the assessment
should be on the raw materials.
• Take into account the maximum daily intake of the medicine and the % wt. of each
ingredient in the finished dosage form.
• Utilise any information provided by the supplier (e.g., supplier questionnaire, agreed limits
on specifications) Test results must be qualified (see clause 5.36)
• Given the typical composition of complementary medicines, unlikely that no testing will be
required – Batchwise testing is not expected

Available methods for calculation Elemental impurity content
USP <2232> ICH Q3D
‘Dietary ‘Individual ‘Summation’ ‘Option 1’ ‘Option 2a’ ‘Option 2b’ ‘Option 3’

Supplement’ Component’ • The sum total • Analysis of • Analysis of • Analysis of
• Analysis
mass (µg) of raw raw raw
• Analysis of • Elemental of finished
each materials materials materials
finished analysis of product
product each RM measured • NMT 10g • Max. daily • Specified
intake amount • Max. daily
• Max. daily • NMT 10g element from • (µg/g) intake
each RM • (µg/g) (µg/day)
intake • (µg/g) • (µg/g)
(µg/day) (µg/day)
All methods directly/indirectly calculated from published Permissible Daily Exposure

values (PDE) (µg/day)
Testing for Elemental Impurities – How much is required?
Established test history of results well

within limits – Scope and frequency of
Scope and frequency of
testing can be reduced

testing
High results
OOS/OOT/~CoA
New Supplier/raw
material source Ongoing Testing
Limited history
and test results Extensive history and test results

Case Study: Raw material OOS for Cadmium
• Raw material procured through a broker
• New source of flaxseed oil identified during CoA review
(including acceptable heavy metal levels)
• Full testing initiated (inc., residual solvents and heavy
metals)
• High limits of cadmium identified
Individual Component
Element Limits (μg/g) USP
CoA results
<2232>
Arsenic (in.) 1.5 0.20 (μg/g)

Cadmium 0.5 0.77 (μg/g)
Lead 0.5 0.02 (μg/g)
Mercury 1.5 0.70 (μg/g)
Contract lab COA New RM supplier
Methylmercury 0.2 0.02 (μg/g) COA

Case Study: Raw material
OOS for Cadmium 1 tablet = 0.5g; Max. serving = 4 tablets (2g);
Number of servings a day = 2
Total Cd
Mass per
Mass per Max Daily
• Company follows USP – ‘Dietary Ingredients Unit (g)
Serving
Intake (g)
Cd (µg/g) (µg/
(g)
Supplement’ or ‘Summation’ methods serving)
available Flaxseed oil 0.09 0.36 0.73 0.77 0.28

• Heavy metal analysis performed on other Microcrystalline
0.15 0.60 1.20 0.23 0.14
Cellulose
batch components of the finished
product. Titanium Dioxide 0.06 0.24 0.48 0.40 0.10
• PDE for cadmium = 5µg/day Iron Oxide 0.09 0.36 0.72 0.30 0.11
• The amount of cadmium present in the Magnesium stearate 0.11 0.44 0.88 0.23 0.10
FP per daily intake found to be less than Total 0.50 2.00 4.00 1.93 0.73
PDE – Batch approved for manufacture
• EI analysis performed on subsequent Result 1.45 (µg/day)
batches of flaxseed indefinitely Result = ∑ (Ci x Wi) x N
Ci = elemental contaminant concentration in the individual component (µg/g)
Wi = weight of each individual component per serving of the FP (g/serving)
N = maximum daily intake of the FP recommended on the label (servings/day)

Residual Solvents – Overview
ICH Q3C (R4) adopted by TGA as an
‘international scientific guideline’ in 2014
S6, TGO 101 introduced in 2021 (tablets
capsules and pills) specifies:
• Ph Eur 5.4
The EP general chapter incorporates the ICH
guideline
Safe residual solvent levels derived from
published literature using the NOEL/LOEL model Residual solvents:
Residual solvent classification:
• Organic volatile chemicals that
• Class 1 – ‘To be avoided’ have not been removed
• Class 2 – ‘To be limited’
• Can be found in drug product,
• Class 3 – ‘Low Toxic Potential’ (PDE substance or excipients
>50mg per day)

Residual Solvents – Assessment
‘It is only necessary to test for solvents that are used or produced in the manufacture or purification of active
substances, excipients, or medicinal product.’ Ph Eur 5.4
1. Assessment of finished dosage form manufacturing

processes for use of solvents
2. Engagement with suppliers of active substances and
excipients on their use of solvents during
production/purification steps
If no solvents are used = no testing required

Ph Eur 5.4
‘If solvents of Class 2 or Class 3 are present at greater than their
Option 1 limits or 0.5 per cent, respectively, they should be
identified and quantified.’ Ph Eur 5.4
However, if solvents are declared periodic testing required.

Residual Solvents – Assignment and
quantification of limits
Limits
• Class 1 – avoided; Class 2 – individual PDE (Table 2); Class - 3 0.5%
• Class 3 Solvents – Can be analysed using non-specific test e.g., Loss on
Drying if concentration levels less than 0.5%
Two main options (class 2 solvents):
• Option 1 – Daily intake ≤10g, limits must meet concentration limits in table 2
based off the following calculation:
Acceptable for drug substances,

excipients or products.
• Option 2 – When a component is above the calculated concentration limits.

− Using the known daily dose and the corresponding mass of the ingredient Table 2 - Ph Eur 5.4
calculate the quantity of residual solvents for each component.
− Sum the quantities of the residual solvent in each ingredient of the finished
dosage form.
− Result should be less than PDE limits specified in Table 2.
Control of allergenic substances when
manufacturing Listed Medicines
• A large number of permissible ingredients for listed

medicines are allergens
• A large proportion of listed medicine facilities also
manufacture food products. Listed medicine cleaning
• Label requirements and substances of concern are listed in validation acceptance
Schedule 1 of TGO 92 criteria:
• Visually clean
• Chapter 5 of the PIC/S guide (PE-009) should be utilised for • Removal of detergents
control strategies for storage, manufacture and handling of • Microbiological limits met
Schedule 1 substances (no toxicological evaluation required
for listed medicine ingredients). None of the above
methods can assure the
absence of allergens!

Allergenic substances – what should you be looking for?
Schedule 1 - Therapeutic Goods Order 92 Scenario: Manufacturer produces various listed
oil medicines.
‘…where there are no circumstances • Cod liver and Calendula oil are
specified in column 2, the presence of the manufactured on the same line using shared
substance or group of substances is equipment.
required to be declared on the label
irrespective of any circumstance, • Company uses an ATP test kit strip on
concentration or amount of the product contact surfaces after cleaning,
substance or group of substances specifically for fish products…
present in the medicine…’ • However...
• The necessary label declaration still applies!
Calendula Oil 200mL
Aust L:XXXXX
(May contain fish)

Example Deficiency – Allergen Controls
Evidence was not available to demonstrate that the manufacturer complied to the
applicable regulatory label requirements for listed medicines (i.e., Therapeutic Goods
Order 92) for example:
• Calendula oil (AUST L XXXXX) shared common manufacturing equipment with the
product ‘Cod Liver oil (AUST L YYYYY), however the corresponding finished product
label for the calendula product did not include the following declaration, ‘Contains
Fish/Fish Products’ as required by the Order.
No controls* were in place to justify the lack of declaration on the finished product label.
• *Controls = Dedicated sampling/dispensing tools, dedicated product contact

manufacturing equipment and potentially dedicated rooms.

Manufacturing with Schedule 1 substances: Assessing Risk
Materials Manufacturing Processes
• Consideration of materials held • Cross contamination risks
onsite • Dust/aerosols
• Cross over points
• Ineffective cleaning
Cleaning validation • Reused cleaning solutions
• Have Schedule 1 substances been • Shared equipment?
incorporated into the worst case • Shared rooms?
assessment for the cleaning
validations? Procedures
• What are the analytical capabilities • Adequate detail?
versus the prescribed limits for • Spills?
Schedule 1 substances? • Labels?

