ISO 20069:2019

INTERNATIONAL ISO
STANDARD 20069
First edition
2019-08
Guidance for assessment and
evaluation of changes to drug
delivery systems
Gestion des changements d’appareils dans les combinaisons de
produits pour l’administration de médicaments
Reference number
©
ISO 2019
© ISO 2019
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Published in Switzerland
ii © ISO 2019 – All rights reserved

Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 2
3 Terms, definitions and abbreviated terms . 2
3.1 Terms and definitions . 2
3.2 Abbreviated terms . 3
4 Process . 4
4.1 General . 4
4.1.1 Process framework . 4
4.1.2 Quality and risk management . 5
4.1.3 Relationships within the organization and with suppliers or external
organizations . 5
4.2 Phase A — Define and assess . 6
4.2.1 Define change (Figure 1, box 1) . 6
4.2.2 Identify change types (Figure 1, box 2) . 6
4.2.3 Assess impact of change (Figure 1, box 3) . 7
4.3 Phase B — Execute activities . 9
4.3.1 Plan (Figure 1, box 4) . 9
4.3.2 Execute (Figure 1, box 5) . 9
4.4 Phase C — Final evaluation . 9
4.4.1 General. 9
4.4.2 Review data (Figure 1, box 6) .10
4.4.3 Evaluate clinical comparability (Figure 1, box 7) .10
4.4.4 Decision to proceed with change (Figure 1, box 8) .10
Annex A (informative) Templates .11
Annex B (informative) Example of completed templates for assessing and evaluating a change .15
Bibliography .36
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/patents).
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expressions related to conformity assessment, as well as information about ISO's adherence to the
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.org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 84, Devices for administration of medicinal
products and catheters.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/members .html.
iv © ISO 2019 – All rights reserved

Introduction
This document provides guidance to organizations wishing to implement a systematic approach to
assess and evaluate changes to needle-based injection systems, needle-free injectors and aerosol
delivery devices for medical use (see Clause 1) throughout their lifecycles. In particular, an organization
can use the approach for changes to the drug delivery system from entry into pivotal or registration
clinical studies through the end of commercial supply.
Due to the breadth of potential change circumstances, this document does not contain prescriptive
technical requirements for assessing and evaluating drug delivery system changes but rather provides
illustrative guidance for consideration.
This document does not replace or alter existing statutory and regulatory requirements for assessing
drug delivery system changes.
Prior to using the process outlined in this document, the organization should have determined the
objective of the change including the various opportunities/options for fulfilling the objective.
This document might also be useful for assessing and evaluating change to drug delivery systems other
than needle-based injection systems, needle-free injectors and aerosol delivery devices for medical use.
The process can be applied to multiple product lifecycle stages, including design and development,
production, storage and distribution, installation, servicing and final decommissioning/disposal of
the drug delivery system or associated activities (e.g. up-dating of software). It can also be used by an
organization's suppliers and external parties (e.g. raw materials, components, subassemblies, medical
devices, sterilization services, calibration services, distribution services, maintenance services).
This document is not intended to replace or alter quality management systems, risk management,
or usability engineering requirements in assessing these changes. Rather, it provides a common
framework using a scientific and risk-based approach consistent with
[4]
— ISO 13485 ,
[5]
— ISO 14971 , and
[8]
— IEC 62366-1 .
Although this process focuses on user safety and drug delivery system performance, it also addresses
lifecycle management and includes consideration of appropriate medicinal product guidance (e.g. ICH
Q8, ICH Q9, ICH Q10 and ICH Q12). This will help assess the potential impact of changes on the quality,
safety, and efficacy of the finished product for the target patient population.
Over the course of a finished product's lifecycle, there will be a broad array of drivers for change. These
changes and their various design solutions can be motivated by, but are not limited to the following:
a) adverse event/complaint data;
b) voice of the customer, user feedback or market research;
c) usability studies;
d) changes in processes for production, production scale and supply chain logistics;
e) changes in material or source of supply;
f) impact of changes to the medicinal product that affect the drug delivery system.
