Regulatory Highlights

pubs.acs.org/OPRD

Regulatory Highlights
INTRODUCTION
Compared to last year, 2015 may seem in comparison quiet in
terms of new regulations; however, across a series of guidance
areas, there has been a concerted reection focused on practical
implementation of the guidelines concerned. In the case for
example of ICH Q3D1 elemental impurities, there have been
a considerable number of symposia and publications centered
on practical implementation, culminating in the continued de-
velopment of training material by the ICH Q3D implementa-
tion group. In June of this year, the nalized ICH Q7 Q&A2
document was published; the content of which and the impli-
cations are explored in more depth later in the review. Similarly,
there have been continued eorts to address the implementa-
tion challenges posed by ICH Q11,3 although there have been
no further public disclosures upon which to comment. 2015 has
also seen the evolution of a working framework for the eagerly
anticipated ICH Q12 Product Life Cycle Management. What
therefore may seem a quiet period ultimately turns out to have Figure 1. Derek predictions versus Leadscope predictions for 801
been an intriguing period; the actual as well as eventual output compounds tested in the Ames assay.
from ongoing developments will ultimately form the basis of
practical implementation for many guidelines integral to drug
A chemist seeking to validate the drug substance process and the
substance development.

associated control strategy will desire assurance that the limits

DNA REACTIVE (MUTAGENIC) IMPURITIES ICH M7
ICH M7,4 Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk, was approved (Step 4) in June 2014. Within
this was a time scale for implementation, that being for new
products 18 months from publication, and hence it is therefore
expected that organisations will have implemented the
guideline by the beginning of 2016. Previous reviews have
sought to examine the key challenges faced by the industry
from a chemists perspective.5,6 One area in particular that has
remained the focus of signicant attention is structural
evaluation. ICH M7 specically denes the need to assess
mutagenicity using two dierent methodologies, one rule based,
and the other statistical. The challenge relates to the
management of predictions between the two models and the
role of expert evaluation within this process. Recently two
reviews have examined this, Greene et al.7 and Barber et al.8
Both examine in depth the potential scenarios; Figure 1 shows
this in Venn diagram form.
Greene et al.7 showed that, when combining systems, nearly
one-third of predictions were contradictory, demonstrating that
proposed are likely to be accepted by regulatory authorities.
Establishing such limits is though dicult as data quality is often
variable. To address this and other issues, a working group was
established to develop an addendum table to ICH M7. In June
this year the addendum table was issued as a step 2 document.9
This contains within it a table reproduced below (Table 1)
containing proposed limits for some 16 reagents, in each case
outlining the permitted limit as well as the method of calculation.
In addition to the compounds described a series of other
assessments were established by the working group for reagents
for which there were extrapolated concerns over their
mutagenicity. In many cases, for example mesityl oxide and
acetamide, these concerns were shown to be unwarranted.
Finally, concurrent to this regulatory review a special edition
of OPRD has been constructed focused on ICH M7. This seeks
to examine a number of dierent aspects linked to the
guideline, including:
The topic of avoidance;
The practicality of seeking to eliminate the use of
mutagenic reagents;
The challenge of assessing the potential formation of
mutagenic degradants.

in such circumstances expert review signicantly enhanced pre-
dictive performance. Barber et al.8 illustrated what such an expert
review may look like when graphically represented (Figure 2).
While such an expert review clearly needs an in-depth knowledge
of the systems and the methodological basis for their predictions,
it also requires a detailed knowledge of the underlying chemistry.
Again to stress a point made previously in this review, this must
therefore involve a chemist in the process.
Critical to any control strategy is establishing the level that
must be achieved; this is amplied when addressing mutagenic
impurities where the permitted levels are often very low.
ELEMENTAL IMPURITIES (EIs)
At the end of 2014, immediately after nalization of ICH
Q3D,2 ICH took the unprecedented step of immediately
establishing an implementation working group (IWG) to
support the roll out of the nalized guideline, recognizing the
practical challenges faced in its implementation. The primary
purpose of the IWG is to produce training material to support

