DOSSIER-LE-ONE TAB (Levofloxacin 500mg)

Dossier Le-One Tab.
500mg
(Levofloxacin ….500mg)
LEVOFLOXACIN(LE-ONE) TABLETS 500MG

Product Registration Dossier
Submitted To The
General Directorate of Pharmaceutical
Affairs – Afghanistan
REGISTRATION DOSSIER
FOR
AFGHANISTAN
Submitted by:
WELLBORNE
PHARMACHEM & BIOLOGICALS
ADDRESS: Head Office & Plant
Plot No. 51/1, 52/2 Phase I & II Industrial Estate, Hattar – Pakistan
PHONE: +92-0995617333
E-mail: [email protected]
Manager Quality Control Manager Quality Assurance

Dossier Le-One Tab. 500mg
DETAILS OF SECTIONS:
I. Section One: General Information

II. Section Two: Administrative Data and Product Information
III. Section Three: Active Pharmaceutical Ingredients
IV. Section Four: Finished Pharmaceutical Products
V. Section Five: Summary of Pharmacology, Toxicology and
Efficacy of the Product

ADMINISTRATIVE DATA AND

PRODUCT INFORMATION
1. Cover Letter
1. The covering letter submitted with the application for registration should include a clear
statement by the responsible person submitting the dossier on the product owner’s original
letterhead, indicating the contact details (telephone number, e-mail, and fax) of the person to
whom all correspondences should be addressed.
2. The letter should be dated and signed by the responsible person who can be the managing
director, president or equivalent person who has overall responsibility for the company
organization.
Noted: Afghan business partner will submit this Letter Locally
2. A Completed and Signed Application Form

1. A completed, signed and dated application form should be submitted for each finished
pharmaceutical product.
2. A competent qualified person shall fill all application forms. He/she shall ensure that all
information provided to the GDPA is true and correct to the best of his/her knowledge. The
applicant shall be aware that if he/she makes any false statement, representation or
declaration in connection with an application to the GDPA, he/she will have committed an
offence.
3. The submission should include hard and soft copies in PDF and Microsoft Word on
DVD/CDs.
Noted: Application Form for Product Registration - Attached
3. Letter of Authorization
1. Applicant should provide a copy of the Letter of Authorization from the product owner forthe application
of registration of products (not applicable if the applicant is the product owner).
2. The letter of authorization should be on the product owner’s original letterhead and be datedand signed by
the Managing Director, President, or an equivalent person who has overallresponsibility for the company or
organization.
Noted: Letter of Authorization - Attached
4. Certifications
For Imported Products:
a) A copy of “Manufacturing License”*(issued by the competent authority in the country

of origin)- Attached
b) A copy of “Certificate of Pharmaceutical Product”* (issued by the competent authorityin the country of
origin according to the current WHO format)
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c) A copy of “Site Master File” of manufacturer (All site master file, if productionoccurred in different
sites.)
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d) A copy of “GMP Certificate” of the manufacture*
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e) A copy of “Certificate of Analysis” (CoA)
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f) A copy of “Registration Certificate”* of the product in in one another country
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Notes:
* Copies of the documents must be duly endorsed by the three organs (Ministry of Health, Ministry
of Commerce and Ministry of Foreign Affairs) of the country of origin and Afghanistan Embassy, in
the absence of Afghanistan Embassy in that country; the un-resident embassy can endorsed the
certificates / licenses.
5. Product Labeling Requirement

1. Applicant should provide samples or proposed drafts of product labeling for the applicationof registration
of products.
2. Language used for labeling shall be English, Dari or Pashto.
3. Samples or proposed drafts of the product labeling are for unit carton, inner label andblister/strips:
Check-List for Unit Carton:

1 Product Name (generic name must be
greater than brand name)
2 Dosage Form
3 Name of Active Ingredient(s)
4 Strength of Active Ingredient(s)
5 Batch Number
6 Manufacturing Date
7 Expiration Date
8 Route of Administration
9 Storage Condition
10 Country’s Registration Number
11 Name and Address of Importer
12 Name and Address of Manufacturer ofthe finished pharmaceutical product
13 Warning (if applicable)
14 Pack sizes (Unit/Volume)
15 The words “Keep Out of Reach of Children
------ Draft Copy Attached------

Check-List for Blister:
1 Product Name (generic name must begreater than brand name)
2 Dosage Form
3 Name of Active Ingredient(s)
4 Strength of Active Ingredient(s)
5 Batch Number
6 Manufacturing Date
7 Expiration Date
8 Route of Administration
9 Storage Condition
10 Country’s Registration Number
11 Name and Address of Manufacturer ofthe finished pharmaceutical product
12 Pack sizes (Unit/Volume)
16 The words “Keep Out of Reach of Children
6. Product Information
1. Applicant should provide samples or proposed drafts of “Patient Information Leaflet” for
theapplication of registration of products.
2. Language used for product information shall be English and/or Dar/Pashto.
3. Samples or proposed drafts of the product information are for Patient Information Leaflet(PIL).
Parameters of Patient Information Leaflet(PIL)

1. Product Name (generic name must be greater than brand name) √
2. Dosage Form and Packing Available √
3. Name of Active Ingredient(s) √
4. Strength of Active Ingredient(s) √
5. Product Description √
6. Pharmacodynamics/ Pharmacokinetics √
7. Indication (must be only in English language) √
8. Recommended Dose √
9. Rout of Administration √
10. Contraindication √
11. Warnings and Precautions (if applicable) √
12. Interactions With Other Drugs √
13. Pregnancy and Lactation √
14. Undesirable Effects or Adverse Effect √
15. Overdose and treatment √
16. Storage Condition √
17. Name and Address of Importer √
18. Name and Address of Manufacturer of the finished pharmaceuticalproduct√
19. Date of Revision of Patient Information Leaflet

SECTION THREE
ACTIVE PHARMACEUTICAL
INGREDIENT(S) (APIs)
The information on the Active Pharmaceutical Ingredient(s) [API(s)] can be submitted according to
the following order of preference .Provide at least the following information for each active
pharmaceutical ingredient:
1-) Nomenclature
 International Non-proprietary Name (INN)
 Compendial Name if relevant
 Chemical Name(s)
 Company or laboratory code, if applicable
 Other nonproprietary name(s) (e.g., National Name, United States Adopted Name
(USAN),British Approved Name (BAN) and Japanese Accepted Name (JAN) ); and
 Chemical Abstracts Service (CAS) registry number.
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2-) Properties of Active

Pharmaceutical Ingredient(s)
 2.1. API Described in Recognized Pharmacopeia (BP, USP, EP, JP & IP)
  API described in recognized pharmacopoeia, proof of structure can be demonstrated
by
 comparison of spectral data [in particular overlay Infrared (IR) and/or Nuclear
Magnetic
 Resonance (NMR) spectra] with an official reference standard;

 2.2. API NOT Described in Recognized Pharmacopeia (BP, USP, EP, JP& IP)
 Provide the following information
 Chemical structure, including relative and absolute stereochemistry, (e.g. racemate,
pure (S)-isomer, 50/50 mixture of (Z) - and (E)- isomers), the molecular formula, and
the relative molecular mas;
 Isomeric nature including stereochemical configuration;
 Provide documented evidence of correctness of structure and stereochemistry, such as
infrared, nuclear magnetic resonance, ultraviolet, mass and X-ray spectra, together
withinterpretation of the relevant parts of spectra. Correlation of the spectral data with
datafrom peer reviewed literature may also be used for confirmation;
 Physicochemical and other relevant properties of the API, such as solubility in water,
other solvents such as ether, ethanol, acetone, and solubility in buffers of different pH;
including at pH 1.2, acetate buffer at 4.5 and phosphate buffer at pH 6.8; partition
coefficient; existence/absence of polymorphic forms and water/solvent of
crystallization; results of hygroscopicity testing and particle size.
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3-)Site(s) of Manufacture- Active

 State the name, street address (including the block or unit number), telephone, fax,
email, and responsibility of each manufacturer, including contractors, and each
proposed production site or facility involved in manufacturing and testing should be
provided. Include any alternative manufacturers.
 The facilities involved in the fabrication, packaging, labeling, testing and storage of the
API should be listed. It should be clearly indicated, if certain companies are responsible
only for specific steps (e.g. milling of the API).
 A valid manufacturing authorization (license) should be provided for the production of
APIs. A certificate of GMP compliance in the format of a WHO-type GMP certificate from
the competent authority of the country of manufacture should be provided.
Route(s) of Synthesis of Active Pharmaceutical Ingredient (s)

3.1. API Described in Recognized Pharmacopeia (BP, USP, EP, JP& IP)
 If the API is the subject of a monograph in a recognized pharmacopoeia, provide an
outline of the route of synthesis (a flow chart and a qualitative description of the
manufacturing method, including the names of solvents, reagents and catalysts)
However, note that pharmacopoeia monographs are designed to control impurities
from those routes of synthesis that were considered during monograph development,
and impurities from other routes of synthesis may not be controlled. In the case of the

 European pharmacopeia, provide a European certificate of suitability together with a

report. When certificates of suitability is not available, and in the case of other
pharmacopoeias, provide evidence that the monograph is able to control the impurities
that actually occur following this route of synthesis. Normally the evidence will
comprise the results of chromatographic tests (using at least two chromatographic
systems) on several batches. Additionally, specifications may be requested by
evaluators for starting materials, solvents, reagents and intermediates whose purity is
critical to the impurity profile of the final API.
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4-)Specification for the Active

Pharmaceutical Ingredient (s)
 4.0:Copy of the API specifications, dated and signed by authorized personnel (e.g. the
person in charge of the quality control or quality assurance department) should be
provided in the dossier, including specifications from each API manufacturer as well as
those of the Finished Pharmaceutical Products.
 The specification reference number and version (e.g. revision number and/or date)
should be provided for version control purposes.
 4.1. API Described in Recognized Pharmacopeia (BP, USP, EP, JP& IP)
 Provide a copy of the monograph together with any test methods referenced in the
monograph. that the current monograph should always control the quality of the API.
 Any additional tests, with limits, not appearing in the monograph should be described
in sufficient detail to be replicated by another laboratory. Additional tests may for
example include synthesis- (process-) specific impurities not covered by the
monograph, and requirements that are important for the pharmaceutical product (for
instance particle size and crystal form when there are polymorphs).
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5-) Batch Analysis

 Provide certificates of analysis for at least two batches produced at each site of
manufacture by each synthetic method, including results for impurities. The
information provided on batch analysis should include batch number, batch size, and
date and production site of relevant API batches used in comparative bioavailability
studies, preclinical and clinical data, (if relevant), stability, pilot, scale up and, if
available, production scale batches. These data are used to establish the specifications
and evaluate consistency in API quality.
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6-) Container Closure System
 Provide a description of the container closure system(s), including the identity of

materials of construction of each primary packaging component and their
specifications.
 The specifications should include description and specific test for identification (and
critical dimensions with drawings, where appropriate).
 Provide only a brief description for non-functional secondary packaging components
(e.g., those that do not provide additional protection). Provide additional information
on functional secondary packaging components.
 The suitability should be discussed with respect to, for example, choice of materials,
protection from moisture and light, compatibility of the materials of construction with
the API, including sorption to container and leaching, if applicable, and/or safety of
materials of construction.
 Copies of the labels applied on the secondary packaging of the API should be provided
and should include the conditions of storage. In addition, the name and address of the
manufacturer of the API should be stated on the container.
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7-) Stability Testing of the Active

 Provide the results of stability testing of the active pharmaceutical ingredient. If the
API is well established, information on its stability may be provided in the form of
papers from the scientific literature.
 Results should be included for physical as well as chemical tests, e.g., (where relevant)
particle size and polymorphic form. The study should be designed to show whether
trends occur over time.
 Provide specifications for the primary packaging materials used in stability testing and
those proposed for routine storage and transport of the API, including the nature of
each material.
 Data from stability testing of not less than three primary batches of the API should be
provided.
 The batches should be manufactured by the same synthesis route as production
batches, and using a method of manufacture and procedure that simulates the final
process to be used for production batches.
 The information on stability studies should include details such as storage conditions,
batch number, batch size, container closure system and proposed test intervals.
 Describe the methodology used during stability studies; if this is identical to
methodology described elsewhere in the dataset, a cross-reference will suffice. If
different methodology was used, provide validation of tests for impurities and assay,
and for other tests as necessary (e.g. particle size testing).
 The minimum data required at the time of submitting the dossier (in the general case):
Study Storage Condition Relative humidity Minimum time

(ºC) (%) period(months)
Accelerated 40 ± 2 75 ± 5 6
Long-term 30 ± 2 65 ± 5or 75 ± 5 12
Provide the post-approval stability protocol and stability-testing commitment, when applicable.
A storage statement should be proposed for the labeling (if applicable), which should be based on the
stability evaluation of the API.
The shelf life should be derived from the stability information, and the approved shelf life should be
displayed on the container label and certificate of analysis.
The WHO guideline on Stability testing of active pharmaceutical ingredients and finished
pharmaceutical products, WHO Technical Report Series, No. 953, Annex 2 should be considered.
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SECTION FOUR
FINISHED PHARMACEUTICAL
PRODUCTS (FPPs)
The information on the Finished Pharmaceutical Products (FPP) should be submitted

according tothe following order of preference:
1. Description of the Finished Pharmaceutical Product

