Regardless of a product’s route or
country of registration, one constant
across the pharmaceutical industry
is the requirement to keep dossiers
updated and current. Whether changes
are driven by technical and scientic
improvements or cost reduction,
post-approval lifecycle management
activities are a key responsibility of
marketing authorisation holders
(MAHs). As regulatory agencies across
the world evolve, the methods of
submitting and processing variations
have begun to harmonise.
European variations
Alongside the European legislation that
denes variation types, a guideline lays
out a harmonised list of anticipated
variations with classication codes.
1
A dened list of variations for European
MAs has existed since implementation
of the Mutual Recognition Procedure
(MRP) in 1998. However, the legislation
governing European variation
procedures was not fully adopted at
the national level by many EU member
states at that time. Legislation has
periodically been updated and in
the most recent update, in August
2013, implementation was made
mandatory at the national level and the
variation process has been completely
harmonised across the EU. The
classication codes are as follows:
• Type IA/IAIN. Changes that fall
under this category are commonly
referred to as “do and tell” variations
because the applicant is required
to implement the change and then
notify the agency of the details.
This level of variation is reserved
for administrative changes that are
anticipated to have no impact on the
safety or ecacy of a product.
Variations that can be submitted
as Type IA must be implemented
and then the required submission
made within one year of the
implementation date. For changes
that are categorised as Type IAIN the
applicant must notify the agency
within 14 days of implementation.
Multiples of these variations for a
single product can be made at the
same time, as long as all of them
fall within the required submission
deadline.
• Type IB. Minor variations that require
assessment of supporting data and
are anticipated to potentially have
an impact on product safety or
ecacy are classied as Type IB. These
are also referred to as “tell and do”
variations. The applicant must make
the submission, including all required
supporting data, and await agency
approval before implementing the
change. The process follows a dened
assessment period of 30 days, but
with agency questions it can often
take up to three months.
• Type II. This classication is reserved
for major variations which are
expected to aect the safety and
ecacy of a product and require
careful assessment before the
applicant can implement the change.
Key points in regulatory management of variations
• Lifecycle management of pharmaceutical products varies between the EU and US in terms of dierent submission
requirements and assessment timelines. However, similarities do exist in regional approaches to general categorisation of
post-approval changes (variations) and in many cases also the principles of implementation.
• Post-approval variations in the EU and US can be administrative in nature, simple changes requiring minor review, or major
changes which are often complex.
• Administrative: EU regulators go as far as to dene “administrative” as a category in their classication guideline, whereas
in other regions they fall into the lowest variation category and have signicant crossover with minor variations, eg new
addresses. Many agencies accept that these changes can be implemented without the need for approval. Prior approval
of administrative changes is time-consuming for agencies and costly for industry. Additionally, in certain cases such as a
marketing authorisation holder (MAH) moving address, the change would actually need to take place prior to submission.
• Minor: Minor variations are generally considered to have either no impact on the quality of the product or have a very low
chance of impact; and hence lower risk. Consequently, the level of agency review, and hence the time required is reduced.
As regulatory frameworks have developed, agencies have introduced means to allow the most minor of variations to be
implemented before review. For example, in the EU, when a Type IA variation is submitted the MAH must state which of a
pre-dened list of conditions applies to its change, thereby reducing the amount of review required. With minor variations,
many agencies have documentation requirements that are well-established and must be met before variations are
submitted. This ensures that MAHs know what is expected before a submission and can prepare sucient supporting data.
This leads to faster review times as assessors have less need to request further data from applicants.
• Major: Where notable alterations to product registration are required, these are expected to have an impact on a
product’s quality and ecacy and as such are tightly controlled, requiring in-depth assessment and review. The MAH
must demonstrate that the product will retain the same level of quality and ecacy. Comparative data is a signicant
requirement for such changes and must reliably show the proposed changes do not impair product quality. Assessment
times for such variations are often much longer, as agencies carefully review submissions and frequently make requests for
additional data and answers to questions and concerns.
Understanding the need for variations and avoiding unnecessary variations is core to regulatory
management of product lifecycles. This continuing development supplement – the rst in a quarterly
lifelong learning series – looks at the most common types of variations. It covers the European procedure
for Type IA, Type IB and Type II variations, including line extensions, grouping and worksharing processes,
versus the US, highlighting key similarities and dierences.
