ASMOH LABORATORIES LIMITED

(DELHI ) INDIA

3.2.P.2
PHARMACEUTICALDEVELOPMENT

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Section Title
3.2. P.2.1 Components of Drug Product
3.2. P.2.1.1 Drug Substance
3.2. P.2.1.2 Excipients
3.2. P.2.2 Finished Pharmaceuticals Product
3.2. P.2.2.1 Formulation Development
3.2. P.2.2.2 Overages
3.2. P.2.2.3 Physicochemical and Biological Properties
3.2. P.2.3 Manufacturing Process Development
3.2. P.2.4 Container Closure System
3.2. P.2.5 Microbiological Attributes
3.2. P.2.6 Compatibility

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3.2.P.2.1
COMPONENTS OF DRUG PRODUCT

3.2. P.2.1 Components of drug product:

BILASTO (Bilastine Tablets 20 mg)
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Compendial Name : Bilastine
Pharmacopoeia : Bilastine
Chemical Name : 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl] piperidin-1-yl] ethyl]
phenyl]-2-methylpropionic acid.
CAS No. : 202189-78-4
Molecular Formula : C28H37N3O3
Molecular Weight : 463.61 g/mol
Potential Isomerism : NA
Structure :

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3.2. P.2.1.1
DRUG SUBSTANCE

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3.2. P.2.1.1 Drug substance:
Physiochemical characteristics of drug substance:
Bilastine
Appearance : A white to off white powder
Solubility : Slightly soluble in methanol, very slightly soluble in dimethyl sulphoxide,
practically insoluble in water.
Water Content : NMT 1.0 %
Reference : IHS

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3.2. P.2.1.2 Excipients:
Selection of excipients:
Following criterion was selected for selection of Excipients -
 Prior knowledge and variability with respect to physicochemical and functional properties of
all the Excipients used in the formulation design.
 Excipients compatibility study. The Excipients selected for the final formula of the drug
product and their functions are detailed below:
S. No. Name of Ingredients Specification Function

1. Microcrystalline Cellulose BP Diluent

2. Sodium Starch Glycolate BP Disintegrant

3. Silica Colloidal Anhydrous BP Glidant

4. Magnesium Stearate BP Lubricant

Compatibility of the active substance with excipients:

Compatibility studies of active ingredient Bilastine were carried out by differential scanning
calorimeter. A differential scanning calorimeter was used for the thermal analysis of the drug and
mixtures of the drug and the excipients in a 1:1 w/w ratio. Individual samples of the drug and the
selected excipients were weighed to approximately 10 mg in a DSC aluminum pan and scanned in
the temperature range of -20º to 400ºC under an atmosphere of nitrogen. The heating rate was
10ºCmin-1, and the obtained curves were observed for any type of interaction. Enthalpy
calculations were completed using Pyris software.
Compatibility Study of Bilastine IHS with excipients (1:1)

Sr.
Drug Substance+Excipients (Ratio 1:1) Compatibility
No.

1. Bilastine: Microcrystalline Cellulose No Change

2. Bilastine: Sodium Starch Glycolate No Change
3. Bilastine: Silica Colloidal Anhydrous No Change
4. Bilastine: Magnesium Stearate No Change

No evidence of physical change was found for the drug substances alone and in combination with
excipients indicating that Bilastine compatible with all the excipients studied.
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Conclusion: From the above observation it was found that the active Ingredient was compatible
with the excipients mentioned above and hence can be used for formulation development.

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3.2. P.2.2
FINISHED PHARMACEUTICALS
PRODUCT

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3.2. P.2.2 Drug Product:
3.2. P.2.2.1 Formulation Development:
3.2. P.2.2.1.1 Summary of development of drug product:
The aim of this product development is to formulate robust, essentially similar, stable and
bioequivalent generic formulation of BILASTO (Bilastine 20 mg Tablets) to that of the
innovator product Ilaxten 20 mg tablets manufactured by A. Menarini Farmaceutica
Internazionale SRL
Characterization of Innovator (Reference) Product: Ilaxten 20 mg Tablets The reference
product is Ilaxten 20 mg tablets manufactured by A. Menarini Farmaceutica Internazionale
SRL, Reference product Ilaxten 20 mg tablets has been analysed for physical characterization
and chemical characterization.
Sr. No. Description Details
1. Description Oval biconvex scored white tablets
2. Label claim Each tablet contains 20 mg of Bilastine
3. Dosage form Tablets
Packaging details:
Pack: The medicinal product is packaged in a blister, consisting of two parts:
Laminate, consisting of oriented polyamide (outer side of laminate), aluminum and PVC (inner
side of laminate).
Aluminum foil: The aluminum foil is thermosealed with a heat-seal lacquer (PVC-PVAC
copolymer and resins of butylmethacrylate) to the laminate after molding and filling of the tablets.
Each blister contains 10 tablets. The blisters are packaged in cardboard boxes.

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Chemical Characterization: The reference product Ilaxten 20 mg tablets evaluated for chemical
characteristics i.e., Assay. The results are given in below mentioned table.
Test Result
Reference product Ilaxten 20 mg Tablets
Assay 99.94 %

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3.2. P.2.2.1.2 Rationale of development:
The aim of this product development is to formulate robust, essentially similar, stable and
bioequivalent generic formulation of BILASTO (Bilastine Tablets 20 mg) to that of the
reference product Ilaxten 20 mg Tablets manufactured by A. Menarini Farmaceutica
Internazionale SRL. The primary aim of this development is to develop a stable formulation and
to match the pharmacokinetics & therapeutic effects with the reference product. The entire
formulation development work was done by considering above mentioned as reference product.
Quality Target Product Profile for the Regulatory Product
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 into account
safety and efficacy of the drug product.” The QTPP is an essential element of a QbD approach and
forms the basis of design of the generic product. For regulatory, the target should be defined early
in development based on the properties of the drug substance (DS), characterization of the RLD
product and consideration of the RLD label and intended patient population. The QTPP includes
all product attributes that are needed to ensure equivalent safety and efficacy to the RLD. By
beginning with the end in mind, the result of development is a robust formulation and
manufacturing process with a control strategy that ensures the performance of the drug product.
A critical quality attribute (CQA) is “a physical, chemical, biological or microbiological property
or characteristic that should be within an appropriate limit, range, or distribution to ensure the
desired product quality.” The identification of a CQA from the QTPP is based on the Severity of
harm to a patient should the product fall outside the acceptable range for that attribute.
All quality attributes are target elements of the drug product and should be achieved through a
good quality management system as well as appropriate formulation and process design and
development. From the perspective of pharmaceutical development, we only investigate the subset
of CQAs of the drug product that also have a high potential to be impacted by the formulation
and/or process variables. Our investigation culminates in an appropriate control strategy.
Based on the clinical and pharmacokinetic (PK) characteristics and physicochemical
characteristics of the Reference drug, a quality target product profile (QTPP) was defined for
Generic Bilastine Tablets 20 mg.