The description of the FPP should include the physical description, available strengths, releasemechanism
(e.g. immediate, modified (delayed or extended), as well as any other distinguishablecharacteristics, e.g.
“The proposed XYZ 50mg Tablets are available as white, oval, film-coatedtablets, de-bossed with ‘50’ on
one side and a break-line on the other side”
Description:
Product Name LE-ONE 500mg Tablets

Generic Name Levofloxacin (as Hemihydarte) 500 mg
Off white color oblong film coated tablet with a break line on one face,
Description blister in Alu – Alu packingwith multicolor printing on off white color
carton.
Each film coated tablet contains
Label Claim
Levofloxacin Hemihydrate USP Eq. to Levofloxacin 500 mg
Identification Zone Comparison
Average wt per tablet 640mg (5% +/-)
Disintegration time NMT 30 minutes
Weight Deviation NMT + 5.0%
Assay:
Levofloxacin 630mg/tab--------------------650mg/tab
Hemihydrate eq. to 90%---------------------------110%
Levofloxacin
Dosages form Film Coated Tablets
Shelf Life Three Years
Storage Condition Store in a cool, dry place and protect from light.
Standard
Packing 1 x 10 Alu-Alu Pack 50,000 Tablets
Batch Size

2. Formulation
Provide the composition, i.e. list of all components of dosage form in a tabular format as bellow:
- List of all components of the dosage form, and their amount on a per unit basis (includingoverages, if any),
the function of the components, and a reference to their quality standards(e.g. compendial monographs or
manufacturer’s specifications). If an excipient performsmultiple functions the predominant function should
be indicated. Use the table below topresent the information on the composition of the FPP.
UNIT FORMULA:-
Pack Size 1 x 10’s
Batch Size 5,000 Packs
S# Ingredient Functions Quality Qty/Unit(Tab.) Qty/Batch 5000

Standard Mg/ml Packs (KGS)
%
1 Levofloxacin Active (API) USP 500mg 25 - KGS
In-Active Ingredients
Kyron Disintegrant BP 13mg 0 0.650-KGS
Lactose Monohydrate Diluent BP 32.57mg 0 1.628-KGS
PVP K 30 Binder BP 30.00mg 1.50-KGS
IPA Solvent BP 0.21ml 0 10.50-Lits.
Mangnesium Sterate Lubrican BP 13.00mg 0 0.650-KGS
Sodium Starch Glycolate Disintegrnt BP 26.00mg 0 1.30-KGS
SUB TOTAL – 1 614.78mg 41.228-KGS
HPMC E 5 Coating Material BP 18.00mg 0 0.900-KGS
Titanium Dioxide Opacifier BP 4.00mg 0 0.200-KGS
PEG 6000 Plasticizer BP 2.00mg 0 0.100-KGS
IPA Solvent BP 0.23ml 0 11.5-Lits.
R/OWater Solvent BP 0.104ml 0 5.20-Lits.
SUB TOTAL – 2 24.334mg 17.900-KGS
Total 639.114mg 59.128
Remarks:
The Standard quantity of Levofloxacin is considering on the basis 100% Assay & 0% LOD/Water.
The required quantity of Levofloxacin should be calculated on the basis of Assay result, from Q.C. Raw
Material Report by the following formula:
Batch Size (in numbers) X (Label Claim + overage %) X 100 X 100
= -------------------------------------------------------------------------------------------- = kg
Assay value (OAB) X (100 - % LOD) X 1000 X 1000

3. Pharmaceutics Development
Provide either the results of development pharmaceutics or a review of literature information on the
same topic, including for example:
- The definition of the quality target product profile (QTPP) as it relates to quality, safety and
efficacy, considering, for example, the route of administration, dosage form, bioavailability,strength and
stability;
- Identification of the potential critical quality attributes (CQAs) of the FPP so as to adequatelycontrol the
product characteristics that could have an impact on quality;
- Studies of the chemical and physicochemical compatibility of the API with potentialexcipients, and with
other APIs if present;
- Dissolution rate of pilot formulations, and the selection and justification of the dissolutionmethod and limit
for the final product. Provide dissolution profiles for at least threeconsecutive batches manufactured
according to the final formulation and manufacturingprocedure;
- Comparative dissolution of the batch used in pharmacokinetic or bioequivalence studiescompared with an

acceptable reference product or innovator product should be submitted.Recommendations for conducting
and assessing comparative dissolution profiles can befound in Annex VI.
- Stability of pilot formulations under accelerated conditions and under the maximum
recommended conditions of storage;
- Rationale for the selection of excipients and the function of each in the formulation.
For well-established products, a product quality review can be provided in lieu of the
developmentpharmaceutics. For this purpose, a well-established product is one that has been marketed by
theapplicant or manufacturer associated with the dossier for at least ٥ years and for which at least
10production batches were produced over the previous year, or, if less than 10 batches were producedin the
previous year, not less than 25 batches were produced in the previous three years.

P3.1: Information on development studies:
N/A as product is generic formulation
P3.2: COMPONENTS OF THE DRUG PRODUCT

LEVOFLOXACIN HEMIHYDRATE
ACTIVE INGREDIENTS:Each film coated tablet contains
Levofloxacin Hemihydrate USP
eq. to Levofloxacin………500 mg
Physical and chemical properties:
Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration.
Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)(S)-enantiomer of the racemic
drug substance ofloxacin.
Molecular formular:
The empirical formula is C18H20FN3O4• ½ H2O
Molecular weight:
The molecular weight is 370.38
Chemical Name:
Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a
zwitterion at the pH conditions in the small intestine.
Molecular structure:
P.3.3.2 Excipients
The drug product was developed by following the established SOP where various trials were conducted to
achieve the intended profile comparable to concerned brand. The excipients profile is compatible, non-
reactive and safe.

The following table shows the excipients used in the manufacturing process of LE-ONE 500MG tablets,
their influence in the drug product performance as well as their quantity in the formulation:
S# Name of excipients Functions Qty/Unit(Tab.) Specifications

Mg/ml
%
1 Kyron Disintegrant 13mg 0 BP
2 Lactose Monohydrate Diluent 32.57mg 0 BP
3 PVP K 30 Binder 30.00mg 0 BP
4 *IPA Solvent 0.21ml 0 BP
5 Mangnesium Sterate Lubrican 13.00mg 0 BP
6 Sodium Starch Disintegrnt 26.00mg 0 BP
Glycolate
7 HPMC E 5 Coating 18.00mg 0 BP
Material
8 Titanium Dioxide Opacifier 4.00mg 0 BP
9 PEG 6000 Plasticizer 2.00mg 0 BP
10 *IPA Solvent 0.23ml 0 BP
11 *R/O Water Solvent 0.104ml 0 BP
*Will not appear in the final product

P3.3.1 Formulation Development

1.0 Report Approval:
This document describes the research and development report on LE-ONE (Levofloxacin-as
Hemihydrate) 500 mg Tablets.
The document has been prepared, reviewed and approved by R & D OFFICER, R & D MANAGER, and PLANT
MANAGER.
2.0 Objective:
To develop LE-ONE (Levofloxacin-as Hemihydrate) 500 mg Tablets. comparable to innovator product
of same strength product with the following objectives
1. Producing an optimal formula and process.

2. Establishing specifications for process/ formulation variables to ensure that Dry Mix specifications will
be meet.
3. Proposing in process tests for critical process variables and raw material specifications for critical
formulation variables when appropriate.
4. Documenting above information.
3.0 Scope:
This development report is applicable to development of LE-ONE (Levofloxacin-as Hemihydrate) 500
mg Tablets. using the facility of WellBorne Pharmachem & Biologicals Pvt. Ltd, Pakistan.
4.0 A Systematic Approach:
A Systematic approach to LE-ONE (Levofloxacin-as Hemihydrate) 500 mg Tablets. design and

product development activities were sub divided in to literature search, formulation development and
process development. The various studies carried out during these phases were given below.

P3.3.1:PREPARATORY WORK
 TRAIL BATCHES FOR LEVOFLOXACIN (AS HEMIHYDRATE) 500 mg TABLETS
BATCHES DETAILS
S.
No Ingredients Trial 01 Trial 02 Trial 03 Trial 04
.
1 Levofloxacin(As Hemihydrate) 25-KGS Kg 25-KGS Kg 25-KGS Kg 25-KGS Kg
2 Kyron 0.650-KGS 0.650-KGS 0.650-KGS 0.650-KGS
3 Lactose Monohydrate 1.628-KGS 1.628-KGS 1.628-KGS 1.628-KGS
4 PVP K 30 1.50-KGS 1.50-KGS 1.50-KGS 1.50-KGS
5 *IPA 10.50-Lits. 10.50-Lits. 10.50-Lits. 10.50-Lits.
6 Mangnesium Sterate 0.650-KGS 0.650-KGS 0.650-KGS 0.650-KGS
7 Sodium Starch Glycolate 1.30-KGS 1.30-KGS 1.30-KGS 1.30-KGS
8 HPMC E 5 0.900-KGS 0.900-KGS 0.900-KGS 0.900-KGS
9 Titanium Dioxide 0.200-KGS 0.200-KGS 0.200-KGS 0.200-KGS
10 PEG 6000 0.100-KGS 0.100-KGS 0.100-KGS 0.100-KGS
11 *IPA 11.5-Lits. 11.5-Lits. 11.5-Lits. 11.5-Lits.
12 *R/OWater 5.20-Lits. 5.20-Lits. 5.20-Lits. 5.20-Lits.
Batch Size 5000-Packs 5000-Packs 5000-Packs 5000-Packs
The option for this formulation is justified by the demonstrate advantages namely:
- The pharmaceutical form manufactured by Well-Borne Pharmachem & Biologicals (Pvt) Ltd. is
optimum for oraladministration.
- Ensure a good stability for the Drug substance, fact demonstrated through stability studies
- Patient compliance beside this pharmaceutical form
- Easy dosing
The excipient from the composition of LE-ONE 500mg Tablets (Levofloxacin Hemihydrate INN
equivalent to Levofloxacin 500.00 mg) in each tablet does not interact with Drug substance. These
excipients are currently used in pharmaceutical industry and their quality corresponds to
BP & inhouse specification
As we said, for determining theLE-ONE 500mg Tablets formulation we start from the qualitative
formulation of the product Tanavic 500 mg Tablet (Hoechst Marion Roussel Ltd).
 Comparative Dissolution Report

A Comparative Dissolution studies were done where test product and reference product were as follows:

Test product: LE-ONE 500MG TABLETS

Well-Borne Pharmachem & Biologicals
Each tablet contains Levofloxacin Hemihydrate INN equivalent to
Levofloxacin 500 mg
Reference product: TANAVIC 500 mg TABLET

(Hoechst Marion Roussel Ltd, England)
Each tablet contains Levofloxacin Hemihydrate equivalent to
Levofloxacin 500 mg
On the basis of the studies Comparative Dissolution Report is provided below:
Comparative Dissolution Report of LE-ONE 500mg Tablets with Tanavic 500 mg Tablet
Dissolution
Tablet Concentration (% ) of the
No. labeled amount
Ingredient Tolerance Remarks
LE-ONE Tanavic 500 mg
500 mg Tablet
Tablets
Levofloxacin 1 95.25 94.33 Not less than 80% (Q) Satisfactory
2 94.79 93.87 of the labeled amount of
3 96.32 95.85 Levofloxacin
4 93.06 96.01 ( C18H20FN3O4) is
5 94.87 93.89
dissolved in 30 minutes
6 93.88 94.55
Average 94.70 94.75
Comments: Dissolution values of LE-ONE 500mg Tabletsand Tanavic 500 mg Tablet are very close
together. Hence Dissolution Profile of LE-ONE 500mg Tabletsis comparable to Tanavic
500 mg Tablet.
It was considered that the product was to be developed LE-ONE 500mg Tabletscan be formulated
qualitatively similar of Drug product Tanavic 500 mg Tablet-manufactured by Hoechst Marion Roussel
Ltd, England.
P3.3.2: Overages:
Overage 5% is needed to ensure the declared concentration of the active substance at the end of shelf
life
Overage is to cover loss of potency on storage.
Overages 5 %, Overages taken due to waste of raw materials that occur during manufacturing of finished
products.

