ECA Good Practice Guide –

GMP Auditors Reference Handbook

– Attachment 3: Audit Areas and Criteria –

A guidance document by the ECA Foundation

Version 3.0; May 2025
ECA Good Practice Guide –
GMP Auditors Reference Handbook
Attachment 3 – Audit Areas and Criteria

Contents

A. Pharmaceutical Quality System .................................................. 2

B. Equipment / Utilities / Systems .................................................. 6
C. Warehouse and Logistics ........................................................... 7
D. Premises ................................................................................. 7
E. Environmental Conditions .......................................................... 9
F. Handling of Goods .................................................................... 9
G. Processes .............................................................................. 10
H. Quality Control ....................................................................... 11
I. Microbiology........................................................................... 13
J. Evaluating Testing Process & Methods ....................................... 15
K. Evaluating major Equipment and Instruments ............................ 16
L. Utilities.................................................................................. 17
M. Maintenance .......................................................................... 18
N. Non-sterile and sterile Solid Dosage Forms Production Area ......... 18
O. Particulars for sterile Dosage Forms .......................................... 20
P. Water and Sanitisers ............................................................... 23
Q. How to audit a medical Cannabis Grower ................................... 23
R. Preparing Audits for Cell and Gene Therapies (CGT) based Advanced
Therapy Medicinal Products (ATMPs) ......................................... 26
1 ATMP-specific Challenges .........................................................................27
2 How to audit ATMPs - managing the Complexities of allogenic CGT
Manufacturing ........................................................................................27
2.1. The Challenges of the Supply Chain ........................................................................................... 27
2.2. Where to start at the Manufacturer .......................................................................................... 28
2.3. ATMP OOS Batches being used .................................................................................................. 28
2.4. QP Certification of ATMP and Import......................................................................................... 29
2.5. Transport and Storage of ATMPs ............................................................................................... 30

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Attachment 3 – Audit Areas and Criteria

A. Pharmaceutical Quality System

A company’s pharmaceutical quality system (PQS) should describe the procedures and
controls in place to ensure reliable operations across the organisation.
The PQS should ensure all operations follow current GMP requirements and local
regulatory expectations and comply with licensing requirements.
Audits of the PQS are detailed in various guidelines, but especially in chapter one of the
EU-GMP guidelines. Examples of what to look for when auditing the PQS are indicated in
this chapter.

Aspect Possible details to evaluate

Structure of the PQS Consistency across the process?

Are all processes clearly defined?

Are elements of the PQS reviewed and approved by

management and the Quality Unit?

Are responsibilities clearly defined?

Regulatory status Is the company operating within its authorised licences?

Company organisation Is an organisational diagram in place illustrating roles and

responsibilities of key roles?

Is the company staffed appropriately?

Is the Quality Control Unit operating independently of

production?

Release system Who is responsible for batch confirmation, certification and

release?

Who actually performs batch confirmation, certification, and

release, and can decisions be made independently of other
management functions?

Is all relevant documentation and information related to each

batch available at the point of review, confirmation,
certification and release?

Are the functions involved appropriately resourced to ensure

a full overview?

Deviation handling Is there a clear definition of a deviation and how deviations

are classified (e.g. incident, minor, major, critical)? Note:
different organisations may use different terms when
referring to these processes, and this is acceptable as long as
the definitions are clear and all processes are covered.

Who is responsible for investigating and reporting deviations?

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Aspect Possible details to evaluate

Who is responsible for reviewing and approving the

investigation report?

Who assesses the impact of the deviation on the final batch

before confirmation, certification and release?

Are flow charts available for associated processes?

What actions are taken when serious deviations are reported,

and how are actions justified and documented?

Are all personnel trained in the processes?

How many deviations are overdue, and how are they treated
(deviation, extension, etc.)?

Corrective and Preventive Are there clear definitions of the terms used (e.g. corrections,
Action (CAPA) corrective actions and preventive actions)?

Are CAPAs defined when needed? And if no CAPA is opened,

how is this justified / documented?

How are effectiveness checks realised?

Is the Quality Unit involved in defining, closing and approving

CAPAs?

Are all personnel trained in the processes?

Root cause analysis (RCA) Is the RCA process clearly defined in a procedure?

Has the organisation defined and provided useful RCA tools?

Are RCA processes logical and scientifically sound, and have

the potential root causes and contributing factors been
identified?

Are the defined CAPAs based on root causes?

How is the Quality Unit involved in defining, closing and

approving an RCA?

Are all personnel trained in the processes?

Are there any repeated RCAs (e.g. ‘human error’) reported

with no clear corrective action to resolve the issue?

Change Control Are types of changes and relevant responsibilities defined?

Is the process / are further batches halted until the change is

fully implemented (when appropriate)?

Is an impact analysis available for the change and each

action that leads to the change, and is there a requirement

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Aspect Possible details to evaluate

for an effectiveness check for each change / action? If not,
how is this justified?

How many changes are overdue? How are they handled

(deviation or extension, etc.)?

Is the Quality Unit involved in closing and approving a

change?

Are all personnel trained in the processes?

Supplier management Does the audit programme define the frequency of audits? A
company may use a risk-based approach, as described in
chapter 3 of this guide. An auditor should check this approach
and the associated documentation.

Are the audits performed as defined in the programme?

Are the audits performed by trained auditors?

How is supplier performance monitored and linked to the

qualification?

Do the responsible positions (QP, Purchasing) have access to

relevant data and audit reports? Are they aware of possible
deficiencies and the corrective actions agreed upon?

Is there a formal assessment of the impact on product quality

when serious deficiencies are reported?

Are quality agreements in place for every outsourced

activity? Is the Quality Unit involved (e.g. in review and
approval)?