This document provides examples of drug delivery system changes using a process flow (see Figure 1).
These examples and the conclusions provided are purely illustrative and are intended to provide
guidance on how to utilize this document.
It is the responsibility of organizations to provide evidence that the approach adopted is commensurate
with the level of risk to ensure the quality, safety and performance of the drug delivery system. While
the focus of this document is the changed drug delivery system, it is also possible that changes to
the medicinal product might impact the drug delivery system (e.g. change in viscosity or volume of
medicinal product resulting in changed drug delivery system performance). It is also possible that
changes to the drug delivery system might impact the medicinal product (e.g. increased injection forces
resulting in changed treatment). As such, one key aspect of this process is assessing the change for
its potential impact on overall quality given the critical interface between the drug delivery system
and the medicinal product. Organizations should evaluate potential impact to the medicinal product
in accordance with relevant regulations and guidelines pertaining to medicinal products (e.g. ICH
guidelines) to ensure the quality, safety and efficacy.
The core of this document is the process flow, which attempts to guide an organization through a risk-
based approach based on drivers of change as mentioned above impacting the
— drug delivery system design,
— manufacturing process, and
— labelling and user interface.
The expectation is that such changes are evaluated through the risk assessment of how the change
could impact system form, fit and function (including medicinal product flow paths) such that users are
not negatively impacted in terms of quality, safety and performance of the drug delivery system. Given
that a single change can affect more than one of the change types (e.g. a material change can also drive
a process change), all change types should be assessed and evaluated.
The identification, analysis, evaluation and control of change are common regulatory requirements
in the post approval phase of a product’s lifecycle, but are also important in the clinical phase of
development. Organizations should demonstrate that as the drug delivery system design evolves, the
link between the drug delivery system and the medicinal product as tested in the clinical setting (for
which market authorization is granted or is intended) is maintained.
vi © ISO 2019 – All rights reserved

INTERNATIONAL STANDARD ISO 20069:2019(E)
Guidance for assessment and evaluation of changes to drug
delivery systems
1 Scope
This document provides guidance for assessment and evaluation of planned changes to drug delivery
systems that are integral with, packaged with, or cross-labelled for use with a specified medicinal
product. This document is applicable to the drug delivery system’s lifecycle from registration clinical
studies to end-of-life. This document is applicable to the assessment of changes within the following
drug delivery systems:
— needle-based injection systems for medical use;
— aerosol drug delivery devices;
— needle-free injectors for medical use.
NOTE These are covered by the ISO 11608 series, ISO 20072 and ISO 21649, respectively.
This document might also be useful for assessing and evaluate changes to other drug delivery devices
or systems.
Examples of changes that are within the scope of this document include but are not limited to the
following:
a) the same route of administration (e.g. change resulting in including a marketed prefilled syringe to
an autoinjector);
b) changes to the drug delivery system design (e.g. change in configuration or layout of electrical and
mechanical components);
c) changes to the medicinal product that affect the drug delivery system; including the primary
container closure (e.g. viscosity, particle size);
d) changes in production or handling of the drug delivery system (e.g. process scale, manual
to automated assembly, glue bond to sonic weld, mould cavitation, sterilization, storage,
transportation, work instructions or methods);
e) changes in component materials or source of supply;
f) changes in software, including changes related to cybersecurity, encryption and connectivity;
g) changes in the user interface, including packaging;
h) changes to labelling and/or instructions for use.
Revisions or additions of software are within the scope of this document. The software can either be
integrated into the physical drug delivery system, separate, or both.
The applicability of this document to non-integrated software is relevant to the extent that those
software changes can impact the drug delivery system and/or impact how users interact with it.
Depending on the nature of the change, there can be additional assessments and resulting activities,
which can be outside the scope of this document.
This document does not provide guidance for defining the objective of the change, nor the various
potential opportunities/options for fulfilling this objective.
2 Normative references
There are no normative references in this document.
