CTD Dossier

Expected CMC Queries and Things to Remember

Manu Babbar
B.Pharm, M.Pharm, MBA
manu0101@yahoo.com
Skype: manu.babbar
www.cantonpharmaconsultants.com
1st Floor, Shop No.1, DDA Market Naraina Delhi
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We provide: Dossiers writing services, GMP inspection services

and corporate regulatory training. Come and meet us Tuesday, July 15, 2014

REQUIREMENT

BLACK FONT: QUERY TREND

GREEN FONT: OPTIONAL

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Things to Remember

RED FONT: REGULATORY

Expected Queries

COLOR CODED PRESENTATION

Tuesday, July 15, 2014

3.2.P.1 Description and Composition of the Drug Product

Write the pharmaceutical form as per the current

version of standard term

Size of the tablets to comply with
EMA/CHMP/QWP/180157/2011 for administration to
children
Size
3 to 5 mm
5-10 mm
10-15 mm
15 mm +
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Age of Patient
Below 2 years
Below 6 years
Below 12 years
Below 18 years

Status
Not Accepted
Not Accepted
Not Accepted
Not Accepted
Tuesday, July 15, 2014


USFDAs Draft Guideline

Tablets
RLD Largest
Dimension

Generic

17mm

Can be 20% larger in dimension subject

to max size 17 mm
Can be 40% larger in volume

17 mm

No larger than RLD in any single

dimension or volume

Tablet to have largest dimension as 22 mm

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Tuesday, July 15, 2014


Capsules

RLD
Size 3 or less
Size 2 or 1
Size 0

Generic
Same or +1
Same or +1 if justified
Same

Capsule not to exceed size 00

Tuesday, July 15, 2014


Multiple strengths to be distinguished adequately by

virtue of shape, dimension and color

The imprinting/embossing digit should not
misinterpret the dose of the preparation

Tuesday, July 15, 2014


All excipients to be listed (including the ones lost during

processing) along with reference to quality standard

Composition of pre-mixed powders /coating
suspensions/imprinting inks/capsule shell to be provided
% of imprinting ink per unit to be provided
E-numbers to be mentioned wherever applicable
Quantity of each excipient to be below toxic levels.
Stability overages not allowed accept incase of vitamins
Manufacturing overage if any not to be included in unit
composition.

Tuesday, July 15, 2014


Calculation for the actual quantity required for API and

adjusting excipient to be specified.

Use LOD/water content for above calculation to match
API specification
For colorants and imprinting ink, compliance to EC
directive to be provided
Azo dyes and other synthetic coloring agents not to be
used in medicinal products for paedriatric use
(EMEA/CHMP/QWP/396951/2006).
Use of sunset yellow is not acceptable for Paediatric
formulations.
Tuesday, July 15, 2014


Qualitative composition of flavoring agent to be

provided.

Use of Diethyl phthalate is questionable.

Me Paraben and Propyl Paraben should be used inline
with reflection paper EMA/CHMP/SWP/272921/2012

Me Paraben 0.2% (All age groups)

Propyl Paraben 5 mg/kg/day ( Age 2+)

EFSA to be refered for quantity of ingredients used as

food additives.

Tuesday, July 15, 2014

3.2.P.2 Pharmaceutical Development

EU does not mandate QBD format as of now

EU does not specify ratio for drug excipient

compatibility

API PSD limit to be two tier for EU and necessarily
three tier for Australia

Absence of other polymorphic forms to be
demonstrated adequately during manufacture and end
of shelf life

Experimental data to establish use of each excipient to
be included in the dossier
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Tuesday, July 15, 2014


Functionality

related tests to be discussed in

development report

Use of excipients other than Ph.Eur to be discussed
and justified

Incase products containing antioxidants are packed in
containers with desiccant. Any significant fall in
antioxidant content to be justified.

Differences between clinical formulations and the
formulation described in 3.2.P.1 to be discussed

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Tuesday, July 15, 2014


Impurity profile of Applicants product should be

comparable with that of reference product.

For limit beyond ICH qualification limit, justification
for the same should be given based on the literature
references, toxicity report or stability data generated on
reference product.

