QUALITY BY DESGN APPROACH

QUALITY BY DESGN
APPROACH
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16.0 QUALITY BY DESIGN (QbD)
Quality by design is a systematic scientific approach for the development that involves the
identification of the critical parameters, critical quality attributes (CQA) (of both product &
process) and is characterized by the establishment of a design space, and enhanced process
understanding. The aim of pharmaceutical development is to design a quality product and its
manufacturing process to consistently deliver the intended performance
of the product.
Information from pharmaceutical development can be a basis for quality risk management.
16.1 Quality target product profile (QTPP)
The pharmaceutical development and manufacturing strategy for Acitretin Nanoemulsion and
Telmisartan Nanoemulsion drug product is guided by the products quality target profile (QTPP).
Note: The quality target product profile (QTPP) is a “prospective summary of the quality
characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking
in to account safety and efficacy of the drug product.”
The QTPP is an essential element of a QbD approach and forms the basic of design for the
development of the product.
Table- 23
PRODUCT
TARGET
ATTRIBUTE
Dosage form
Is this a
JUSTIFICATION
CQA
Acitretin: Hard Gelatin capsules
Yes
filled with solid Nanoemulsion
Pharmaceutical equivalent
requirement same dosage form
Telmisartan: Soft gelatin capsule
filled with clear fill
Identification
Positive for active
Yes
Though identification is critical for
safety and efficacy, this CQA can be
effectively controlled by the quality
management system and will be
monitored at drug product release.
Formulation and process variables
do not impact identity.
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Assay of Drug
±5% from the Label claim
Yes
Affect patient safety and Efficacy
Route of
Oral administration
Yes
Pharmaceutical equivalent
administration
requirement same route of
administration as that of RLD
Dosage strength
Acitretin: 25 mg
Yes
Telmisartan: 80 mg
Container –
Acitretin: Blister pack
closure
Telmisartan: HDPE Pack
Pharmaceutical equivalent
requirement same dosage strength
Yes
Needed to achieve the target shelf
life and to ensure the product
integrity during shipping.
Shelf life
24 months below 25ºc
Yes
Equivalent to or better than RLD
shelf life.
Administration
Similar as RLD
Yes
Generic product requirement
Alternate method
None
Yes
None are listed in the RLD label
Drug product
Description
Yes
Pharmaceutical equivalence
quality attributes
Identification
Yes
requirement must meet the same
Assay
Yes
compendial standards or other
Related substances
Yes
applicable standards
Particle size
Yes
To control for the better/Desired
Zeta potential
Yes
product performance
Upper globule size determination
Yes
of administration
in lipid
Disintegration
Pharmacopoeal requirement
Yes
To give the desired release profile
Time
CQA: Critical Quality Attribute
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16.2 Critical Material Attributes:
Initial risk assessment for input materials based on Prior Knowledge applied to CQAs
Table- 24
Drug product Appearance Solubility ID Test
RS
Assay Flow
quality
Residual
properties solvents
Particle Size
Distribution
attributes
Description
High
Low
Low
Low
Low
Low
Low
Low
Assay
Low
High
High
High
Low
Low
Low
Low
Related
Low
Low
Low
Low
Low
Low
Low
Low
Particle size
Low
High
Low
Low
Low
High
Low
High
Zeta
Low
Low
Low
Low
Low
Low
Low
High
High
Low
Low
Low
Low
Low
Low
High
substances
potential
Globule size
determinatio
n in lipid
emulsions
16.3 Justification for initial risk assessment
Table- 25
CPPs
CQAs
Justification and initial statergy
Polysorbate 80 and Cremophor EL is used
Appearance/Description
as an emulsifier for emulsions containing
Dispersion of
triglycerides as the dispersed phase and
Surfactants in
uniform dispersion of Surfactant/CoS is
aqueous phase
required for a stable emulsion formation. The
risk of dispersion may impact the drug product
CQAs like appearance and Dispersion
characteristics
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The risk of primary emulsion formation to
Primary emulsion
Appearance/Description
formation (operating
impact the drug product appearance is high.
condition for in-line
mixer)
Fine emulsion
Assay
Formation of fine emulsion is carried out by
formation (By high
Particle Size
high pressure homogenization. The pH of the
pressure
Zeta potential
fine emulsion is carefully controlled. The risk
homogenization)
Upper globule size
of fine emulsion formation to impact the drug
determination USP <729> product CQAs like assay of drug, particle size,
pH
Filling/Encapsulation
upper globule size and pH are high.
Assay
To get the desired fill volume. The risk of
Related substances
filling to impact the drug product CQAs like
Sterility
assay, RS and sterility are high.
Particle Size
16.4 Selection of the components of the drug product:
16.4.1 Drug Substance

The target profile for Acitretin solid emulsion is met by the investigation and selection of
Acitretin which is the input API for the product. The chemical name of Acitretin is alltrans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid and
available as yellow colored fluffy powder, with the pKa of 5 and molecular weight 326.44,
Acitretin is insoluble in water and slightly soluble in acetone and alcohol.