XXXX American Chemical Society A DOI: 10.1021/acs.oprd.5b00318

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Figure 2. Decision matrix when evaluating two in silico predictions. OOD refers to out of domainthis reecting the inability of the systems
concerned to recognize either the whole or signicant fragments of the molecule.
the process. The material is still under development with no
formal date for nalisation, what is known is that it is likely to
take the form of:
A general overview;
Safetydetermination of PDEs for non-ICH Q3D
elements/limits for other routes of administration/
justication of higher limits/parenterals;
Qualityrisk assessment processes/control strategy;
Case studies.
In addition to material being produced by the IWG, Teasdale
et al. published an article specically focused on the Imple-
mentation of ICH Q3D Elemental Impurities Guideline:
Challenges and Opportunities.10 Within this the assessment
of the drug substance was examined. Potential sources of EIs
are illustrated in Figure 3.
Of the sources highlighted, the greatest risk comes from
intentionally added metals (e.g., metal catalysts used in the
process).
Although manufacturing equipment is a potential source of
EIs, in general control can be achieved through GMP, typically
through conduct of an equipment compatibility assessment.
Indeed the most commonly used materials of construction such
as Hastelloy, stainless steel, and glass, are selected due to their
specic chemical resistance.
Solvents used in the manufacture of drug substances are also
unlikely to represent a signicant risk of EI contamination.
Solvents are typically puried by distillation, and few involve
the direct use of metal catalysts in their manufacture.
Overall it can be concluded that, while drug substance manu-
facturing often involves a complex series of processes, the risk of
EI contamination is low. Indeed simple scientic principles can be
applied to clearly demonstrate that elemental impurity levels in
the nal drug substance are controlled to appropriate levels.
ICH Q7 QUESTION AND ANSWERS
In June 2015 the nalized Q&A document was published by the
ICH Q7 Implementation Working Group (IWG).2 The IWG
was established to address the following problem statement:
B DOI: 10.1021/acs.oprd.5b00318
Regulatory Highlights
The ICH Q7 Guideline is implemented successfully in the
regulatory framework by WHO and most authorities around
the world. However, experience gained with the implementation
of ICH Q7 since the approval in November 2000 shows that
uncertainties related to the interpretation of some sections exist.
Technical issues with regard to GMP of APIsalso in
context with new ICH Guidelinesneed to be addressed in
order to harmonize expectations during inspections.
Specic areas were identied for consideration arising from
changes in requirements and expectations since Q7 was
adopted in 2000, these included:
1. Technical issuesincluding supply chain management
and the management of GMP within contract
manufacturing facilities. Key within this is which activities
can be delegated and which cannot, seeking to clarify the
accountabilities within the quality assurance units within
the customer organization.
2. The alignment of ICH Q7 to new guidelines (ICH Q8/
Q9/Q10/Q11), a specic concern being the variable
interpretation of starting materials, i.e., the point of
introduction of GMP controls.
3. Changes to Process Validation requirements;
4. Changes to Cleaning Validation requirements;
5. Review of existing Q&As from training sessions and
conference documents, particularly information gathered
by Pharmaceutical Inspection Convention and Pharma-
ceutical Inspection Co-operation Scheme (jointly
referred to as PIC/S).
This review relied on input not just from the 6 ICH parties
but also on input from other regions, e.g., Brazil, formal ICH
observers including the WHO and key industry bodies
including PIC/S.
From the areas identied, some 19 dierent areas were
examined through nearly 70 specic questions and answers. Of
those areas, those highlighted in bold represent the bulk of the
Q&As:
1. IntroductionScope
2. Quality Management
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Table 1. Acceptable Intakes (AIs) or Permissible Daily Exposures (PDEs)