Manufacturing with Schedule 1 substances: Controlling Risk
Materials Manufacturing Processes
• Assessment of entire material inventory • Localised extraction
(e.g., therapeutic, food and cosmetics) • Dedicated rooms/tools and equipment
for Schedule 1 substances.
• Separate gowning
• Assessment of Schedule 1 substances
handled at the raw material supplier
(e.g., questionnaire) Procedures
• Cleaning: pictures/diagrams,
assembly/disassembly of equipment.
Cleaning validation • Specific requirements for spillages of
Schedule 1 materials
• Use of Schedule 1 substances as worst
case material. • Appropriate checks for master
product labels
• Use of specific allergen test kits • New product introduction
• Remember column 2 of Schedule 1

Common deficiency: Heavy metals, Residual Solvents, Allergens
The requirements of Clause 1.9 (v) that the finished products contain active ingredients complying with
the qualitative and quantitative composition of the Marketing Authorisation or Clinical Trial
Authorisation, are of the purity required, and are enclosed within their proper containers and correctly
labelled, had not been met, for example:
• The manufacturer performed secondary packaging and release for supply of soft capsule products,
however no evidence of elemental impurity testing relating to batches undergoing release were
available from the site performing RFS or from the bulk product manufacturer.
• The system of evaluating raw materials did not have provision for assessing the potential presence of
residual solvents. It could therefore not be determined if products manufactured onsite contained
acceptable levels of residual solvents at the time of batch release.
• The system for approving master finished product labels did not include provision for verifying if labels
complied with relevant regulations (i.e. TGO 92), noting that a number of Schedule 1 materials were
held onsite.
• The training programs for the Authorised Person and his/her delegates did not include awareness of
regulatory requirements applicable to the dosage forms undergoing release (e.g., TGOs 92, 100, 101).


Paul Crossley
Assistant Director
Medicinal Cannabis: Complying with TGO 93
Maurice Makdessi
Senior GMP Inspector, Team Leader
GMP Inspection Section
Remote Inspections: the past, present and future

Australian Sponsors & GMP
Stephen Farrell
Director
Overview
• GMP?....But I’m a Sponsor not a manufacturer!

• So what are your Responsibilities….the 4 key areas
• Best practice for GMP Clearance

GMP?...But I’m a sponsor
not a manufacturer! “The ultimate responsibility for the
performance of a medicinal product over its
lifetime, its safety, quality and efficacy, lies
with the Marketing Authorisation Holder
(MAH)”
Reference – PIC/S Annex 16 Therapeutic Goods Administration – tga.gov.au

GMP?...But I’m a Sponsor not a manufacturer!
• It is acknowledged that many

Sponsors are not directly engaged in
the manufacture of medicines
• However, the GMP guide contains
several references to Sponsors and
their GMP related responsibilities
• These are spread over various
chapters and annexes and range
from the general to the specific
Pop quiz!

GMP?...But I’m a Sponsor not a manufacturer!
• Modern supply chains are complex and

may consist of global organisations and
shared Pharmaceutical Quality Systems
(PQS).
• The GMP Guide does not provide for
reduced Sponsor responsibilities even
when the Sponsor and manufacturer
belong to the same overall group of
companies.
• Whilst certain tasks may be delegated to
other groups or entities within the global
organisation, the actual responsibilities
may not be delegated.

“It is assumed that the requirements of the Marketing
Authorisation relating to the safety, quality and
efficacy of the products, are systematically
incorporated into all the manufacturing, control and
release for supply arrangements of the holder of the
Manufacturing Authorisation”
Reference – Eudralex Volume 4 - Introduction Therapeutic Goods Administration – tga.gov.au

Themes So what are
your responsibilities?
1 Communication
4 key areas
Outsourced Activities and
2 GMP Agreements
Establishing effective two-way

3 Product Quality Reviews communication processes and/or
systems between Sponsors and relevant
parties throughout the product lifecycle
is the critical aspect underpinning these
Quality Defects,
4 Complaints and Recalls
responsibilities

Communication
Communication
• Sponsors should have effective two-way communication
processes with the following parties:
o TGA
o Manufacturing sites
o Authorised Persons (APs)
• This helps ensure that:
o Manufacturers and APs have visibility
of what is registered in the MA and any
commitments that have been agreed
with TGA
o Manufacturers are informed of any
changes in a timely manner (packaging,
labels, specifications etc.)
o Sponsors are informed of the change management
activities at the sites

Communication
Effectiveness and frequency of

communication:
• Sponsors should ensure their communication
processes are effective and of the required
frequency
• Action should be taken when communication
issues arise
Documenting communication processes:

• How communication processes are
documented depends on the relationship
between the entities in the supply chain
• Complexity in the supply chain may warrant
more robust communication processes

Outsourced Activities
& GMP Agreements

Outsourced Activities & GMP Agreements
• You cannot delegate responsibilities, but

you can delegate certain tasks
• These should be described in writing
and agreed to by the relevant parties
• Sponsors have a responsibility to ensure
that the person or entity a task has been
delegated to possess the required
competence, information & knowledge to
carry it out
• Not all tasks can be delegated, and
certain tasks always require direct action
by the Sponsor

Outsourced Activities & GMP Agreements
Areas you should consider in your GMP Agreements include:

• Document retention – Given the role of certain
documentation in supporting the MA, you should be
satisfied with the policies and practices of the manufacturer
• PQRs – You should have defined roles and
responsibilities for the creation, compilation and
evaluation of the PQR
• Use of Ionising radiation – There should be agreement
on the design of the radiation cycle and notification of
unplanned interruptions. Document retention should
also be agreed.
• Reference & Retention samples – Agreement should cover
the responsibility for taking and storing samples, AP access to
samples and the control of samples across multi-site supply chains

Product Quality Reviews

It is acknowledged that generating the PQR

primarily sits with the manufacturer.
However…….
• Chapter 1 is quite prescriptive on the Sponsor’s

responsibility
• There is a clear obligation on the Sponsor,
when they are not the manufacturer, to evaluate
the results of the PQR
• Specific reference to the need for an agreement
between the parties to define the roles and responsibilities
• Delegation of this responsibility to the manufacturer should not
occur

Sponsors can play a crucial role in the generation and review of the
PQR by:
• Ensuring all the required information that they
may hold directly is included in the PQR (i.e.
product complaints received directly from the
market)
• Focussing their review on the marketing
authorisation compliance
• Cross-referencing the information in the PQR
with their own records for accuracy
• Reviewing the change-control section to ensure
these have been adequately managed

Quality Defects, Complaints
and Recalls

Quality Defects, Complaints and Recalls
• Sponsors are required, along with manufacturers

and any other party, to define and agree on roles &
responsibilities
• Responsibilities to notify TGA of potential supply
restrictions and/or product recalls as a consequence
of quality defects
• Sponsors should ensure the contract clearly outlines
the requirement for the manufacturer to notify them
in a timely manner
• Recall management activities – particularly mock
recalls and whether these should be performed

Best practice for GMP Clearance
• Demonstrating that you have effective

communication practices in place gives
us confidence
• Ensure your GMP agreements adequately
cover the expectations outlined here today
• Keep up to date with the changing GMP
requirements that affect your role
• Prepare for GMP Clearance assessments to
focus on these requirements
• Reach out to us

Scan the QR code below or click the link in your calendar

Raise your hand to ask a verbal question. A member of
to access Slido via your mobile device. You can submit
the GMP Forum staff will provide a roaming
your question, and vote on other questions submitted.
microphone.