Training system Is there a GMP / GDP training programme for new

employees?

Is training recorded, and is it possible to track staff training

to the tasks they performed?

How is training realised (online, classroom, shop floor)?

Who trains, and what are the requirements to become a

trainer?

How are effectiveness checks done and documented?

How are personnel disqualified for processes, if necessary?

How is disqualification recorded and communicated?

Internal audits Is there an SOP in place to describe the IA process?

Is there an annual plan / schedule in place?

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Aspect Possible details to evaluate

Does the company adhere to the schedule, and how are

overdue IAs addressed?

Who is performing IAs and how are the auditors trained?

Are the actions arising incorporated into the Corrective and

Preventive Action (CAPA) system?

Document management Is there a version control for each GMP-relevant document

including unique number and version number?

Are documents distributed and tracked appropriately?

Is the documentation hierarchy clear, and are documents

structured?

Are the documents reviewed periodically as defined in the

Document Management procedure, or earlier if required?

Is there a link between the Change Control and Document

Management procedures to ensure documents are reviewed
and updated if impacted by a change?

Quality Risk Management Is there a QRM procedure in place, and is it applied

(QRM) appropriately?

Which QRM tools are used, and are they appropriate?

Are all personnel trained in the processes?

Management review Does the management review process follow ICH Q10
requirements?

Is the management review conducted regularly based on a

pre-defined agenda covering all relevant quality-related
activities of the organisation?

Are key personnel involved?

Is the protocol / report signed off by management?

Are the actions arising incorporated into the CAPA system?

Product Quality Review Are Quality Reviews in place, and are they conducted
(PQR)/ Annual Product regularly?
Review (APR)
How is the QP involved?

Is the protocol / report signed off by management?

Are the actions arising incorporated into the corrective and

preventive action (CAPA) system?

Recall system Is there an SOP in place to describe the recall system?

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Aspect Possible details to evaluate

Are roles and responsibilities in a recall process clearly

defined?

Who makes the final decision on a recall?

In case of a recall, who is informed, including the local

regulatory authority?

How are the activities documented?

Who makes the final decision on a recall?

Complaint handling How are complaints received by the company?

Are they investigated appropriately (see deviations, RCA,

CAPA, etc.)?

Are appropriate actions taken (CAPA)?

How is feedback provided to the complaint provider?

B. Equipment / Utilities / Systems

Aspect Possible details to evaluate

Qualification How is equipment designed, qualified, monitored and

maintained?

Is equipment qualified before use and re-qualified after any

significant changes or repairs?

Is equipment identified unambiguously?

How are cleaning processes defined, and are they validated?

How is equipment labelled?

Maintenance Is a maintenance programme in place?

Are maintenance plans (for individual equipment) in place?

Are pre-defined frequencies complied with?

Logbooks Are logbooks available?

Are they regularly checked by personnel who can draw

conclusions and, for example, adapt maintenance plans?

Outsourcing Are maintenance / calibration activities outsourced, and are

contracts in place?

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Aspect Possible details to evaluate

Do external partners have to comply with the auditees’ SOPs,

and, if so, how are they kept up-to-date?

Status labelling Is the status (clean / to be cleaned) clearly identified?

Are holding times for clean / dirty equipment defined?

C. Warehouse and Logistics

Aspect Possible details to evaluate

Storage How are the product and its components stored before,
during and after the process?

What are the storage time limits and conditions for each
stage?

How are the storage areas controlled and monitored?

Transport How are the personnel, material, waste and product flows
managed in each area?

What are the transportation methods and routes used for

each item (unidirectional flow)?

How are the transportation conditions controlled and

monitored?

D. Premises

Aspect Possible details to evaluate

Warehouse How is access controlled?

What is the status and maintenance condition of the facility

(holes and cracks in walls and floors, broken windows, rusty
equipment, etc.)?

Are there water or solvent stains that might be caused by

incoming water during the rainy season or leakages in pipes /
vessels?

What is the overall quality of starting materials (missing

labels, rusty or damaged drums, insufficient sampling and
quality control tests)?

Is a status labelling of materials defined and adhered to?

Are cleaning processes in place and controlled?

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Aspect Possible details to evaluate

Are there API drums from third parties which might just be
re-labelled?

Are areas, rooms, and key equipment qualified and key

processes validated?

Are medicinal products stored directly on the ground (making

sufficient cleaning impossible)?

Is there adequate separation between the receipt, dispatch

and storage areas?

Is there a defined room capacity for cool rooms, and is this

qualified and controlled?

Outer premises Is there a fence or other protective measures against

unauthorised access?

How are visitors registered?

Is there CCTV coverage of the outer area?

How are incoming and outgoing trucks registered?

Is there any outside storage or stacking of materials, and if

so, how is it justified and controlled?

External (contracted) Do contracted premises exist?

premises
Do contracted premises have their own certification?

How are these premises qualified and monitored?

Are transportation activities between sites validated and

monitored?

Pest control Is there an adequate system in place?

Is there an unregulated usage of biocides?

What happens if animals are caught?

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Attachment 3 – Audit Areas and Criteria

E. Environmental Conditions

Aspect Possible details to evaluate

Storage conditions How are storage conditions maintained in different climatic

conditions (heat in summer, cold periods in winter, rain
periods)

Are seasonal variations taken into consideration during

qualification and validation activities?

Is the equipment used to control or monitor environmental

conditions calibrated at defined intervals based on a risk
assessment?

How are (temperature) deviations managed?

Mapping Was an initial temperature mapping carried out before the

Note: For small premises consisting warehouse was put into use?
of a few square meters, an
assessment of potential risks (e.g. Was temperature mapping performed under representative
heaters) can be conducted and conditions?
temperature monitors positioned
accordingly. Are temperature monitoring devices located according to the
results of the mapping exercise (positioned in the areas that
experience extreme fluctuations)?