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Quality Target Product Profile (QTPP) for
BILASTO (Bilastine Tablets 20 mg)
QTPP Element Target Justification
Pharmaceutical equivalent
Dosage form Solid
requirement: same dosage form
For oral administration requirement to
Dosage design Uncoated tablet
meet label claim
Pharmaceutical equivalent
Route of
Oral requirement: same route of
administration
administration
Pharmaceutical equivalent
Dosage strength 20 mg
requirement: same strength
Pharmacokinetics Half-life is 12–14.5 h Bioequivalent requirement
At least 36 months self- Equivalent with reference product
Stability
life at room temperature. shelf life
Physical Attributes
Pharmaceutical equivalent and must
Identification
Drug product quality meet the same compendia or other
Assay
attributes applicable standard (Identity, assay,
Disintegration Time
purity & Quality).
Dissolution
Packing system qualified As per requirement of regulatory,
Container and closure
as suitable for drug ensure drug product integrity during
system
product shipping.
Administration/
Similar food effect with As per innovator and regulatory
concurrence with
reference product requirement.
labelling
Alternative method of
None None, Not required.
administration

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Below table summarizes the quality attributes of generic Bilastine Tablets 20 mg and indicates
which attributes were classified as drug product critical quality attributes (CQAs). For this product
assay, uniformity of weight and disintegration time identified as the subset of CQAs that have the
potential to be impacted by the formulation and/or process variables and, therefore, will be
investigated and discussed in detail in subsequent formulation and process development studies.
On the other hand, CQAs including identity which are unlikely to be impacted by formulation
and/or process variables will not be discussed in detail in the pharmaceutical development report.
However, these CQAs are still target elements of the QTPP and are ensured through a good
pharmaceutical quality system and the control strategy.

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Critical Quality Attributes (CQAs) of
Bilastine 20 mg Tablets
Is this
Quality Attributes of the
Target a Justification
Drug product
CQA?
Appearance is directly linked to
safety and efficacy as
Appearance should be formulation is to be given by
Appearance complying as per Yes oral administration. Thus, this
requirements CQA will be evaluated
throughout product and process
Physical development.
attributes This CQA is directly linked to
safety and efficacy as
As per requirements formulation is to be given by
Average
& target to proper Yes oral administration. Thus, this
Weight
dosing of drug. CQA will be evaluated
throughout product and process
development.
Identification The principal peak in Though identification is critical
By HPLC the chromatogram for safety and efficacy, this
obtained with the test CQA can be effectively
solution is similar to in controlled by the quality
retention time to the management system and will be
principal peak in the monitored at drug product
Yes
chromatogram obtained release. Formulation and
with the reference process variables do not impact
solution identity. Therefore, this CQA
will not be discussed during
formulation and process
development.

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Disintegration Time NMT 15 Minutes Yes Disintegration Time is directly
linked to safety and efficacy as
formulation is to be given by
oral administration. Thus, this
CQA will be evaluated
throughout product and process
development.

Dissolution NLT 75%(Q) of the Dissolution affects safety and

labelled amount of efficacy. Both formulation and
Bilastine dissolved in process variables impact
Yes
30 min Dissolution, so this CQA will
be evaluated throughout product
and process development
Variability in uniformity of
weight will affect safety and
efficacy. Both formulation and
Confirm uniformity of process variables impact fill
Uniformity of weight
weight Yes weight uniformity, so this CQA
will be evaluated throughout
product and process
development.
Assay Assay variability will affect
Each uncoated tablet 18.0 mg to 22.0 mg safety and efficacy. Process
contains: (NMT 90% to 110% variables may affect the assay
Bilastine 20 mg of labelled amount) Yes of the drug product. Thus, assay
will be evaluated throughout
product and process
development.

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3.2. P.2.2.1.3 Development strategies
Various trials were executed to finalise the prototype formulation with following objectives:
1. To develop a stable and pharmaceutically bioequivalent generic product.
2. To match the pharmacokinetics & therapeutic effects with the reference product.
3. To develop a robust manufacturing process and formula which will give consistent physical
and chemical attributes of the product and suitability of production at commercial scale.
Details of all development trials are summarized below:
The aim was to develop BILASTO (Bilastine Tablets 20 mg). Various Trials were conducted by
taking different API manufacturer of Bilastine to obtain desired limit of specification and after
that trial number 3 was selected because of desired results. Further its Extensive process
optimization studies were carried out to evaluate the significance of changing process parameters
on the quality and performance of the formulation.
Formulation compilation of BILASTO (Bilastine 20 mg Tablets).

Qty./ batch (kg)

S. Approved Name of Trial-1 Trial-2 Trial-3
Spec. Function
No. Ingredients ATB-001 ATB-002 ATB-003
(Mfg. A) (Mfg. B) (Mfg. C)
1. Bilastine IHS 2.0 2.0 2.0 API
2. Microcrystalline BP
23.711 23.711 23.711 Diluent
Cellulose
3. Sodium Starch BP
1.4 1.4 1.4 Disintegrant
Glycolate
4. Silica Colloidal BP
0.154 0.154 0.154 Glidant
Anhydrous
5. Magnesium Stearate BP 0.735 0.735 0.735 Lubricant
Description: White coloured, round shaped, biconvex, both sides plain, uncoated tablet.
Averages weight: 280 mg ± 5%

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Manufacturing Flow Diagram:

WEIGHT WEIGHING
Check for sieve size

SIFTING

BINDER PREPARATION

DRYMIXING

GRANULATION

DRYING

SIFTING & MILLING

Check for lubrication material

BLENDING & LUBRICATION

Check for dies & punches

In process checks for compression
COMPRESSION

PACKING
Packing material dispensing Finished product Sample for analysis

DISPATCH

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Manufacturing description:
PRODUCT INFORMATION
Product Name BILASTO
Generic Name Bilastine Tablets 20 mg
Each uncoated tablet contains:
Label Claim Bilastine 20 mg
Excipients q.s
Dosage form Uncoated tablets
Standard Batch Size 1,00,000 Tablets
1 x 10 Tablets
Packing (10 tablets packed in Alu/ Alu blister and one such blister packed in
printed unit carton along with package insert.)
White coloured, round shaped, biconvex, both sides plain, uncoated
Product Description
tablet
Shelf Life 36 months
Store below 30°C. Protect from light and moisture.
Storage Condition
Keep the medicine out of reach of children.