P2.3.3 : Physicochemical and biological properties parameters
Physicochemical Properties:
AVERAGE WEIGHT OF TABLETS:

Weigh twenty tablets taken at random, and determine the average weight in mg as given below:
Weight of 20 Tablets
Average weight = --------------------------------------
20
WEIGHT VARIATION:
Take 20 tablets and weigh individually. Calculate the maximum and minimum weight variation of the tablet as
follow.
Maximum Weight Variation = Max weight of the tablet - Avg. weight of the tablet
Avg. weight of the tablet
Minimum Weight Variation = Min weight of the tablet - Avg. weight of the tablet
Avg. weight of the tablet

P.3.3.3 Physicochemical and Biological Properties
Detail description of the physical and chemical tests conducted on drug product during the development:
Sr. # PARAMETERS SPECIFICATIONS

Off white color oblong film coated tablet with a
1 Description. break line on one face, blister in Alu – Alu packing
with multicolor printing on off white color carton.
2 Identification Levofloxacin must be positive
3 Average weight 670 mg (+/- 5%).
Uniformity of dosage units
4 Meets the requirement
5 Specific optical rotation -92.0o to -106.0o

6 Disintegration NMT 30 minutes
7 Dissolution NLT 80% should be dissolved in 30 minutes.
Claim: 500 mg / Tablet
8 Assay: Levofloxacin (C18H20FN3O4)
90 – 110 % of the label claim.
P.3.2.4 Manufacturing Process Development
Not applicable
P.3.2.5 Container Closure System

LE-ONE 500mg tablets (Levofloxacin 500mg/ tablet.) is packed into a Alu- Alu blister, 1 blister is packed
a carton box together with the leaflet. The package system preserves them from moisture and light. The
stability studies have established the compatibility of the drug product with the primary container.
Summary of Packaging Materials

ITEM ITEMS STANDARD
UNIT
CODE QUANTITY
PRIMARY PACKING COMPONENTS
1 Printed Aluminum Foil for LE-ONE Tablets 500 3.500
kg
mg (0.74gm/blister)
2 Alu Alu Foil 100 mm for LE-ONE Tablets 500 17.500
mg kg (2.93gm/blister)
SECONDARY PACKING COMPONENTS
3 Printed Unit Carton ( 1 X 10 tablets) for LE- 5,000
ONE Tablets 500 mg Nos
4 Printed Leflet for LE-ONE Tablets 500 mg Nos 5,000
5 Outer Carton for LE-ONE Tablets 500 mg (400 56

Unit Packs) Nos
6 Gum Tape Nos Q.S

Tertiary Packing Components

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 cartons, which protects the cartons from humidity and other damages.
The corrugated fiberboard boxes are made of export worthy material and are sealed with a 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 & closure as described above used for the storage, transportation (shipping) and use of the
product, is suitable & compatible for LE-ONE (Levofloxacin (as Hemihydrate) 500 mg Tablets) is protected
from moisture and light. Stability study also proves the container closure system to be effective for the
product during the shelf life.
P.3.2.6 Microbiological Attributes

Not applicable
P.3.2.7 Compatibility
As the results of stability studies of the preparation, all excipients are compatible with each other and with
the medicinal substance and not form complexes, which may adversely affect the efficiency and quality of
the drug.
FLOW CHART OF MANUFACTURING

Approved raw materials & Excipients
Granulation (Sifting) (sieve no. As per BMR)
Preparation of Binder Solution

Dry Mixing (Time as per BMR)

Wet Granulation (time & tem. as per BMR)
Drying (Time as per BMR)
Dry Screening (Time & Tem. as per BMR)
Lubrication (Time as per BMR)
Compression
Dedusting
Coating
Final Packing
Transfer to Finished Goods Store
Dispatch

P3.4 Manufacturing Process Development
To achieve the LE-ONE 500 mg tablets of required specifications, the Raw Materials mentioned in Formula
are gone through the following steps.
Granulation:
Granulation is carried out according to the following steps.
a) Premixing:
Manually sieve following materials through #30 Mesh Screen.

INGREDIENTS QUANTITY
UNIT
Levofloxacin hemihydrate Kg 25.75
Kyron Kg 0.65
Mix Throoughly all above sieved materials in to Hobart Mixer for 30 min. Add recovered materials (if any)
already crushed and passed through 12# mesh.
b) Preparation Of Binding Solution:

For the preparation of Binding solution, following ingredients are required:
INGREDIENTS UNIT QUANTITY
Povidone (PVP k- 30) Kg 1.500

Water Lit 5.200
To a container add water and dissolve PVP K 30 with spatula until clear solution obtained.
c) Kneading:
Add the prepared binder solution in step 3.1 to the premix of step 2.1 in a stream line and mix the entire
bulk for 10 min till the completion of kneading process with Hobart mixer.
d) Wet Granulation:
The kneaded mass obtained in step (c) through mesh # 6 or directly, dry in the form of lumps. Spread the
contents in the S.S Trays for drying.
e) Wet Drying
Dry the wet granules of step (d) in a fluidized bed dryer for 60 mins at a temperature not exceeding 70 o C.
f) Dry Granulation:
Using OSC granulator, sieve the dried granules obtained in step (e) through mesh # 12.
g) Final Drying:
If required, further dry the granules in fluid bed dryer at a temperature not exceeding 60 C to a L.O.D. not
more than 2%. Avoid over drying.
h) Final Mixing& Lubrication:

Load the final dried granules of above step in S.S. Mixer. Weigh accurately the following ingredient on
Digital Weighing Balance and sieve them through 12# S.S. screen and mix with the granules for 15
minutes.

INGREDIENTS UNIT QUANTITY

Sodium Starch Glycolate Kg 1.300
Mag Stearate Kg 0.650
Lactose Monohydrate Kg 1.628
IPA 10.500
Maximum Time should not exceed >60 min
Take Clearance from Quality Control Lab by sampling the final mixture.
Compression:
Clean the compression section and the ZP-17 rotary compression machine, adjust the following dies and
punches on it
DESCRIPTION SIZE SHAPE
Upper Punch 20 mm Oblong, BiConvex,
Lower Punch 20 mm Oblong, BiConvex,
Dies 20 mm Oblong
After setting of the machine, Label it properly and ask the Q.C.D. to issue area clearance certificate.
After getting release slip and analysis report of the granules, adjust the machine speed and pressure and
compress few tablets according to the following parameter.
PARAMETER SPECIFICATIONS
Average Weight 640 mg (± 3%)
Average Hardness NLT 5.0 Kg
Average Thickness 5.5 mm ± 5%
Send request to the Q.C.D. to collect the sample of the tablets for physical analysis. After getting results of
the physical analysis from the Q.C.D., start compression. Carry out the periodic check for average weight,
Hardness, Thickness, and Physical appearance and record on compression control sheet.
After completion of compression send request to the Q.C.D. to take Sample of compressed tablets for
analysis and give release for film coating.
Store the core in suitable properly labeled containers with double polythene bags and a packet of silica gel
between the two bags. Note the weight of the cores.
Film Coating
After getting release slip and analysis report of cores for film coating, proceed for the film coating. Clean
the area and all the Machines & equipments, Label them properly and ask the Q.C.D. to issue the Clearance
Certificate.
Coating Suspension Preparation:

Weigh accurately the following ingredients on a Digital Weighing Balance
INGREDIENTS QUANTITY
UNIT
HPMC E 5 Kg 0.900
IPA Kg 11.500
Titanium Dioxide Kg 0.200
PEG 6000 Kg 0.100
Using container of 30 Lit add following in sequence while Silver Son Mixer is switched on. Mix the entire
solution for 50 min till it becomes homogenized. Manually sieve the suspension through 100 # Mesh screen.
Film Coating Process:

De-dust the cores using 10 # S.S. sieve and charge them into clean film coating pan. Transfer the coating
suspension to the pressure tank of the film-coating unit. And set as follows
Atomizing Pressure 2.0 Bar

Gun Pressure 2.5 Bar
Tank Pressure 0.4 Bar
Air Pressure 3.0 – 4.0 Bar
Pre heat the core to about 40 C, open the exhaust and start the film coating process by spraying the
coating suspension on the cores. Complete the film coating process in the same manner. During film
coating process, take care not to over heat the tablets and also avoid over wetting.
After completion of film coating, send request to the Q.C.D. to take Sample of film coated tablets for
analysis and give release for packing.
Store the Film Coated Tablets in suitable properly labeled containers with double polythene bags and a
packet of silica gel between the two bags. Note the weight of the Film Coated Tablets.
Note: Carry out the film coating process in controlled conditions of relative Humidity (NMT 45%)
IN Process Control
 Physical appearance
 Weight variation
 Disintegration
 Hardness,
 Friability,
 Length,
 Thickness,
 Capping, Optical checking

PRECAUTIONS WHILE DISPENSING &MANUFACTURING OPERATION:

 Good manufacturing practices shall be followed throughout manufacturing process. Ensure area and equipment is
clean before commencing manufacturing operation.
 Check that all materials are released by Quality control prior to dispensing. Ensure that the ‘Release’ labels carry
complete/filled details by QC.
 Check the pressure differential in each processing area and ensure that it is within limit.
 Check that all balances which are to be used, are calibrated and are cleaned between dispensing of two different
raw materials.
 Ensure that Product container and Equipments are labeled at all stages of Manufacturing.
 Transfer all the dispensed material from store to manufacturing area at one time. Counter check and record
identity and weights of all the ingredients received .Do not use any material, which does not comply in weight or
analytical report numbers.
 Maintain and record the environmental conditions of all process areas. The temperature shall not exceed 25C and
relative humidity shall not be more than 60 % during processing and storage of in process materials.
 Use hand gloves and mask while handling the product / material & swab hand gloves with disinfectant but ensure
they are dry before dispensing.
 Follow the current Standard Operating Procedures.
 Check that manufacturing area & production line is clean and free of previous product prior to start of work.
 All entries in BMR must be completed and duly signed by responsible persons soon after completion of the step.
 Record all abnormality or out of specification, if any, in the deviation report.
 Store the material, in process material, semi- finished and finished material in designated area properly labeled
mentioning status of the material and batch details.
*The blend and tablets shall not be stored for more than 07 days during the manufacturing process and Compression

A. LIST OF THE EQUIPMENTS FOR LINE CLEARANCE RECORD:
Check the following equipments for the cleanliness and cleaned status before use cleaning to be done as per
SOP.
 EQUIPMENT DESCRIPTION FOR THE MANUFACTURING OF TABLETS (LE-ONE TABS 500 mg)
Sr. # Equipment Name Type & Capacity Identification #.
1. Ribbon Mixer (S S) 100 Kg LOCAL
2. Double Cone Mixer(S S) 100 Kg LOCAL
3. Rotary Granulator (S S) 100 kg LOCAL
4. Oscillating Granulator(S S) 50 kg LOCAL
5. Fluid Bed Dryer(S S) 30 kg/Load LOCAL

7. Tray Dryer (S S) 100 kg LOCAL
8. Tablet Rotary Machine ZP-17 200,000 Tabs/8Hr CHINA
9. Coating Pan-1 50 kg LOCAL
10 Coating Pan-2 10 Kg LOCAL

EQUIPMENT DESCRIPTION FOR THE PACKAGING TABLETS
11. Alu-Alu Blistering Machine-1 30 Strokes/min CHINA
12. Tablet Compression Machine ZP-25 400,000 Tabs/8 Hr CHINA
13. Coating Solution Mixer(S S) 20 L LOCAL
15. S.S Top Packing Tablets 6 – Nos. LOCL

16. HVAC – System
Air Handling unit
17 General Tablet - 6.5 Ton PAKITAN
18. G.T (Mixing Section) 6- Ton PAKISTAN
19 G.T (Drying Section) 10 – Ton PAKISTAN
 EQUIPMENT DESCRIPTION FOR THE Q. C. TESTING OF TABLETS (LE-ONE TABS 500 mg)
QUALITY CONTROL EQUIPMENTS LIST

S.No Equipment Name Model Made By Q.C Identification
WP/QC/INST/001
01 HPLC CE150W Germany
WP/QC/INST/002
02 Melting point Apparatus GMP L1 UK
03 pH Meter 511212 USA WP/QC/INST/003
04 Hardness Tester MH-1 Galvano WP/QC/INST/004
scientific
05 Analytical Balance D449517180 Japan WP/QC/INST/005
06 Moisture Analyzer AG53 Switzerland WP/QC/INST/006
WP/QC/INST/007
07 Hot plate Magnetic stirrer 78-1 China
Galvano
08 Friabiliator FT-L WP/QC/INST/008
scientific
Galvano WP/QC/INST/009
09 D.T Apparatus 122LR
scientific
WP/QC/INST/010
10 Dissolution Apparatus GDT6(L) China
11 Particle counter IEC828-1 California WP/QC/MI/011
12 Water bath DH6-9030A China WP/QC/INST/012
13 Distillation Plant --- China WP/QC/INST/013
3326S/N35310
14 Hot Incubator USA WP/QC/MI/014
-6278
15 Cold Incubator SPX-150 China WP/QC/MI/015
16 Microscope 891159 Japan WP/QC/MI/016
17 Colony counter manual 501A Japan WP/QC/MI/017
18 Dry Heat Sterilizer ANC-677 China WP/QC/MI/018
WP/QC/INST/019
19 Ultrasonic bath VGT-1730QD China
A-Heico
20 Stability Chamber(Real time) DSX-300H WP/QC/INST/020
Company
21 U.V Spectrophotometer UV/VIS China WP/QC/INST/021
Vortex Mixer ---- WP/QC/INST/022
22 China
TDS, Conductivity & pH H19811-5
23 Europe WP/QC/INST/023
Meter
24 Biological Air Sampler MB-1 UK WP/QC/MI/024
25 Anemometer 8340 USA WP/QC/MI/025
26 Micropipette CE-092677 China WP/QC/MI/026
27 Autoclave ---- China WP/QC/MI/027
28 Millipore Filtration Assembly --- China WP/QC/MI/028
29 Laminar Flow Hood --- China WP/QC/MI/029
DISTEK WP/QC/INST/030
30 UV Spectrophotometer China
13599
31 Vacuum Pump AS20 --- WP/QC/INST/031
32 Sealing Apparatus KARTELL ITALY WP/QC/INST/032
33 Refractive Index ABBE China WP/QC/INST/033
34 pH meter 290A USA WP/QC/INST/034
35 Vacuum Pump XX5500000 China WP/QC/MI/035
36 Refrigerator --- DAWLANCE WP/QC/MI/036
37 TOC Analyzer SIEVER 800 USA WP/QC/INST/037
Stability Chamber Caravell
38 Mec-450 WP/QC/INST/038
(Accelerated) Pakistan
39 pH meter bench top 3010M Jenco WP/QC/INST/039
40 Electronic Micro Meter --- China WP/QC/INST/040

41 Digital Vernier caliper --- China WP/QC/INST/041
42 Atomic absorption Z-9000 Hitachi Out of order
43 Distillation plant --- -- Out of order
44 Dissolution apparatus DT:6(1.S) Germany Out of order
45 pH Meter 511212 USA Out of order
46 UV Spectrophotometer UV-2800 China Out of order
47 Colony counter Digital 3327 USA Out of order
48 Atomic absorption Z-9000 Hitachi Out of order
 EQUIPMENT DESCRIPTION FOR THE UTILITIES/SERVICES OF TABLETS (LE-ONE TABS 500

mg)
Sr. # Equipment Name Type & Capacity Equipment Identification #.