Is the mapping exercise repeated according to the results of

a risk assessment or whenever significant modifications are
made to the facility or the temperature controlling
equipment?

Have all relevant areas been mapped?

F. Handling of Goods

Aspect Possible details to evaluate

Returned goods If returned to stock, has it been demonstrated by the

Note: for medicinal products customer that products have been transported, stored and
requiring specific temperature handled in compliance with their specific storage
storage conditions such as low requirements?
temperature, returns to saleable
stock can only be made if there is If returned to stock, have they been examined and assessed
documented evidence that the
product has been stored under the
by a sufficiently trained and competent person authorised to
authorised conditions throughout the do so?
entire storage period. If any
deviation has occurred, a risk
assessment has to be performed to
determine the integrity of the
product.

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Aspect Possible details to evaluate

Dispensing and intermediate Are there multi-purpose drums for internal transport and
storage areas storage?

Is there a risk of mix-ups (labelling of raw materials and

intermediates)?

How is (cross-)contamination of drums avoided (dust,

multiple use, cleaning)?

Storage of solvents Which solvents are used and how are they stored (focus on
toxic solvents)?

How are tanks and pipes identified / labelled?

How is the recovery and testing of solvents performed?

How is (cross-)contamination of storage tanks avoided?

G. Processes

Aspect Possible details to evaluate

Qualification and validation Is there a list of critical equipment?

Is there a validation master plan (VMP)?

Is the company's approach to qualification and validation

correctly described?

Are there proper documentation requirements for the risk

assessment, validation plan, protocol, report?

How often is re-qualification realised, and how is it justified?

Are worst-case and bracketing approaches applied and

justified?

Are deviations treated appropriately in the various systems?

Is there a process in place to disqualify equipment, etc.?

Is there a possibility to use non-validated equipment /

processes?

How are the qualification and validation results recorded and

analysed?

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H. Quality Control

Auditing a quality control laboratory involves evaluating various areas such as, but not
limited to, the laboratory facility, including stability chambers, sample management,
equipment calibration and maintenance, result creation and reporting, OOS/OOE/OOT
investigations and storage of reagents and reference substances.

Aspect Possible details to evaluate

Laboratories How are the rooms classified, qualified and maintained?

How is the equipment classified, qualified, calibrated and

maintained?

Is there sufficient space for the preparation of samples and

reagent with good labelling control / documentation
practices?

How are waste and leftovers dealt with?

Are equipment logbooks available, and do they include

entries on at least the following: operations performed
(including product), maintenance (planned / breakdown /
calibration), checks and verifications, and cleaning?

Maintenance of analytical equipment

Equipment calibration In-house calibration:

Are personnel trained (training plan and records should be
clear)?
Traceability of the standard used.

External calibration:
• Is the service provider qualified / approved?
• How is equipment transported?
• How does the contractor transport and store the
standards?
• Traceability of the standard used.

Does the calibration certificate include the following?

• Equipment identification
• Results (pass / fail) – incl. specification
• Uncertainty measurements
• Traceability to international standard of measurement
• Limitation on use (if any)
• Date of calibration

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Aspect Possible details to evaluate

• Signature of the accepting calibration company, if
outsourced
• Next due date for calibration

Does the calibration label include the following?

Equipment identifier
Date of calibration performed
Date of expiry / Date of next calibration
Performed by

Are out of limit / specification results investigated according

to an SOP, including notification / information and an impact
assessment on prior tests / results?

Reference substances / Are reference substances / standards correctly labelled, have

standards (RS) an expiry date and indicate purity on the label or CoA?

From where do RS originate?

Is there a certificate for each RS?

Are storage conditions for the RS adhered to?

Is there a usage log for each RS?

How are expiry dates handled?

Out of specification, out of Do processes comply with GMP requirements and instructions
trend and out of expectation / SOPs?
results (OOS, OOT, OOE)
How are such results investigated, recorded and reported?

Was all glassware and instrumentation retained in the state it

was used until results were deemed acceptable to report?

Is re-measurement only allowed using the approved protocol

which specify the purpose and intent of the test? It should
not be used to “fix” the result.

Is re-testing only allowed after both laboratory and

production investigations have been completed and both
have been deemed inconclusive?

Is re-sampling only allowed if evidence is available indicating

that the original sample was not taken correctly or
compromised before analytical testing started? This should be
done following the same procedure as the original sample.

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Attachment 3 – Audit Areas and Criteria

I. Microbiology

When auditing microbiological laboratories, it is essential to ensure that processes and

methods comply with marketing authorisation and meet necessary standards and
requirements.
By following a systematic approach and thoroughly examining key areas such as
laboratory facilities, documentation, personnel, sample management, culture media,
reference cultures, sterilisation indicators, method validation, major equipment,
environmental monitoring and record keeping, auditors can ensure the laboratory's
quality management system is well-established and meets necessary requirements.
Note: this is a highly specialised subject, therefore the auditor conducting a full audit of
these facilities should have adequate knowledge of microbiology and microbiological test
methods or consult with / bring an expert.

Aspect Possible details to evaluate

Sample receipt Is there a dedicated area assigned for receipt of samples?

How does the company prevent sample mix-ups?

Are storage conditions observed where necessary? Sample

receipt requires adherence to defined storage requirements
and may include frozen (-80°C) or cold (5°C), a defined time
before cold storage and adherence to correct labelling.

Do sampling processes comply with GMP requirements and

instructions / SOPs? How is it documented (at minimum are
the lot number, expiry date, storage conditions and the
test(s) required)?

How are the samples labelled?