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Manufacturing process:
1.CHECKING OF WT.: Check the weight of all ingredients. The quantities of each ingredient
are checked and counter checked by approved technical staff. Tally the weights with those in flow
sheet and it is initialed by the pharmacist in charge.
2. SIEVING: All the dispensed raw materials are sifted using vibratory sifter, individually. Care
is taken to prevent cross-contamination and mixing with other products. Materials are sifted using
definite mesh size as per the requirement to obtain uniform particle size, which is further
important in mixing and bioavailability. Sifting is carried out till all the Ingredients pass through
their respective sieves.
3. Dry Mixing: Charge the materials of step 2 are put in mass mixer for uniform mixing. All
above material mixed up to 30 minutes for complete mixing. Send the mixed powder for the test
of uniformity of mixing.
4. BINDER PREPARATION: Prepare paste of starch in Purified Water* in a SS steel jacketed
vessel & cool this paste to room temperature.
5. BINDING & GRANULATION: Pour the binder solution of step 4 to mixed material of step 3
and mix in RMG till the desired size granules obtained.
6. DRYING: Put the trays with wet mass in Fluidized Bed Drier (FBD) for drying for 1 hour in
FBD. Dry the granules in tray drier at 50°C to 60°C.
7. DRY MILLING/SCREENING: Pass the dried granules of step 6 through No.20# by
Mechanical Sifter. Pass coarse granules through multi mill at medium speed. Using screen 1.5
mm. Weigh and record the weight of granules. Collect all the granules in clean, dry polythene
bags and store in suitable containers. Label with regard to Product Name, B. No., Quantity, and
Container No., till Lubrication stage. Check moisture content of granules.
8.LUBRICATION: Charge the dried granules of step 7 in clean, dry, Blender and for 20 minutes
and lubricate with specified lubricants
9.UNLOADING: Unload the lubricated granules into clean, dry polythene bags and store them in
suitable containers. Weigh and record the weight of lubricated granules. Label the containers with
regard to Batch No., Product Name and Container No. Total quantity of lubricated granules should
be as per flow sheet.
10. COMPRESSION: After getting approval from QC Department send the granules to
compression section for tableting.
11. ANALYSIS OF UNCOATED TABLETS: Only after ensuring the average weight Diameter,
thickness, friability within the IHS specifications continue regular production. Also check the

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above parameters intermittently during production, and adjust accordingly. Intimate QC Dept for

random sampling of uncoated tablets.

12. IN PROCESS CONTROL: Draw samples at regular intervals during compression & check
for:
S. NO. IN PROCESS STANDARD LIMITS PERIODICITY
CHECK
1 Physical White coloured, round shaped, biconvex, Every ½ Hr
appearance both sides plain, uncoated tablet
2 Average Weight 280 mg ±5% Every ½ Hr
3. Uniformity of 5% of Average Weight Every 1 Hr
Weight
4. Hardness NLT 3.0 kg/cm2 Every 1 Hr
5. Friability NMT 1.0 % w/w Every 1 Hr
6. Disintegration Every 1 Hr
NMT 15 Minutes
Time

13. INSPECTION: Dedust the tablets and inspected visually for any defects.
14. PACKING: Packaging belt should be thoroughly checked to ensure that there should not be
any material left behind of the previously run product. Batch No., Mfg. Date, Expiry Date and any
other necessary instructions for labels and printing should be checked well before starting the
batch. It should be duly signed by competent authority and the sample of such product should be
kept as record.
Master packing procedure:
Product : BILASTO (Bilastine 20 mg Tablet)
Standard Batch Size : 100000 Tablets
Machine : Blister packing machine
Packing:
1 x10 tablets
(10 tablets packed in Alu/Alu blister and one such blister packed in printed unit carton along with
pack insert).

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Tablets packed in Alu/Alu blisters. Alu/Alu blisters after checking packed in cartons and finally
packed in corrugated boxes duly taped & strapped.
After completion of the packing, all the packed material is to be transferred to the finished goods
store along with the complete records.
After getting release certificate from the Quality Control Department, the material is ready for
dispatch. It should be labeled as released.
3.2. P.2.2.1.3 Testing Analytical methods:
Details of analytical methods for drug product are as follows:
The analytical test procedures on BILASTO (Bilastine 20 mg Tablet) were performed according
to the control tests of IHS Specification. Specifications & Analytical test procedures of BILASTO
(Bilastine 20 mg Tablet) manufactured at Asmoh Laboratories Ltd.
S. No Tests Specifications
1. Description White coloured, round shaped, biconvex, both
sides plain, uncoated tablet
2. Identification The principal peak in the chromatogram obtained
By HPLC with the test solution is similar to in retention time
to the principal peak in the chromatogram
obtained with the reference solution
3. Average weight 280.0 mg ± 5%
4. Uniformity of dosage units LI<15, L2<25
5. Disintegration Time NMT 15 minutes
6. Friability NMT 1.0%
7. Hardness NLT 3.0kg/cm2
8. Dissolution NLT 75%(Q) of the labelled amount of Bilastine
dissolved in 30 min
9. Microbial Limit Test:
a. Total aerobic microbial NMT 102 cfu/g
count (TAMC)
b. Total combined yeasts & NMT 101 cfu/g
molds count (TYMC)
c. Escherichia coli Should Be Absent
10. Assay: 18.0 mg to 22.0 mg
Each uncoated tablet contains (NLT 90% and NMT 110% of the labelled amount

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Bilastine 20 mg of C28H37N3O3)

