Focus – Chemistry, manufacturing & controls
Regulatory responses to the use of various
lean stability strategies in early drug development
Authors
Anita L Freed, Global Chemistry, Manufacturing & Controls;
Elise Clement, Analytical Research & Development; Robert
Timpano, Analytical Research & Development; Pfizer
Worldwide Research & Development, Groton, CT, US.
Keywords
Investigational medicinal product dossier (IMPD);
Investigational new drug application (INDA); Early
development (ED); Phase I; Phase IIa; Drug substance (DS);
Drug product (DP); Clinical trial application (CTA): Lean
stability; Accelerated Stability Assessment Program (ASAP).
Abstract
This paper discusses drug substance (DS) and drug product
(DP) lean stability strategies applied to compounds in early
development (ED, Phases I and IIa) and the responses of various
regulatory agencies to these approaches. Clinical stability
programmes are designed to support and underwrite DS review
periods and DP use period assignments at specified storage
conditions and packaging configurations. Specific applications
of science-based and risk-based approaches used to develop
lean stability strategies in support of these assignments will
be discussed. This includes the use of these approaches in the
clinical dossiers in the absence of traditional (“ICH-like”
– Note: ICH guidances are written for compounds to be
commercially registered and not in scope for early clinical
studies) stability data and the use of reduced testing designs.
Specifically, a reduction in time points and/or testing and
determining the necessity of placing batches on stability after
manufacturing changes will be presented. The regulatory
response to each of these strategies will be discussed.
Introduction
Many countries and regions have differing expectations of
the stability information needed for clinical trial applications
(CTAs) to support the proposed ED clinical trials. Most regions/
countries differentiate their expectations based on the stage
of development; however, there may be subtle but important
differences among the level of information expected. For example,
the US guidance for Phase I studies1 states that “although stability
data are required in all phases of the IND [investigational new
drug] to demonstrate that the new drug substance and drug
product are within acceptable chemical and physical limits for the
planned duration of the proposed clinical investigations, if very
short-term tests are proposed, the supporting stability data can
be correspondingly very limited.” The related guidances in the
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EU2 and Canada3 likewise seem to differentiate their expectations
based on stage of development, eg, Phase I versus Phases II
and III. However, unlike the US Phase I and Phase II guidances,1,4
they cite that the DS review period (EU and Canada), the DP use
period and stability protocol (Canada) and use period extension
(EU) protocols should be included in the CTA.
There are also a few countries/regions that continue to expect
industry to apply ICH Q1 guidance requirements for early stage
clinical programmes. This includes: (1) requiring clinical use
periods to not exceed for example X + 12 M for room temperature
supplies,5 and (2) new stability studies for changes in packaging
configurations (eg, switching from bottles to blisters).6 Although
this is a minority of the countries, it can result in challenges for
the supply chain, especially when the use period is required to be
included on the clinical supply label.
DS and DP clinical stability programmes should be designed to
ensure the quality of the material for the duration of its use. The
varying countries/regions agree that a commitment to assess
the stability of the clinical (or representative) supplies in parallel
to the clinical studies and throughout its duration should be
included in the dossiers. Science- and risk-based approaches,
which consist of tailoring each case based on scientific
understanding to ensure they are fit for purpose,7–12 should be
considered. This application may allow the use of lean stability
strategies, which reduce cost and/or lead time by minimising nonvalue added tests, conditions and pull points. Potential strategies
to consider for stability studies to support early development
(Phase I and IIa) programmes and the regulatory responses to
each will be discussed.
Examples of lean stability strategies in early development
Topic A: Establishing initial review and use periods. Stress testing
can provide an initial understanding of the stability of the DS and
DP, as well as the need for any storage and/or package restrictions
(temperature, light, humidity). As such, it can be employed to set
initial DS review periods7 and DP use periods12 in lieu of traditional
stability (“ICH-like” – Note: ICH guidances are applicable at
registration) data (see examples 1 and 2 below) and can be
described in the CTA to allow clinical programmes to start earlier.