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Tuesday, July 15, 2014

Bio-Waiver for Lower Strengths

A)

Same Manufacturing Process

B) Same Qualitative Composition

C) Composition of the strengths are quantitatively
proportional

D) Appropriate in vitro dissolution data should
confirm
the adequacy of waiving additional
in vivo bioequivalence testing

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Tuesday, July 15, 2014

condition c is still considered fulfilled if

condition i) and ii) or i) and iii) below
apply

i) active substance(s) is less than 5 %

ii) amounts of the different core excipients are same

and only amount of active is different. For GR

preparations, it is recommended to consider
proportionality of coating in terms of surface area

Iii) Only the amount of a filler is changed to account
for the change in amount of active substance

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Tuesday, July 15, 2014

In-vitro comparison

In-vitro dissolution of Reference Product Vs

Applicants Bio strength should be reported in three

media and QC media

F2 less than 50 should be justified

In-vitro dissolution of Applicants bio strength Vs

lower strengths should be compared in three media and

QC media

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Tuesday, July 15, 2014

F2 Matching

A minimum of three time points (zero excluded)

The time points should be the same for the two

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formulations
Twelve individual values for every time point for each
formulation
Not more than one mean value of > 85% dissolved for
any of the formulations.
The relative standard deviation or coefficient of
variation of any product should be less than
20% for the first point and less than 10% from second
to last time point.
Tuesday, July 15, 2014

Development of QC release media

Sink Condition to be justified

FDA recommended dissolution method can only be

referenced for US filings

No surfactants

For gelatin containing compositions, use of enzymes is
permitted.

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Tuesday, July 15, 2014


Hold time study to be performed

Breakability study to be performed wherever

applicable

Photostability to be demonstrated

Rationale for not performing MLT for non-sterile
products to be included

CoAs of bio-batches not to differ more than 5% for
assay and to be provided from site of bio-study.

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Tuesday, July 15, 2014

3.2.P.3.1 Manufacturer

Details of all manufacturers for all functions to be
included
3.2.P.3.2 Batch formula

Manufacturing overages wherever justified should also
be the part of batch formula.

Minimum 100000 packed units or one tenth of the
commercial batch whichever is more

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Tuesday, July 15, 2014


Range of batch sizes may be proposed wherever

Agency does not ask for validation report

Distribution of common blend to be proposed suitably
to allow maximum combinations of batch sizes.

Comparative dissolution profile testing should be
performed on first three production batches against BE
batch

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Tuesday, July 15, 2014


3.2.P.3.3 Description of manufacturing process and

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Process controls
Flow diagram and narrative description to be provided
Equipment may be specified with the phrase or
equivalent to minimize post approval changes
Sieve no. may not be committed wherever not critical
Proposal for reprocessing to be justified
Start of shelf life to be defined as per relevant
guideline

Tuesday, July 15, 2014


3.2.P.3.4 Control of critical steps and intermediates

Frequency of in-process tests to be provided

SOPs not to be committed in the dossier, rather

mention the system stating as per currently followed

SOP.

3.2.P.3.5 Process Validation and/or evaluation

Process validation report to be provided for nonstandard processes

Applicant to clearly state if they consider the process
to be standard or non-standard
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Tuesday, July 15, 2014

3.2.P.4

3.2.P.4.1 Excipient specifications

Compliance to EC directive to be included wherever

applicable

TSE/BSE certification to be provided inline with
current guidelines even for non-animal origin products.

OVI certification to be provided.

Functionality tests to be a part of excipient
specifications.

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Tuesday, July 15, 2014


3.2.P.4.4.Justification of specification

CoA from in-house testing to be provided.

CoA from vendor not to be included in EU

submissions.

3.2.P.4.5

Current CEP for excipients of animal origin to be

included

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Tuesday, July 15, 2014

3.2.P.5.1 Specification

Identification of drug substance to be included using

two separate principles

Identification of colorant to be included
Subdivision of tablets to be included
Assay limits to be inline with respective Agency
Dissolution limits to comply with EU guidelines for
modified release formulations

1st time point between 20%-30% release

2nd time point around 50% release

3rd time point 80%Q

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Tuesday, July 15, 2014


Antimicrobial preservative limits to be 90-110 at

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release and inline with PET at shelf life

Degradant impurities to be included in the FP specs
Related substances to be within ICH recommendations
Related substances limits to be tightened basis actual
data
Residual solvents limits to be included if used during
manufacturing of FP
Specification for reconstituted product to be included

Tuesday, July 15, 2014


3.2.P.5.2 Analytical Procedure

For Australia, assay to be performed using 20 units.

RRT of all impurities process or degradant to be included in

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STP for any possible reinterpretation of data.

3.2.P.5.3
Validation range to support test procedure and possible
widening of specs.
3.2.P.5.4 Batch Analysis
To be supported with back up chromatograms for US
filings
3.2.P.5.5 Characterization of impurities
Characterization of impurities other than DMF/CEP to be
discussed.