Matt Davis
Senior Inspector
PIC/S Annex 1
Medicinal Cannabis: complying with
TGO 93
Paul Crossley and Maurice Makdessi

Manufacturing and Quality Branch
Overview
• TGO 93 requirements – a refresher

• GMP Evidence
• Focus on quality
• GMP inspections
• Your questions answered

TGO 93 requirements: refresher
TGO 93: the quality standard for Medicinal Cannabis Products
– updated in March 2022
• New GMP requirement:

each step of manufacture, in relation to a medicinal
cannabis product, that occurs outside Australia must
meet one of the GMP standards set out in section 13(2)
of TGO 93
• GMP requirements, microbiological quality requirements
and labelling/packaging changes apply to all products
released for supply on or after 1 July 2023.

TGO 93 requirements: refresher
• TGO 93 sets out the minimum

requirements for product quality
• Type of products
• GMP
• Labelling/packaging
• Testing
• Microbiological attributes
• Harmonises with Regulations: GMP
already applies to Australian products

GMP Evidence for Imported Products
• Each step of manufacture outside Australia must be in accordance with GMP.

• Australian sponsor must obtain/hold acceptable written evidence
• TGA will recognise certification by specified foreign regulators
• TGA inspection can be requested (certificate not a clearance)

• ‘Starting material’ exemption when going to a GMP site
• ‘Starting material’ for this purpose is ‘plant material’; or ‘oil extracted directly
from the cannabis plant’

Points to remember
• Unless a compounding site has a GMP licence,

all starting material needs to have been
manufactured under GMP
• Australian sponsor must hold GMP evidence,
ready to provide to the TGA if requested
• Every participant in the chain needs to be
satisfied that a medicinal cannabis product is
compliant with TGO 93
• Quality means more than just a GMP certificate
or ‘putting something into a box’ in Australia.

Regulation focused on quality
Need to justify decisions:

• When to do testing
• Whether testing is under GMP
• Expiry dates based on stability studies
TGA will investigate reports of quality:
• Packaging issues
• Active ingredients within requirements
• Labelling
• Expiry dates

GMP Inspections
What you need to know:
• Application submission/review
• Inspection scope
• Knowledge of regulations
• Key standard requirements
• Self assessment
• Readiness
Applying for an inspection
Application for GMP inspection
• Application would require 9-12 months review/inspection scheduling
Scope of Inspection:
• Awareness of scope (Product type/ steps of manufacture)
• Mapping processes/ identify where GMP starts/ Justification
Knowledge of Regulations and GMP Standards

• Awareness of regulations/ any GMP exemptions?
• Current PIC/S Guide / Interpretation guidance
• Default standards
• Relevant TGOs
Getting ready for inspection
Personnel
• Suitably qualified/ Gowning/Hygiene requirements
• Training
• General and specific/ training
effectiveness measures
Quality System
• Deviations, Out of specifications, Change Controls,
Complaints/Returned Goods, Reworks, Risk Management
• Depth and effectiveness of investigation/root cause identification
• Appropriate impact and risk assessment
• Appropriate CAPA /correction/prevention
• Rework/ reprocessing feasibility documented/justified/ Quality Control
Documentation system Management/ controlled documents/ adequate reviews
Production (Storage/Manufacturing/Packaging/cleaning/ cross
contamination)
• Clean storage and temperature monitoring
• Processes clear steps-controls /in-process checks
• Cleaning/ Clearance: Pre- and post checks/
verifications/ labelling system
Engineering – Maintenance/Calibration programs

• Traceability/appropriate frequency
• Conducted to equipment specifics/thoroughly documented
Utilities- HVAC, water systems, compressed air/gases

• Description/Schematics/Controls/Monitoring
• Data Management/Trends
Validation Program
• Covering process/equipment/cleaning/computerized
systems/analytical
• Study protocols: Specific, who, how, justification,
acceptance criteria
• Report to protocol/data analyses/clear conclusions
• Assessment of Revalidation policy/frequency
Quality control testing (Chemistry and Microbiology)

• Representative sampling/ Supplier approval
• Approved methods/specifications/Standards/Reagents
• Suitably calibrated and maintained instruments
• Test records/reports/links/traceability/Data integrity
Getting ready for an inspection
Batch Documents
• Covered all steps of manufacture
• Equipment/area cleaning/clearance
• Checks and verifications of major steps
• Yield/reconciliations
• RFS (satisfy relevant TGOs)
Product Quality Review (Best in batch real time)

• Ensure covering all elements of the PICS Guide
• Data analytics/process capability/consistency
• Incidents assessments/ trends
• Conclusions/improvement recommendation
Self- Assessment/ GMP inspection readiness

Further information
TGO 93 guidance and FAQs
available on the TGA
website
medicinalcannabisrefor
ms@health.gov.au

Cath Brown
Director, Medicine Shortages Section
Medicines Shortages Strategies to mitigate supply

chain disruptions
PIC/S Revision of Annex 1
Matt Davis
Inspections Team Leader
Common concerns with Annex 1
No, the
we simply
changes clarified
to the
The
Annex
Thenewnew
1 Annex
now
Annex
applies
1will
is a existing
Annex
requirements,
have been and
render
significant
to non-sterile
my existing
increase
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site
in No, new
specifically
provided itwritten
doesn’t*
guidance
to allow
(I need
where
existing
there towasn’t
explain)
technologies any
non-compliant!
requirements!
before!

Annex 1 and non-sterile medicines
This room is controlled in

accordance with the
classification, gowning and
monitoring requirements of
Grade D as specified in this
document
This room is What does that

grade D mean?
Grade D?
• Construction?
• Gowns?
• Classification?
• Filtration?
• Monitoring?
• ΔP?
• Etc?
Deficiencies for non-sterile goods cannot be raised using Annex 1 clauses!

Principles - QRM
2.2 “Processes, equipment, facilities and manufacturing activities should

be managed in accordance with QRM”
Implementation Effective
Appropriate
of well designed monitoring
facility design
procedures systems
QRM applies to this document in its entirety and will not, normally, be referred to in specific
paragraphs. Where specific limits or frequencies or ranges are specified, these should be
considered as a minimum requirement. They are stated due to historical regulatory
experience of issues that have been identified and have impacted the safety of patients.
Contamination Control Strategy elements Quality Risk Management
Organisational and Technical Measures

Knowledge; Continuous Improvements
Risk assessments; Monitoring; Data

Personnel
Production & Process

Premises, Equipment& Utilities
Materials & Quality Control
Outsourced activities
• Cultural • Location • Process design • Specifications • Vendor assurance
considerations • Design • Sterility Assurance • Materials • Materials
• Appropriate • Capability • In-process controls management management
education • Capacity • Process risk • Parameters & • Component suppliers
• Suitable knowledge • Authorisations assessments attributes of • Sterilisation steps
and experience • Process Validation •API • Validation experts
Review
• Validation life cycle
• Clothing • Intermediate •Excipients • Contracts
• Operating conditions
considerations specifications •Components
• Planned Preventative • Access to data
• Gowning processes • PUPSIT •Process aids
maintenance • Performance
• Training strategy • Operating conditions •Packaging monitoring
• Monitoring and
• Qualification for controls • Cleaning and •Intermediates
aseptic processing disinfection
• Cleaning and •Bulk
disinfection • Materials •Finished product
• Consumables Management
• Water Sources
• Steam (s)
• HVAC design
• Gases
Pharmaceutical Quality System