Example 1: Initial DS review period assignment of 18 months
based on 70⁰C/75%RH one week stability data:
The data were submitted from this stressed study in the CTA,
and a commitment made to monitor a batch representative of
the clinical material at the pertinent traditional conditions, eg,
5°C/60% RH, 25°C/60% RH, 40°C/75% RH, concurrent with the
clinical studies for the pertinent stability related attributes, eg,
appearance and purity. This approach has been filed for drug
substances stored at room temperature (15–30°C) in the initial
Phase I CTAs in a few instances in the US and once in Canada and
in Belgium, without any queries or comments in the former two
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Focus – Chemistry, manufacturing & controls
Table 1: ASAP stability protocol.
Condition
Duration
5ºC/5% RH (Control)
14 days
50ºC/75% RH
14 days
60ºC/40% RH
14 days
70ºC/5% RH
14 days
70ºC/75% RH
1 day
80ºC/40% RH
2 days
cases. Note, however, that the DS review period was not included
in the US filing (only the related information, data and above
cited commitment). The Belgian regulatory agency approved the
CTA, but did comment that additional stability results should be
presented in future applications for this compound.
Example 2: Initial DP use period assignment of not more than
(NMT) 12 months based on an Accelerated Stability Assessment
Program (ASAP):
The conclusions from a statistically designed 14-day stability
study (ASAP) were submitted. The design of the ASAP study was
based on work in the literature that demonstrates the modelling
degradation observed in solid oral dosage forms using an
isoconversion paradigm and a moisture corrected Arrhenius
equation.13 Here, a tablet was compressed that consisted of low
drug loading, eg, 1%, to represent the highest excipient to drug
ratio for this product. Therefore, the possible drug–excipient
interactions and thus the degradation of the DS in the formulation
will be maximised. The tablets were stored in open containers to
allow for equilibration of the samples with the set humidity point,
thereby allowing for a better correlation on the impact of water on
degradation kinetics.
The stability samples were subsequently evaluated for
appearance and concentration(s) of the main degradation
product(s). The textual results were given, eg, “no changes in
appearances…”, “RRT X.XX is the use period-limiting degradant”.
The conditions and durations were presented in the CTA and
are shown in Table 1.
A commitment was made in the CTA to monitor representative
batches of the clinical material at the pertinent traditional
conditions, eg, 5°C/60% RH, 25°C/60% RH, 40°C/75% RH, in
the clinical packaging configuration concurrent with the clinical
studies to demonstrate that the clinical supplies meet the
standards of identity, strength, quality and purity at the time of
use. For CTAs submitted in the EU and pertinent emerging market
(EM) countries (those that receive Section P.8 Stability), a protocol
was given in tabular format.
This approach has been submitted in numerous CTAs for ED
studies in the US, Canada, EU and pertinent EM countries (those
that require and thus received Section P.8 Stability) with various
compounds. Queries have been received from South Korea, Czech
Republic and Ukraine.
In the case of South Korea, the Agency stated that threemonth data at the long term storage condition must be provided
in order for an initial use period assignment of 12 months to be
accepted. Updates in the stability expectations in this country
have been experienced since this query was received; however,
this expectation seems to remain.
In the Czech Republic Agency, previous experiences have
shown that the Agency follows ICH Q1E5 for setting DP use periods,
ie, 2 X long-term stability data but not exceeding X + 12 months for
15–30°C storage conditions. As such, the sponsor enquired about
the possibility of meeting with the Agency in advance of the CTA
submission, but was informed that a request could not be granted.
Therefore, additional technical information on ASAP was provided
for the regulatory agency to review as part of the CTA package.
Despite this additional information and the informal discussions,
the team was unsuccessful in obtaining approval of this approach,
and the use period was required to be set as per the ICH Q1E
guideline.