3 Terms, definitions and abbreviated terms
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
3.1 Terms and definitions
3.1.1
component
single item, or assembly of items (subassembly) within a drug delivery system (3.1.2)
3.1.2
drug delivery system
medical device or system whose primary purpose is the administration of a medicinal product such as
drugs and biologics
Note 1 to entry: This term applies to combination of components and subassemblies of the system that are
intended to be integrated with the medicinal product with the purpose of providing a method of administration
of the medicinal product.
3.1.3
finished product
drug delivery system (3.1.2) and the medicinal product it is intended to deliver
Note 1 to entry: A finished product can be as a single integrated product combining both the drug delivery system
and medicinal product as released by its manufacturer. It can also be a drug delivery system and medicinal
product that are produced separately and integrated into its final, usable form by the end user.
Note 2 to entry: It is not intended to imply the status of a marketed product or manufacturing responsibility as
defined by individual markets.
3.1.4
flow path
pathway the medicinal product or other liquid, gas or powder flow to the targeted site
3.1.5
organization
person or group of people that has its own functions with responsibilities, authorities and relationships
to achieve its objectives
Note 1 to entry: The concept of organization includes, but is not limited to, sole-trader, company, corporation,
firm, enterprise, authority, partnership, association, charity or institution, or part or combination thereof,
whether incorporated or not, public or private.
Note 2 to entry: Regulatory bodies and others can use other terms for organization, such as manufacturer.
[SOURCE: ISO 9000:2015, 3.2.1, modified — the original Note 2 to entry was deleted and a new Note 2
to entry was added.]
2 © ISO 2019 – All rights reserved

3.1.6
quality
degree to which a set of inherent characteristics of an object fulfils requirements
Note 1 to entry: The term “quality” can be used with adjectives such as poor, good or excellent.
Note 2 to entry: “Inherent”, as opposed to “assigned”, means existing in the object.
[SOURCE: ISO 9000:2015, 3.6.2]
3.1.7
verification
confirmation, through the provision of objective evidence, that specified requirements have been
fulfilled
Note 1 to entry: The objective evidence needed for a verification can be the result of an inspection or of other
forms of determination such as performing alternative calculations or reviewing documents.
Note 2 to entry: The activities carried out for verification are sometimes called a qualification process.
Note 3 to entry: The word “verified” is used to designate the corresponding status.
[SOURCE: ISO 9000:2015, 3.8.12]
3.1.8
validation
confirmation, through the provision of objective evidence, that the requirements for a specific intended
use or application have been fulfilled
Note 1 to entry: The objective evidence needed for a validation is the result of a test or other form of determination
such as performing alternative calculations or reviewing documents.
Note 2 to entry: The word “validated” is used to designate the corresponding status.
Note 3 to entry: The use conditions for validation can be real or simulated.
[SOURCE: ISO 9000:2015, 3.8.13]
3.2 Abbreviated terms
ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use
App Application
BSE/TSE Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathy
IFU Instructions For Use
PK/PD PharmacoKinetics/PharmacoDynamics
uFMEA user Failure Modes and Effects Analysis
pFMEA process Failure Modes and Effects Analysis
dFMEA design Failure Modes and Effects Analysis
HFE Human Factors Engineering
URS User Requirements Specification
PRS Product Requirements Specification
API Active Pharmaceutical Ingredient
pH potential of Hydrogen, a measure of acidity
cP centiPoise, a measure of viscosity
4 Process
4.1 General
4.1.1 Process framework
The process outlined in this document provides a framework to assess and evaluate changes to a drug
delivery system. It does not provide a framework to assess and evaluate changes to a medicinal product
(e.g. reformulation driven by adverse event data). However, if the change to a medicinal product has the
potential to impact the drug delivery system (e.g. reformulation increases viscosity impacting delivery
forces), then the framework should be used to assess and evaluate the impact on the drug delivery system.
The process is initiated when a change has been proposed for potential implementation. Every change
should be assessed based on the individual circumstances of the change. Where multiple changes are
occurring simultaneously or concurrently, they should also be assessed for their ability to interfere with
each other and/or to collectively impact the product in a manner different to their individual impacts.