ANALYTICAL REPORT OF IN PROCESS TEST FOR TRIAL BATCHES OF

BILASTO (Bilastine 20 mg Tablet)
Results
S. Test
Specification ATB-001 ATB-002 ATB-003
No. Parameters
(Mfg A) (Mfg B) (Mfg C)
1) Description White White coloured, White White coloured,
coloured, round shaped, coloured, round shaped,
round shaped, biconvex, both round shaped, biconvex, both
biconvex, both sides plain, biconvex, both sides plain,
sides plain, uncoated tablet sides plain, uncoated tablet
uncoated tablet uncoated
tablet
2) Identification The principal The principal The principal The principal
By HPLC peak in the peak in the peak in the peak in the
chromatogram chromatogram chromatogram chromatogram
obtained with obtained with obtained with obtained with
the test solution the test solution the test the test solution
is similar to in is similar to in solution is is similar to in
retention time to retention time to similar to in retention time
the principal the principal retention time to the principal
peak in the peak in the to the peak in the
chromatogram chromatogram principal peak chromatogram
obtained with obtained with in the obtained with
the reference the reference chromatogram the reference
solution solution obtained with solution
the reference
solution
3) Average weight 280.0 mg ± 5% 271.35 mg 289.14 mg 280.21 mg
4) Uniformity of LI≤15 Complies Complies Complies
dosage units L2≤25

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5) Disintegration NMT 15 03 min to 04 02 min to 03 03 min to 04
Time minutes min min min
6) Friability NMT 1.0% 0.28 % 0.25 0.21%
7) Hardness NLT 3.0kg/cm2 3.29 kg/cm2 3.32 kg/cm2 3.20 kg/cm2
8) Dissolution NLT 75%(Q) of
the labelled
amount of 81.65%- 85.88%-
80.21%-82.18%
Bilastine 82.18% 86.24%
dissolved in 30
min
9) Microbial Limit Test:
a. Total aerobic
microbial count NMT 102 cfu/g 48 cfu/g 39 cfu/g 28 cfu/g
(TAMC)
b. Total
combined yeasts
NMT 101 cfu/g 09 cfu/g 11 cfu/g 07 cfu/g
& moulds count
(TYMC)
c. Escherichia Should Be
Absent Absent Absent
coli Absent
10) Assay: 18.0 mg to 22.0
Each uncoated mg
tablet contains (NLT 90% and
18.85 mg 19.24 mg 19.85 mg
Bilastine 20 mg NMT 110% of
(94.25%) (96.20%) (99.25%)
the labelled
amount of
C28H37N3O3)
Stability Data Compilation: Stability performed at 40°C/ 75% RH

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ANALYTICAL REPORT FOR FINISHED PRODUCT OF THE TRIAL BATCH

(ATB-003) (Mfg. C) of BILASTO (Bilastine 20 mg Tablet)
S. Results
No Test Parameters Specification ATA-003
. (Mfg. C)
Description White coloured, round White coloured, round
1 shaped, biconvex, both sides shaped, biconvex, both
plain, uncoated tablet sides plain, uncoated
tablet
Identification The principal peak in the The principal peak in
By HPLC chromatogram obtained with the chromatogram
the test solution is similar to obtained with the test
in retention time to the solution is similar to in
2
principal peak in the retention time to the
chromatogram obtained with principal peak in the
the reference solution chromatogram obtained
with the reference
solution
3
Average weight 280.0 mg ± 5% 280.21 mg

4 LI≤15 Complies
Uniformity of dosage units
L2≤25
5
Disintegration Time NMT 15 minutes 03 min to 04 min

6
Friability NMT 1.0% 0.21%

7
Hardness NLT 3.0kg/cm2 3.20 kg/cm2

8 Dissolution NLT 75%(Q) of the labelled 85.88%-86.24%

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amount of Bilastine dissolved
.
in 30 min
9 Microbial Limit test

a. Total aerobic microbial NMT 102 cfu/g

28 cfu/g
count (TAMC)
b. Total combined yeasts & NMT 101 cfu/g
07 cfu/g
moulds count (TYMC)
c. Escherichia coli Should Be Absent Absent
10. Assay: 18.0 mg to 22.0 mg
Each uncoated tablet contains (NLT 90% and NMT 110% 19.85 mg
Bilastine 20 mg of the labelled amount of (99.25%)
C28H37N3O3)

Observation & Conclusion:

The development of BILASTO (Bilastine 20 mg Tablet) is carried out on the basis of
physiochemical properties of molecule, so that it is decided to choose accordingly the suitability
and compatibility of the excipients with drug.

Trial I: Ingredients used in the formulations are Bilastine, Microcrystalline Cellulose, Sodium
Starch glycolate, Silica Colloidal Anhydrous, Magnesium Stearate.
Result: Formulation complying with specification but need more improvements.
Conclusion: For improving the result we planned next trial with changing manufacturer A to B.

Trial II: Ingredients used in the formulations are Bilastine, Microcrystalline Cellulose, Sodium
Starch glycolate, Silica Colloidal Anhydrous, Magnesium Stearate
Result: Formulation complying with specification but need more improvements.
Conclusion: For improving the result we planned next trial with changing manufacturer B to C.

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Trial III: Ingredients used in the formulations are Bilastine, Microcrystalline Cellulose, Sodium
Starch glycolate, Silica Colloidal Anhydrous, Magnesium Stearate.
Result: Formulation complying all specification with satisfactory results.
Conclusion: The batch resulted in satisfactory physical, chemical & microbial parameters. Hence,
this formula was considered as prototype formula.