In Ukraine, previous experiences have also shown that this
Agency required real-time stability data for setting DP use periods
via ICH Q1E.5 As such, in advance of a CTA for an ED study, the
sponsor requested the Agency via written format to consider
an extrapolation approach for assignment of use period for ED
products and provided supportive additional information. The
Agency responded by requesting data and an extrapolation
diagram of the key degradants for that specific drug product. This
Table 2: ASAP protocol and data of use period limiting degradants for Compound A 0.5% compacts.
Condition
Duration
5°C/5% RH (Control)
14 days
0.25%
50°C/75% RH
14 days
0.31%
60°C/40% RH
14 days
0.42%
70°C/5% RH
14 days
0.52%
70°C/75% RH
1.5 day
0.36%
80°C/40% RH
2 days
0.66%
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Amounts (%) of use period limiting degradant(s) RRT X.XX
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Focus – Chemistry, manufacturing & controls
Figure 1: Graph of RRT X.XX levels with extrapolated clinical use periods for Compound A at various storage conditions.
0.600
% of total area
0.500
25C/60%RH
0.400
30C/65%RH
30C/75%RH
0.300
0.5% Spec
0.200
0.100
0.000
0
3
6
9
12
15
18
20
24
Time (months)
information was provided in advance of and again with the CTA. In
this instance, the Agency agreed to the proposed use period for this
compound. The sponsor now routinely includes this extrapolation
information and data for the key degradant in CTAs submitted in the
EU, European Neighborhood Policy (ENP), European Economic Area
(EEA) (see following specific example). Additional CTAs including
this information have been approved in Ukraine.
In a global Phase IIa CTA, Compound A included its initial use
period at 12M based on ASAP and included the extrapolation
information and data for key degradants (see Figure 1 and Table 1,
respectively), as discussed in the above paragraph for Ukraine. No
queries or comments were received from regulatory agencies in the
US, Canada, Bulgaria, Hungary, India, Romania, Serbia, Slovakia,
Philippines, South Africa, Taiwan, or Turkey (the latter four of which
do not require this information and thus did not receive it) for its
initial Phase IIa CTA. Serbia and Romania requested additional
stability information to support this use period assignment. At that
point, additional stability data were available and were provided.
Ultimately, the proposed shelf life was accepted.
Topic B: Assessing manufacturing changes. The decision to
conduct stability studies after changes in the manufacturing
process or packaging configurations are based on the stability
knowledge of the compound, the scientific understanding of
the shelf life limiting attributes and the types of changes being
made.9,13 The decisions are routinely based on internal risk
assessments that often use a comparison of the results from
the accelerated/stressed (70°C/75%RH for DS, ASAP for DP).
Examples 3 and 4 below discuss a DS manufacturing change
and the implementation of a new DP container closure system,
respectively.
Example 3: Assess need for additional stability studies after DS
process changes:
The internal risk assessment typically has not been described
in the CTA in early development studies unless the changes
were significant (eg, new form). This approach has been filed in
numerous examples of ED CTA submissions in the US, Canada,
the EU and the pertinent EM countries (Section S.7 Stability
is not required and thus not provided in all EM countries) with
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various compounds, and no queries or comments have been
received to date.
For Compound A, a different processing/workup used in steps 1
and 3 of the 3-step process for one batch, while the DS was
recovered and purified from the mother liquor for a second batch.
All processes were described in Section S.2 Manufacturing of the
Phase IIa CTA, but the stability risk assessment was not discussed
in the CTA. No queries or comments were received from the US,
Canada, Bulgaria, Hungary, India, Romania, Slovakia, Philippines,
Taiwan or Turkey (the latter three of which do not require this
information and thus did not receive it).
Example 4: Assess need for additional stability studies after
implementation of a new DP container closure system:
The justification has typically been included in the CTA for new
container closures and the plans to support the use period are
clearly defined.
There are numerous examples of submissions of this approach
in the US, Canada, the EU and pertinent EM countries (where
Section P.8 Stability was required) with various compounds.