KEYWORDS: Lifecycle management; Post-approval; Variations; Harmonisation; Europe; US; Type IA/Type IB/Type II variations; Line extensions
Lifecycle management:
EU and US variation requirements
CPD with
Regulatory
Rapporteur
Issue 1 (1), i-iv
© TOPRA 2017
topra.org/CPDsupplements i
They require considerable supporting
documentation and must be assessed and
signed o by an appropriately qualied
expert in their respected eld before being
submitted.
• Line Extensions. Certain changes which
aect the fundamentals of the terms
of the authorisation cannot be granted
via a variation and are submitted as an
“extension application”: changes to the
active substance(s); changes to strength,
pharmaceutical form and route of
administration. The invented name will
remain the same for the “extension”.
Post-approval changes in the US
Changes to products licensed by the US FDA
are achieved via the provision of supplements
to the original new drug application (NDA). The
supplements are as follows (see Table 1):
• AR: Annual Report. Changes that can be
submitted in an annual report are of a minor
nature and have minimal potential to eect
quality, safety or ecacy of the product.
The aected product can be distributed
at any time after the change has been
internally approved and before the details
are reported in the Annual Report. At the end
of a reporting period, any changes that have
been implemented in the previous year are
included together in a single notication to
the agency.
• CBE-0: Changes Being Eected 0. Changes
classied as CBE-0 are minor (albeit moderate)
changes to the product which can be
implemented from when the FDA receives
the supplemental NDA (sNDA) application.
The product can also be distributed when
the sNDA is received. CBE-0 changes are
considered approved six months after receipt,
if there are no technical issues raised by the
FDA. However, if the change is not approved
then distribution must cease and a product
recall may be required.
• CBE-30: Changes Being Eected 30. Changes
classied as CBE-30 are also deemed as
minor (albeit moderate). Changes in this
classication can be implemented and
product distributed at risk, 30 days after
the FDA receives the sNDA, unless the FDA
noties the applicant otherwise. Approval
should be completed after six months.
However, if the submission is rejected, a recall
may also be required.
• PAS: Prior Approval Supplements. This
category covers major changes that are
considered to have a substantial potential
to adversely aect the identity, strength,
quality, purity or potency of the drug product.
Product aected by these changes cannot be
distributed until approval which should take
up to four months, assuming there are no
technical issues.
Agency comparisons
The denitions and terms used to describe
variation types and processes vary across
the regions, however, changes all fall into
three general denitions which share many
similarities: administrative, minor and major
(as summarised in Table 1). The EU, in 2010,
amended Type IA variations to be “do and
tell” changes where the MAH may make the
change before submitting a notication. When
the guidelines were reviewed in 2013, certain
existing Type IB variations with established
requirements were downgraded to the level
of Type IA where the authorities felt there
was no impact on product quality. Quality
implementation is when the company makes
the change in its own Quality System. For
product information, implementation is when
the company internally approves the revised
product information (which is then used in
the next packaging run). In cases where the
variation assessment is unfavourable, the MAH
must immediately cease applying the rejected
variation. The Agency may ask the MAH to
complete a suspected quality defect notication
form and provide a risk assessment report
for the product on the market. This concept
appears to reect the AR system seen in the US
and has since been adopted by other agencies
worldwide.
Submission of EU variations is also possible
via Grouping and also Workshare procedures,
whereas in the US, multiple changes (eg,
multiple study reports) can be led under a
single sNDA.
Conclusion
Activities to improve international
harmonisation of lifecycle management
processes and guidelines allow agencies to
share assessments and reduce individual
workloads, improving their quality and speed
of assessment. Such improvements are of
considerable benet to industry, seeing
changes implemented faster and reducing
the cost for many manufacturers. Finally,
for regulatory professionals, it reduces the
inevitable burden that stems from numerous
national requirements and allows them to apply
their skills and knowledge globally.
Reference
1 European Commission. http://ec.europa.eu/health/
documents/eudralex/vol-2/index_en.htm (accessed
December 2016).
Additional reading
• The Commission Regulation (EC) No 1234/2008 of
24 November 2008, concerning the examination of
variations to the terms of marketing authorisations
for medicinal products for human use and
veterinary medicinal products. ec.europa.eu/
health/files/eudralex/vol-1/reg_2008_1234/
reg_2008_1234_en.pdf (accessed 05 December
2016).