Qualitative and Quantitative formula:

Product Name: BILASTO (Bilastine 20 mg Tablet)
Composition:
Each uncoated tablet contains
Bilastine 20 mg
Excipients q.s. Shelf Life: 36 Months
Batch size: 100000 Tablets
Overages Qty./
S. Name of Claim Qty/Tab
Spec. Batch. Use
No. Ingredients (mg) (mg)*
(Kg)

1 Bilastine IHS 20 Nil 20* 2.0 API

Microcrystallin
2 BP --- --- 237.11 23.711 Diluent
e Cellulose

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Sodium Starch Disintegra
3 BP --- --- 14 mg 1.4
Glycolate nt
Silica Colloidal
4 BP --- --- 1.54 0.154 Glidant
Anhydrous
Magnesium
5 BP --- --- 7.35 0.735 Lubricant
Stearate
* Quantity calculated on the basis of 100% Assay and 0% LOD.
Overages: Nil
Abbreviations: BP: British Pharmacopeia, IHS-In-house, API: Active Pharmaceutical
Ingredient
Description: White coloured, round shaped, biconvex, both sides plain, uncoated tablet.
Averages weight: 280 mg ± 5 %

Manufacturing Procedure for Trial Formulations:

Equipment’s Checklist:
Name of
S.
the Equipment Design Installation Operational Performance
N
Equipment ID Qualification qualification qualification qualification
o.
’s
Weighing
ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/
1. balance 5
206 206-DQ/010 206-IQ/012 206-OQ/014 206-PQ/016
kg

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Weighing
ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/
2. balance 15
207 207-DQ/028 207-IQ/030 207-OQ/032 207-PQ/034
kg
Weighing
ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/ ASM/WB/
3. balance 20
208 208-DQ/040 208-IQ/042 208-OQ/044 208-PQ/046
kg
Vibro ASM/VS/ ASM/VS/ ASM/VS/ ASM/VS/ ASM/VS/
4.
Sifter 105 105-DQ/050 105-IQ/052 105-OQ/054 105-PQ/ 056
Rapid
ASM/ ASM/RMG/ ASM/RMG/ ASM/RMG/ ASM/RMG/
5. mixer
RMG/123 123-DQ/060 123-IQ/062 123-OQ/064 123-PQ/066
Granulator
Fluid bed ASM/FBD/ ASM/FBD/ ASM/FBD/ ASM/FBD/ ASM/FBD/
6.
dryer 326 326-DQ/070 326-IQ/072 326-OQ/074 326-PQ/076
ASM/ML/ ASM/ML/ ASM/ML/ ASM/ML/ ASM/ML/
7. Multimill
145 145-DQ/080 145-IQ/082 145-OQ/084 145-PQ/086
ASM/BL/ ASM/BL/ ASM/BL/ ASM/BL/ ASM/BL/
8. Blender
536 536-DQ/090 536-IQ/092 536-OQ/094 536-PQ/096
Compressi
ASM/CM/ ASM/CM/ ASM/CM/ ASM/CM/ ASM/CM/
9. on
0425 0425-DQ/102 0425-IQ/104 0425-OQ/106 0425-PQ/108
Machine
Dissolutio
ASM/DL/ ASM/DL/ ASM/DL/ ASM/DL/ ASM/DL/
10. n
0258 0258-DQ/230 0258-IQ/232 0258-OQ/234 0258-PQ/236
Apparatus
ASM/ ASM/ ASM/ ASM/
HPLC ASM/
11. HPLC/333- HPLC/333- HPLC/333- HPLC/333-
Machine HPLC/333
DQ/242 IQ/244 OQ/246 PQ/248
Disintegrat
ASM/DT/ ASM/DT/ ASM/DT/ ASM/DT/ ASM/DT/
12. ion
0450 0450-DQ/250 0450-IQ/252 0450-OQ/254 0450-PQ/256
Apparatus
ASM/FB/
Friability ASM/FB/ ASM/FB/ ASM/FB/ ASM/FB/
13. 0313-
Apparatus 0313 0313-IQ/262 0313-OQ/264 0313-PQ/266
DQ/260

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Hardness ASM/HD/ ASM/HD/ ASM/HD/ ASM/HD/ ASM/HD/
14.
Tester 220 220-DQ/270 220-IQ/272 220-OQ/274 220-PQ/276
Electrical
jacketed S.
ASM/EJ/
S. Kettle ASM/EJ/ ASM/EJ/156- ASM/EJ/156-
15. ASM/EJ/156 15600-IQ/
with 156-DQ/0082 OQ/0086 PQ/0088
0084
Manual
Stirrer.
Blister
ASM/BP/ ASM/BP/ ASM/BP/ ASM/BP/ ASM/BP/
16. Packing
710 710-DQ/0132 710-IQ/0134 710-OQ/0136 710-PQ/0138
Machine

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3.2. P.2.2.2 OVERAGES

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3.2. P.2.2.2 Overages:
NA

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3.2. P.2.2.3
PHYSICOCHEMICAL
AND
BIOLOGICALPROPERTIES

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3.2. P.2.2.3 Physicochemical and biological properties:
S. No Tests Specifications
1. Description White coloured, round shaped, biconvex, both
sides plain, uncoated tablet
2. Identification The principal peak in the chromatogram obtained
By HPLC with the test solution is similar to in retention time to
the principal peak in the chromatogram obtained
with the reference solution
3.
Average weight 280.0 mg ± 5% (266.0 mg to 294.0 mg)

4.
Uniformity of weight Average weight ± 5%

5. Uniformity of Dosage Unit LI≤15%,

L2≤25%
6. Disintegration Time NMT 15 minutes

7. Friability NMT 1.0%

8. Hardness NLT 3.0kg/cm2

9. Dissolution NLT 75%(Q) of the labelled amount of Bilastine

dissolved in 30 min
10. Microbial Limit Test:
a. Total aerobic microbial NMT 102 cfu/g
count (TAMC)
b. Total combined yeasts & NMT 101 cfu/g
moulds count (TYMC)
c. Escherichia coli Should Be Absent
11. Assay: 18.0 mg to 22.0 mg
Each uncoated tablet (NLT 90% and NMT 110% of the labelled amount of
contains C28H37N3O3)
Bilastine 20 mg