The process should be divided into three phases as illustrated in Figure 1:
a) Phase A — Define and assess;
b) Phase B — Execute activities;
c) Phase C — Final evaluation.
Phase A, define and assess, starts with the thorough definition of the proposed change, i.e. the
purpose with and scope for the proposed change, a change description including the current state and
the proposed state after implementation. The next step is the identification of the change types based
on the information collected in the definition step. The last step of this phase is an impact assessment
on the performance, safety, stability, compatibility, process, usability, software, clinical data and
regulatory compliance.
Phase B, execute activities, consists of two steps, the planning and the execution of the planned
activities. During the planning step, all activities that need to be performed in order to prepare a proper
implementation of the change should be determined. These activities can include but are not limited to
design and development verification, design validation and process validation. The activities depend on
the change type (see 4.2.2) and its associated risks and on the specific properties and requirements of
the individual change and should be defined on a case by case basis. The planning step is concluded with
the confirmation of readiness to perform the planned activities. In the execution step, all the planned
activities are performed and completed, e.g. design and development verification work is conducted as
per the verification plan established in the planning step. Completion of the activities is a prerequisite
for change implementation and to enter the final evaluation Phase C of the change.
Phase C, final evaluation, includes an evaluation supporting a decision as to whether the change
should be implemented based on the results obtained in Phase B.
As an organization proceeds through the process, knowledge and perspective obtained through the
assessments (e.g. unacceptable risks, non-fulfilment of the objective or unforeseen difficulties in
implementing the change) and/or changes in business needs (e.g. cost/time) can result in a decision to
not proceed with the change. The basis for the decision should be documented.
Annex A provides an example of a template to guide the assessments and execution of the activities
included in Figure 1. Annex B provides examples of completed templates.
4 © ISO 2019 – All rights reserved

Figure 1 — Process flow for assessment and evaluation of changes to the drug delivery system
4.1.2 Quality and risk management
The process should be performed within the organization's quality and risk management system
requirements. This process should be aligned with ISO 13485, in particular control of design and
development changes. Risk assessment should be performed and risk controls should be implemented
where needed in accordance with ISO 14971 during all phases of this process.
4.1.3 Relationships within the organization and with suppliers or external organizations
Due to the nature of drug delivery systems, it is common for separate functions within a single
organization responsible for the drug delivery system to have responsibilities for different aspects
of the finished product (e.g. formulation scientists responsible for the medicinal product aspects and
device engineers responsible for the drug delivery system aspects). When there is a change to the
drug delivery system, it is recommended to define internal roles and responsibilities for the change
process and to establish a cross-functional team comprising the relevant levels and functions within
the organization to be involved in each phase of this process.
Additionally, it is also common for one or more separate organizations to have responsibilities for
different aspects of the product (e.g. component suppliers, medicinal product manufacturer and device
manufacturer) and to work collaboratively. Where these relationships exist, it is essential to ensure
that roles and responsibilities with regards to notification of and approval of changes between the
parties are defined. Quality agreements with suppliers and other external organizations are one way
to ensure that changes that can impact the drug delivery system are transparent to the drug delivery
system owner.
Depending on the intended application, changes made within the defined specification range can still be
impactful for the drug delivery system. For example, shifting the nominal, as an improvement, within
the acceptable range for a particular attribute (e.g. silicone level) can impact the functionality of an
injection device. The assessment of this change from a supplier can have no impact as the component
still meet specification, but could result in a change in drug delivery system functionality.
4.2 Phase A — Define and assess
4.2.1 Define change (Figure 1, box 1)
This process is about defining the objective for the change and providing a description of the change
with the appropriate details. It can also be useful to identify what is not changing (e.g. no change to the
primary container and medicinal product flow path).
An objective for the change can include but is not limited to improved safety, improved performance, or
substitution of a component.
4.2.2 Identify change types (Figure 1, box 2)
The “current state” and “proposed state” of the drug delivery system as a result of the change should be
described. The change types should be identified based on the specifics of the change. The assessments
in Table A.1 can be useful to perform the preliminary change type identification.