3. Personnel 13. Change Control

4. Buildings and FacilitiesContainment 14. Rejection and Reuse of Materials
5. Process EquipmentCleaning 15. Complaints and Recalls
6. Documentation and Records 16. Contract Manufacturers (including Laboratories)
7. Materials Management 17. Agents, Brokers, Traders, Distributors, Repackers, and
8. Production and In-Process Controls Relabellers
9. Packaging and Identication Labeling of APIs and 18. Specic Guidance for APIs Manufactured by Cell
Intermediates Culture/Fermentation
10. Storage and Distribution 19. APIs for Use in Clinical Trials
11. Laboratory Controls The questions and their related answers are all cross-
12. Validation referenced to specic sections of the guideline itself and are
C DOI: 10.1021/acs.oprd.5b00318
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Figure 3. Potential sources of elemental impurities in the drug substance.
constructed based on the principle of outlining what to do.
It is important to also reect on what the Q&A was expressly
aiming to avoid. It is not prescriptive, there being no attempt to
provide how to do guidance, nor does it seek to enlarge the
scope of ICH Q7 or establish new requirements.
EXAMPLE QUESTION AND ANSWERS
It is recommended that the document be read in its entirety;
however, from a chemists perspective there are specic Q&As
that are likely to be of the most interest. Those are reproduced
in Table 2, including some personal reections on their
potential signicance or impact.
ICH Q12
In June 2015 the Expert Working Group (EWG) for Q12
issued a work plan for development of the guideline.12 This
indicates that the step 2a document for public consultation will
be issued mid 2016, in line with timings originally set out in the
concept paper.13 Ahead of this it is however possible to gain an
insight at least into the thinking associated with ICH Q12. The
associated concept paper articulates the proposed harmoniza-
tion, the relationship to other key guidelines, i.e., ICH Q8, Q9,
Q10, and Q11, and the current barriers to the idealized
state. Specic attention is paid within the concept paper to the
issue of change management, this being highlighted as an
integral part of any quality system and seminal to any aective
post-approval change process. Within this specic areas are
highlighted:
1. Regulatory Dossierthe need for Q12 to develop a
harmonized approach to regulatory commitments;
including the need for guidance pertaining to the
appropriate level of detail and information necessary
for regulatory assessment and inspection in the dossier.
2. Pharmaceutical Quality System aspects (ICH Q10)for
Q12 to dene criteria that would allow a risk based
approach to be taken in the evaluation of the impact of
any change on quality, safety, and ecacy.
3. Knowledge management systems and how such systems
ensure product quality and the capture of process
information throughout the product lifecycle.
D DOI: 10.1021/acs.oprd.5b00318
Regulatory Highlights
4. Post-Approval Change Management Plans and Proto-
cols: (a) this will seek to articulate how a post-approval
management plan may be used to proactively identify
postapproval changes and the mechanisms for both
submission and review; (b) establish criteria for
postapproval change management protocols that can be
adopted by the ICH regions.
As well as highlighting areas the guideline will seek to
address, the concept paper also highlights the anticipated
benets. One area likely to be of particular interest from a
chemists perspective is the desire that Q12 will facilitate the
early adoption of new technological advances, such as
continuous processing and the use of PAT. This itself is not
a new concept indeed the FDA 21st Century Initiative
instigated in 200414 highlighted the need for more eective
implementation of new technologies. During a recent
presentation15 Christine M. V. Moore, Ph.D. FDA Acting
Director, Oce of Process and Facilities candidly reected on
the lack of progress, highlighting that focus has been on
enhanced product and process understanding rather than
advanced Manufacturing Controls. That often the enhanced
knowledge gained was not used to justify regulatory exibility
(e.g., design space), that in reality there had been little
advancement in achieving true continual improvement. The
presentation highlighted the blockers to such innovation, these
mirroring those also dened in the ICH Q12 concept paper.
It also examined how the concepts described above, articulated
in the Q12 concept paper, will help to address the current
blockers. There are clear expectations that knowledge and risk
management processes will facilitate the desired operational
exibility lowering the barriers to continual improvement and
innovation including the successful implementation of new
manufacturing processes and the use of PAT.
It is important to recognize that currently both EMA and
FDA have existing protocols, e.g., Post Approval Changes to
Manufacturing Process (PACMPs) and comparability protocols
addressing post approval change; indeed the EMA and FDA
have an ongoing pilot for Parallel Assessment or Con-
sultative Advice for QbD applications.16 This specically
focuses on protocols for exibility of post-approval changes and
new technologies and was recently extended to April 2016.
Japan MHLW announced in June that they would incorporate
PACMPs into law as part of implementation of Q12. Similarly
from the positive perspective, the FDA Established conditions
draft guidance issued in June this year in line with current
thinking in EWG.
The potential benets of Q12 are far-reaching, and should
it achieve its primary goals, it may well nally bring about
the exible, innovation-driven industry envisioned for the 21st
century.
ICH Q3C
In June 2015 a revision to ICH Q3C (R6)17 was published as a
step 2 document for consultation; the deadline for comments is
December 31, 2015. This focuses on two specic solvents,
triethylamine (TEA) and methylisobutyl ketone (MIBK). In
the case of TEA a specic Permitted Daily Exposure (PDE) has
been proposed based on new toxicological data. In the case of
MIBK, a revision of the PDE, based on new toxicological data,
is proposed. In the case of MIBK, the change to the proposed
limits results in it is reclassication as a class 2 solvent; however,
in reality the newly calculated PDE of MIBK of 22.6 mg/day is
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Table 2
question answer reflection
Should GMP ICH Q7 does not apply to steps prior to the introduction of the API In many ways the answer is self-explanatory; ICH Q7 does not apply
according to ICH Q7 starting material. However, there is an expectation that an appropriate to steps prior to the API starting material. What though is interesting
be applied for manu- level of controls suitable for the production of the API starting material is the comment that an appropriate level of control is required to
facturing steps before should be applied [ICH Q7, Section 1.3]. ensure the quality of the manufactured starting material. This cuts to
the defined API Normally, the API-starting material is defined in the regulatory filing by the heart of much of the current discussions around the definition of
starting material ? the applicant and approved in the regulatory reviewing process. starting materials and the need to ensure the quality of the starting