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Biological properties
Category
BILASTO (Bilastine 20 mg Tablet)
1. Category Pharmacotherapeutic group: Antihistamines for systemic use, other
antihistamines for systemic use.
2. Mode of action Bilastine is a non-sedating, long-acting histamine antagonist with
selective peripheral H1 receptor antagonist affinity and no affinity for
muscarinic receptors. Bilastine inhibited histamine-induced wheal and
flare skin reactions for 24 hours following single doses.
3. Pharmacokinetics
Absorption: Bilastine is rapidly absorbed after oral administration with a time to
maximum plasma concentration of around 1.3 hours. No accumulation
was observed. The mean value of bilastine oral bioavailability is 61%.
Distribution: In vitro and in vivo studies have shown that bilastine is a substrate of P-
gp “Interaction with ketoconazole, erythromycin and diltiazem”) and
OATP. Bilastine does not appear to be a substrate of the transporter
BCRP or renal transporters OCT2, OAT1 and OAT3. Based on invitro
studies, bilastine is not expected to inhibit the following transporters in
the systemic circulation: P-gp, MRP2, BCRP, BSEP, OATP1B1,
OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and NTCP, since
only mild inhibition was detected for P-gp, OATP2B1 and OCT1, with
an estimated IC50 ≥ 300 μ M, much higher than the calculated clinical
plasma Cmax and therefore these interactions will not be clinically
relevant. However, based on these results inhibition by bilastine of
transporters present in the intestinal mucosa, e.g. P-gp, cannot be
excluded. At therapeutic doses bilastine is 84-90% bound to plasma
proteins.
Biotransformation Bilastine did not induce or inhibit activity of CYP450 isoenzymes in in-
: vitro studies.
In a mass balance study performed in healthy adult volunteers, after
Elimination: administration of a single dose of 20 mg 14C-bilastine, almost 95% of
the administered dose was recovered in urine (28.3%) and faeces (66.5%)
as unchanged bilastine, confirming that bilastine is not significantly

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metabolized in humans. The mean elimination half-life calculated
inhealthy volunteers was 14.5 h.
4. Use/Indications Symptomatic treatment of allergic rhino-conjunctivitis (seasonal and
perennial) and urticaria.
Bilastine is indicated in adults and adolescents (12 years of age and
over).
Assay: 18.00 mg to 22.00 mg
NLT 90.0% and NMT 110.0% of the labelled amount of Bilastine.

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3.2. P.2.3
MANUFACTURING PROCESS
DEVELOPMENT

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3.2. P.2.3 MANUFACTURING PROCESS:
FLOW CHART OF MANUFACTURING PROCESS OF BILASTO (Bilastine 20 mg
Tablet)
Procedure:

WEIGHT WEIGHING
Check for sieve size

SIFTING

BINDER PREPARATION

DRYMIXING

GRANULATION

DRYING

SIFTING & MILLING

Check for lubrication material

BLENDING & LUBRICATION

Check for dies & punches

In process checks for compression
COMPRESSION

PACKING
Packing material dispensing Finished product Sample for analysis

DISPATCH

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Qualitative and Quantitative formula:

Product Name: BILASTO (Bilastine 20 mg Tablet)
Composition:
Each uncoated tablet contains
Bilastine 20 mg
Excipients q.s. Shelf Life: 36 Months
Batch size: 100000 Tablets
Overages Qty./
S. Name of Claim Qty/Tab
Spec. Batch. Use
No. Ingredients (mg) (mg)*
(Kg)

1 Bilastine IHS 20 Nil 20* 2.0 API

Microcrystallin
2 BP --- --- 237.11 23.711 Diluent
e Cellulose
Sodium Starch Disintegra
3 BP --- --- 14 mg 1.4
Glycolate nt
Silica Colloidal
4 BP --- --- 1.54 0.154 Glidant
Anhydrous
Magnesium
5 BP --- --- 7.35 0.735 Lubricant
Stearate
* Quantity calculated on the basis of 100% Assay and 0% LOD.
Overages: Nil
Abbreviations: BP: British Pharmacopeia, IHS-In-house, API: Active Pharmaceutical
Ingredient
Description: White coloured, round shaped, biconvex, both sides plain, uncoated tablet.
Averages weight: 280 mg ± 5 %

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Manufacturing description:
PRODUCT INFORMATION
Product Name BILASTO
Generic Name Bilastine 20 mg Tablet
Each uncoated tablet contains
Label Claim Bilastine 20 mg
Excipients q.s
Dosage form Uncoated tablets
Standard Batch Size 1,00,000 Tablets
1 x 10 Tablets
Packing (10 tablets packed in Alu/Alu blister and such blister packed in printed
unit carton along with package insert.)
White coloured, round shaped, biconvex, both sides plain, uncoated
Product Description
tablet
Shelf Life 36 months
Store below 30°C. Protect from light and moisture.
Storage Condition
Keep the medicine out of reach of children.

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Precautions:
To ensure a quality product, all current good manufacturing practices should be followed such as:
1. AREA AND EQUIPMENTS:
a) The area should be free from unwanted materials as well as materials from the last batch.
b) The equipment to be used should be labelled for product, batch no. and date prior to use.
c) The equipment to be used should bear a “clean equipment” tag and wash water analysis report
releasing the equipment is available in case of product changeover.
d) All the areas i.e. manufacturing and packaging should be cleaned as per the respective S.O.P
2. PERSONNEL:
a) All personnel should be in good health and should practice good sanitation habits.
b) Personnel engaged in the manufacture, processing, packaging or holding of drug product
should wear protective apparel such as head, face, hands and arm coverings, necessary to
protect the product from contamination.
3. RAW MATERIALS AND PACKING MATERIALS:
a) All ingredients and packaging materials must be tested for conformance to written
specification.
b) Check physically all containers of active ingredients and excipients for physical appearance,
color, odors & absence of foreign contamination.
c) Weigh all the ingredients by checking the actual quantity for Batch & Q.C, Release No. in the
presence of Storekeeper, Manufacturing and Quality Control Chemist.
d) All the dispensed raw materials should be double checked by the Manufacturing Chemist &
Quality Control Chemist.
4. PRODUCTION AND PROCESS CONTROL:
a) Production records must be complete and accurate reflecting all the procedure and process
adopted during production.