Given that a single change can fall under more than one of the change types (e.g. a material change can
also be a process change), it should be assessed whether the change is included in each of the change
type categories to ensure an assessment.
Change types that should be identified include, but are not limited to the following:
a) Materials: Change of material of the drug delivery system components or its packaging including,
but not limited to, type, grade, chemistry, formulation, additives, colorants, supplier/sub-suppliers,
manufacturing materials and/or processing aids.
b) Form and fit: Change in physical attributes, such as component dimensions relative to interface/
interaction with other components and sub-assemblies.
c) Function: Change in system function as defined in the design input requirements and associated
design specifications (e.g. dose accuracy, environmental and mechanical robustness, functions that
support label claims such as deliverable volume).
d) Process change: Change in processes for production and handling of the drug delivery system.
Process changes include, but are not limited to changes to the component manufacture, sub-
assembly and system assembly processes including the following: process control, packaging,
different production sites, sterilization, environmental conditions and storage.
e) User interface change: Change impacting the user interface. User interface changes include, but
are not limited to changes to the user population, intended users, form factor, packaging, labelling,
instructions for use, software, printed materials and training.
f) Software: Change to embedded or connected software, including change of separate software that
relates to the use of the drug delivery system (e.g. dosing app).
g) Medicinal product: Change to the medicinal product that can impact the drug delivery system.
6 © ISO 2019 – All rights reserved

4.2.3 Assess impact of change (Figure 1, box 3)
An assessment should be performed to identify potential impact to design inputs, user requirements
and risk control measures to determine whether verification and/or validation activities are required
to implement the change. Table A.2 can be a helpful guide when assessing impact of key areas (e.g.
performance, shelf-life, clinical evaluation, etc). Based on the assessment, additional verification and/or
validation studies should be planned.
For areas that could be potentially impacted by a change, it should be assessed whether existing
evidence is adequate to support the change. The assessment should include a review of best available
information and objective evidence (data, modelling, literature, etc.).
It should be considered whether the change has the potential to fulfil the objective(s), to cause any new
hazard(s), or has the potential to modify the established risk profile and/or the performance of the
drug delivery system. Changes should be assessed in relation to potential impact, direct and indirect,
on each of
a) the drug delivery system,
b) the medicinal product,
c) the users,
d) manufacturing systems, and
e) compliance with applicable statutory and regulatory requirements.
The assessments should identify required updates of the design and development documentation for the
drug delivery system, including, but not limited to drawings, 3-D models, other specifications, software,
electronics, hardware, tolerance stack-ups, test equipment, test methods and operating parameters.
4.2.3.1 Assess drug delivery system performance
The drug delivery system performance should be assessed for each type of drug delivery system change.
Existing drug delivery system design input requirements should be assessed in order to determine
which requirements might be affected or added due to the change. The functional robustness should be
assessed – including robustness to shipping, aging, drop, shock, etc.
It should be assessed whether a physical change relates to surfaces that contact the medicinal product
liquid or air (in the case of inhaled products). Changes to surface treatments and physical attributes of
the drug delivery system components should also be assessed for potential impacts to performance.
A medicinal product change that can potentially impact how the drug delivery system performs should
be assessed.
Changes to the interface/interaction with other system components, e.g. sub-assemblies, needles,
spacers, primary packaging such as container closures and blisters, and/or other changes of parts/
components included in the drug delivery system, should be assessed.
4.2.3.2 Assess safety
It should be assessed whether the change has an impact on the safety of the finished product.
Assessments should include, but are not limited to, electrical safety, mechanical safety, biocompatibility,
BSE/TSE, material composition (such as whether the material is made with natural rubber, latex, etc.),
as appropriate based on the design inputs for the product. Sterility performance should be considered,
if applicable.
If the changed material has contact with the medicinal product’s flow path, its impact on the quality,
safety and performance of the drug delivery system and the quality, safety and efficacy of the medicinal
product should be assessed. It should also be assessed whether the material is permitted by applicable
statutory and regulatory requirements (e.g. regulation on restricting the use of hazardous substances,
requirements for phthalates, biologically derived materials, bisphenol A (BPA)).