Additional guidance is provided to define and justify API starting material is maintained. It is likely therefore that primary within the
material derived from various sources [ICH Q11, Section 5]; for master controls expected prior to the starting material is effective change
cell banks, see [ICH Q5B; ICH Q5D]. management. Also of importance is cleaning and the effective control
of residues from other materials manufactured in the same facility.
When are dedicated ICH Q7 expects dedicated production areas for highly sensitizing materials What is in some ways most interesting is the absence of any direct
production areas ex- such as penicillins and cephalosporins because of the patient risk (e.g., reference to the recently published EMA shared facilities guideline.1
pected? anaphylactic shock in penicillin-allergic patients) from trace amounts of One obvious reason is that the guideline in question is specific to
these compounds in other medicines [ICH Q7, Section 4.40]. one region, i.e., Europe. It does though nevertheless still beg the
For materials of an infectious nature or high pharmacological activity or question, does the EMA guideline have any relevance to API
toxicity, a risk-based approach should be used to determine appropriate manufacture?
containment measures, which may include validated inactivation,
cleaning, and/or dedicated production areas [ICH Q7, Section 4.41].
While ICH Q7 does not define high pharmacological activity or toxicity,
these are generally determined by evaluating relevant animal and human
data collected during research and development. Important consid-
erations in this evaluation of pharmacological activity or toxicity may
include Occupational Exposure Limit (OEL), Permitted Daily Exposure
(PDE), Acceptable Daily Exposure (ADE), Threshold for Toxicological
Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S
Guidelines, ICH E2E, Section 2.1.1], and the consequences of cross-
contamination [ICH Q9, Section 4.3].
What is expected in Different phrases are used to describe the expectation for evaluation of This again is an important question and answer in the context of Q11
terms of evaluation of suppliers of materials [ICH Q7, Sections 7.11, 7.12, 7.31], including and the definition of starting materials. A central concern of
suppliers of materials? traders, if any. [ICH Q7, Section 7.12] states that all materials are regulators is the lack of visibility/control of stages preceding starting
purchased against a specification and from suppliers approved by the materials. In practice many starting materials are likely to be supplied
quality unit [ICH Q7, Section 7.31]. Prior to approval of any supplier, an to the ultimate API manufacturer, and hence the points outlined are
evaluation should be conducted using a risk-based approach [ICH Q9, clearly germane to the management of SM suppliers and their
Appendix II.5; ICH Q7, Section 7.31]. More extensive evaluation is evaluation. It is certainly useful to see the Q&A document advocate a
needed for suppliers of those materials classified as critical [ICH Q7, risk based approach linked to criticality.
Section 7.11].
Can yield ranges de- Yes. Differing yield ranges [ICH Q7, Section 8.14] may be described and This would for example be a filter heel or drier heel. It should not be
fined for the first justified in the manufacturing procedure/master batch record explaining construed to mean that inadequate cleaning resulting in variable
batch differ from lat- the ranges [ICH Q7, Section 6.41]. For example, the first batch in the yield is in any way acceptable
ter batches within a series of production of batches of the same material (campaign) may
campaign? leave residual material in the equipment, resulting in a low yield in the
first batch and contributing to an increased yield in a subsequent batch of
the campaign.
Can the range of a No. However, information from the investigation into a process deviation There is a clear link here to the principles outlined in Q11. The overall
process parameter be (s) can be used to support expanding the range of a process parameter. theme is that changes need to be supported by good science.
expanded based only Additional work and studies are normally needed to adequately
on a process deviation demonstrate that the expanded range for the process parameter
(s)? consistently produces API of the necessary quality [ICH Q7, Sections
2.16, 12.11, 13.13].
Would additional proc- Any change in the API starting material should be assessed for impact on Again there is a clear correlation with the concepts outlined in Q11
ess validation studies be the API manufacturing process and the resulting API quality [ICH Q7, relating to API starting material. There should be sufficient
need- Section 7.14]. Additional validation studies of the API process may be understanding of the fate of impurities in the new SM. If more/
ed to support a change warranted if the change in the API starting material is deemed significant. different impurities carry through to the API, then validation would
in the source of an API In most cases, validation would be expected for a different source of the be expected.
starting material? starting material unless otherwise justified [ICH Q7, Sections 12.1,
13.13].
Is a retrospective ap- Prospective validation is normally expected for processes introduced since The most intriguing aspect of this is the point relating to redefinition
proach to validation the publication of ICH Q7. The concept of retrospective validation of a step as critical. One specific area where this may be envisaged in
still acceptable? remains acceptable as an exception for existing, well-established products is relation to the nonacceptance of a proposed SM. In such a
prior to the implementation of ICH Q7 [ICH Q7, Section 12.44]. scenario it is very likely that the applicant will have produced launch
stocks of the API, and yet the step in question if it precedes the
proposed SM will likely not have been validated. This might offer the
potential to retrospectively validate the step in question while
permitting the use of the existing launch stocks.
If regulatory discussions redefine a step as critical, which had previously
been considered noncritical, a protocol describing retrospective analysis
of data together with the commitment for concurrent or prospective
validation may be an option.
Regardless of the type of validation, the quality system should confirm the
ongoing robustness of the process (e.g., product quality review).
Is validation expected It depends. Recovery of material(s) from mother liquor is a process and the
for the recovery of need for validation should be assessed as for any other process step [ICH
material from mother Q7, Section 14.40]. Recovery of material from mother liquor in any
liquor? process step that must be controlled within predetermined criteria to
ensure the API meets its specification is, by definition, a critical process
step and should be validated. For example, recovery of API from mother
liquor would be considered a critical process step and should be validated
[ICH Q7, Sections 12.11, 12.12, 14.41, 14.43, 20see Glossary for
definitions of critical, materials, mother liquor, and validation].