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b) Batch should be fabricated strictly as per the written procedures and any deviation in the
process should be approved by Q.C.
5. GENERAL INSTRUCTIONS:
a) To prevent mix-ups during production stages, material under-process shall be conspicuously
labelled to demonstrate their status. All equipment used for production shall be labelled with
their current status.
b) Packaging lines shall be independent and adequately segregated. It shall be ensured that all left-
over of the previous packaging operations, including labels, cartons and caps are cleared before
the closing hour.
c) Before packaging operations are begun, steps shall be taken to ensure that the work area,
packaging lines, printing machines, and other equipment are clean and free from any products,
materials and spillages. The line clearance shall be performed according to an appropriate
checklist and recorded.
Following practices should be done during the handling of the product:
1. Work surfaces should be covered with disposable plastic backed absorbent paper.
2. Surgical facemasks of good quality should be worn.
3. Adequate washing facilities & suitable eyewash should be easily available for immediate use in
the event of contamination of the eyes, mucous membranes and skin. Copious amount of tap
water should be used if eyewash is for any reason not available.
4. Protective goggles or glasses should be used.
Receive of Raw Material and Packing Material: -
Manufacturing chemist should prepare the requisition slip for the procurement of Raw Materials,
Packing Materials according to the batch size. The Analytical Chemist should counter check it.
Only signed requisition slip should be sent to the store in charge.
All the raw materials must be issued from the tightly closed containers and the containers must be
pasted with the approved green slips having Batch No., Date of Manufacturing, Date of Expiry,
Quality Control Reference No. along with other details. All the raw materials must be transferred
aseptically to the sterile area duly labelled showing name of the product along with gross weight
& net weight. All the packing materials must be issued from the store, as mentioned in requisition
slip. Only those packing materials should be issued which confirm the norms/specifications fixed
by the company, passes the specifications given in Official Pharmacopoeia and pasted with green
slips marked with ‘passes’ along with Q.C. Reference No. Before to start the manufacturing
process a requisition slip indicating the commencement of batch is prepared and sent to the Q. C.

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Deptt., so they can withdraw samples for bulk testing from anywhere they want and also check the
manufacturing is been carried out as per the WHO cGMP guidelines.

MANUFACTURING PROCESS:
1.CHECKING OF WT.: Check the weight of all ingredients. The quantities of each ingredient
are checked and counter checked by approved technical staff. Tally the weights with those in flow
sheet and it is initialed by the pharmacist in charge.
2. SIEVING: All the dispensed raw materials are sifted using vibratory sifter, individually. Care
is taken to prevent cross-contamination and mixing with other products. Materials are sifted using
definite mesh size as per the requirement to obtain uniform particle size, which is further
important in mixing and bioavailability. Sifting is carried out till all the Ingredients pass through
their respective sieves.
3.Dry Mixing:
Charge the materials of step 2 are put in mass mixer for uniform mixing. All above material mixed
up to 30 minutes for complete mixing. Send the mixed powder for the test of uniformity of
mixing.
4.BINDER PREPARATION: Prepare paste of starch in Purified Water* in a SS steel jacketed
vessel & cool this paste to room temperature.
5.BINDING & GRANULATION: Pour the binder solution of step 4 to mixed material of step 3
and mix in RMG till the desired size granules obtained.
6. DRYING: Put the trays with wet mass in Fluidized Bed Drier (FBD) for drying for 1 hour in
FBD. Dry the granules in tray drier at 50°C to 60°C.
7. DRY MILLING/SCREENING: Pass the dried granules of step 6 through No.20# by
Mechanical Sifter. Pass coarse granules through multi mill at medium speed. Using screen 1.5
mm. Weigh and record the weight of granules. Collect all the granules in clean, dry polythene
bags and store in suitable containers. Label with regard to Product Name B. No., Quantity, and
Container No. Stage, till Lubrication, Check moisture content of granules
8.LUBRICATION: Charge the dried granules of step 7 in clean, dry, Blender and for 20 minutes
and lubricate with specified lubricants

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9.UNLOADING: Unload the lubricated granules into clean, dry polythene bags and store them in
suitable containers. Weigh and record the weight of lubricated granules. Label the containers with
regard to Batch No., Product Name and Container No. Total quantity of lubricated granules should
be as per flow sheet.
10. COMPRESSION: After getting approval from QC Department send the granules to
compression section for tableting.
11. ANALYSIS OF UNCOATED TABLETS: Only after ensuring the average weight Diameter,
thickness, friability within the USP specifications continue regular production. Also check the
above parameters intermittently during production, and adjust accordingly. Intimate QC Dept for

random sampling of uncoated tablets.

12. IN PROCESS CONTROL: Draw samples at regular intervals during compression & check
for:
S. NO. IN PROCESS STANDARD LIMITS PERIODICITY
CHECK
1 Physical White coloured, round shaped, biconvex, Every ½ Hr
appearance both sides plain, uncoated tablet
2 Average Weight 280 mg ±5% Every ½ Hr
3. Uniformity of 5% of Average Weight Every 1 Hr
Weight
4. Hardness NLT 3.0 kg/cm2 Every 1 Hr
5. Friability NMT 1.0 % w/w Every 1 Hr
6. Disintegration Every 1 Hr
NMT 15 Minutes
Time

13. INSPECTION: Dedust the tablets and inspected visually for any defects. Compressed air at
70-125 psi, keeping on the hot air blower adjusted at a temperature of 70 0 C. After completion of
spraying, the coated tablets are dried under rolling using hot air blower adjusted at a temperature
of 50-55˚C for 5 min. Blowers adjusted at room temperature cool the tablets. Check the moisture
content by IR moisture balance.
17. PACKING: Packaging belt should be thoroughly checked to ensure that there should not be
any material left behind of the previously run product. Batch No., Mfg. Date, Expiry Date and any

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other necessary instructions for labels and printing should be checked well before starting the
batch. It should be duly signed by competent authority and the sample of such product should be
kept as record.
Master packing procedure:
Product : BILASTO (Bilastine 20 mg Tablet)
Standard Batch Size : 100000 Tablets
Machine : Blister packing machine
Packing:
1 x 10 tablets
(10 tablets packed in Alu/Alu blister and such blister packed in printed unit carton along with pack
insert). Tablets packed in Alu/Alu blisters. Alu/Alu blisters after checking packed in cartons and
finally packed in corrugated boxes duly taped & strapped. After completion of the packing, all the
packed material is to be transferred to the finished goods store along with the complete records.
After getting release certificate from the Quality Control Department, the material is ready for
dispatch. It should be labeled as released.