Pharmaceutical Quality System
+3.1 i) An effective risk +3.1 ii) The manufacturer
management system is QRM, CCS &
Process
has sufficient knowledge
integrated into all areas monitoring and expertise in relation
of the product life cycle to the products
manufactured
+3.1 vii) Persons

responsible for the
certification/release of
sterile products have
Authorised
Person PQS Knowledge
and Expertise
appropriate access to +3.1 v) Senior

manufacturing and management should
quality information and effectively oversee the
possess adequate state of control
knowledge and throughout the facility
experience in the Senior and product lifecycle.
manufacture of sterile management
products
Premises - Cleanroom Classification/Qualification
+4.25 v) microbial and
Cleanroom Maximum limits for Total particle Maximum limits for Total particle
airborne
clean air and surface
equipment Grade ≥ 0.5 μm/m3 ≥ 5.0 μm/m3
Grade Air sample Settle plates Contact plates
contamination
qualification is the overall
CFU/m3 (diameter 90 (diameter 55 mm)
+ 4.31 sampling
process locations
of assessing the at rest
based
level ofon risk
compliance of a in operation mm)
at rest
CFU/plate
in operation
assessment and the or
classified cleanroom CFU/4 hours (a)
results
clean airobtained
equipmentfromwith A A 3 520 3 520 No growth
Not specified
Not specified
room classification,
its intended use… air
visualization studies and B 3 520 352 000 Not specified 2 900
+4.27 classification,
process
particles
knowledge B 10 5 5
+ both “atequal
rest” to
andor “in C 352 000 3 520 000
greater than 0.5 and 5 to 2 900 29 000
operation” states need
µm should
be qualified C 3 520 000
100 50
29 000 Not
25
be measured…both at Not
predetermined
D
rest and in simulated predetermined
operations. D 200 100 50
Premises-Cleanroom Monitoring
+9.2
+9.9 Temperature,
Total particle monitoring
%RH and
‘other
+9.17 specific characteristics’ Maximum limits for Total particle Maximum limits for Total particle
- Both ≥0.5 and ≥5 µm Grade ≥ 0.5 μm/m3 ≥ 5.0 μm/m3
+9.2 Aseptic Processing
monitored Grade Air sample Settle plates Contact plates
Simulation (APS)
- Sample rate … 28L/min
at least CFU/m3 (diameter 90 (diameter 55 mm)
+9.20 If contaminants present: at rest in operation mm) at rest CFU/plate
in operation
frequency sufficient to CFU/4 hours (a)
demonstrate compliance pre and A A 3 520 3 520 No growth
29 29
post exposure
B B 3 520 10 352 000 5 29 25
900
+9.25 Viable particle monitoring
- Includes personnel C 352 000 3 520 000
+9.31 All A&B isolates identified
C 100 502 900 25000
29
to species level 3 520 000 29 000 Not

C&D isolates ID when >limit or D
D 200 Not 100 50
predetermined
predetermined
problematic organisms

APS
+9.39
+9.41 Manual
+9.34 filling:
Interventions:
Unit inclusion/exclusion
- Each
Known process
inherent
Only reject and
units operator 3
interventions
typically
APS
-rejected
Include during
worst-case
normal
-interventions
APS each operator every 6
operations
months
- Frequency and manner
Process knowledge - Units
-reflective
APS = routine
rejected during batch
of routine
set-up size
operations
or line
-clearance
Based onincubated
design of –process
but not
and risk to
included in sterility
acceptance criteria
+ 9.46 Design
+9.36 Target now ZERO…any
of APS:
- Shifts = failed APS.
growth Image courtesy of SKAN AG
Campaign3 operations
- Normally repeat APS
- Use of chaser fills
required
+9.47
+9.35 APS canshouldonlynot
bebe
aborted
used
where similar
to justify circumstances
practices that pose
would result incontamination
unnecessary batch
cancellation
risks. + investigation
Barrier technologies
+ 4.21 System integrity:
Isolators:
RABS:
- Regular system
Sterilisation and glove
of gloves before
leak testing
installation
- At least at the
Sterilisation orbeginning
bio- and
end
+4.22 ofValidated
each batch/campaign
decontamination prior to each
- Systematic visual
decontamination
manufacturing inspection
methods
campaign -
during use after exposure
sporicidal
- Disinfection
to background environment,
+ Evidence
e.g. that cleaning
door opening
agent doesn’tvisual
- Systematic affectinspection
product
produced
during use, integrity testing
periodically
+Automated decontamination
for isolators, validated for
RABS
Images courtesy of SKAN AG Therapeutic Goods Administration – tga.gov.au

Sterilisation
+
+8.63
+8.628.59SIP
Porous loads:
+ 8.38prevention
min/max load of container
-•distortion
equilibration time
Validated
sterilisation validated
-• Cycles
exposure time
monitored
+ 8.39 Annual revalidation of
-• +ve
+8.64 correlation
pressure of pressure
super-heated water and
maintained
worst case load
cyclestemperature
– spray/drain
patters…other loads checks
•+8.82
minimum/maximum
Design of filtration
revalidated based on CCS
temperature
system range during
•+8.85
exposure
+ 8.50 redundancy
Validated in control
in line with
and monitoring systems
ISO13408-2
+ 8.59 Liquids
8.52PUPSIT
+8.87 Load probeloads:
temperature,
temperature
+8.94 timeofand/or
Single control
use prior to
filters F0
cycle commencement
Autoclaves:
+ 8.60 Weekly leak test for
vacuum phase cycles and
when used to hold sterile
equipment
+8.61 Daily air-removal test,

or use of air detector
Critical Operations - Aseptics
+5.2 For aseptics - all direct
and indirect contact parts
sterilised
+8.16SUS Risks SUS Mitigation
- Authorised list of
• Fragile bags • Supplier qualification
interventions
• Number and complexity of manual operations • Sterilization qualification
- Interventions
• Complexitydesigned
of assembly– • Design & validation
QRM – Media
• Risk of holefills
and leakage • Checking of each unit upon reception
• Risk of particulate
- Engineering solutionscontamination
for all • Manufacture conditions
• Extractables/leachables
interventions/tools • Correct handling &set up
• Potential forinterventions
- Non-qualified compromised system integrity • Visual inspection
during unpacking
managed as a deviation
+8.131
Single use systems

IPQC
+10.3 Visual
+8.22
+8.31 Bioburden
Fusion sealed SVP –
inspection
representative
-100% integrity
Controlled of worst case
tested
conditions
- Annual qualification
+10.4 Automated
+8.32
+8.22 Organisms
Fusion identified
systems
sealed LVP –
and impact
-Reduced
Knapp on sterilisation
testing
sampling where
process
-justified: assessed
Challenge units during set-
up
- Consistency of process
+8.33
- High Monitoring, recording
level of process
andcontrol
trending of defects
+8.23
+8.30 Non-fusion sealed:
Visual inspection
-- Sampling whereofjustified:
Categorization defects
-- Investigation
Knowledge of CC
of OOT system
results
-- If Supplier
AQL is used, no criticaland
management
process
defects knowledge
permitted (addresses
-USP High process
<790>) control

Next steps
• Adoption strategy
• Gap analysis
• Engagement with SM-TWG

Scan the QR code below or click the link in your calendar

Raise your hand to ask a verbal question. A member of
to access Slido via your mobile device. You can submit
the GMP Forum staff will provide a roaming
your question, and vote on other questions submitted.
microphone.

Lynn Talomsin
Senior GMP Inspector
Adoption of future PIC/S revisions

Medicine Shortages Strategies to
mitigate supply chain disruptions
Cath Brown
Director
Pharmacovigilance Branch
Overview
• TGA’s role in managing medicine shortages

• Reasons for shortages
• What sponsors and manufacturers can do to prepare
• Summary

A question for ou
Scan the QR code and select:
POLL – Question No.1
Slido Question 1
What is the biggest supply chain
challenge for your organisation?
Mandatory reporting of shortages
Medicine shortage:
A medicine is in 'shortage' if its supply in Australia will not, or will not likely, meet the demand for it
at any time in the next 6 months, for all the patients in Australia
who take it or who may need to take it.
TGA’s Medicine Shortage Reports Database
• Since Jan 2019, sponsors of all Australian

registered prescription medicines and a limited
number of over-the-counter medicines must report
shortages and discontinuations to the TGA
• All current shortages and discontinuations are
published on the Medicine Shortage Reports
Database
• Downloadable csv files for active and archived
shortage reports
The role of the TGA in Medicine Shortages
Our Goal
Monitor the
Assess
supply of
To reduce the impact of the shortage
medicines
medicine shortages for
Australian consumers and
health professionals.
Act and Determine a
To facilitate continual communicate response
access of medicines,
where possible.