4.2.3.3 Assess drug delivery system stability
For the drug delivery system change, the existing stability testing performed or historical data
supporting the stability (e.g. shelf-life and in-use-life) should be assessed. If necessary, additional
stability testing to support the change should be performed (e.g. real-time aging, accelerated aging,
photo-stability).
4.2.3.4 Assess drug delivery system/medicinal product compatibility
The potential risks associated with types of drug delivery system change that impact how the drug
delivery system and medicinal product interact should be assessed.
It should be assessed whether there is a potential impact on the medicinal product’s quality attributes,
which include physical, chemical, biological, or microbiological properties or characteristics that should
be within an appropriate limit, range, or distribution to ensure the desired quality. If the medicinal
product quality attributes are potentially impacted, then assessment and evaluation should be
performed taking into account relevant regulations and guidelines.
In some organizations, assessments such as container closure integrity, airflow resistance, medicinal
product shear, particulates, break loose, extrusion/glide and extractables/leachables can be considered
part of the medicinal product characterization. These assessments can also be considered as relating to
the drug delivery system.
4.2.3.5 Assess manufacturing processes
It should be assessed if the proposed change potentially impacts the existing process validation.
The elements of processes for manufacturing, such as moulding, forming, assembly, sterilization
environmental conditions, test methods, equipment should be assessed as well as in-process control
and release.
4.2.3.6 Assess usability
The impact on the existing use-related risk assessments and usability data should be assessed to
determine whether additional data is needed. Changes to user interface can include, but are not limited
to, changes to a component colour, symbols, required user force, labelling, packaging, and software.
NOTE IEC 62366-1 specifies a process for a manufacturer to analyze, specify, develop and evaluate the
usability of a medical device as it relates to safety.
4.2.3.7 Assess software
It should be assessed whether the proposed change potentially impacts any software and whether
validation of software is needed. This includes any embedded or connected software, including change
of separate software that relates to the use of the drug delivery system (e.g. dosing app). Assessment of
changes to software should be performed in accordance with IEC 62304.
4.2.3.8 Assess clinical data set
It should be assessed if the change is supported by the existing clinical data set. If not, new clinical data
can be needed.
8 © ISO 2019 – All rights reserved

Where the changed drug delivery system is intended to achieve comparability to the unmodified drug
delivery system, this review can help identify the type and scope of clinical data necessary to bridge
the gap.
EXAMPLE A change in adhesive material could require additional clinical data in relation to skin adherence
and irritation.
4.2.3.9 Assess regulatory compliance
It should be assessed if the changed drug delivery system fulfils current, applicable regulatory
requirements. If not, appropriate data and documentation should be generated and appropriate
measures should be taken. It should be assessed if reporting or submission activities might be needed
to maintain or obtain authorization from the competent authority.
4.3 Phase B — Execute activities
4.3.1 Plan (Figure 1, box 4)
Based on the assessments recommended in 4.2.3, the verification and validation activities related to
the change should be planned. Table A.2 can be a useful guide in the planning of these activities. The
original verification and validation plans, protocols and reports could be used as a guideline. Multiple
changes can be verified and/or validated individually and/or in aggregate depending on the risks.
Similarly, depending on the risks, change may be planned on the basis of implementation across all
elements of the manufacturing systems at once (e.g. all tool cavities, all assembly lines), or piloted at
first on a smaller scale. For those areas which have the potential to be impacted by a change, it should
be evaluated whether existing evidence for the verification/validation activity is adequate to support
the change. If no additional activities are deemed necessary, a justification should be included in the
appropriate change management documentation.
Verification and/or validation activities related to the change can include additional design and
development verification testing (e.g. in vitro testing), design validation testing (e.g. usability testing,
clinical studies) and/or process validation. Some of these activities could potentially be carried out in
parallel rather than sequentially, depending on the outcome of risk assessments as appropriate.
If the objective is to establish comparability, then conformance to specifications might not be sufficient.
In these circumstances, the statistical and/or clinical differences between the existing and changed
drug delivery systems should be considered.