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3.2. P.2.4
CONTAINER CLOSURE SYSTEM

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3.2. P.2.4. Container Primary Packaging Components:
Type of Packing: 1X10 Tablets
(10 tablets packed in Alu/Alu blister; such blister packed in a printed carton along with pack
insert.)
Closure System
Primary Packing Components
 Aluminum printed foil
 Aluminum Foil
Secondary Packing Components
 Printed Carton
 Pack Insert
Tertiary Packing Components
 Corrugated Box
The cartons are to be packed in a corrugated fiberboard box depending on the type of packing
details. All the cartons are poly-laminated in a group carton, which protects the cartons from
humidity and other damages. The corrugated fiberboard boxes are made of export worthy material
and are sealed with BOPP tape.
Transportation: Should be transported with precautions.
The cautions like
 Not for loose handling
 Protect from water
 Avoid vigorous transportation
 Care should be taken.
The container is found to be suitable for storage, transport & use for the BILASTO (Bilastine 20
mg Tablet) also stability study also proves the container closure system to be effective for the
product during the shelf life.
Compatibility & Safety: There are no compatibility/safety issues with proposed commercial
packing material. They are listed as “Generally recognized as safe (GRAS)” or “suitable for direct
or indirect contact with food” as per 21 CFR 177-2000.
Performance: The packing system is designed to provide adequate protection for the drug product
until use. The stability data supports the use of the packing system. The proposed packing for
BILASTO (Bilastine 20 mg Tablet) 1 X 10 Tablets (10 tablets packed in Alu/Alu blister; such
blister packed in a printed carton along with pack insert.)

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3.2. P.2.5
MICROBIOLOGICAL ATTRIBUTES

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3.2. P.2.5 Microbiological Attributes:
A) Total Aerobic Microbial Count:
Take sample approx. 10 ml/gm and diluted to 50 ml with nutrient broth (Presterilized) and mix
thoroughly. Now take 2 sterile Petri dish and put 1ml in each plate & pour Nutrient agar /Soya
bean casein digest agar approx. 15-20 ml in each plate, shake in a wrist action to mix
uniformly.1.0 ml sample is inoculated also in 10 ml nutrient broth for enrichment.
Incubation: Incubate the plates at 30 - 35 °C for 48 hrs and the broth at 36°C-38°C for 24 hrs.
Observations: After incubation count the colonies and calculate as follow:
Total Viable Aerobic Count = Avg. count x dilution factor
Limits: Total Viable Aerobic Count should not Exceed 102 cfu/g
Acceptance Criteria: NMT 102 cfu/g
B) Total Combined Yeast and Moulds Count
Take approximately 10 ml/gm sample and dilute to 100 ml with pre-sterilized nutrient broth and
mix thoroughly, now take 2 sterilized petri-dishes and put 1 ml in each plat and pour about 20 ml
nutrients agar / seaboard dextrose agar in each plate shake in a wrist action to mix and to make a
uniform layer.
Incubation: Incubate the plates at 20. - 25°C for 5 to 7days.
Observations: After incubation count the colonies and calculate as follow:
Total yeast and molds count = Average count x dilution factor
Limits: Total yeast & molds count should not exceed 101 cfu/g
Acceptance Criteria: NMT 101 cfu/g
C) Escherichia Coli: Using Casein soyabean digest broth. As a diluent make T in 10 dilution of
more than 1 g of the product as mentioned under Total aerobic viable count m Microbial
contamination in nonsterile products and use l0 ml or the quantity corresponding to ,1 g or 1 ml of
the product to inoculate a suitable amount' (determined as under Validity of the Test method) of
Casein soyabean digest broth, incubate at 30° to 35° for 18 to 24 hours. After incubation shake the
broth and transfer 1 ml to 10.0 ml of MacConkey broth (Medium 7). Incubate at 42° to 44° for 24
to 48 hours. Subculture on a plate of MacConkey agar (Medium 8) and incubate at 30° to 35“'for
18 to 72 hours. Growth of pink, non-mucoid colonies indicates the possible presence of
Escherichia coli. This should be confirmed by identification test. If there is no growth of such type
of colonies, or the identification tests are negative it indicates absence of E. coli and the product
passes the test.
Result: Should be absent.

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3.2. P.2.6
COMPATIBILITY

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3.2. P.2.6 Compatibility Studies
Batch No: ATB-003 (Mfg. C) Stability condition: 40°C ± 2°C, 75± 5% RH
Test Specification Initial 3 Months 6 Months
Description White coloured, White coloured, White coloured, White coloured,
round shaped, round shaped, round shaped, round shaped,
biconvex, both biconvex, both biconvex, both biconvex, both
sides plain, sides plain, sides plain, sides plain,
uncoated tablet uncoated tablet uncoated tablet uncoated tablet
Identification The principal The principal The principal The principal
By HPLC peak in the peak in the peak in the peak in the
chromatogram chromatogram chromatogram chromatogram
obtained with the obtained with the obtained with the obtained with the
test solution is test solution is test solution is test solution is
similar to in similar to in similar to in similar to in
retention time to retention time to retention time to retention time to
the principal the principal the principal the principal
peak in the peak in the peak in the peak in the
chromatogram chromatogram chromatogram chromatogram
obtained with the obtained with the obtained with the obtained with the
reference reference reference reference
solution solution solution solution
Uniformity of LI≤15,
Complies Complies Complies
dosage units L2≤25
Friability NMT 1.0% 0.21% 0.24% 0.27%
Hardness NLT 3.0kg/cm2 3.20 kg/cm2 3.21 kg/cm2 3.24 kg/cm2
Disintegration
NMT 15 minutes 03 min to 04 min 03 min to 04 min 03 min to 04 min
Time
Dissolution NLT 75% (Q) of 85.88%-86.24% 85.71%-87.31% 85.44%-87.24%
the labelled
amount of
Bilastine
dissolved in 30

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min.
Microbial Limit Test
Total aerobic
microbial count NMT 102 cfu/g 28 cfu/g 61 cfu/g 68 cfu/g
(TAMC)
Total combined
yeasts & molds NMT 101 cfu/g 07 cfu/g 14 cfu/g 17 cfu/g
count (TYMC)
Escherichia coli Should Be Absent Absent
Absent
Absent
Assay: 18.0 mg to 22.0
Each uncoated mg
tablet contains (NLT 90% and
19.85 mg 19.77 mg 19.64 mg
Bilastine 20 mg NMT 110% of
(99.25%) (98.85%) (98.20%)
the labelled
amount of
C28H37N3O3)

CONCLUSION:
Based on the quality parameters, development data and proposed manufacturing process for
BILASTO (Bilastine 20 mg Tablet) manufactured by Asmoh Laboratories Limited, it is
concluded that Asmoh Laboratories Limited, India has developed a stable, robust and
bioequivalent product BILASTO (Bilastine 20 mg Tablet) to reference product Ilaxten 20 mg
Tablets manufactured by A. Menarini Farmaceutica Internazionale SRL.

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