How is traceability ensured?

Where are the samples stored?

Sample preparation Do processes comply with GMP requirements and instructions

/ SOPs? How are they documented?

Are balances checked regularly within appropriate ranges and

masses, ensuring that they are situated on stable platforms,
are clean and unaffected by environmental conditions?
Is volumetric glassware of the correct grade used, washed
and stored?

Documentation Are laboratory notebooks assigned to specific individuals,

version controlled and appropriately stored and archived?

Are results sheets pre-printed, and what is the procedure for

this? What is the reconciliation process of pre-printed sheets?

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Aspect Possible details to evaluate

Are specifications consistent with the dossier and / or quality

agreement?

Data and reporting How is raw data defined?

Are test results independently checked to ensure there are no

errors?

Is system suitability testing performed before the start of the

test?

How are reports reviewed and approved?

Who has the authority to approve reports, and how is this

defined?

How is data transferred to the certificate of analysis (CoA)?

How is it ensured that CoAs meet customer requirements /

specifications?

Are IT, computer system validation and data integrity

requirements being met?

Microbiology laboratory tour How are access, gowning and changing rooms managed and
checked?

Is the size, housekeeping and cleanliness of the laboratory

adequate?

Are there dedicated areas for sample and culture media

preparation, incubation, reference microbial cultures, bio-
hazardous waste collection, endotoxin and sterility testing,
sampling and material storage (e.g. freezers)?

Is equipment labelled, qualified and maintained? Are

logbooks available, and do they confirm these activities?

Personnel How is protective gowning practised, including hygienic hand

washing (e.g. the use of antimicrobial soap and duration),
disinfection and drying?

Are garments for the laboratories dedicated to the micro lab

fresh and sterilised, non-shedding and with no external
pockets? Do garments for sterility testing (sterile zone)
include closed footwear, a hair net, gloves, a mask and
goggles?

Sample management How are contaminated biohazardous samples, used culture

media, containers, plates and tubes decontaminated?

How is it ensured that the correct media is used for testing?

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Aspect Possible details to evaluate

Culture media, including Is there an SOP for media preparation, and how are the
reference and working processes validated?
cultures
Have heat / cold shock studies for assessment of media
transportation been performed?

Which tests are run for identity and purity (genotypic

analysis)?

How is identity and purity confirmed for incoming cultures?

How long can the working culture be used under the defined
storage condition, and how was this defined?

Indicators for sterilisation / Which BI is used, and from where was it purchased?
biological indicators (BI)
Is the supplier qualified and regularly audited, and did the
supplier audit cover the verification of the D-value claimed by
the supplier?

Is the bacterial population (and purity) confirmed for every BI

lot?

Review procedure on Are standard solutions of strains suitable, available and

microbial identification controlled?

Is the database suitable (with representative organisms used

within the lab facility)?

J. Evaluating Testing Process & Methods

Aspect Possible details to evaluate

Sterility testing Are procedures for testing and transferring sterility samples
and media into the test environment in place (including
media usage, incubation time, closure integrity), and do they
comply with requirements?

What actions are taken after a sterility failure?

Bacterial endotoxin testing Are there procedures in place for preparation of a standard
endotoxin stock solution and for preparation of test solutions?

Is the test method validated appropriately, and how often is

validation / re-validation checked?

How is test sensitivity confirmed with a new LAL reagent lot?

Microbial limit testing Is there a procedure in place for a growth promotion test?

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Aspect Possible details to evaluate

Is media use effective (media should not only recover the

target microorganism, but also other inhibitors)?

Is the incubation process sufficient (correct temperature,

duration and conditions)? How are the conditions defined?

K. Evaluating major Equipment and Instruments

Aspect Possible details to evaluate

Autoclave Is the sterilisation autoclave separated from the

decontaminating autoclave?

Is the autoclave qualified, including calibration of sensors, a

timer, type of thermocouples, etc.?

Are sterilisation processes validated?

Incubator Is air equally distributed (incl. during the heat-up phase)?

How are details like door opening (causing a temperature

drop) handled and documented?

Is there a log for temperature / humidity excursions?

Is the incubator qualified, including temperature / humidity

sensors, a timer, a gas supply and an alarm?

Was mapping performed for the location of the probes?

Water bath How is the water level monitored?

What quality of water is used (only distilled water should be

acceptable)?

How is closure integrity of samples controlled?

How are samples labelled?

How are samples cleaned after removing them from the

water bath and before testing?

How are the samples dried?

Biosafety cabinet Where is it placed, and how is cabinet seal integrity

controlled?

How are filter integrity tests and glove integrity tests

performed?

Is the decontamination process appropriate (including

frequency, monitoring, verification)?

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Aspect Possible details to evaluate

How is the decontamination agent chosen, controlled and

verified?

L. Utilities

Aspect Possible details to evaluate

Air and gas quality How are specifications for the quality of the gases used
defined?

How is the air and gas quality ensured in each area?

Air supply Do air supply systems provide adequate filtration, ventilation,

humidity, temperature control, air speed, number of air
exchanges per hour and unidirectional flow (in laminar flow
compartments)?

Do they meet the microbial and particulate limits for each

grade?

Do they have regular testing and (re-)validation?

Compressed air How is the compressed air quality ensured for pneumatic
purposes?

Does it meet the requirements for purity, dryness, pressure

and flow rate?

Does it have regular testing and validation? How were the

specifications set?

Steam How is the steam quality ensured for sterilisation purposes?

Does it meet the requirements for purity, dryness, pressure

and temperature?

Does it have regular testing and validation? How were the

specifications set?

Other gases (N2, etc.) How are other gases used in the process quality controlled?

Do they meet the requirements for purity, dryness, pressure

and flow rate?