Compound B used this approach in a Phase IIa CTA, concluding
the ongoing stability study in high-density polyethylene (HDPE)
bottles with desiccant to be representative, but including a
commitment to run an abbreviated confirmatory stability study
in the new packaging (aclar/foil blisters). Information from an
ASAP assessment was included in the justification within the
CTA. The only query received was in the case of South Korea
for Compound B, which filed CTAs for a Phase IIa study using
blisters. No queries were received from the US, Canada, Bulgaria,
Hungary, India, Romania, Serbia, Slovakia, Philippines, South
Africa, Taiwan or Turkey (the latter four of which do not require this
information and thus did not receive it). Unfortunately, the South
Korean Agency agreed in the final approval letter (no opportunity
to discuss further) to our shelf life only after three-month data in
the blisters was provided. This required a South Korea-specific
use period to be assigned and the supplies already staged for
shipment to be re-labelled. Updates in the stability expectations
in this country have taken place since this query was received;
however, this expectation seems to remain.
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Focus – Chemistry, manufacturing & controls
Topic C: Eliminating non-value adding testing. Example 5
discusses the removal of assay testing in the DS stability
programme when the DS batch on stability and the working
standard it is tested against are the same batch of material.
Example 5: The exclusion of assay testing in the initial DS stability
programme when the batch is the same as that of the working
standard:
The following justification for not testing assay was provided in
the CTA:
l T
he DS batch currently on clinical stability is also used as
reference standard in analytical testing. Therefore, performing
assay at each stability checkpoint would mean that the DS
would be tested against itself and variability in “assay” values
obtained on stability would be reflective of method accuracy,
not degradation.
l R
eference standards are generally stored under the same
condition as clinical supplies.
l T
he HPLC method employed for monitoring degradation
products has been developed to be stability indicating, ie, all
known degradation products are resolved from the main band.
Degradation products, if any, are quantified versus the main
band at this stage of development, assuming the equivalent
response factors. Data on appearance and purity/degradation is
provided.
This approach has been submitted numerous times in ED
CTAs to the US, Canada, the EU and pertinent EM countries
(those that require Section S.7 Stability) with various
compounds. No queries or comments have been received, apart
from two recent queries from Canada and one comment (not
contingent on approval) from Belgium.
In Canada, we presented our rationale and justification
in a general (non-project related) teleconference. Additional
details were provided on the practices for developing a stabilityindicating method and assuring initial DS stability. The Agency
agreed “that the analytical results for assay would not be stability
indicating”. However, it suggested that other options be explored
to generate meaningful assay results on stability, eg, additional
purification of the reference standard, storing it under more than
stringent conditions, alternative analytical methods.
In the case of Belgium, the Agency approved the CTA. However,
it recommended assay be included in the stability testing protocol
during further development of the product. It was requested that
this point be taken into consideration and readdressed at the time
of assessment of future applications related to the investigational
medicinal product. To date, no further applications have been
submitted to Belgium for this product.
review period and use period assignments, respectively, and to
manage regulatory risk and expectations.
Acceptance of lean stability strategies, not only during clinical
trials but throughout the developmental lifecycle, will require
further collaboration between industry and the regulators. The
authors advocate a continued dialogue at scientific conferences,
through publications and on project-specific basis when these
opportunities arise, as our patients will ultimately benefit.
Acknowledgements
Steve Colgan, Aine Kane, Julia Claus, Doug Farrand.
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for stability: an industry perspective (Part IV), Pharmaceutical
The lean stability strategies described herein have been widely
accepted by regulatory agencies in varying countries/regions
through the standard clinical trial application filing and query
response process. When this was not the case, acceptance was
gained in some instances by providing further understanding and
justification to the agency(ies) through additional written material
and/or verbal discussion.
When selecting DS and DP stability strategies for early
development programmes, the sponsor should consider applying
science- and risk-based strategies to support and underwrite
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