1. Hygrometer Zeal England
3. Digital Weighing Balance
4. Digital Weighing Balance
6. Dehumidifier (General Tablet) 90L/hr Sabro
7. Dehumidifier (Cephalosporin) 90L/hr Sabro
8. Dehumidifier (RMS Ceph) 60L/hr Local
9. Dehumidifier (RMS General) 25L/hr Local
10. Dust collector (Miscellaneous)
11. Insect Killers (Different sets)
12. Induction Sealing Machine(manual)
13. Bottle Blowing Machine (Syrup)
14. Dispensing Hood
15. Sampling Hood
16. Split Air-conditioners
17. Window Air Conditioners
18. Hand Pallet Fork Lifter
19. Working in Engineering Dept
20. Working in Production area
21. Air Curtains
22. Air Handling Systems (Cleaning)
23. Air Handling Unit (Operation)
24. Air Handling Units SOP.
25. Photocopier
26. Fire Extinguisher

4. In vitro Dissolution or Drug Release

 The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g.
apparatus, rotation speed, medium) should be provided. Data should also be submitted to
demonstrate whether the method is sensitive to changes in manufacturing processes and/or
changesin grades and/or amounts of critical excipients and particle size where relevant.
 The dissolution method should be sensitive to any changes in the product that would result in a
change in one or more of the pharmacokinetic parameters. Use of a single point test or a
dissolution range should be justified based on the solubility and/or biopharmaceutical classification
of the API.
 For slower dissolving immediate-release products (e.g. Q = 80% in 90 minutes), a second time point
may be warranted (e.g. Q = 60% in 45 minutes).
 Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used
for routine quality control. Preferably this test should possess in vitro-in vivo correlation. Results
demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the
type of dosage form.
 For extended-release FPPs, the testing conditions should be set to cover the entire time period of
expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test
intervals for longer duration of release).
 One of the test points should be at the early stage of drug release (e.g. within the first hour) to
demonstrate absence of dose dumping. At each test period, upper and lower limits should be set
for individual units. Generally, the acceptance range at each intermediate test point should not
exceed 25% or ±12.5% of the targeted value. Dissolution results should be submitted for several
lots, including those lots used for pharmacokinetic and bioavailability or bio waiver studies.

 5. Sites of Manufacture - Finished Product:-
5.1. Imported Products:

A valid manufacturing authorization for pharmaceutical production, as well as a marketingauthorization
(registration), should be submitted to demonstrate that the product is registered orlicensed in
accordance with national requirements in the country of origin or country ofmanufacture.
Valid Manufacturing License - Attached
For each site where the major production step(s) is/are carried out, when applicable submit a valid
GMP Certificate and attach an original Certificate of a Pharmaceutical Product (CoPP) issued by the
competent authority in terms of the WHO Certification Scheme on the Quality of Pharmaceutical
Products Moving in International Commerce.
Valid cGMP - Attached

Valid COPP– Attached

6. Detailed Description and Validation of the Manufacturing Procedure for

theFinished Product
 Provide a detailed description of the manufacturing procedure for each strength and
formulation o the finished product, including packaging. Provide a flow diagram showing
where materials enter the process.
 Identify any critical steps and points at which in-process controls apply. Provide a copy of
the master formula and a copy of a manufacturing record for a real batch (this should be
the bio batch i.e. the batch used for the bioequivalence or comparative dissolution studies,
(if applicable).
 A narrative description of the manufacturing process, including packaging that represents
the sequence of steps undertaken and the scale of production should also be provided.
Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer)
and working capacity, where relevant.
 Provide process validation data (manufacturing process validation protocol and manufacturing
process validation report) for critical manufacturing steps as described in WHO’s Supplementary
guidelines on good manufacturing practices: Validation. As a minimum, identify the parameters that
must be controlled during the critical manufacturing steps. Define optimum numerical values for
each identified parameter.
6.1 PROCESS VALIDATION AND/OR EVALUATION

SUMMARY
This report covers the Process validation, carried out for 3 batches of LE-ONE Tablets 500 mg
(Levofloxacin (as Hemihydrate) 500 mg Tablets) by anticipated monitoring of parameters of the critical
manufacturing stages that are having impact on product quality and by drawing sample at each critical
manufacturing stage and testing the same in order to ensure the efficiency of the process.
INTRODUCTION
Retrospective validation is carried out for 3 consecutive production batches for LE-ONE Tablets 500 mg
(Levofloxacin (as Hemihydrate) 500 mg Tablets); critical steps are monitored and validated.
The objective of this process validation report for LE-ONE Tablets 500 mg (Levofloxacin (as
Hemihydrate) 500 mg Tablets); is to establish documented evidence that the process is capable of
consistently producing a product of predetermined specifications and quality attributes.

BATCHES USED FOR VALIDATION
Batch No Batch Size(Unit Pack) Mfg Date Exp Date

1
446 27500 May-2018 May-2021
Batch No Batch Size Mfg Date Exp Date

2
751 5,000 May-2017 May-2021
Batch No Batch Size Mfg Date Exp Date

3
860 5,000 May-2018 May-2021
PROCESS VALIDATION DATA ATTACHED

P3.3.4 (Batch No. 8988) Attached

 P.7. Specifications for Excipients
 Provide a list of tests and limits for results for each excipient, including solvents, liquids to adjust
pH, coatings, capsule shell, and inked imprint (on the dosage form). Include test methods in
sufficient detail for them to be replicated by another laboratory.
 If the ingredient is tested on the
basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph
together with any test methods referenced but not duplicated in the monograph. Include
microbiological limits for materials of natural origin.
 Only colors and other excipients permitted by
national regulation may be used*.
 For excipients of human or animal origin, provide information on
the control of adventitious agents such as transmissible spongiform encephalopathies.
 For oils of plant origin (e.g. soy bean or peanut oil), provide information on the control of aflatoxins
and other possible contaminants such as pesticides.
 7.1. Excipients Described in Recognized Pharmacopeia (BP, USP, EP, JP& IP)
Provide a copy of the monograph together with any test methods referenced in the monograph but
not duplicated in the monograph. Note that the current monograph should always control the quality
of the excipient. Provide details of any specifications additional to those in the pharmacopoeia.
 Certificate of analysis for one batch of each excipient should be provided.
 7.2. Excipients NOT Described in in Recognized Pharmacopeia (BP, USP, EP, JP& IP)
 For non-compendial excipients and those used for the first time in a FPP or by a new route of
administration, full details of manufacture, characterization, and controls, with cross references to
supporting safety data (non-clinical and/or clinical) should be provided. Certificate of analysis for
one batch of each excipient should be provided.
 * Colors permitted in the EU may be found in the European Commission’s List of permitted food
colors. Colors permitted by FDA are listed in the on-line database Summary of Color Additives for
 Use in United States in Foods, Drugs, Cosmetics, and Medical Devices.

7.1 SPECIFICATIONS
The Excipients used in the manufacturing of LE-ONE 500mg Tablets (Levofloxacin (as Hemihydrate))
are pharmacopoeia and comply with British Pharmacopoeia, United State Pharmacopoeia & In House
Specification.
S.N INGREDIENTS SPECIFICATIONS

1 Kyron BP, IHS
2 PVP K-30 BP
3 Mag. Stearate BP
4 Lactose Monohydrate BP
5 Sodium Starch Glycolate BP
6 IPA BP
7 HPMC E 5 BP
8 Titanium Dioxide BP
9 PEG 6000 IHS
10 R/O Water BP

7.2 ANALYTICAL PROCEDURES

The Excipients used in the manufacturing of LE-ONE 500mg Tablets are pharmacopoeia and comply
with British Pharmacopoeia.
1- Microcrystalline Cellulose (Avicel 200) BP
Sr. # PARAMETERS SPECIFICATIONS Reference

A white or almost white, fine or granular
01 Physical Form BP
powder.
Practically insoluble in water, in acetone,
in ethanol, in toluene and in dilute acids
02 Solubility. BP
and in a 50g/l solution of Sodium
Hydroxide.
03 Identification. Chemical Test BP
04 pH 5.0-------------------7.50 BP
05 Starch No blue color develops BP
06 Loss on Drying NMT : 6.0% BP
07 Total Microbial Count NMT : 1000cfu/gm BP
(i) Salmonella Should not be present BP
(ii) E. Coli Should not be present BP
(iii) Yeast and Mould NMT : 100cfu/gm BP
(iv) Pseudomonas Should not be present BP
(v) Styphylococcus Should not be present BP
Appearance:
A white or almost white, fine or granular powder.
Solubility:
Practically insoluble in water, in acetone, in ethanol, in toluene and in dilute acids and in a 50g/l solution of
Sodium Hydroxide.
IDENTIFICATION:
ıA. Place about 10mg on a watch-glass and disperse in 2ml of iodinated zinc chloride solution R . The
substance becomes violet-blue.
TESTS:
pH (2.2.3):
Shake 5.0 g with 40.0 ml of carbon dioxide-free water R for 20 minutes and centrifuge. The pH of
supernatant liquid is 5.0 to 7.5.
Starch:
To 10gm add 90ml of water Rand boil for 5 minutes. Filter whilst hot. Cool and add to the filtrate 0.1ml of
0.05M Iodine. No blue color is produced.
Loss on drying (2.2.32):

Not more than 6.0 per cent, determined on 1.000 g by drying in an oven at 100°C to 105 0C for 3 hrs.
Microbial Contamination:
Total viable aerobic count (2.6.12) not more than 103 micro-organism per gram and with a limit for fungi of
102 per gram, determind by plate count. It complies with the tests for Esherichia coli, for Pseudomonas
aeruginosa, for Staphylococcus aureus and for Salmonella. ( 2.6.13) .
2-POVIDONE (PVP K-30) BP

White or yellowish-white, powder or
1 Description. BP
flakes, hygroscopic.
Freely soluble in water, in Alcohal and in
2 Solubility. Methanol, Slightly soluble in acetone, BP
practically insoluble in Ether.
B Chemical Test
BP
3 Identification. C Chemical Test
Internal
D Chemical Test
4 pH 3.0 to 7.0 BP
5 Residue on Ignition Nmt : 0.1% BP
6 Water NMT: 5.0% BP
CHARACTERS
Appearance
White or yellowish-white, powder or flakes, hygroscopic.
Solubility
Freely soluble in water, in Alcohal and in Methanol, Slightly soluble in acetone, practically insoluble in Ether.
IDENTIFICATION
B. To 0.4 ml of solution S1 add 10 ml of water R, 5 ml of dilute hydrochloric acid R and 2 ml of
potassium dichromate solution R. An orange-yellow precipitate is formed.
C. To 1 ml of solution S1 add 0.2 ml of dimethylaminobenzaldehyde solution R1 and 0.1 ml of
sulphuric acid R. A pink colour is produced.
D. To 0.1 ml of solution S1 add 5 ml of water R and 0.2 ml of 0.05 M iodine. A red colour is
produced.
TESTS
Solution S
Dissolve 1.0 g in carbon dioxide-free water R and dilute to 20 ml with the same solvent. Add the substance
to be examined to the water in small portions, stirring using a magnetic stirrer.
Solution S1
Dissolve 2.5 g in carbon dioxide-free water R and dilute to 25 ml with the same solvent. Add the substance
to be examined to the water in small portions, stirring using a magnetic stirrer.
Water
Maximum 5.0 per cent, determined on 0.500 g.
pH:
The pH of Solution S is 3.0 to 7.0.
3-ISOPROPYL ALCOHOL BP

01 Description. A Clear, colourless liquid. BP
Miscible with water, with alcohol and with
02 Solubility. BP
ether.
A Relative Density
03 Identification. B Refractive Index BP
C Chemical Test
Not more than 0.6 ml of 0.01 M sodium
04 Acidity or Alkalinity hydroxide is required to change the colour BP
of the indicator to pale pink.
05 Water Maximum 0.5 %. BP
Non-volatile
06 The residue weighs a maximum of 2 mg. BP
substances
CHARACTERS
Appearance
A Clear, colourless liquid.
Solubility
Miscible with water and with alcohol and with ether.
IDENTIFICATION
A. Relative density 0.785 to 0.789.
B. Refractive index 1.376 to 1.379.
C. To 1 ml add 2 ml of potassium dichromate solution R and 1 ml of dilute sulphuric acid R. Boil. Vapour is
produced which changes the colour of a piece of filter paper impregnated with nitrobenzaldehyde solution R
to green. Moisten the filter paper with dilute hydrochloric acid R. The colour changes to blue.
TESTS
Appearance
The substance to be examined is clear and colourless . Dilute 1 ml to 20 ml with water R. After 5 min, the
solution is clear.
Acidity or alkalinity
Gently boil 25 ml for 5 min. Add 25 ml of carbon dioxide-free water R and allow to cool protected from
carbon dioxide in the air. Add 0.1 ml of phenolphthalein solution R. The protected from carbon dioxide in
the air. Add 0.1 ml of phenolphthalein solution R. The solution is colourless. Not more than 0.6 ml of 0.01 M
sodium hydroxide is required to change the colour of the indicator to pale pink.
Non-volatile substances
Evaporate 100 g to dryness on a water-bath after having verified that it complies with the test for peroxides
and dry in an oven at 100-105 °C. The residue weighs a maximum of 2 mg (20 ppm).