Do they have regular testing and validation? How were the

specifications set?

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M. Maintenance

Aspect Possible details to evaluate

Maintenance and repair Are rooms maintained properly, employing suitable cleaning
and disinfection agents and procedures?

Are rooms qualified before use and re-qualified after any

significant changes or repairs?

Equipment maintenance Is there a procedure in place describing what the company

expects from preventative maintenance?

Who is authorised to realise it, and how is it documented?

Is there a clear definition for replacement parts and final

assessment / review of the impact of any parts? Is there a
handover process from an engineer to the laboratory?

How is it ensured that the equipment is performing as before

and if its validated status is maintained?

Is there a clear description of what parts are in the

programme and how often?

Are personnel qualified to perform the tasks in question?

How is the glassware washer maintained (drains check, sieve,

signs of wear, cleaning of trolleys and jet nozzles)?

N. Non-sterile and sterile Solid Dosage Forms Production Area

Solid dosage forms come in various styles such as powders, granules, tablets, capsules
and suppositories. Each form has its own unique characteristics and administration
methods. Therefore, it is important to consider these characteristics when auditing
facilities involved in the manufacture and testing of such products.
Sterile dosage forms are products that are intended to be administered bypassing the
patient’s digestion system, making them a potentially life-threatening source of infections
if they are contaminated with microorganisms and pyrogens. Usually they are
administered by injection, infusion, implantation or inhalation. To ensure the quality and
safety of these products (sterility), auditors need to ask key questions and focus on
certain areas during an audit.
When auditing the production of these dosage forms, it is important to pay attention to
the specific requirements relating to the product. This includes ensuring that the raw
materials used in production meet the required specifications, the processes follow the
established validated processes and that the finished product is fully produced (and
tested) in line with the Marketing Authorisation (MA) and cGMP requirements.
If an auditor has access to the relevant technical sections (Module 2, 3) of the product
Marketing Authorisation (MA), the auditor can check the manufacturing documentation
against these documents to identify any non-compliance issues.

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To review the manufacturing process, the auditor may select a batch based on one of the
following:
o A batch that was reported in a non-compliance investigation or a deviation /
complaint / OOS, etc.
o A batch that was impacted by significant change (equipment, procedures, layout,
etc.)
o A re-processed or reworked batch
o A rejected batch
o Other considerations (new product, volume, specificity, etc.)
o Or simply selection of one of the last three batches manufactured recently.

Alternatively, auditors can review a proposed batch by the auditee, but this may not
guarantee a representative document. Auditors should check if there is a system
controlling the 'blank' batch records and check if that is controlled by the change control
procedure. The auditor can then check the compliance of this template with the
validation documentation or MA. Then the selected batch record should be checked to
ensure the process is followed correctly.
When auditing without having access to the MA, auditors can use process validation as a
starting point. If there is no access to the MA and the process validation, an auditor can
review the manufacturing process as per the evaluation focus areas.

Aspect Possible details to evaluate

Audit with Marketing Does process validation (batch size, scale up, yield) follow
Authorisation (MA) the defined master formula?

Do executed batch records correspond to the master batch

records (including packaging)?

Do critical IPC test results and acceptance limits match with

pre-defined IPC checks and acceptance limits?

Do QC test methods, incl. IPC, comply with validated

methods?

Do QC test results comply with product specifications?

Is the holding time of bulk product(s) documented and

justified?

Was the equipment used for manufacturing also used during

validation (type, model, including packaging)?

Are listed suppliers of starting materials qualified?

Audit without marketing Process validation in comparison with master batch records
authorisation (MA)
• Manufacturing process flow
• Equipment and rooms
• Starting / Raw materials

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Aspect Possible details to evaluate

• Sampling
• IPC checks
• Acceptance criteria
• Environmental conditions
• Cleaning process

Audit without Marketing Check overall GMP compliance

Authorisation (MA) or
process validation

O. Particulars for sterile Dosage Forms

Aspect Possible details to evaluate

Room design Are rooms designed to follow a clean room cascade,

preventing contamination from lower-grade areas to higher-
grade areas?

How are the (air over-) pressure cascades established and

controlled? Do they prevent the ingress of contaminants from
lower-grade areas to higher-grade areas? Do they account for
the different activities and operations in each area?

How are the rooms classified, qualified and maintained?

Do they comply with the relevant standards and regulations,

such as Annex 1 and the US FDA aseptic guide?

Are rooms easy to clean and disinfect?

Are the rooms free from drains in grade A and B areas (as
they can be a source of microbial contamination)?

Monitoring Are the rooms monitored regularly for microbial and

particulate counts using appropriate methods and locations?

How are rooms, environment, surfaces monitored?

What methods and instruments are used for monitoring?

How often and where are the samples taken?

How are the results recorded and analysed?

Contamination control How is contamination and degradation of the product and its
components prevented?

Are there adequate cleaning and sterilisation processes and

procedures in place?

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Aspect Possible details to evaluate

Are cleaning and sterilisation processes validated?

Personal hygiene How are personnel adequately monitored and controlled?

Do personnel follow strict hygiene and gowning requirements

for each area and perform their tasks correctly and
consistently following standard operating procedures (SOPs)
based on applicable GMPs? How is this ensured?

Do personnel undergo regular media fill tests to demonstrate

their aseptic skills?

When (i.e. based on which criteria) are qualified personnel

dis-qualified to continue working in the aseptic environment?

How is it ensured that personnel minimise their interventions

and movements in critical areas where aseptic operations
take place?

Aseptic process simulation How are media fills performed to simulate the aseptic filling
process according to specifications and instructions?

What are the media fill methods, materials and frequency

used for each product type and container size?

How are the media fill results recorded and analysed?