Our shortage management activities
Inventory Management Prescribing Dispensing Communication
Work with pharmaceutical Work with medical Allow community Publish shortages
companies to: colleges and pharmacists to information on the TGA
• Constrain professional website
substitute specific
• Bring forward or organisations to
develop joint medicines without prior
increase orders approval from the
statements and Coordinate consistent
endorse clinical prescriber via Serious shortage information for
Prevent stockpiling and guidelines Scarcity Substitution health professionals and
facilitate equitable Instruments (SSSIs) consumers
distribution of stock E.g. Alerts to subscription
Recommend
list, PHNs, communication
Approve overseas- temporary changes
to consumer groups, etc
registered products to to PBS prescribing
rules
fill supply gaps (Section
19A Approvals)

Impact of COVID-19 on medicine shortages
The COVID-19 pandemic has highlighted supply chain issues and changed the
way signals are received and shortages are managed
Our Goal
Medicine Shortage reports Assess
To reduce the impact of
Introduction of New vs Total the shortage • Consistent number of
mandatory
medicine shortages
shortage Startfor
of the Series1 new and total reports
reporting COVID-19
800 Australian consumers
Pandemic Series2
700 and health professionals. • Increased complexity of
Act and Determine a
600 communicat response shortages
To facilitate continual e
500
access of medicines, • Increased supply
400 where possible. monitoring
300
200 • Increased engagement
100
0 • Increased methods used
in managing shortages
Shortage Reasons – manufacturing #1
2019 2020
2021 2022

Manufacturing site problems - 2021

Manufacturing site problems - 2022

What sponsors and
manufacturers can do
to mitigate supply
chain vulnerabilities

Know your medicines
Consider:
• market share
• indications (including off-label)
• alternatives (exact, similar and
appropriate) and their availability
• patient groups
• relevant health professional groups

Keep dossiers up to date
Maintain GMP clearance

• most critical to pivot quickly
Where possible, consider:
• Align Australian products with those made

overseas
• Add new manufacturing sites

Optimise processes
supply and demand monitoring
demand forecasts
aim for early detection and

communication of issues
consider mapping supply chain

and developing contingencies

Contact TGA medicine shortages team as early as possible
Contact us even if you’re not sure if the shortage will eventuate and before
mandatory reporting timeframe
TGA can help with:

• supply constraints
• stakeholder engagement
• consistent communication
• clinical advice and conservation
measures
• expediting assessments of
regulatory applications
• need for emergency or direct supply?
• pharmacy substitution

Focus on the goal - minimise patient impact
Put patients at the centre of planning

Regulatory pathways to assist with supply
To minimise shortage impact, the TGA can consider a range of regulatory options:
• Section 19A approvals to import and supply overseas-registered medicines during

a shortage
• Section 14/14A consent – if the Australian goods don’t meet a standard
• Regulatory submissions:
o Category 3 applications: new manufacturing site, shelf life extension, etc.
o GMP applications
o Section 23 applications for new medicines

Contrast Media Shortage – Case Study
• Chinese manufacturing site affected by lockdowns
• Wide usage for diagnoses of many serious conditions = many stakeholders
• Freight difficulties – heavy and expensive
• Extensive management
Sponsor Contingencies
• Alternative manufacturing site already been included on ARTG
• International test methods already approved for some lines – quickly adapted to
other presentations
• Identification of highest volume products – focussed regulatory approvals and
production to these

What you can do to help
mitigate shortages
Summary
Act now:
• Prepare as much as possible in advance
• Consider supply risk of each medicine
• Optimise processes and consider contingencies
If you face a shortage:

• Contact medicine shortages team as early as possible and before communicating
externally
• Consider patient impact
• Consider regulatory options to increase supply – ARTG or overseas goods
• Mobilise resources
• Consider need for direct/emergency supply
• Communicate
A question for You
Scan the QR code and select the
POLL – Question No.2
Slido Question 2
What is the first step you will take
after this Forum to strengthen your
supply chains and help with
continued patient access?
Website and link references
TGA medicine shortages hub https://www.tga.gov.au/hubs/medicine-shortages
Medicine shortage reports database https://www.tga.gov.au/safety/shortages/medicine-shortage-reports-database
Section 19A: Guidance for industry https://www.tga.gov.au/publication/section-19a-guidance-industry
Section 19A approvals database https://www.tga.gov.au/resources/section-19a-approvals
Serious Scarcity Substitution https://www.tga.gov.au/serious-scarcity-substitution-instruments-sssis
Instruments (SSSIs) https://www.tga.gov.au/serious-scarcity-substitution-instruments-sssis
Medicine shortage alerts https://www.tga.gov.au/safety/shortages/medicine-shortage-alerts/trulicity-dulaglutide-shortage


Alyce Maksoud
GMP for Advanced Therapy Medicinal Products (ATMP)

Adoption of Future PIC/S Revisions
Implementation of PIC/S Guide to GMP
PE009-16
Lynn Talomsin
Overview
• Why adopt the latest PIC/S version

• Implementation strategy
• What are the changes?
• Upcoming revisions

Why adopt the latest version of PIC/S
• Provide guidance for the management of new technologies

• Address gaps in existing compliance requirements
• Facilitate continuous improvement
• In response to identified risks to patients’ health:
• Relevant to our Mutual Recognition Agreements
• Provides assurance of equivalence to international markets

Adoption Process
The TGA doesn’t automatically adopt new versions of PIC/S GMP Guide.
Areas of
concerns
Gap analysis
(technical Consultation with
Feedback Update
requirements) stakeholders (e.g.
assessed Interpretive
TIWGG)
Regulatory burden Guidance
Provides other
guidance
documents

Implementation Strategy
Phase 1
Pre-implementation
activities
Phase 2
Transition Period
Post Go Live activities
Go Live
Phase 3
Full implementation
Post implementation
Full activities
implementation

What are the changes in PE009-16?

Annex 13
Manufacture of Investigational
Medicinal Products

Changes in Annex 13 – Section 2 Pharmaceutical Quality System
Section 2 - The selection, qualification, Section 2.1(3) – Product Specification File to

approval and maintenance of suppliers of also include clinical trial authorisations,
starting materials, together with their randomisation codes, reference and retention
purchase and acceptance, should be sample details, details of supply chain including
documented as part of the pharmaceutical manufacturing, packaging, labelling and testing
quality system to ensure the integrity of the sites for the investigational medicinal products,
supply chain and protect against falsified preferably in the format of a comprehensive
products……. diagram.
• No equivalent clause but not a new • Existing information/documents
requirement.
• Now required to be included in the Product
• Support PE009-15 Clause 5.27 (selection Specification File.
and approval of suppliers) and 1.4vi
(integrity of the supply chain).
• Support PE009-15 Annex 13 Clause 38
(certification of manufacture)

Changes in Annex 13 – Section 5 Documentation
Section 5(1) - …………Documents which are Section 5(2) - The sponsor may have specific
part of the Product Specification File shall be responsibilities for document retention of the
retained for the period of at least 5 years, clinical trial master file…………. should retain
unless otherwise specified in relevant national such documentation for at least 25 years after
laws the end of the trial.
• No equivalent clause but not a new • New requirement
requirement.
• Manufacturer may need to review their
• The requirement is already in PE009-15 document retention policy.
Clause 4.11
Section 5.2 - The manufacturer should retain the order for

the investigational medicinal product as part of the batch
documentation
• Amended clause but no change to expectation.