The Target Profile for Telmisartan Nanoemulsion is met by the investigation and selection
of Telmisartan which is the input API for the product. The chemical name of Telmisartan is
2-[4-[[4-methyl-6-
(1-methylbenzimidazol-2-yl)-2-Propylbenzimidazole-1-yl]
methyl]
phenyl] benzoic acid and available as white crystals, with pKa of 4.5 and molecular weight
514.6169. Telmisartan is practically insoluble in water and sparingly soluble in strong acid
and strong base.
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16.4.2 Excipients:

Excipients used in the preparation of Acitretin nanemulsion are Capmul MCM, Tween 80,
Transcutol HP, Neusilin and sodium hydroxide. Each components performs a specific
function in forming the formulation. Capmul MCM holds the bulk of the Acitretin in a
medium that can be stabilized and dispersed, Tween 80 serves as an emulsifier to stabilize
the small Acitretin-Capmul MCM droplets in aqueous dispersion, and Transcutol maintains
the formulation stable. The Neusilin used as the carrier material.

Excipients used in the preparation of Telmisartan Nanoemulsion are Myglyol 812,
cremophor EL, PEG 400 and Meglumine. Myglyol holds the bulk of the Telmisartan in a
medium that can be stabilized and dispersed, Cremophor EL acts as an emulsifier to
stabilize the small Telmisartan-Myglyol droplets in aqueous dispersion, and PEG 400
maintains the formulation stable Meglumine acts as a basifier to keep the solubility values
on the higher side.
16.5 Establishing Boundaries Of The Design Space
16.5.1 Identify Product Failure Modes
The most common approach to develop a stable emulsion is to identify an control the processing
conditions and variables which destabilize the emulsion. Stable emulsion is considered to be one in
which the dispersed droplets retain their initial character and remain uniformly distributed
throughout the continuous phase for desired shelf life. There should be no phase changes or
microbial contamination on storage, and the emulsion should maintain elegance with respect to
dispersion characteristics, and consistency.
Instability in emulsion may arise from both chemical and physical origin. Chemical instabilities,
such as the development of rancidity in natural oils due to oxidation by atmospheric oxygen, depolymerization of macromolecular emulsifiers by hydrolysis, microbial degradation, increased
acidity and presence of electrolytes destabilize emulsion by neutralizing the repulsive negative
charge on the droplet surface. Physical instability may be attributed to increase in temperature,
agitation and freeze thawing which attributes to increased droplet size with a greater tendency to
coalesce.
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16.5.2 Identify Product-Imposed Boundary on the Design Space
Droplet size distributions and presence of surface charge (zeta potential) in Acitretin emulsion
droplet
and important from both stability and biopharmaceutical considerations. The larger
particle size, the greater the tendency to coalesce and further increase droplet size. Thus, fine
particles generally promote better stability, also the more negative the zeta potential is the greater
the net chare on the droplets and the more stable emulsion is, the droplet size and surface charge
distribution represents the boundary of the design space imposed by the characteristics of the
formulation.
16.5.3 Identify Equipment-Imposed Boundaries on the Design Space:
Differences in manufacturing techniques such as the rate of the heating and cooling cycle, the
extent and order of mixing can cause variations in the consistency and rheology of the resulting
emulsions. The initial particle size of the emulsion depends on the emulsifiers used, the
emulsification equipment, the addition speed, and the phase volume. If the surfactants is paced
in one of the phase prior to emulsification, it will migrate to the other to establish equilibrium.
Thus, emulsification temperatures and cooling rates are important and the time of the mixing
should be sufficient to allow the surfactant to migrate to and equilibrate at the interface throughout
the process.
16.6 Summary :
It is very important
to view product and process development for a stable nanoemulsion
formulation which is an integrated process rather than as a collection of independent activities.
Drug formulaion, the development scientist must be aware of the type of equipment to which the
product will be transferred in the next stage of development. The scientist must also understand
the capability of equipment and must take into account the processing condition which becomes
particularly important in developing emulsion with a droplet size distribution below 1000nm.
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17.0 STABILITY STUDIES: the design of the stability was in compliance with the ICH
guideline, stability storage conditions are selected as follows.
Stability storage conditions
Table- 26
Study
Storage condition
Time period
Long term
25 ºC ± 2 ºC / 60% RH ± 5%
6 months
RH
Accelerated
40 ºC ± 2 ºC / 75% RH ± 5%
3 months
RH
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