Filling How is the product filled into the final containers, and does it
comply with GMP requirements and instructions / SOPs?

Are filling processes validated appropriately and re-validated

after any significant changes or modifications?

What are the filling methods, equipment and parameters

used for each product type and container size? Do they
comply with GMP requirements, process validation and MA?

How are the filling accuracy, uniformity and sterility ensured

and verified?

Are filling processes simulated using media fills to

demonstrate aseptic performance?

Lyophilisation How is the product lyophilised, and does it comply with GMP
requirements and instructions / SOPs?

What are the lyophilisation methods, equipment, and

parameters used for each product type and container size?
Do they comply with GMP requirements, process validation,
and MA?

How are the lyophilisation cycle, temperature, pressure, and

duration controlled and measured?

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Aspect Possible details to evaluate

How are the lyophilised product characteristics, such as

appearance, moisture content and reconstitution time,
ensured and verified?

Crimping and container Do the processes employed comply with GMP requirements
closure integrity (CCI) and instructions / SOPs?

What are the crimping methods, equipment and parameters

used for each product type and container size? Do they
comply with GMP requirements, process validation and MA?

How are the crimping quality, uniformity and integrity

ensured and verified?

How is the container closure integrity (CCI) tested and

validated for each product type and container size?

Sterile filtration Do filtration processes comply with GMP requirements and

instructions / SOPs?

What are the filtration methods, equipment and materials

used for each product type and container size?

How are the filter integrity, efficiency and compatibility

ensured and verified?

Sterilisation Do sterilisation processes comply with GMP requirements and

instructions / SOPs?

What are the sterilisation methods, equipment and materials

used for each product type and equipment?

How are the sterilisation efficacy, uniformity and compatibility

ensured and verified?

Sterilisation of containers Do the sterilisation processes used comply with GMP

Note: Most companies speak about requirements and instructions / SOPs?
“Depyrogenation”, when
“Sterilisation” of containers is the What are the sterilisation methods, equipment and materials
target. Depyrogenation is something used for each item?
that happens when glass containers
undergo thermal treatment for How are the sterilisation efficacy, uniformity and compatibility
sterilisation. Containers may be
“free from pyrogens” – but this does
ensured and verified?
not necessarily mean that they are
sterile!

Visual inspection Do visual inspection processes comply with GMP

requirements and instructions / SOPs?

What are the visual inspection methods, equipment and

materials used for each product type and container size?

How are the visual inspection results recorded and analysed?

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P. Water and Sanitisers

Aspect Possible details to evaluate

Water What quality of water is used for which purpose?

How are the water samples taken (where and when;

rationale)?

Where are the sampling points (rationale)?

Which sample containers are used (glass, sterilised, labelled,

identified; rationale)?

What is the max. time of storage prior to testing? Is it

controlled?

Sanitiser What sanitisers are used and for what purpose (type and
temperature)?

How are sanitising solutions prepared, approved and stored?

How is effectiveness checked and verified?

How are contact time and drying method and time controlled?

Q. How to audit a medical Cannabis Grower

Principles and Background

Auditing a medical cannabis grower introduces several new concepts at the edges of GMP
such as hydroponic cultivation systems, good agricultural collection practice (GACP) and
increased demand for site and product security measures. Some authorities inspect both
GACP and GMP, but others solely inspect GMP. The scope here is mainly limited to GMP
considerations.
Some authorities regard cannabis flowers as APIs, whereas others treat them as
intermediate products and some as finished products. This is an evolving area and the
inspector needs to know the intended markets current requirements.
Laboratory testing of cannabis products frequently needs several test laboratories, and
these are often contractors. Testing facilities at growing sites are often absent or very
basic.
Relevant sections of Eudralex Vol 4 should be followed and include non-sterile production
topics plus relevant annexes such as Annex 7 (Herbals), Annex 11 (Computers) and
Annex 15 (Validation).
Most sites have sophisticated plant monitoring measures to satisfy narcotics regulations.
However there is still a potential for mix-ups, as some sites grow plants from seed,
others may purchase plants and others may clone plants. Normal GMP principles of
segregation, identification and labelling should be included in the inspection.
Annex 7 refers to the Guideline on Good Agricultural and collection practice for starting
materials of herbal origin. The inspector is recommended to read this document before a
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GMP inspection. Annex 7 provides advice on the borderlines between GACP and Part I
and Part II of Eudralex Vol 4. The document reference is EMEA/HMPC/246816/2005.
Some products may be irradiated, with current examples being some products exported
from Canada. Practices differ within the EC. The inspector may have to examine results
and certification from a contracted irradiation facility. Annex 12 is useful in this case. The
effects of irradiation on the multiple components of cannabis, such as terpenes, is the
subject of debate. If products are irradiated, the inspector should ensure that the
recipient is notified of this.
Products may not be the subject of QP release due to their current status. In addition,
QC staff at these sites may be less experienced than those in a mainstream
pharmaceutical factory. Cannabis products can present substantial patient risks from
aflatoxins, ochratoxins and microbial contaminants. Inspectors should ensure that the
finished product specification is appropriate and results are being adequately monitored.
Prior to inspection of these sites, and especially for inspectors new to this topic, it is
recommended that preparation is started early so that any questions can be answered
before commencing the inspection.

Aspect Possible details to evaluate

Preparation What is the sites determined cut-off between GACP and GMP?

Is there a formal QMS for GACP?

Are plants bought in, or grown at the site?

Is the site activity limited to flower growing, or are there

additional activities such as extraction and formulation?

What narcotics licences are held or applied for?

Does the company use hydroponics or soil growing?

What laboratories are used for chemical and microbial

testing?

Is there 24/7 security with manned presence and a security

plan?