Changes in Annex 13 – Section 6 Production
Section 6.2(3) - To avoid cross-contamination, Section 6.3(3) - A reference sample of
written cleaning procedures and analytical comparator product, which has been
methods to verify the cleaning process should be repackaged or over encapsulated for
available. blinding purposes, should be taken at a
• New clause but no new requirements. point representative of the additional
processing and retained, as the additional
• Gives further guidance and supports the processing step could have an impact on
existing clause in PE009-15 Annex 15 Clause stability or be needed for identification
10.3 (cleaning verification) purposes in the event of a quality defect
investigation, which would not be covered by
the commercial retained sample.
Section 6.4(2) - Where products are blinded,
the expiry date assigned to all products should • No equivalent clause but not a new
be stated at the expiry of the shortest dated requirement.
product so that the blinding is maintained.
• Supports the existing clause in PE009-15
• No equivalent clause but not a new Annex 13 Clause 36 (reference and
requirement. retention samples).
• Clarifies the existing expectation.

Section 6.5(1) - Documentation must be Section 6.6(2) - The information which shall
sufficient to demonstrate that appropriate appear on the labelling should comply with any
segregation has been maintained during any relevant national laws or requirements.
packaging operations.
Clauses 27 – 32 and Table 1 which contained
very prescriptive labelling requirements (in
• No equivalent clause but not a new addition to clause 26) have been removed, and
requirement. replaced with a general statement in Section
6.6(2).
• Clarify the existing expectation.
However, the TGA’s expectation is that the

requirements in Clauses 27-32 still apply.
These requirements will be included in the
Interpretation guidance.

PE009-15 Annex 13 Clauses 27-32 and Table 1

Section 6.5(1) - Documentation must be Section 6.6(2) - The information which shall
sufficient to demonstrate that appropriate appear on the labelling should comply with any
segregation has been maintained during any relevant national laws or requirements.
packaging operations.
Clauses 27 – 32 and Table 1 which contained
very prescriptive labelling requirements (in
• No equivalent clause but not a new addition to clause 26) have been removed, and
requirement. replaced with a general statement in Section
• Clarify the existing expectation. 6.6(2).
However, the TGA’s expectation is that the

requirements in Clauses 27-32 still apply.
These requirements will be included in the
Interpretation guidance.

Changes in Annex 13 – Section 7 Quality Control
Section 7 – Retention and reference sample Section 7(11-14) – Retention and reference
retention period samples
• The requirement of to retain retention and • No equivalent clause but not a new
reference sample for at least two years requirement. Clarify the existing
after completion or formal discontinuation of expectation.
the last clinical trial in which the batch was
used, whichever period is the longer was
deleted.
• Align with the requirements with Annex 19
clause 3.1 (duration of storage)

Changes in Annex 13 – Section 8 Release of Batches
Section 8(4) – The assessment by the Authorised Section 8(6) – Where investigational medicinal
Person of each batch for certification prior to release products are produced and packaged at
………… different sites under the supervision of different
• Make reference to Annex 16, and include Authorised Persons, sharing of responsibilities
verification of the supply chain including amongst the Authorised Persons in relation to
manufacturing, packaging, labelling and compliance of a batch must be defined in a
testing sites for the investigational medicinal document formally agreed by all parties.
products.
• Not a new requirement, support PE009-15 Clause
1.4vi (integrity of the supply chain).
• New requirement.
Section 8.7 – Where required to support certification, the

Authorised Person has to ensure that the investigational
medicinal product has been stored and transported
under conditions that maintain product quality and
supply chain security.
• No equivalent clause but not a new requirement.
Clarify the existing expectation.

Annex 16
Certification by the Authorised
Person and Batch Release

Annex 16
Provide guidance to support:
PIC/S Part I Chapter 1, Clause1.4 (xv) – Medicinal products are not sold or supplied before an
Authorised Person has certified that each production batch has been produced and controlled in
accordance with the requirements of the Marketing Authorisation and any other regulations relevant
to the production, control and release of medicinal products.

Annex 16
• New Annex to PIC/S Guide to GMP
• Based on Annex 16 of European cGMP, Eudralex Volume 4 (effective since April 2016
• Almost identical (reference to European ‘Directives’ removed and replaced with more
generic terms)
• Authorised Person (AP) in PIC/S vs Qualified Person (QP) in Eudralex
• Scope:
• Applicable to medicines for human or veterinary use
• Also applies to investigational medicinal products (IMP) for human use
• Applicable to locally manufactured and imported products

Annex 16 Certification by the Authorised
Person and Batch Release
New Annex

Annex 16
• Meet MA requirements
The purpose of controlling • Meet GMP requirements
batch release • Meet other legal requirements
• Detailed knowledge
AP must have • Continuous training - product type, product
processes, technical advances, changes to GMP
• Confirmation = Release for further processing

(RFFP) – template in Appendix 1
Confirmation vs Certification • Certification = Release for supply (RfS) –
template in Appendix 2

Annex 16
Section 1: The Process of Certification
• Section 1.3 – Multi sites
• Section 1.4 – AP
• 1.4.1 AP should have access to the necessary details of MA
• 1.4.3 written agreement showing shared release responsibilities
• Section 1.5 – Medicinal products manufactured outside the jurisdiction of a

National Competent Authority
• Not applicable unless specifically required in the MA

Annex 16
Section 1: The Process of Certification (continued)
• Section 1.7 – List of AP’s responsibilities when performing RfS
• More explicit – TGA is determining the expectations based on risk.
• Section 1.9 – Parallel importation and distribution

• Not applicable as Australia does not permit ‘parallel importation’
• Section 1.10 – Records

• TGA is working through our expectations

Annex 16
• Section 2: Relying on GMP assessment by 3rd party
• clarification of existing requirement
• more explicit
• TGA is determining the expectations based on risk
• Section 3: Handling of unexpected deviations

• Permit batch with unexpected deviations to be released if registered specifications are
met (if appropriate after investigation and risk assessment).
• In Australia, TG Act includes penalties for supply of products not conforming to standards.
Consent to supply must be obtained from the TGA.
• Section 4: The release of a batch

• 4.1 and 4.2 – Shipping under quarantine
‘shipped under quarantine to another site which has been approved for that purpose by
the relevant National Competent Authority’ (= have the relevant licence step), and
the receiving site have adequate safeguards against inadvertent transfer to released
stock ……….

Future Revisions

Future Revisions
• PIC/S PE009-17 including Annex 1 Manufacture of sterile medicinal products
• Annex 14 Manufacture of medicinal products derived from human blood and plasma
• Chapter 4 (Documentation), Annex 11 (Computerised Systems) and Annex 15 (Qualification

and Validation)


Jenny Burnett
GMP Forum 2023 Concluding remarks
GMP for Advanced Therapy Medicinal
Products (ATMP)
Alyce Maksoud
Overview
• Types of therapeutic goods

• How do we fulfill this mission
• Biologicals vs Biological Medicines
• What are ATMPs
• PIC/S Annex 2A Revision
• Key elements of contamination control strategy (CCS)
• The Don’ts of Cleanrooms
• Vulnerabilities - Influencing factors on implementing CCS inspection reviews
• Environmental monitoring
• Contamination control
• Questions

Types of therapeutic goods
Medicines and blood products
• prescription medicines
• over-the-counter medicines
• complementary medicines
• blood, blood components and plasma derivatives and HPCs
Medical devices
• Implants (artificial hip, breast implants)
• In-vitro diagnostics (pregnancy tests, blood glucose monitors, infectious disease testing and NAT testing)
• Low risk medical devices (bandages, tongue depressors, condoms)
Biologicals
• Human stem cells
• Tissue-based products (skin, bone, ocular, cardiovascular and amnion)
• Cell and gene based products

How do we fulfil this mission?
Good Manufacturing Practice or Manufacturing Principles: licensing Australian

1 manufacturers and verifying compliance of overseas manufacturers using either a
clearance pathway or a site inspection.
Premarket assessments: assessing therapeutic goods for quality and safety (the extent of the
22 assessment depends on the type of product and level of associated risk), and for higher risk
products also for efficacy or performance.
3 Post market assessments: monitoring of therapeutic goods and enforcement of standards.