Water
4-SODIUM STARCH GLYCOLATE BP

A white or almost white, fine, free-flowing
1 Description BP
powder, very hygroscopic.
Practically insoluble in methylene chloride.
2 Solubility BP
It gives a translucent suspension in water.
A It complies with the Test for pH
B Chemical Test
3 Identification BP
C Chemical Test
D Chemical Test
4 Loss on drying NMT : 10% BP
5 Total microbial count NMT : 1000cfu/g BP
(i) Salmonella Negative BP
(ii) E. Coli Negative BP
(iii) Yeast and Mould NMT : 100 cfu/g BP
CHARACTERS
Appearance
A white or almost white, fine, free-flowing powder, very hygroscopic.
Solubility
Practically insoluble in methylene chloride. It gives a translucent suspension in water.
IDENTIFICATION:
A. pH
The pH of Solution S1 is 5.5 to 7.5.
B. Prepare with shaking and without heating a mixture of 4.0 g of the substance to be examined
and 20 ml of carbon dioxide-free water R. The mixture has the appearance of a gel. Add 100
ml of carbon dioxide-free water R and shake. A suspension forms that settles after standing.
C. To 5ml of suspension obtained in Identification Test B add 0.05ml of iodine solution R1. A
dark blue color I produced.
D. Solution S2 gives reaction (a) of sodium.
TESTS:
Solution S1:
Centrifuge the suspension obtained in identification test B at 2500 g for 10 min. Collect carefully the
supernatant liquid.
Solution S2:
Place 2.5 g in a silica or platinum crucible and add 2 ml of a 500 g/l solution of sulphuric acid R. Heat on a
water-bath, then cautiously over a naked flame, raising the temperature progressively, then incinerate in a
muffle furnace at 600 ± 25 °C. Continue heating until all black particles have disappeared. Allow to cool,
add a few drops of dilute sulphuric acid R, heat and incinerate as above. Allow to cool, add a few drops of

ammonium carbonate solution R, evaporate to dryness and incinerate cautiously. Allow to cool and dissolve
the residue in 50 ml of water R.
Appearance of solution S1:

Solution S1 is clear and colourless.
pH:
The pH of Solution S1 is 5.5 to 7.5.
Loss on drying:
Not More Than 10.0 per cent, determined on 1.000 g by drying in an oven at 100 °C for 4 h.
Microbial contamination:
It complies with the test for Escherichia coli and Salmonella .
5-MANGNESIUM STEARATE BP

A white or almost white, very fine, light
01 Description BP
powder, greasy to the touch.
Practically insoluble in water and in
02 Solubility BP
anhydrous ethanol.
B Acid Value BP
03 Identification
D Chemical Test BP
04 Loss on Drying Maximum 6.0 %. BP
05
Not more than 0.05 ml of 0.1 M
hydrochloric acid or 0.1 M sodium
06 Acidity or Alkalinity
hydroxide is required to change the colour
of the indicator.
TYMC
Microbial TAMC
07 BP
contamination Absence of E – Coli
Absence of Salmonella
Magnesium Stearate BP (Standard Analytical Procedure)
CHARACTERS:
A white or almost white, very fine, light powder, greasy to the touch, practically insoluble in water and in
ethanol.
IDENTIFICATION:
A. Acid Value 195 to 210.
Dissolve 10.00gm of a ubstance in 50ml of a mixture of equal volume of Ethanol (96%) R
and light petroleum R3, previously neutralized with 0.1M Potassium Hydroxide or 0.1M
Sodium Hydroxide, using 0.5ml of phenolphthalein olution R1 as indicator. If necessary, heat
to about 900C to dissolve the substance. When the ubstance has dissolved, titrate it with

0.1M Potassium Hydroxide or 0.1M Sodium Hydroxide until the pink color persist for at least
15 seconds.
IA = 5.610n/m
Where n = ml of titrant
m = Mass of Substance
D. To 1 ml of solution S add 1ml of dilute ammonia R1; a white precipitate is formed that dissolves on
addition of 1ml of ammonium chloride solution R. Add 1ml of a 120g/L solution of disodium hydrogen
phosphate R; a white crystalline precipitate is formed.
TESTS
Solution S:
To 5.0 g add 50 ml of peroxide-free ether R, 20 ml of dilute nitric acid R and 20 ml of distilled water R and
heat under a reflux condenser until dissolution is complete. Allow to cool. In a separating funnel, separate the
aqueous layer and shake the ether layer with 2 quantities, separating funnel, separate the aqueous layer and
shake the ether layer with 2 quantities, each of 4 ml, of distilled water R. Combine the aqueous layers, wash
with 15 ml of peroxide-free ether R and dilute to 50 ml with distilled water R (solution S). Evaporate the
organic layer to dryness and dry the residue at 100-105°C.
Acidity or alkalinity:
To 1.0 g add 20 ml of carbon dioxide-free water R and boil for 1 min with continuous stirring. Cool and filter.
To 10 ml of the filtrate add 0.05 ml of bromothymol blue solution R1. Not more than 0.05 ml of 0.1 M
hydrochloric acid or 0.1 M sodium hydroxide is required to change the colour of the indicator.
Loss on drying:
Not more than 6.0 per cent, determined on 1.000 g by drying in an oven at 105 °C.
Microbial contamination:
TAMC: Acceptance criteria 103 CFU/g
TYMC: Acceptance criteria 102 CFU/g
Absence of E – Coli
Absence of SAlmonella
6-OPADRY WHITE

01 Description. White powder. IHS
A IR
02 Identification. Internal
B Dispersion Test
03 Loss On Drying NMT : + 5.0%
04 Ash 19.43%-------------26.29%
PHYSICAL ANALYSIS:
Physical form/ Description:

White powder.
Identification:
A. IR spectrum of sample should comply with standard.
B. Dispersion

Place 10ml of IPA and 20ml of Methylene chloride in conical flask. Add 3.7gm sample. Stirr for
few minutes. Poure few ml of sample on watch glass plate and allow solvent to evaporation, a
clean brittle film obtained.
Loss on drying:
Not More Than 5.0 per cent, determined on 1.000 g by drying in an oven at 100 °C for 6 h.
Ash: (Method II)

Heat a silica or platinium crucible to red heat for 30 minute, allow to cool in a desiccators and weigh. Take
1.0000gm of sample in a crucible, dry at 100 to 105 0C for 01 hourand ignite to a constant weight in a
muffle furnance at 5750C to 6250C. Allow the crucible to cool in a desiccator after each ignition. Flame
should not be produced at any time during procedure. If after prolonged ignition a carbon free ash cann’t
be obtained, take up the hot water, filter through an ashless filter paper and ignite the residue and the filter
paper. Ciombine the filtarate with tha ash, carefully evaporate to dryness and ignite to constant weight.
7-METHYLENE CHLORIDE BP

01 Description. A clear, colourless, volatile liquid. BP
Sparangly soluble in water, miscible with
02 Solubility. BP
alcohol and with ether.
A It complies with the Test for Relative Density
03 Identification D Chemical Test BP
E Cloride Test
04 Acidity NMT : 0.15ml of 0.1M sodium Hydroxide BP
05 Relative Density 1.320-------------1.332 BP
06 Refractive Index 1.423-------------1.425 BP

Residue on
04 NMT : 1mg (20 ppm) BP
Evaporation
Appearance
A clear, colourless, volatile liquid.
Solubility
Sparangly soluble in water, miscible with alcohol and with ether.
IDENTIFICATION
A. It complies with the Test for Relative Density.
D. Heat 2ml with 2g Potassium Hydroxide R and 20ml of Alcohol R under reflux condenser for 30 mint.
Allow to cool. Add 15ml of Dilute Sulphuric Acid R and filter. To 1ml of the filtrate add 1ml of a 15g/l
solution of chromotropic acid, salt R, 2ml of water R and 8ml of Sulphuric acid R. A violet color is
produced.
E. 2ml of the filtrate obtained in identification test D gives reaction (a) of chloride.
Acidity:
To 50 ml of Methanol R previously neutralized to 0.1ml of bromothymol blue solution R1 . Add 50gm of
sample. Not more than 0.15ml of 0.1M sodium Hydroxide is required to change the color of the indicator to
blue.
Relative Density:
1.320-------------1.332
Refractive Index:
1.423-------------1.425
Residue on Evaporation:
Evaporate 50 g to dryness on a water bath and dry in an oven at 100-105 °C for 30 mints. The residue
weighs not more than of 1 mg.
8-TARTRAZINE LAKE COLOR YELLOW
Sr. # PARAMETERS SPECIFICATIONS

01 Description A yellow colored powder.
02 Solubility. Insoluble in water and most organic solvents.
03 Identification. Comply with Standard
04 Color Comparison Comply with Standard
05 Ph 3.8----------5.8
06 Bulk Density 0.2------0.5g/ml
07 Loss on Drying NMT : 20%
Physical form/Descriptions:
A yellow colored powder..
Solubility:
Insoluble in water and most organic solvents.
Identification:
Should comply with previously accepted lot.
Color Comparison:
Take 0.1gm samople and 1gm of Talcum Powder in petri dish and mix well with spatula or glass rod and add
Methylene Chloride to make paste. Allow it to dryness at room temperature. Repeat the same process for
standard color, and compare the color shade of sample with the standard.
pH:
Weight 1.0000gm sample in a beaker and add 50ml of Dist. Water. Mix, sonicate for 10 minutes and stir well
for 2.5 hours. Slurry will form. Find out the pH with the help of pH meter.
Bulk Density:
Take a previously dried graduated cylinder and tare its weight on balance. Add sample in a cylinder to a
specified volume. Note down the both, weight in gm and volume in ml. Now divide the weight by the volume,
the resulted answer will be the Bulk Density of the sample in gm/ml.
Loss on Drying:
Take 1gm of sample in pre weighed clean and dry crucible. Place the crucible in the oven, and keeping it in
the oven for drying at 1100Cْfor about 5 hours. Cool in a desiccators allow it to come to room temperature.
Weigh and calculate the loss on drying by the difference between weights before drying and after drying and
dividing by the weight before drying and multiplying with 100.
9- P.E.G 6000 BP

White powder or creamy white flakes,
01 Description BP
free from foreign particles.
Freely soluble in water, soluble in
acetone, in alcohol, in chloroform, in
02 Solubility. BP
ethylene glycol & and it is insoluble in
ether & hexane.
03 Identification It complies with the Test for Melting Point BP
04 pH 4.5----------7.5 BP
05 Water NMT : + 0.5% BP
06 Residue on Ignition NMT : 0.1% BP
07 Melting Point 560C-------------630C BP
Appearance
White powder or creamy white flakes, free from foreign particles.
Solubility
Freely soluble in water, soluble in acetone, in alcohol, in chloroform, in ethylene glycol & and it is insoluble in
ether & hexane.
pH:
Take 5.0gm sample in 100ml of carbon dioxide free water and adding 0.30ml of saturated potassium chloride
solution.
Water
Melting Point.
560C-------------630C
Residue on Ignition.
Not more than 0.1%, a 25g sample and a tared platinium dish being used, and the residue being moistened
with 2ml of sulfuric acid.

 8. Control of the Finished Pharmaceutical Products:

 8.1. Specifications for the Finished Pharmaceutical Product
 A copy of the FPP specification(s) dated and signed by authorized personnel (i.e. the person in
charge of the quality control or quality assurance department) should be provided.
 A list of tests and limits for results of the FPP must be provided, including sufficient detail of test
methods for them to be replicated by another laboratory.
 Two separate sets of specifications may be set out: after packaging of the FPP (release) and at
the end of shelf life. In such cases, both release and end of shelf life specifications should be
provided.
 Any differences between release and shelf life tests and acceptance criteria should be clearly
indicated and justified. Note that such differences for parameters such as dissolution are normally
not accepted.
 Unless there is appropriate justification, the acceptable limit for the API content of the FPP in the
release specifications is (± 5%) of the label claim (i.e. 95 - 105%).