Goods received and storage Are growth media received with suitable certification?

Are chemical nutrients suitably labelled and stored to prevent

degradation?

Do the company adequately address TSE risks in all potential

product-contact items?

Are any printed materials received and suitably checked and

securely stored?

Facility design Are rooms classified to expected GMP standards for non-
steriles?

Are suitable pressure cascades maintained and monitored?

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Aspect Possible details to evaluate

Are air inlets and outlets located to achieve suitable sweeping

and absence of stagnant areas?

What filtration standards are applied to both incoming and

recirculated air?

Is a suitable area provided for cleaning equipment and

solutions?

Clothing Is a suitable changing area provided with adequate space and

washing facility?

What measures are in place to protect workers and inspectors

from light radiation - eye protection, special clothing and
sunscreen?

Are any external laundry facilities audited and approved?

Fertigation controls Is there an automated system controlling key parameters

such as solution preparation, irrigation, temperatures, light
and gas levels?

Has the system been formally validated and approved?

Request and examination calibration records of key sensors.

What controls are in place to stop unauthorised changes or

optimisation?

Pest controls and fungus What pest control measures are in place and how is their
risks efficacy challenged?

What measures are in place to reduce/discourage fungal

growth?

Harvesting, drying, trimming How is flowering monitored to determine a suitable and

and curing consistent point for harvesting?

Are machines used for bucking and trimming?

Is there sufficient instrumentation on automatic machines?

Is there an adequate procedure for cleaning and sanitising

machinery?

Packaging and labelling Is the packing process manual or is machinery required?

What containers are used for the product – are these bought
in or is a local pouch produced?

Is there any use of nitrogen in the packing process and, if so,

is this subject to point-of-use filtration?

Are suitable in-process checks conducted during packing?

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Aspect Possible details to evaluate

If pouches are used, what checks are carried out for pinholes
and integrity of the seal?

Are product labels printed fully in house, or just variable data

such as the batch number and expiry date added locally?

QC testing Are the water sources evaluated for pesticides, heavy metals
and micro levels?

Is there an adequate environmental monitoring programme

in place?

Does the company check for the absence of aspergillus in the

finished product?

Does the company monitor and trend levels of aflatoxins and

ochratoxins in the finished product?

Is there a requirement for the absence of salmonella and

E.coli in the product?

Are cannabinol levels in the finished product controlled and

evaluated?

Are the qualifications and experience of the releasing officer

or QP adequate?

R. Preparing Audits for Cell and Gene Therapies (CGT) based

Advanced Therapy Medicinal Products (ATMPs)

Background
The European Commission has published a separate regulation for Advanced Therapeutic
Medicinal Products (ATMPs) which lays down specific rules concerning the authorisation,
supervision and pharmacovigilance of ATMPs (Regulation 1394/2007). The regulation
defines three types of ATMPs: gene therapy medicines, somatic cell medicines and tissue
engineered medicines.
This article is mainly focused on ATMP based cell and gene therapies (CGT). CGTs can be
described as therapies that offer personalised and targeted treatments for a number of
rare and chronic diseases. These therapies are classified into two main types: autologous
and allogenic.
Autologous CGTs involve using the patient’s own cells, which are collected, modified and
then reintroduced into the patient. This personalised approach minimizes the risk of
immune rejection.
Allogenic CGTs, on the other hand, use cells from a donor. These therapies can be
produced in larger quantities and administered to multiple patients, but they carry the
risk of immune response and require careful matching of donor and recipient.

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1 ATMP-specific Challenges

Due to the specific nature of ATMPs, new challenges need to be addressed. These new
challenges and difficulties regarding sterility, out-of-specification handling, batch release
and EU import testing are situated throughout the entire manufacturing process.
One of the major challenges is the aseptic risk associated with the ATMP manufacturing.
ATMP administration requires injection, infusion or transplantation of the medicinal
product. Therefore, the ATMP product needs to be manufactured under aseptic
conditions. Unlike traditional small molecule medicinal products, sterile filtration or
terminal sterilisation is in most cases impossible, either because these methods impede
the product’s structure or function, or because cells are simply too large to pass through
the pore size of the filter. As stated in Part IV of the EU GMPs (Good Manufacturing
Practice), all processes related to aseptic processing need to be validated before entering
clinical phase I trials. The combination of gowning requirements, clean room qualification
and validation of these aseptic processes by media fill and a validated sterility test
method needs to ensure the sterility of the product and, therefore, requires specific
attention during an audit according to Annex 1, as applicable.

2 How to audit ATMPs - managing the Complexities of allogenic

CGT Manufacturing

2.1. The Challenges of the Supply Chain

The creation of a CGT based ATMP involves the collection or “donation” from an
individual. The donated material is then generally modified, engineered or manufactured
into a therapy product for delivery to the patient. This complex manufacturing and
delivery model is known as the “vein-to-vein supply chain”.
CGTs have not yet been adopted on a large scale, due to a combination of clinical,
regulatory and cost-related hurdles. At present, supply chains are necessarily bespoke
and costly. However, given the potential presented by CGTs and the current focus on
developing them, it seems likely that they will form an integral part of future therapies.
As they become more prevalent, ensuring the ongoing integrity of their supply chains will
be of paramount importance. This also includes the storage and transport of them.
Right from cell collection to the delivery of the therapy product, each step involves
several processes which bring their own risks and require controls.
During the collection process (via apheresis, etc.), preparing and monitoring the patient
and equipment to yield the appropriate quality raw material is essential.
• The raw material and drug products can get affected by factors such as timing,
temperature, microbiological basic load, packaging, etc. and therefore need to be
handled, packed and transported with care. Obtaining a sterile starting material
can be a challenge.