3

What are biological / biotechnological medicines?
Therapeutic Goods Regulations

definition Definition of Biologicals
Are therapeutic goods derived from biological sources and are For the product to meet the definition of a biological, it must be:
regulated as registered medicines. Include
• a medicine (other than an antibiotic) that is: • a thing made from, or that contains, human cells or
human tissues, and that is used to:
i. a vaccine, a peptide, a protein or
 treat or prevent disease, ailment, defect or
polysaccharide-based; and injury
ii. derived from a human, animal or other  diagnose a condition of a person
organism, or produced through recombinant  alter the physiological processes of a person
technology or biotechnology; and  test the susceptibility of a person to disease
iii. of a kind specified in item 1 of Part 1 of  replace or modify a person's body parts
Schedule 10 (includes biotechnology
medicines); or a medicine that is a human
blood product of a kind mentioned in •faecal microbiota transplant products
Appendix A in Part 5 of the Poisons •a thing that comprises or contains live animal cells, tissues or
Standard. organs.
Biotech medicines are a subset of Biological medicines.
Note that the term biologics, biologicals and biological medicines can have different interpretations in
different countries/jurisdictions. Therapeutic Goods Administration – tga.gov.au
Biologicals and Biological Medicines
Biological medicines are not biologicals – specified in the Therapeutic Goods (Things that are
not Biologicals) (Determination No.1 of 2011)
Biological Biological Medicines

• tissue-based products
• cell-based products • recombinant products
• immunotherapy products containing human • plasma derived products (or that contain plasma
cells derived products)
• autologous human cells and tissue products • vaccines (that do not contain viable human cells)
(including stem cells)
• gene-therapy vectors alone
• gene-modified cell therapies
 regulated as prescription medicines
 regulated under the Biological regulatory
framework
Australian Regulatory Guidelines for
Australian Regulatory Guidelines for
Prescription Medicines (ARGPM)
Biologicals (ARGB)

What are ATMPs
Advanced Therapy Medicinal Product (ATMP) is the umbrella term for three drug
product classes:
• somatic cell therapies - cell-based therapy medicinal products (CTMPs)

• gene therapeutics – genetic therapy medicinal products (GTMPs)
• engineered tissue preparations - tissue engineering products (TEPs)
• a combination products.
These ATMPs usually contain or consist of living cells or tissues and are therefore
characterised by a high degree of complexity.

Image is a courtesy of EMA / CAT Therapeutic Goods Administration – tga.gov.au
PIC/S GMP Guideline - Revised Annex 2A for biological
Substances and Products
• Revisions to the Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP Guide addressing the
manufacturing of ATMPs as well as biological medicinal substances and products effective 1 May 2021.
• Annex 2A covers PIC/S GMP requirements for ATMPs, which cover cell and gene therapy products. The
annex is divided into two parts:
Part A - control over seed lots and cell banks through to finishing activities and testing
Part B - more specific guidance on selected product types, such as animal sourced products and
gene therapy products.
• Annex 2A “ … is not a standalone document but it enables reasonable harmonization with the standalone
ATMP guidelines published by the European Commission …” according to a PIC/S statement.

PIC/S Annex 2A Revision
• The revision of the requirements for ATMPs remained an integral part to the existing GMP
guidelines and is not a standalone code. The Annex 2A that is specific to ATMP aimed at
maintaining as close harmonisation as possible, and used the language of the “Guidelines on
Good Manufacturing Practice (GMP) specific to Advanced Therapy Medicinal Products (ATMP)”
where possible (the standard).
• Efforts were made to accommodate language that address challenges such as “diffuse
manufacturing”.
• Efforts were made to accommodate language that permitted the standard to facilitate cross
border movement of ATMP.
• The standard aimed to bridge across all the expectations for these products through all
jurisdictions, even the countries that may not formally adopt it

PIC/S Annex 2A (1)
Compliance with Annex 2A is expected, however, it is acknowledged that there may be

alternative processes but documented sound scientific rationale is required using Quality
Risk Management (QRM) principles
National laws may be applicable to starting materials for ATMPs for example:
• Tissues and cells used as starting materials of ATMPs may be subject to other national
legislation that cover donation, procurement, testing, processing, preservation, storage
and distribution (e.g., TGO 108 and TGO 109 in Australia)
• For blood or blood components used as starting materials for ATMPs, national
legislation - technical requirements for the selection of donors and the collection and
testing of blood and blood components (TGO 102)

PIC/S Annex 2A (2)
Manufacture of ATMPs – product specific

 Different design approaches are possible
• Consider the manufacturing steps for the following:

• Starting materials
• ATMP active substance
• Finished ATMP
• The manufacturing process between ATMP active substance and the final product can
be continuous

PIC/S Annex 2A (3)
Genetically modified:
 The manufacture and control of genetically modified organisms also needs to comply with
other local, national or regional requirements
 Appropriate containment should be established and maintained in facilities where any

genetically modified organism is handled
 Advice should be obtained according to national law in order to establish and maintain the
appropriate Biological Safety Level (BSL)
 GMP should be adhered alongside these requirements
Australia – Office of the Gene Technology Regulator (OGTR) – TGA has not yet adopted a definition
of gene therapy.

PIC/S Annex 2A
Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2A
Example
Application of this Annex (see note (1) )
Products
Gene therapy: Linear DNA template In vitro cell free transcription mRNA purification Formulation, filling
mRNA preparation
Gene therapy: in vivo viral Plasmid manufacturing Establishment of MCB, WCB (2) Vector manufacturing and Formulation, filling
vectors purification
Gene therapy: in vivo non Plasmid manufacturing Establishment of bacterial bank Fermentation and purification Formulation, filling
viral vectors (naked DNA, (2)
lipoplexes, polyplexes, etc.,)
Gene Therapy: ex-vivo Donation, procurement and Plasmid manufacturing Ex-vivo genetic modification of Formulation, filling
genetically modified cells testing of starting tissue / cells
cells
Vector manufacturing (3)
Somatic cell therapy Donation, procurement and Establishment of MCB, WCB or Cell Isolation, culture Formulation, combination
testing of starting tissue / primary cell lot or cell pool (2) purification, combination with filling
cells non-cellular components
Tissue engineered products Donation, procurement and Initial processing, isolation and Cell Isolation, culture Formulation, combination
testing of starting tissue / purification, establish MCB, purification, combination with filling
cells WCB, primary cell lot or cell non-cellular components
pool (2)
1. Application of this annex applies to manufacturing steps illustrated in dark grey. Application of this annex or principles of this annex apply to steps illustrated in light grey apply depending on the requirements of
national legislation.
2. Refer to points 5.32 for establishment of cell banks and seed lots.
3. In the case of gene therapy ex-vivo genetically modified cells, this guide applies to vector manufacturing except where otherwise authorised by national law where principles of GMP should apply.