Tuesday, July 15, 2014


3.2.P.6 Reference standard

Characterization of working standard against reference

standard to be submitted

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Tuesday, July 15, 2014

3.2.P.7 Container and Closure System

Compliance to EC directive to be demonstrated

Test of identification to be built in the specification

CE certification to be provided as applicable

Compliance to TGO 80 w.r.t. child resistant closure to

be provided for Australian filing

Drawing of vial/stopper/seal to be provided

Leachable/Extractable data to be supported

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Tuesday, July 15, 2014

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Risk Associated
with the Route
of
Administration

Likelihood of Package- Drug Interaction

Highest

Inhalation aerosols Sterile powders

and solutions
and
Injections
powders for
injection
Inhalation powders

High

Ophthalmic
solutions
Transdermal
ointments and
patches
Nasal spays

Low

Topical Solutions Topical Powders

Topical and Lingal Oral Powders
aerosols
Oral solutions

High

Medium

Low

Oral Tablets and

Capsules

Tuesday, July 15, 2014

Batch Size/Stability Requirements

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Country

No. Batches

Size

Condition

Duration

EU

2/3

Min 1 lac

25/60
40/75

6M

US

1/3

Min 1 lac

25/60
40/75

6M

Canada

Min 1 lac

25/60
40/75

6M

Australia

2/3

Min 1 lac

25/60
40/75

6M

Brazil

Min 50
thousand

30/75
40/75

12M

Ecuador,
Venezuela,
Peru

30/75
40/75

12M

Other Latam

30/75
40/75

6M
Tuesday, July 15, 2014

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Country

No. Batches

Size

Condition

Duration

Malasiya,
Thailand,
Philippines,
Cambodia,
Myanmar,
Vietnam

2/3

1 lac

30/75
40/75

12M
6M

Singapore

2/3

1 lac

30/75
40/75

6M/12M
6M

Tuesday, July 15, 2014

Zone I, Zone II, Zone III, Zone IV

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Tuesday, July 15, 2014

Mass Balance to be present. If not to be

justified

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Zone

ACC

INT

LT

40C/75 %RH

30C/65% RH

25C/60 %RH

II

40C/75 %RH

30C/65% RH

25C/60 %RH

III

40C/75 %RH

NA

30C/65% RH

IV

40C/75 %RH

NA

30C/65% RH(a)
30C/75 %RH(b)

Tuesday, July 15, 2014

Testing conditions
where
the product is stable

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Required labelling
statement

Additional labelling
statement*, where
relevant

25C/60%RH (long term) None***

40C/75%RH
(accelerated)
or
30C/65%RH (long term)
40C/75%RH
(accelerated)

Do not refrigerate or
freeze

25C/60%RH (long term) Do not store above 30C

30C/60 or 65%RH
or
(intermediate) or
Store below 30C
30C/65%RH (long term)

Do not refrigerate or
freeze

Tuesday, July 15, 2014

25C/60%RH (long term) Do not store above 25C

or
Store below 25C

Do not refrigerate or
freeze

5C 3C (long term)

Do not freeze

Store in a refrigerator
or
Store and transport
refrigerated ****
**

Below zero

Store in a freezer
or
Store and transport frozen
*****
**

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Tuesday, July 15, 2014

* Depending on the pharmaceutical form and the properties of the

product, there may be a risk of deterioration due to physical
changes if subjected to low temperatures. Low temperatures may
also have an effect on the packaging in certain cases. An additional
statement may be necessary to take account of this possibility.
** The SPC and Package Leaflet (PL) should include a reference to
the temperature range e.g. (2C to 8C)
*** The following SPC and PL statements are required: This
medicinal product does not require any special storage conditions.
**** The stability data generated at 25C/60%RH (acc) should be
taken into account when deciding whether or not transport under
refrigeration is necessary. The statement should only be used in
exceptional cases.
*****The statement should only be used when critical

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Tuesday, July 15, 2014

3.2.R

LoAs to be provided

Process validation protocol/report to be provided

For US executed batch records to be included

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Tuesday, July 15, 2014

3.2.S

Starting material to be simple and commercially

available

Particle size limits to be two tier.

Residual solvent limits to meet ICH guidelines or
those mentioned in the CEP

Method validation reports to be provided for in-house
tests not claimed by DMF holder

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Tuesday, July 15, 2014

THANK YOU

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Tuesday, July 15, 2014