8.1. Specifications for the Finished Pharmaceutical Product
P8.1 Specification
Product Name LE-ONE 500mg Tablets
Generic Name Levofloxacin (as Hemihydarte) 500 mg
Off white color oblong film coated tablet with a break line
Description on one face, blister in Alu – Alu packingwith multicolor
printing on off white color carton.
Each film coated tablet contains
Label Claim Levofloxacin Hemihydrate USP Eq. to Levofloxacin 500
mg
Identification Zone Comparison
Average wt per
670mg
tablet
Disintegration time NMT 30 minutes
Weight Deviation NMT + 5.0%
Assay:
Levofloxacin 450mg/tab--------------------550mg/tab
Hemihydrate eq. to 90%---------------------------110%
Levofloxacin
Dosages form Film Coated Tablets
Shelf Life Three Years
Storage Condition Store in a cool, dry place and protect from light.
Standard
Packing 1 x 10 Alu-Alu Pack 5,000 Packs
Batch Size

8.2. Analytical Procedures

 All analytical test procedures, including biological and microbiological methods where relevant,
must be described in sufficient detail to enable the procedures to be repeated if necessary.
 If the product is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide
a copy of the monograph together with any test methods referenced in the monograph but not
duplicated in the monograph. Provide details of any specifications and test methods additional to
those in the pharmacopoeia.
 8.2. Analytical Procedures
P.8.2 ANALYTICAL PROCEDURES
ASSAY:
Physical form.
Off white color oblong film coated tablet with a break line on one face, blister in Alu – Alu packingwith
multicolor printing on off white color carton.
Thickness:
Measure the Thickness of the tablet with the help of calibrated hardness Tester. It should be according to
specifications.
Weight Deviation:
Weigh 20 tablets and record the weights selected at random and determined the average weight of single
table and from that determine the deviation in weight. It should be + 5.0 %.
Identification:
Zone Comparison
Disintegration Time:
Introduce one tablet with disc into each tube in the assembly. Suspend the assembly in the beaker
containing Dist. Water and operate the apparatus. Check the all tablets and note down the time, all zix
tablets should be disintegrated.
Assay: METHOD OF ANALYSIS:
Media and Organism

Antibiotic reference standard
Phosphate Buffer pH 8
Antibiotic Medium 1(for carrying organism).
Antibiotic Medium 11(for microbial assay).
Test tubes (10ml of sterile saline TS).
Specified test organism i.e. Bacillus Pumilus:
Safety Considerations:
Wear protective gloves and mask.
Don’t leave the infected wire loop on working bench without disinfecting it with IPA 70%.
Avoid mouth pipetting
Procedure:
Test Organism:
Maintain the test organism Bacillus pumillus antibiotic medium No. 1.
Inoculate fresh sterile antibiotic medium No.1 with culture of test organism and incubate at 37 oC for 18-24
hrs.
Preparation of Inoculums:
Take loop full growth of test organism and suspend in 10ml of sterile saline TS.
Adjust the turbidity of suspension according to the turbidity of standard (Take 0.5ml of 1.17% of BaCl 2
solution and 99.5 ml of 1% w/v H2SO4 solution and makeup volume up to 100 ml).
The quantity of inoculums may be adjusted according to the response of test organism.
Sterile Phosphate Buffer pH 8.00:

Dissolve 16.73g of dibasic potassium phosphate and 0.523g of monobasic potassium phosphate add
sufficient water to produce 1000ml solution.
Check the pH and adjust with 18 N Phosphoric Acid or 10 N Potassium Hydroxide.
Autoclave at 15 lbs pressure for 15 minutes.
Preparation of Antibiotic Medium No. 1(for carrying Organism):

Dissolve 3.05gm powder in 100ml of purified water.
Mix thoroughly.
Heat with frequent agitation and boil for one minute to completely dissolve the powder.
The media is autoclave for 15 minutes at 15 lbs and 121 oC.
The pH of medium should be 6.4 to 6.6.
Preparation of Antibiotic Medium No. 11(for Microbial Assay):
Dissolve 4.58 gm powder in 100ml of purified water.

Mix thoroughly.
Heat with frequent agitation and boil for one minute to complete dissolve the powder.
The media is autoclave for 15 minutes at 15 lbs psi pressure and 121 oc.
The pH of medium should be 7.7 -8.1.
Preparation of Petri Dishes:

Dried plates after proper washing and sterilize petridishes (bottom covered with top of the plate) in hot oven
at 200oC for 30min.
Place four Petri Dishes on a leveled surface.
Open Petri dishes under aseptic condition and pour 50 ml of antibiotic medium No.11 in each Petri dishes
with the help of sterile pipette.
Allow to solidify at room temperature.
Flask containing remaining medium is placed on hot plate.
Take bacterial suspension and add in flask having remaining antibiotic medium No.11 and mix gently.
Then add 30ml of inoculated medium on each Petri dish (having 50 ml of solidified medium).
To avoid the air bubbles.
Allow to solidify at room temperature.
Preparation of Standard:
Weigh 500mg of reference standard of Levofloxacin of known potency and dissolve in 100ml of phosphate
buffer pH8.0.
Then prepare the standard dilution from s1to s5with phosphate buffer.
Volume of stock
Sr.# Dilution Volume up to
solution
1 S1 0.6 ml 100ml
2 S2 0.8 ml 100ml
3 S3 1.0ml 100ml
4 S4 1.25 ml 100ml
5 S5 1.56 ml 100ml
Preparation of Sample:
Measure accurately 650 of sample Levofloxacin to be tested and dilute to 100ml with phosphate buffer pH 8
to give the concentration of label claim.
Concentration of sample solution is equivalent to S 3 dilution of standard.
Punching and Pouring the Petri Dishes:

Punch four holes in each Petri dishes with the help of sterile borer.
Remove the agar plug taking care not to damage the hole.
Mark the holes with particular sample and standard dilutions.
Pour appropriate quantity of sample and standard dilution in each hole rinsing the pipette with respective
solution between each different solution used.
Repeat the same procedure for remaining Petri dishes and complete each Petri Dish without interruption.
Allow the dilution to absorb for at least one hour at room temperature and then incubate at 30 - 35 oC for 18
–24 hrs.
Measurement of Zone of Inhibitions:

Measure the diameter of zone of inhibition by using vernier caliper of both standard and sample. Calculate
the percentage by using following formula.
% age = Zones of Inhibition of Sample
Zones of Inhibition of Standard

8.3. VALIDATION OF ANALYTICAL PROCEDURE:

 ALL NON COMPENDIAL TESTS PROCEDURES NEED TO BE VALIDATED. RESULT OF THE
VALIDATION STUDIES, COMMENTS
 ON THE CHOICE OF ROUTINE TESTS AND STANDARDS MUST BE PROVIDED. FOR
PHARMACOPOEIA METHODS, PROVIDE DATA TO DEMONSTRATE THAT THE METHOD IS
APPLICABLE TO THIS FORMULATION.
 WHO GUIDELINE: VALIDATION OF ANALYTICAL PROCEDURES USED IN THE EXAMINATION OF
PHARMACEUTICAL MATERIALS, THE WHO GUIDELINES FOR REGISTRATION OF FIXED-DOSE
COMBINATION MEDICINAL PRODUCTS SHOULD BE TAKEN INTO ACCOUNT.
NOTE:
IN THE USP 32 NF 27, PAGE NO 733 CONTAINS MONOGRAPH (1225) NAME VALIDATION OF COMPENDIAL.
IN THE MONOGRAPH, IT IS GIVEN THAT (ACCORDING TO THESE REGULATIONS [21 CFR 211.194 (A) (2)]
USERS OF ANALYTICAL METHODS DESCRIBED IN USP-NF ARE NOT REQUIRED TO VALIDATE THE
ACCURACY AND RELIABILITY OF THESE METHODS)

 P8.4. Batch Analysis

 Results of not less than three batch analyses (including the date of manufacture, place of
manufacture, batch size and use of batch tested) must be presented. The batch analysis must
includethe results obtained for all specifications at release. Copies of the certificates of analysis for
thesebatches should be provided and the company responsible for generating the testing results
should beidentified.
8.4 BATCH ANALYSES

Description and test results of all relevant batches
TEST Batch No. 5735 Batch No. 5717 Batch No. 5159 LIMITS
Off white color oblong Off white color oblong Off white color oblong Off white color oblong
film coated tablet with a film coated tablet with a film coated tablet with film coated tablet with
break line on one face, break line on one face, a break line on one a break line on one
Description blister in Alu – Alu blister in Alu – Alu face, blister in Alu – Alu face, blister in Alu – Alu
packing with multicolor packing with multicolor packing with multicolor packing with multicolor
printing on off white printing on off white printing on off white printing on off white
color carton. color carton. color carton. color carton.
Identification Positive Positive Positive Zone Comparison
Avg. Weight 675mg 678mg 670mg 670mg
Disintegration time 22 Mints 16 Mints 12 Mints NMT : 30 minutes
Weight Deviation Complies Complies Complies ± 5%
Assay:
Levofloxacin
509.75mg/tab 503.85mg/tab 514.85mg/tab 450mg/tab--550mg/tab
Hemihydrate eq. to 101.95% 100.77% 102.97% 90%---------------110%
Levofloxacin
CERTIFICATE OF ANALYSIS – LE-ONE 500mg Tablets (ATTACHED)


 9. Container Closure System(s) and Other Packaging:

 The suitability of the container closure system used for the storage, transportation (shipping) and
use of the FPP should be discussed. This discussion should consider, e.g., choice of materials,
protection from moisture and light, compatibility of the materials of construction with the dosage
form (including sorption to container and leaching) safety of materials of construction, and
performance (such as reproducibility of the dose delivery from the device when presented as part of
the FPP).
 Give a detailed description of the container closure system(s), including any liner or wadding, and
provide details of the composition of each component.
 Provide the specifications for any part of thecontainer closure system(s), which comes into contact
with the product or is protective.
 Forimportant products such as parenteral and ophthalmic products, components that will at any
stagecome into contact with any part of the product must comply with requirements specified by
the BP,USP, EP, JP and IP.
 The specifications for the primary packaging components should include description and
identification (and critical dimensions, with drawings where appropriate).
 Non-compendial methodswith validation should be included where appropriate. Primary packaging
components are those thatare in direct contact with the API or FPP.
 Describe other (e.g. outer) packaging, and state the materials they are made from.

P9 CONTAINER CLOSURE SYSTEM
ITEM ITEMS STANDARD

UNIT
CODE QUANTITY
PRIMARY PACKING COMPONENTS
1 Printed Aluminum Foil for LE-ONE Tablets 500 3.500
2 Alu Alu Foil 100 mm for LE-ONE Tablets 500 17.500

SECONDARY PACKING COMPONENTS

3 Printed Unit Carton ( 1 X 10 tablets) for LE- 5,000
ONE Tablets 500 mg Nos
4 Printed Leaflet for LE-ONE Tablets 500 mg 5,000

Nos
5 Outer Carton for LE-ONE Tablets 500 mg 56

(400 Unit Packs) Nos
6 Gum Tape Q.S

Nos
Tertiary Packing Components

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 cartons, which protects the cartons from humidity and other damages.
The corrugated fiberboard boxes are made of export worthy material and are sealed with a 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 & closure as described above used for the storage, transportation (shipping) and use of the
product, is suitable & compatible for LE-ONE (Levofloxacin Hemihydrate 500 mg Tablets) is protected
from moisture and light. Stability study also proves the container closure system to be effective for the
product during the shelf life.

 DETAILS OF PACKAGING MATERIALS
 Printed Unit Carton Specifications:

Off white color carton with multicolor
01 Description. Internal
printing in English and Urdu version.
Height 20mm + 2mm
02 Size. Length 135mm + 5mm Internal
Width 75mm + 3mm
Design, colour &
03 Must complies to reference standard. Internal
Printed Metter
04 Grammage 280 g/m2+ 10% Internal
STANDARD ANALYTICAL PROCEDURE – PRINTED UNIT CARTON
PURPOSE :
To insure the analysis of incoming Packing material and to confirm the parameters according to specifications.
SCOPE:
It is established for the analysis of Unit Cartons in Quality Control Department.
PROCEDURE:
EQUIPMENTS & APPARATUS

1. Name of Equipment/Apparatus
2. Analytical Balance
3. Ruler
4. Metal Piece 5X5 cm
5. Knife or cutter.
PHYSICAL ANALYSIS:
Grammage
Place 5x 5 cm calibrated metal piece on unit Carton and mark the area. Cut the marked area with the help of
knife or cutter. Weigh it on analytical balance. The grammage is calculated by multiplying the weight With 400.
The grammage so obtained should be within the specifications.
Size:
Check length, width and height of the Unit carton with calibrated measuring instrument (ruler). The size should
be according to the specifications.
Printed matter:
Read the printed matter on the Unit Carton and compare it with the standard Unit Carton. The new unit carton
should be printed with new batch No and expiry date. The printed mater should be according to specimen.
Design and colours:

Compare the design and colours of the unit carton with the standard specimen with naked eye. It should be
according to specimen.