• Certain complex manipulations and activities are performed during the

manufacturing process and are crucial if the end product is to meet specifications.
These are often performed manually and require great skill and consistency.
• Understanding the GMP requirements, equipping the team with the necessary
skills and rigorous training is critical.

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• Lot genealogy, including chain of identity (COI) and chain of custody (COC), are
two critical data sets that maintain the record of all the materials, processes,
testing and outputs of a batch to ensure that patients are treated using the
specific product meant for them.

• It must be ensured that the qualification and performance of vendors meet the
required standards, especially since many of them do not operate in a GMP
environment.

• Standardised processes and controls ensure that the products are safe and fit for
the intended use and comply with regulatory requirements.

• Risks have to be identified, and mitigation measures established using an

integrated process for both quality and risk management.

• Continuous improvement has to be set up through monitoring of processes and

performance, track and trend investigations, root cause and CAPA analysing of
supply chain performance and managing risks.
A robust audit process is critical for ensuring patient safety, mitigating risks, reducing
failure and increasing operational efficiency.

2.2. Where to start at the Manufacturer

When manufacturing an ATMP, it is important to pay attention to the choice of raw

materials used. These materials influence the entire process, from clinical development
to market authorisation. GMP guidelines contain important considerations.
This requires specialist expertise, with careful consideration and impact assessment
undertaken, which is not routinely available for the dense supplier management needed.
Agreements with suitable suppliers such as blood centres are required to facilitate
delivery of these specialist materials to be of suitable specified quality. Audits and
continuing oversight arrangements should confirm the technical quality and suitability of
the services documented in a quality and technical agreement.
Therefore, when auditing manufacturers, an essential focus should be on raw material
supplier management.

2.3. ATMP OOS Batches being used

Due to a higher variability and the quality of raw materials, a higher level of deviations
and OOS results is more likely. In case of an OOS result, there is the possibility to
release the batch and administrate it to the patient. This contrasts with traditional
medicinal products, where a product which does not comply with the specifications
cannot be certified and released.
During an audit the following should be checked with regard to OOS documentation:
• A description of the OOS with a risk analysis by the manufacturer on the impact
on the following:

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• The quality of the product, including the percentage of batches that is OOS on
the total of commenced productions and a reflection on the production process
(root cause analysis and CAPAs (Corrective Action and Preventive Action)),

• Role of the QP

• The safety and efficacy of the product in relation to the patient;

• There should also be a feedback loop in place to the critical quality attributes
(CQAs), which have been identified during the quality target product profile
(QTTP) process to define the quality, safety and efficacy attributes of the
desired final product during the risk-based process development (e.g. quality
by design)
• A confirmation of the physician to the manufacturer to accept the product;

• A declaration from the MAH (marketing authorisation holder) as to whether or not

the product has been administered.
A Q&A document on how to handle an OOS for authorised batches was first published by
the EMA in April 2019.

2.4. QP Certification of ATMP and Import

According to EU directive 2001/83/EC, a registered qualified person (QP) is responsible

for the certification of medicinal products prior to their release. This and the applicable
responsibilities of a QP do not differ for ATMPs. However, the difficulties which might be
faced by a QP are different throughout the entire manufacturing process.
• A QP cannot certify an OOS ATMP batch, the release of these batches is based on
a documented request by a treating physician.
The QP needs to assure that verification according to GMP Part IV – 11.27 has
been performed. Prerequisites to release the OOS batch are mentioned in GMP
Part IV – 11.5.
As a reminder, QP certification is a written signed statement that the manufacture
and testing of a batch has been conducted in accordance with GMP and the
relevant approved marketing authorisation or clinical trial application before the
batch can be released.

• The obligation to perform import testing in case a medicinal product is

manufactured in a third country, does not always apply to ATMPs (e.g. for
ATIMPs, import waiver). There are exemptions from EU batch retesting laid down
in paragraph 11.17 of GMP Part IV. In case of exemptions, the manufacturing of
the ATMP needs to be performed according to EU GMP. This implies that an audit
prior to first importation is required. As the QP takes on the responsibility of
certifying this batch from a third country, the audit is preferably performed by the
QP. A Q&A document on the exemption from batch controls carried out on ATMPs
imported into the European Union from a third country was published first by the
EMA in July 2019

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2.5. Transport and Storage of ATMPs

Much of the discussion in the ATMP industry today focuses on the complexity of
manufacturing. However, the ultimate success of an ATMP rests on the ability to deliver a
viable, potent product to the patient.
In order to ensure that this “living” drug is delivered to the right patient at the right time,
location and temperature is essential to patient safety and product effectiveness and
therefore should not be forgotten when auditing.
The logistics of these types of medicines are complex, due to specific requirements
regarding temperature, reliability and traceability. For example:
• Frozen storage requirements: Cryogenic storage and distribution capabilities are
established for many ATMPs. Distribution in deep-frozen or cryogenic conditions
needs specialist shippers, to keep the temperature stable and track the location
and conditions during the shipment.

• Short shelf lives —ATMP or their starting materials may have an extremely short
shelf life. This could even mean that not all test results are available at the time
points of release or even administration. A risk assessment, risk mitigation and
processes (e.g. what happens if a specification is not met) need to be in place.
Any deviation from storage, distribution or traceability requirements has the potential to
impact the quality of the ATMP and, therefore, the safety of patients. Storage and
distribution under GMP and good distribution practice (GDP) guidelines are applicable for
CGTs, too.
The challenges of CGT for pharma logistics are as followed:
• Delays due to inspection and compliance checks

• Complexity calls for experienced logistics partners

• Limited visibility in logistics because of low quantity

• Scalability of transport methods

• Unforeseen disruptions in supply chains

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