PIC/S Annex 2A

Key elements of Contamination Control Strategy (CCS)
Design consideration
Products and
Materials
Premises &
Processes
Equipment
Procedures People

Importance of holistic end to end contamination
control strategy (CCS) design
• Gap analysis (GA)- review all potential sources of contamination
• Identify vulnerabilities
• Complete risk assessments (RA)
Initial • Identify critical control points (CCP)
• Review GA, vulnerabilities and completed RA

• Implement risk reduction strategies & ensure visibility is maintained for all vulnerabilities
• Undertake validations
Implementation • Implement robust risk based CCS strategy monitoring program
• Review data and implement continuous verification (OOT/OOE)

Ongoing
• Re-open RA when new input data available (i.e. deviations, OOS, CC)
review
• Maintain ongoing visibility on vulnerabilities

Vulnerabilities - Influencing factors
Environmental
on implementing CCS monitoring
inspection reviews
Clean
People CCS room/HVAC
design
Disinfectants &
decontamination

Vulnerabilities-Influencing factors on implementing CCS
inspection reviews
• Risk based
approach • Training
• non-viable • Qualification
• Viable-Micro • Monitoring
samples • behaviour
• Evaluation/trending
and continuous Environmental
People
verification monitoring
• Specific areas
Cleaning work • Positive or
practices negative
Clean pressure
• Effectiveness Disinfectants & room/HVAC
of disinfectants decontamination (containment)
design • Pass through
• Verification of
effectiveness hatches
against EM • Process/people
organisms * material flow

Vulnerabilities - Influencing factors on implementing CCS
inspection reviews: Inspection hot spots
• Monitoring worst case- monitoring critical control points
• Monitoring periods cover manufacturing duration and activities
• Media qualified
Environmental monitoring • Incubation periods/temperatures qualified
• Organisms identified for significance and action taken
• Review of disinfectant effectiveness against isolates
• Appropriate OOS investigations undertaken
• Training both initial and on-going relevant and complete

• Monitoring of personnel results match training/qualification
• Differences in ENV results against peers (i.e. OOT/OOE)
People • Personnel attire, gowning / degowning observed and consistent
with procedures and GMP
• Personnel clean room behaviour consistent with procedures
and GMP

Vulnerabilities - Influencing factors on implementing CCS
inspection reviews: Inspection hot spots
• Disinfectants within Expiry & clearly labelled
• Sterile disinfectants used or prepared in-house
• Validation of disinfectant efficacy worst case- includes at expiry
Disinfectants & decontamination disinfectants
• Sporicide used
• All materials entering clean room assessed as part of CCS
• Work practices and records match validation
• Adequate physical separation –airlocks

• Air pressures match design (negative or positive pressure)-
Pressure trend records match qualification-no missing data
Clean room/HVAC design • Maintenance records demonstrate suitability & recommendations
actioned
• Transfer Hatches suitable and qualified.
• Material transfer through Pass Through hatches validated, routine
records match

Lifecycle approach to contamination control
Verification or
Identify/Assess
investigation
risks
Implement
Review risk
reduction
Monitor

Lifecycle approach to contamination control
Contaminant Contaminant
from from
Operators Equipment
Contaminant Contaminant
from from
Environment materials
Contamination
Contributing causes
274
inspection reviews: Materials and Products - one
• High contamination risk-Autologous

(lower)/allogeneic (higher)
• Contamination -
Apheresis/leukapheresis collection-i.e.
Patient skin disinfection/venepuncture)
• Staff collecting material
Starting • Patient collected material-micro
material contamination
• Storage/transport
• Outsourced collection activities

inspection reviews: Materials and Products - two
• Container closure integrity/sterility

• Media/buffer/process aid preparation
• Material specification
• Testing regimes-inhibition of
microorganisms
Materials • Stability
• Adequate records of receipt,
quarantine, inspection, release,
preparation, disposal, expiry
• Labels robust during storage-legibility
inspection reviews: Materials and Products - three
• Viral vector/plasmid- source,

traceability, characterisation,
qualification, storage, stability
• Manufacture of MCB/WCB
Process/ • Dedicated Facility for MCB/WCB/viral
seed lots
Product • Testing, stability, storage, inventory,
labels-legibility
• Back-up storage/Disaster recovery
plan
• Impurities – intrinsic/extrinsic

inspection reviews: Premises and Equipment
What clean rooms do
Clean rooms provide an
enclosed space in
Over pressures prevent Room segregation which airborne
allows to have differing particles, contaminants,
ingress of contaminants & air quality spaces and and pollutants and HEPA filtered air/pressure
continuously supply prevent contamination controlled within limits. cascade
filtered air to each room via pressure In biologicals this
differentials means control of
microorganisms and
non-viable particulates
Clean rooms provide an

environment that Effective flushing –non
Temperature/humidity control minimises contaminants
accumulation of contaminants

The Don’ts of Clean rooms
Don’t have
high
Don’t block operational
return air temperatures Don’t neglect
vents or humidity maintenance
Don’t place Don’t change Don’t have

equipment any validated poorly
near supply HVAC settings designed
air vents manufacturing
operations

Critical Role of Decontamination
Risk reduction Contamination risk

inspection reviews: Premises and equipment
Pass Through (PT) design contamination risk – Passive PT
Lower classification area door open Higher classification area door open
Air flow
direction

Lower classification area door closed Higher classification area door closed
Entrapped lower classification air

Lower classification area door closed Higher classification area door open
lower classification air released into higher classification space

Pass Through (PT) design contamination control risk reduction
HEPA Filter Higher classification area door closed

Lower classification area door open
Exhaust /return air
Additional safe guards: interlocking doors on timer:- validated contact time

Environmental Monitoring – verifies contamination control
strategies remain effective – Monitoring Plan - one

Environmental Monitoring – verifies contamination control
strategies remain effective – Monitoring Plan - two

Contamination Control – Inspection Focus (one)

Contamination Control – Inspection Focus (two)

Verbal questions:

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1: Welcome and opening remarks

2: Forward vision: regulation and manufacture supply

Adjunct Professor John Skerritt

• TGA GMP and clearance statistics

Therapeutic Goods Administration – tga.gov.au

Satisfactory compliance (of completed inspections) 139 (66%) 99 (71%)

Marginal compliance (of completed inspections) 35 (17%) 25 (18%)

Therapeutic Goods Administration – tga.gov.au

Satisfactory compliance 41 (76%) 80 (77%)

Marginal compliance 4 (7%) 17 (16%)

Unacceptable 1 (2%) 2 (2%)

Compliance under assessment 8 (15%) 5 (0%)

Number (% of Total completed)

6,778 (93%) 8,103 (91%)

7,302 (100%) 8,902 (100%)

• Increased reliance on Contract Manufacturing Organisations – New

Robust adherence to GMP principles helped mitigate many of these risks

Therapeutic Goods Administration – tga.gov.au

Therapeutic Goods Administration – tga.gov.au

For overseas manufacturing sites, TGA either performs:

But the TGA needs to

Therapeutic Goods Administration – tga.gov.au

• Levels are small however

• Generated during manufacturing or storage

Therapeutic Goods Administration – tga.gov.au

After 1 July 2023

Therapeutic Goods Administration – tga.gov.au

Manufacture of the stabilising and delivery system of the mRNA

Therapeutic Goods Administration – tga.gov.au

Therapeutic Goods Administration – tga.gov.au

Priority review (max 150 working days)

Comparable Overseas Regulator pathway

ACCESS Worksharing initiative

Therapeutic Goods Administration – tga.gov.au

• Requirement to include Product Information hard copy in injectables being reviewed

Therapeutic Goods Administration – tga.gov.au

Therapeutic Goods Administration – tga.gov.au

Psychedelics – final decision

Therapeutic Goods Administration – tga.gov.au

• Pholcodine was used widely in OTC cough syrups and

Therapeutic Goods Administration – tga.gov.au

• Currently 40-50 critical medicine shortages – shortages of antibiotics, diabetes, warfarin,

Therapeutic Goods Administration – tga.gov.au

• Commonwealth and State/Territory funding of initiatives

Therapeutic Goods Administration – tga.gov.au

Therapeutic Goods Administration – tga.gov.au

Therapeutic Goods Administration – tga.gov.au

• Grow medtech manufacturing in Victoria

• Increase local content in procurement of health products

• Improve collaboration between government, indudtry and

Therapeutic Goods Administration – tga.gov.au

Especially an issue for clinical trials – scale up from clinical

Therapeutic Goods Administration – tga.gov.au

• New faecal microbial transplant regulatory framework

Therapeutic Goods Administration – tga.gov.au

Many activities cannot be directly attributed to a particular

Therapeutic Goods Administration – tga.gov.au

• Compliance and enforcement – 33,000 investigations