4.3.2 Execute (Figure 1, box 5)
Based on the planning outcomes, implementation, verification and validation related to the change
should be executed in accordance with ISO 13485.
Results from the verification and validation activities should be assessed for conformance with the
acceptance criteria defined as part of the planning activities recommended in 4.3.1. Additionally, as the
organization proceeds through the execution plan, outcomes can identify additional activities needed
to support the change.
4.4 Phase C — Final evaluation
4.4.1 General
Final evaluation should be performed to determine whether the data set supports implementation of
the change to the drug delivery system.
If any of the evaluations detect new or higher risks, the organization should, at a minimum, conduct
a risk/benefit analysis in accordance with ISO 14971 to determine whether the change should be
implemented or revisited.
Where the change to the drug delivery system is intended to achieve comparability to the unmodified
drug delivery system (e.g. change of resin suppliers for same internal component design), this review
process will help determine if existing data and the new data generated is sufficient.
4.4.2 Review data (Figure 1, box 6)
After the change has been verified and validated, the new data along with all existing data from the
unmodified drug delivery system relevant to the modified drug delivery system should be reviewed.
The aggregated data should support the proposed change. This will include, but is not limited to, clinical
data and post-marketing data, both published and internal.
4.4.3 Evaluate clinical comparability (Figure 1, box 7)
If the objective is to establish comparability to the existing clinical data set, then conformance to
specifications might not be sufficient.
The modified drug delivery system should be considered comparable to the unmodified drug delivery
system if, after assessing all supportive data
a) the modified drug delivery system conforms to the performance specification of the unmodified
version,
b) there are no clinically relevant differences between the unmodified and modified versions,
c) the established risk profile of the drug delivery system is not adversely impacted,
d) there are no unresolved gaps between the original and new data sets, and
e) there are no new safety or performance issues.
If comparability is not established, the organization should determine what, if any, additional clinical
data are needed to support proceeding with the change.
4.4.4 Decision to proceed with change (Figure 1, box 8)
Based on the evaluation of the change to the modified drug delivery system, a decision to proceed or
discontinue the change should be made and documented. The last section of Table A.3 can be useful to
document this decision. Any reporting or submission activities needed to obtain authorization from the
competent authority should be performed prior to implementation of the change.
10 © ISO 2019 – All rights reserved

Annex A
(informative)
Templates
The templates given in Annex A are provided as guidance for assessing, evaluating and documenting a
change decision. The framework, structure, and details are suggestions only. They are not exhaustive
and should be refined based upon the nature of the change under consideration. The templates are
organized and designated to reflect the process as defined in Figure 1.
Table A.1 is intended to provide an overview for defining, identifying and assessing a change (see
4.2 and Figure 1, Phase A, boxes 1, 2 and 3). It identifies the type of change as described in 4.2.2 and
comprises the impact assessment as described in 4.2.3.
Table A.2 is intended to capture the initial assessment of potential impact based on the change and then
be updated to document the results from the verification and validation activities defined and executed
(see 4.3 and Figure 1, boxes 4 and 5).
Table A.3 is intended to capture the final evaluation of the change (see 4.4 and Figure 1, boxes 6, 7 and
8) considering all available data. Finally, based on review of the data, a decision of whether or not to
proceed with the change as described in 4.4.4 should be documented.
Table A.1 — Template for defining, identifying and assessing a change
Phase A — Define and assess (Figure 1, boxes 1, 2 and 3)
Name of change (brief designation)
Instructions: Designate/name the change and scope of change for identification purposes.
1. Define change
Instructions: Define the objective for the change and provide a description of the change with appropriate details,
e.g. increased safety, increased performance of the drug delivery system or need to substitute a component of the
drug delivery system. It can also be useful to identify what is not changing.
2. Identify change type(s)
Instructions: Describe the change in appropriate detail and classify each change type, e.g. materials, form and fit,
function, process, user interface, software, medicinal product. There can be other change types.
Be sure to describe the “current state” and “proposed state”. Indicate in this section if the chang
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