 Printed Leaflets Specifications:

White color leaf insert having black color
01 Description. printing in English and Urdu version Internal
having brief description of Levofloxacin.
Length 185mm + 5mm
02 Size Internal
Width 80mm + 4mm
03 Grammage 55 g/m2+ 10% Internal
STANDARD ANALYTICAL PROCEDURE – PRINTED LEFLET
PURPOSE :
To insure the analysis of incoming Packing material and to confirm the parameters according to specifications.
SCOPE:
It is established for the analysis of printed leaflets in Quality Control Department.
PROCEDURE:

2. Ruler
4. Knife or cutter.
PHYSICAL ANALYSIS:
Grammage
Place 5x 5 cm calibrated metal piece on leaflets and mark the area. Cut the marked area with the help of knife or
cutter. Weigh it on analytical balance. The grammage is calculated by multiplying the weight With 400. The
grammage so obtained should be within the specifications.
Size:
Check length, width of the leaflet with calibrated measuring instrument (ruler). The size should be according to
the specifications.
Printed matter:
Read the printed matter on the Leaflet and compare it with the standard Leaflets. The printed mater should be
 Printed Aluminum Foil Specifications:

Silver color al. foil with red color printing
in English and urdu version.
Thickness 0.025mm + 0.005mm
02 Size 02
Width 250mm + 2mm
03 Design, colour & Must complies to reference standard. Internal
Printed Metter
STANDARD ANALYTICAL PROCEDURE – PRINTED ALU. FOIL
1. Title: Printed Aluminum Foils
2. Purpose:
To ensure the analysis of Packing Material and to confirm the contents according to specifications.
3. Scope:
It is established for the analysis of Aluminum foil in Quality Control Department.
4. Procedure:
S.NO. Name of Equipment/Apparatus

2. Vernier Caliper
4. Knife or cutter.
5. Magnifying glass.
6. Micrometer.
PHYSICAL ANALYSIS:
Dimensions:
Check width and thickness of the aluminum foil with calibrated measuring instrument (ruler and micrometer). The
dimensions should be according to the specifications.
Printed matter:
Read the printed matter on the aluminum foil and compare it with the standard specimen. The printed mater
should be according to specimen.
Printed colours:
Compare the Printed colours of the aluminum foil with the standard specimen with naked eye. It should be
 Plain Aluminum Foil Specifications:

Silver color Alu Alu having reko logo with
complete version in black color
Thickness 0.150mm + 0.005
02 Size Internal
Width 250mm + 2mm
Design, colour &
03 Must complies to reference standard. Internal
Printed Metter
 Shipper Specifications:


Brown color outer shipper with beehives having
01 Description. 5ply with Product information printed on front Internal
& back panels in blue color printing.
Height 220mm + 5mm
02 Size. Length 415mm + 5mm Internal
Width 270mm + 5mm
03 Grammage NLT 750g/m2. Internal
04 Ply Must be 5-Ply Internal
STANDARD ANALYTICAL PROCEDURE – SHIPPER
1. Title: Shippers
2. Purpose:
To ensure the analysis of Packing Material and to confirm the contents according to specifications.
3. Scope:
It is established for the analysis of Shippers in Quality Control Department.

4. Procedure:
S.NO. Name of Equipment/Apparatus

2. Inch tape
4. Knife or cutter.
PHYSICAL ANALYSIS:
Grammage
Place 5x 5 cm calibrated metal piece on shipper and mark the area. Cut the marked area with the help of knife
or cutter. Weigh it on analytical balance. The grammage is calculated by multiplying the weight With 400. The
grammage so obtained should be with in the specifications.
Size:
Check length, width and height of the shipper with calibrated measuring instrument (inchi tape). The dimensions
should be according to the specifications.
Ply:
Check the ply of the shipper with necked eye. It should be according to specifications.

 10. Stability Testing of the Finished Product:

 The design of the formal stability studies for the finished product should be based on knowledge of
the behavior and properties of the API and the dosage form.
 Provide the results of stability testing of the formulation in each of the proposed marketing packs.
 Results of testing related formulations and/or the same formulation in other packaging may be
provided as supporting information. Describe the methodology used during stability studies; if this
is
identical to methodology described elsewhere in the dataset, a cross-reference will suffice.
 Ifdifferent methodology was used, the test procedures applied (for impurities and assay, and for
othertests as necessary (e.g. particle size testing)) to the stability tests on the finished product
should bevalidated or verified, and the accuracy as well as the precision (standard deviations)
should berecorded.
10.1. Stability-Indicating Quality Parameters
 Stability studies should include testing of those attributes of the FPP that are susceptible to change
during storage and are likely to influence quality, safety and/or efficacy.
 Characteristics studied should be those in the finished product specification that are likely to be
affected by storage and/or not monitored routinely at the time of manufacture, but which may be
indicative of the stability/instability of the particular dosage form. These include:
 Physical characteristics (such as organoleptic properties, physical properties characteristic
to the dosage form, important quality parameters, e.g., in vitro dissolution, moisture content
and change of polymorphs, if relevant). As regards tablets and capsules packed with
semipermeable
blister films, loss or uptake of water must be tested during stability studies.
 Efficacy of additives, such as antimicrobial agents, to determine whether such additivesremain
effective and within the accepted validated range throughout the projected shelf life.
 Chemical characteristics (assay of the API, content of degradation products, content ofother
ingredients such as preservatives, antioxidants).
 Study of the container and closure interaction with the contents, when applicable.
 Where the product is to be diluted or reconstituted before being administered to the patient
(e.g. a powder for injection or a concentrate for oral suspension). “In use” stability datamust be
submitted to support the recommended in-use storage time and conditions for thosestorage forms.
 Shelf-life acceptance criteria should be derived from consideration of all available stability

information. It may be appropriate to have justifiable differences between the shelf-life and release
acceptance criteria based on the stability evaluation and the changes observed on storage. Any
differences between the release and shelf-life acceptance criteria for antimicrobial preservative
content should be supported by a validated correlation of chemical content and preservative
effectiveness demonstrated during development of the pharmaceutical product with the product in
itsfinal formulation (except for preservative concentration) intended for marketing.
 A single primarystability batch of the FPP should be tested for effectiveness of the antimicrobial
preservative at theproposed shelf-life for verification purposes, regardless of whether there is a
difference between therelease and shelf-life acceptance criteria for preservative content.
10.2. Selection of Batches

 At the time of submission data from stability studies should be provided on at least three primary
batches of the FPP.
 The primary batches should be the same formulation and packaged in the samecontainer closure
system as proposed for marketing. The manufacturing process used for primarybatches should
simulate that to be applied to production batches and should provide product of thesame quality
and meeting the same specification as that intended for marketing.
 One of the three batches should be of production scale and the remaining two batches should be at
least pilot scale batch. The composition, batch size, batch number and manufacturing date of each
ofthe stability batches should be documented and the certificate of analysis at batch release should
beattached.
10.3. Container Closure System

 Stability testing should be conducted on the dosage form packaged in the container closure system
proposed for marketing. Any available studies carried out on the FPP outside its immediate
containeror in other packaging materials can be considered as supporting information, if applicable.
10.4. Testing Frequency

 The frequency of testing at the long term storage condition should normally be every 3 months
over
the first year, every 6 months over the second year, and annually thereafter through the proposed
shelf life, to establish the stability characteristics of the FPP.
 At the accelerated storage condition, a minimum of three time points, including the initial and final
time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended.
10.5. Storage Conditions

 In general, a FPP should be evaluated under storage conditions with appropriate tolerances, its
sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of
studieschosen should be sufficient to cover storage, shipment, and subsequent use with due regard
to theclimatic conditions for Climatic Zone IV.
 Stability testing of the finished product after constitution or dilution, if applicable, should be
conducted to provide information for the labeling on the preparation, storage condition, and in-use
period of the constituted or diluted product. This testing should be performed on the constituted or
 diluted product through the proposed in-use period on primary batches as part of the formal
stabilitystudies at initial and final time points.
 The long term testing should cover a minimum of 6 or 12 months duration at the time of
submissionand should be continued for a period of time sufficient to cover the proposed shelf life.
 Data from the accelerated storage condition can be used to evaluate the effect of short-term
excursions outside the label storage conditions (such as might occur during shipping).
 The minimum data required at the time of submitting the dossier (in the general case):
Study Storage Condition Relative humidity Minimum time

(ºC) (%) period (months)
Accelerated 40 ± 2 75 ± 5 6
Long-term 30 ± 2 65 ± 5* 12
* Stability studies conducted at 75% relative humidity are also acceptable
 Other storage conditions are outlined in the WHO stability guideline for FPPs packaged in
impermeable and semi-permeable containers and those intended for storage in a refrigerator and in
a freezer. FPPs intended for storage below -20°C should be treated on a case-by-case basis.
10.6. Stability Result

Provide the summary of accelerated and long term testing parameters (studies conducted) in the
below table:
Storage Strength and Batch Size Container Completed (and
Conditions (◦C, % Batch Number Closure System Proposed) Test
RH) Intervals
Provide the summary of the accelerated and long term stability results in the below table:
Test Results
Description
Moisture
Impurities
AssayEtc.
 For most types of product, results should be included for physical as well as chemical tests, e.g.
(where relevant) the presence of particles in a solution and the dissolution rate of solid oral
dosageforms.
 If the product contains an antimicrobial preservative, then preservative efficacy should be
demonstrated at batch release and at the end of the shelf life.
 For sterile products sterility should be reported at the beginning and end of shelf life. For
parenteralproducts, sub visible particulate matter should be reported frequently, but not
necessarily at everytest interval. Weight loss from plastic containers should be reported over the
shelf life.
 In-useperiods for parenteral and ophthalmic products should be justified with experimental
data.
 The information on the stability studies should include details such as storage conditions,
strength,batch number, including the API batch number(s) and manufacturer(s), batch size,
container closuresystem and orientation (e.g. erect, inverted, on-side) where applicable, and
completed (andproposed) test intervals.
 The discussion of results should focus on observations noted for the various tests, rather than
reporting comments such as “all tests meet specifications”. This should include ranges of
analyticalresults and any trends that were observed. For quantitative tests (e.g. individual and
total degradation
 product tests and assay tests), it should be ensured that actual numerical results are provided
rather than vague statements such as “within limits” or “conforms”.
 Applicants should consult ICH’s Q1E guideline for details on the evaluation and extrapolation of
results from stability.
Proposed storage statement and shelf life

 The proposed storage statement and shelf life (and in-use storage conditions and in-use period, if
applicable) for the FPP should be provided. This should be justified in terms of the results of the
stability testing, the difference between release and expiry specifications, and the labeled storage
conditions. In interpreting the results of stability studies, the proposed storage conditions should be
realistic and achievable in the Afghanistan.
 Provide the proposed shelf life and storage conditions in the below table:
Container closure system Storage statement Shelf-life

The recommended labeling statements for use, based on the stability studies, are provided in theWHO stability
guideline.
10.7. Stability Commitment

Primary Stability Study Commitment
 When the available long-term stability data on primary batches do not cover the proposed re-test
period (shelf-life) granted at the time of approval, a written commitment should be made to
continuethe stability studies post-approval in order to firmly establish the re-test period (shelf-life).
 The stability protocol used for studies on commitment batches should be the same as that for the
primary batches, unless otherwise scientifically justified.
Commitment Stability Studies

 The long-term stability studies for the Commitment batches should be conducted through the
proposed shelf life on at least three production batches of each strength in each container closure
system. Where stability data was not provided for three production batches of each strength, a
written commitment (signed and dated) should be included in the dossier.
Ongoing Stability Studies

 After a marketing authorization has been granted, the stability of the FPP should be monitored
according to a continuous appropriate program that will permit the detection of any stability issue
(e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the
container closure system in which it is marketed. The purpose of the ongoing stability program is to
monitor the product over its shelf-life and to determine that the product remains, and can be
expected to remain, within specifications under the storage conditions on the label.
 Unless otherwise justified, at least one batch per year of product manufactured for each strength
and every container closure system, if relevant, should be included in the stability program (unless
none is produced during that year) a written commitment (signed and dated) to this effect should
be included in the dossier.
 Any differences in the stability protocols used for the primary batches and those proposed for the
commitment batches or ongoing batches should be scientifically justified.

SUMMARY OF PRODUCT STABILITY
STABILITY DATA PROTOCOL
Drug Product: LE-ONE 500mg tablets

(Levofloxacin Hemihydrate)
Strength: 500 mg
Study Type: Real & Accelerated Stability
Objective: Stability profile of the drug product for storage under

real time and accelerated conditions.
Period of Months: ACCELERATED: 6 - Months

LONG-TERM: 12 - Months
Storage Conditions: Store below 30 °C. Protect from light & moisture. Keep all medicines
out of the reach of Children
Packaging: 1 x 10 Alu-Alu of Tablets packed in Carton.
Originating Site: WELLBORNE PHARMACHEM & BIOLOGICALS (PVT.) LTD.

Plot No. 51/1, 52/2 Phase I & II Industrial Estatse, Hattar – Pakistan.