• Regulation (EU) 712/2012. ec.europa.eu/health/
files/eudralex/vol-1/reg_2012_712/reg_2012_712_
en.pdf (accessed 05 December 2016).
• Heads of Medicines, Variation Procedural Guidance.
http://www.hma.eu/96.html (accessed 06
December 2016).
• EMA Procedural Advice on Variations. http://
www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_001782.
jsp&mid=WC0b01ac0580b18c7b (accessed 06
December 2016).
Table 1: Summary of variations and anticipated implementation dates in Europe and US.
Europe US
Variation Type Anticipated implementation
time
Guideline
approval
timeline
Type Anticipated implementation time Guideline
approval
timeline
Admin Type IA
IN
14 days before submission N/A AR Up to 1 year before submission N/A
Type IA Up to 1 year before submission N/A
Minor Type IB Up to 3 months after submission
*
30 days CBE-0 On receipt of submission by FDA N/A
CBE-30 30 days after receipt of submis-
sion
6 months
Major Type II Up to 6 months after submission
*
60 days PAS Up to 6 months after submission
*
4 months
*The noted anticipated dates are based on experience with submitting variations to the relevant agencies and incorporate the time taken for validation, application assessment, applicant’s
response to questions (clock stop) and assessment of responses.
This supplement oers regulatory
professionals an accessible way to use
Regulatory Rapporteur as starting
point for recording their LLL hours
and help gain or maintain MTOPRA
status.
Supplements will be archived online
and will build up to become a
repository of CPD exercises – pitched
at dierent levels of regulatory
experience – that members can access
free as and when they require them.
topra.org/CPDsupplementsii
Acknowledgements
The content of this supplement is drawn from Regulatory Rapporteur, 12(4), 2015, in particular:
• “Harmonisation of variation requirements, categorisation and implementation: A global view” by Richard O’Keeffe; and
• “A guide to the EU variation procedure from a quality viewpoint” by Cornelia Nopitsch-Mai and Susanne Winterscheid.
We thank the authors for their permission to use their content for this CPD supplement.
Case study:
Avoiding unnecessary variations
A precise description of the
manufacturing process including
operation conditions and details on
equipment may trigger a variation
procedure if these details are changed.
To avoid this, the description of the
manufacturing process should only
include information which is considered
necessary for the assessment of the
procedure. It should not include, for
example, details of the name of a producer
of special equipment; instead, the dossier
should refer to an “adequate” device.
The same is applicable for analytical
methods. If the description of an analytical
method includes details on the producer
of a special column, a variation procedure
will become necessary on switching
to another producer. For description
of analytical methods, the applicant
is advised to consult the European
Pharmacopoeia for the descriptive
principles.
Packaging materials for blisters or
container closure systems for oral
solutions should never be accompanied
by details of the suppliers. This will
automatically lead to a variation
procedure for any change concerning the
supplier, even if there is just a company
name change.
Reference to monographs in the European
Pharmacopoeia or a national member
state Pharmacopoeia should always be
furnished with the note to the “current
edition” of the particular Pharmacopoeia
– rather than a specic edition. This
prevents the need to notify the competent
authorities of an updated monograph.
As a general rule too many details, not
required for approval of the medicinal
product, should be avoided.
Example:
The changes listed in Table 1 have been
proposed by the Marketing Authorisation
Holder (MAH) for tablets containing
morphine sulphate as an active substance.
The method for determination of
impurities has been revised (former
method: thin layer chromatography (TLC));
proposed method: high performance
liquid chromatography (HPLC). As a
consequence the release specication
was changed. Grouping of the dierent
variations in Table 1 (type IB, type IB by
default, 3x type IA) are possible as they
are considered as consequential changes
due to the replacement of the analytical
method.
The following sections in the Common
Technical Document (CTD) should be
updated:
• 3.2.P.5.1 Specication: Revised release
and shelf life specication
• 3.2.P.5.2/5.3 Analytical Procedure/
Validation: Description of the new
method including validation data
• 3.2.P.5.4 Batch Analyses: Batch
analyses data under consideration of
the revised specication
• 3.2.P.5.6 Justication of
Specications: The limit for any other
impurity is justied with reference to
the Guideline on Impurities in New
Drug Products, CPMP/ICH/2738/99
1
where the identication/qualication
threshold is 0.2% under consideration
of the maximum daily dose of 120 mg
for morphine sulphate tablets.