E DOI: 10.1021/acs.oprd.5b00318
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unlikely to have a signicant impact on existing processes. QuestionsandAnswersonCurrentGoodManufacturingPracticescGMP

Equally the proposed limit for TEA of >50 mg/day and
denition as a class 3 solvent is also likely to have little impact
either.
Andrew Teasdale*
AstraZeneca, Maccleseld SK10 2NA, United Kingdom
forDrugs/UCM176374.pdf (accessed Oct 8, 2015).
(15) An FDA Perspective on Post-Approval Change Management for
PAT and RTRT, IFPAC 2015, January 26, 2015. http://www.
infoscience.com/JPAC/ManScDB/JPACDBEntries/1425486934.pdf
(accessed Oct 8, 2015).
(16) http://www.fda.gov/downloads/InternationalPrograms/

FDABeyondOurBordersForeignOces/EuropeanUnion/
AUTHOR INFORMATION UCM259808.pdf (accessed Oct 8, 2015).
(17) Impurities: Guideline for Residual Solvents Pde for Triethyl-
Corresponding Author amine and PDE of Methylisobutylketone http://www.ich.org/
*E-mail: andrew.teasdale@astrazeneca.com leadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/

Q3C/Q3C_R6__Step_2.pdf (accessed Oct 8, 2015).

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F DOI: 10.1021/acs.oprd.5b00318
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