The limit of 1.0% for total impurities is
justied by data found during stability
studies.
The deletion of a non-signicant
parameter like the test on codeine
phosphate has been justied taking
into account that this impurity is not
considered as a degradation product of
the drug product.
Conclusion
The European variations procedures have
been created to avoid the possibility
that changes to a medicinal product
may give rise to public health concerns.
However, it should be kept in mind that
any amendment to documentation,
any deletion and/or any change to
the content will lead to a variation
procedure. In some cases it is helpful to
assess information which is critical to
the agencies, and update outdated or
overly detailed documentation in order
to avoid further variations. Analytical
validation protocols included in the
documentation, for example, may be
important for inspections but will result
in a combination of variations in the
regulatory framework for an approved
drug product.
Reference
1 Guideline on Impurities in New
Drug Products, CPMP/ICH/2738/99.
Available at www.ema.europa.eu/docs/
en_GB/document_library/Scientic_
guideline/2009/09/WC500002676.pdf
(accessed 9 February 2015).
Table 1: Present situation and proposed changes.
Present situation Proposed change Change according to Classication Guideline
Determination of Impurities
by TLC
Determination of Impurities
by HPLC
Type IB with reference to B.II.d.2d) - other changes to a
test procedure (including replacement or addition)
Release Specication:
Pseudomorphine:
NMT 0.5%
Codeine Phosphate:
NMT 0.5%
Release Specication:
Pseudomorphine:
NMT 0.4%
Any other impurity:
NMT 0.2%
Total impurities:
NMT 1.0%
Type IB by default with reference to B.II.d.1a)
– Tightening of specication limits; condition 4 (test
procedure remains the same) is not met.
Type IA with reference to B.II.d.1d)
– Deletion of a non-signicant specication parameter.
Type IA with reference to B.II.d.1c)
– Addition of a new specification parameter
Type IA with reference to B.II.d.1c)
– Addition of a new specification parameter.
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Professionals in healthcare regulatory
aairs work in an environment of constantly
changing legal, technical and scientic
requirements. They need to undertake
continuing professional development (CPD)
to ensure they remain safe and eective in
their daily practice.
All members of TOPRA are bound by the
statement of values, which requires them to
‘continually improve performance and update
or refresh their skills and knowledge’. TOPRA
has developed a range of competences to help
regulatory professionals develop throughout
their career.
We all learn throughout our lives; during
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talking to our colleagues and from training
courses, whether online or face to face.
Continuing professional development is
the life long learning you do to enhance or
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qualities in order to uphold a high standard of
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Competences are the skills, knowledge
and behaviours that are required for you
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medicines, medical devices, chemicals,
food additives, pesticides, and veterinary
medicines is available at topra.org/
regulatorycompetences.
The list also includes IT competences and the
so-called ‘soft skills’ such as negotiating and
inuencing, presenting, leadership and crisis
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Working with a group of members and an
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TOPRA is currently developing competences
for each stage of the career journey.
A strong personal programme of CPD properly
recorded, will also build your condence and
credibility at work and give you an evidence
base for appraisals. TOPRA members can use
our online CPD recording tool to keep track of
their various activities, from training courses to
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Any TOPRA courses you take will automatically
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reect on what you learned and how you will
use this to validate the hours.
Participation in TOPRA In activities or TOPRA
SPIN events can be added to the CPD record by
going to the tool at the link below and clicking
the plus sign on the top right hand corner of
the ‘Hours from other activities’ section.
You can nd the tool and more information at
topra.org/cpd.
1. Which types of post-approval changes are considered to be administrative in nature?
a) EU Type IB + US CBE-0 + US CBE-30
b) EU Type IAIN & Type IA + US AR
c) EU Type IAIN & Type IA + US PAS
2. Which change is considered to be an EU line extension?
a) Changes to route of administration
b) Changes to the indication
c) Changes to the drug product shelf-life
3. What is the anticipated implementation time of a Major EU and US post approval change?
a) Up to 1 year before submission
b) Up to 3 months after submission
c) Up to 6 months after submission
Demonstrate your
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CPD Supplement Editor
Davina Stevenson, Deputy Editor of
Regulatory Rapporteur
Publisher
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Publishing Director, TOPRA
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