STABILITY DATA REPORT
Accelerated & Long Term Stability Sheets Attached

SECTION FIVE
SUMMARY OF PHARMACOLOGY, TOXICOLOGY AND

EFFICACY OF THE PRODUCTD
 For each of the following types of application, provide full information on safety and efficacy as
defined in guidelines by the European Union, the US Food and Drug Administration, or the Japanese
 Ministry of Health and Welfare or ICH guidelines:
1. New active ingredients,
2. New indications,
3. New routes of administration,
4. New dosage forms,
5. All modified-release dosage forms
6. New combinations of active ingredients.
 Pharmacological Properties
LE-ONE TABLETS 500MG ( LEVOFLOXACIN HEMIHYDRATE)
 For the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:
Corynebacterium species, Staphylococus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae,
Streptococcus (Groups C/F/G), Viridans group streptococci, Acinetobacter lwoffii, Haemophilus influenzae,
Serratia marcescens.
 Pharmacodynamics: Levofloxacin, a fluoroquinolone antiinfective, is the optically active L-isomer of

ofloxacin. Levofloxacin is used to treat bacterial conjunctivitis, sinusitis, chronic bronchitis, community-
acquired pneumonia and pneumonia caused by penicillin-resistant strains of Streptococcus pneumoniae,
skin and skin structure infections, complicated urinary tract infections and acute pyelonephritis.
 Mechanism of action: Levofloxacin inhibits bacterial type II topoisomerases, topoisomerase IV and DNA
gyrase. Levofloxacin, like other fluoroquinolones, inhibits the A subunits of DNA gyrase, two subunits
encoded by the gyrA gene.
 This results in strand breakage on a bacterial chromosome, supercoiling, and resealing; DNA replication and
transcription is inhibited.
 Absorption: Absorption of ofloxacin after single or multiple doses of 200 to 400 mg is predictable, and the
amount of drug absorbed increases proportionately with the dose

 Mechanism of Actions
 Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial
activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of Levofloxacin and other
fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of
which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and
recombination.
 Drug Resistance:Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or
topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.
 Fluoroquinolones, including Levofloxacin, differ in chemical structure and mode of action from
aminoglycosides, macrolides and b-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore,
be active against bacteria resistant to these antimicrobials.
 Resistance to Levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9to 10-10).
Although cross-resistance has been observed between Levofloxacin and some other fluoroquinolones, some
microorganisms resistant to other fluoroquinolones may be susceptible to Levofloxacin.
 Activity in vitro and in vivo: Levofloxacin has in vitro activity against a wide range of Gram-negative and
Gram-positive microorganisms.
 Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
 Aerobic Gram-Positive Microorganisms
 Enterococcus faecalis (many strains are only moderately susceptible)
 Staphylococcus aureus (methicillin-susceptible strains)
 Staphylococcus epidermidis (methicillin-susceptible strains)
 Staphylococcus saprophyticus
 Streptococcus pneumoniae (including multi-drug resistant strains
 Streptococcus pyogenes
 MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the
following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime;
macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
 Aerobic Gram-Negative Microorganisms
 Enterobacter cloacae, Escherichia coli , Haemophilus influenza , Haemophilus parainfluenzae
 Klebsiella pneumonia , Legionella pneumophila , Moraxella catarrhalis , Proteus mirabilis
 Pseudomonas aeruginosa, Serratia marcescens

 As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly
rapidly during treatment with Levofloxacin.
 Other Microorganisms
 Chlamydophila pneumonia, Mycoplasma pneumonia
 Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels
as a surrogate marker in a rhesus monkey model for anthrax (post-exposure).
 Aerobic Gram-Positive Microorganisms
 Staphylococcus haemolyticus, β-hemolytic Streptococcus (Group C/F), β-hemolytic Streptococcus (Group G)
 Streptococcus agalactiae, Streptococcus milleri
 Viridans group streptococci
 Aerobic Gram-Negative Microorganisms
 Acinetobacter baumannii, Acinetobacter lwoffii, Bordetella pertussis, Citrobacter koseri, Citrobacter freundii
 Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella oxytoca, Morganella morganii
 Pantoea agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas fluorescens
 Anaerobic Gram-Positive Microorganisms
 Clostridium perfringens, Susceptibility Tests, Susceptibility testing for Levofloxacin should be performed, as it is
the optimal predictor of activity.
 Dilution techniques:
 Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC values).
These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC
values should be determined using a standardized procedure. Standardized procedures are based on a
dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized
concentrations of Levofloxacin powder. The MIC values should be interpreted according to the criteria
outlined in Table 9.
 Diffusion techniques:
 Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of
standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg Levofloxacin
to test the susceptibility of microorganisms to Levofloxacin.
 Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg
Levofloxacin disk should be interpreted according to the criteria outlined in Table 9. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for Levofloxacin.
Table 9: Susceptibility Interpretive Criteria for Levofloxacin

Minimum Inhibitory Disk Diffusion
Concentrations (mcg/mL) (zone diameter in mm)
Pathogen S I R S I R
Enterobacteriaceae ≤2 4 ≥8 ≥ 17 14–16 ≤ 13
Enterococcus faecalis ≤2 4 ≥8 ≥ 17 14–16 ≤ 13
Methicillin-susceptible ≤2 4 ≥8 ≥ 17 14–16 ≤ 13
Staphylococcus specie
s
Pseudomonas ≤2 4 ≥8 ≥ 17 14–16 ≤ 13
aeruginosa
Haemophilus ≤ _b _b ≥ 17c _b _b
influenzae 2a
Haemophilus ≤ _b _b ≥ 17c _b _b
parainfluenzae 2a
Streptococcus ≤ 4d ≥ 8d ≥ 17e 14–16e ≤ 13e
pneumoniae 2d
Streptococcus ≤2 4 ≥8 ≥ 17 14–16 ≤ 13
pyogenes
 S = Susceptible, I = Intermediate, R = Resistant
 a These interpretive standards are applicable only to broth microdilution susceptibility testing
with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.1
b The current absence of data on resistant strains precludes defining any categories other than
“Susceptible”. Strains yielding MIC /zone diameter results suggestive of a “nonsusceptible” category should be
submitted to a reference laboratory for further testing.
c These interpretive standards are applicable only to disk diffusion susceptibility testing with Haemophilus
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.2
d These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-
adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
e These zone diameter standards for Streptococcus spp. including S. pneumoniae apply only to tests
performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.
 A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable. A report of Intermediateindicates that the result
should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically
feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This
category also provides a buffer zone which prevents small uncontrolled technical factors from causing major
discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if
the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should
be selected.
 Quality Control:
 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the
technical aspects of the laboratory procedures. For dilution technique, standard Levofloxacin powder should
give the MIC values provided in Table 10. For diffusion technique, the 5 mcg Levofloxacin disk should provide
zone diameters provided in Table 10.
Table 10: Quality Control for Susceptibility Testing

Microorganism Microorganism MIC (mcg/mL) Disk Diffusion

QC Number (zone diameter in mm)
Enterococcus faecalis ATCC 29212 0.25 – 2 --
Escherichia coli ATCC 25922 0.008 – 0.06 29 – 37
Escherichia coli* ATCC 35218 0.015 – 0.06 --
Haemophilus influenza ATCC 49247 0.008 – 0.03a 32 – 40b
Pseudomonas aeruginosa ATCC 27853 0.5 – 4 19 – 26
Staphylococcus aureus ATCC 29213 0.06 – 0.5 --
Staphylococcus aureus ATCC 25923 -- 25 – 30
Streptococcus pneumonia ATCC 49619 0.5 – 2c 20 – 25d
 a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM).1
b This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion
procedure using Haemophilus Test Medium (HTM).2
c This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth
microdilution procedure using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.
d This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion
procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.
* Careful maintenance of this organism is required as the strain may lose its plasmid.
 Pharmacodynamic Properties:
 Pharmacotherapeutic group: Antiifectives for systemic use – Antibacterials for systemic use – Quinolone
antibasterials – Fluoroquinolones
 ATC code: J01MA12
 Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the
racemic drug substance ofloxacin.
 Mechanism of action
 As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and
topoisomerase IV.
 PK/PD relationship
 The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in
serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).
 Mechanism(s) of resisance
 Resistance to levofloxacin is acquired through a stepwise process by target site mutations in both type II
topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as permeation
barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also affect susceptibility to
levofloxacin.
 Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the mechanism of
action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.
 Breakpoints
 The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately
susceptible organisms and intermediately susceptible from resistant organisms are presented in the below
table for MIC testing (mg/L).
 EUCAST clinical MIC breakpoints for levofloxacin (version 2.0, 2012-01-01):

Pathogen Susceptible Resistant

Enterobacteriacae ≤1 mg/L >2 mg/L

Pseudomonas spp. ≤1 mg/L >2 mg/L
Acinetobacter spp. ≤1 mg/L >2 mg/L
Staphylococcus spp. ≤1 mg/L >2 mg/L
S.pneumoniae 1
≤2 mg/L >2 mg/L
Streptococcus A,B,C,G ≤1 mg/L >2 mg/L
H.influenzae2, 3 M.catarrhalis 3
≤1 mg/L >1 mg/L
Non-species related breakpoints 4
≤1 mg/L >2 mg/L
 The breakpoints for levofloxacin relate to high dose therapy.
 2. Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l) may occur but there is no
evidence that this resistance is of clinical importance in respiratory tract infections with H. influenzae.
 3. Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The
identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is
confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical
response for confirmed isolates with MIC above the current resistant breakpoint they should be reported
resistant.
 4. Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500 mg x 1 to
500 mg x 2.
 The prevalence of resistance may vary geographically and with time for selected species and local information
on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be
sought when the local prevalence of resistance is such that the utility of the agent in at least some types of
infections is questionable.
Commonly susceptible species
Aerobic Gram-positive bacteria
Bacillus anthracis
Staphylococcus aureus methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, group C and G
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic Gram- negative bacteria
Eikenella corrodens
Haemophilus influenzae
Haemophilus para-influenzae
Klebsiella oxytoca
Moraxella catarrhalis
Pasteurella multocida
Proteus vulgaris
Providencia rettgeri
Anaerobic bacteria
Peptostreptococcus
Other
Chlamydophila pneumoniae
Chlamydophila psittaci

Chlamydia trachomatis
Legionella pneumophila
Mycoplasma pneumoniae
Mycoplasma hominis
Ureaplasma urealyticum
Species for which acquired resistance may be a problem
Enterococcus faecalis
Staphylococcus aureus methicillin-resistant#
Coagulase negative Staphylococcus spp
Aerobic Gram- negative bacteria
Acinetobacter baumannii
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Anaerobic bacteria
Bacteroides fragilis
Inherently resistant Strains
Enterococcus faecium
# Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including
levofloxacin.
 Pharmacokinetic Properties:
 The mean ± SD pharmacokinetic parameters of Levofloxacin determined under single and steady-state
conditions following oral tablet, oral solution, or intravenous (IV) doses of Levofloxacin are summarized
in Table 8.
Table 8: Mean ± SD Levofloxacin PK Parameters

Regimen Cmax Tmax AUC CL/F1 Vd/F2 t1/2 CLR
(mcg/mL) (h) (mcg∙h/mL) (mL/min (L) (h) (mL/min)
)
Single dose
250 mg oral tablet3 2.8 ± 0.4 1.6 ± 27.2 ± 3.9 156 ± 20 ND 7.3 ± 142 ± 21
1.0 0.9
500 mg oral tablet3* 5.1 ± 0.8 1.3 ± 47.9 ± 6.8 178 ± 28 ND 6.3 ± 103 ± 30
0.6 0.6

500 mg oral solution12 5.8 ± 1.8 0.8 ± 47.8 ± 10.8 183 ± 40 112 ± 7.0 ± ND
0.7 37.2 1.4
500 mg IV3 6.2 ± 1.0 1.0 ± 48.3 ± 5.4 175 ± 20 90 ± 11 6.4 ± 112 ± 25
0.1 0.7
750 mg oral tablet5* 9.3 ± 1.6 1.6 ± 101 ± 20 129 ± 24 83 ± 17 7.5 ± ND
0.8 0.9
750 mg IV5 11.5 ± ND 110 ± 40 126 ± 39 75 ± 13 7.5 ± ND
4.04 1.6
Multiple dose
500 mg every 24h oral 5.7 ± 1.4 1.1 ± 47.5 ± 6.7 175 ± 25 102 ± 22 7.6 ± 116 ± 31
tablet3 0.4 1.6
500 mg every 24h IV3 6.4 ± 0.8 ND 54.6 ± 11.1 158 ± 29 91 ± 12 7.0 ± 99 ± 28
0.8
500 mg or 250 mg every 8.7± 4.07 ND 72.5 ± 51.27 154 ± 72 111 ± 58 ND ND
24h IV, patients with
bacterial infection6
750 mg every 24h oral 8.6 ± 1.9 1.4 ± 90.7 ± 17.6 143 ± 29 100 ± 16 8.8 ± 116 ± 28
tablet5 0.5 1.5
750 mg every 24h IV5 12.1 ± ND 108 ± 34 126 ± 37 80 ± 27 7.9 ± ND
4.14 1.9
500 mg oral tablet single dose, effects of gender and age:
Male8 5.5 ± 1.1 1.2 ± 54.4 ± 18.9 166 ± 44 89 ± 13 7.5 ± 126 ± 38
0.4 2.1
Female9 7.0 ± 1.6 1.7 ± 67.7 ± 24.2 136 ± 44 62 ± 16 6.1 ± 106 ± 40
0.5 0.8
Young10 5.5 ± 1.0 1.5 ± 47.5 ± 9.8 182 ± 35 83 ± 18 6.0 ± 140 ± 33
0.6 0.9
Elderly11 7.0 ± 1.6 1.4 ± 74.7 ± 23.3 121 ± 33 67 ± 19 7.6 ± 91 ± 29
0.5 2.0
500 mg oral single dose tablet, patients with renal insufficiency:
CLCR 50–80 mL/min 7.5 ± 1.8 1.5 ± 95.6 ± 11.8 88 ± 10 ND 9.1 ± 57 ± 8
0.5 0.9
CLCR 20–49 mL/min 7.1 ± 3.1 2.1 ± 182.1 ± 51 ± 19 ND 27 ± 10 26 ± 13
1.3 62.6
CLCR < 20 mL/min 8.2 ± 2.6 1.1 ± 263.5 ± 33 ± 8 ND 35 ± 5 13 ± 3
1.0 72.5
Hemodialysis 5.7 ± 1.0 2.8 ± ND ND ND 76 ± 42 ND
2.2
CAPD 6.9 ± 2.3 1.4 ± ND ND ND 51 ± 24 ND
1.1
 1 clearance/bioavailability
 2 volume of distribution/bioavailability
 3 healthy males 18–53 years of age
 4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose
 5 healthy male and female subjects 18–54 years of age

 6 500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of
the respiratory tract or skin
 7 dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling
 8 healthy males 22–75 years of age
 9 healthy females 18–80 years of age
 10 young healthy male and female subjects 18–36 years of age
 11 healthy elderly male and female subjects 66–80 years of age
 12 healthy males and females 19–55 years of age
 * Absolute bioavailability; F = 0.99 ± 0.08 from a 500 mg tablet and F = 0.99 ± 0.06 from a 750 mg
tablet;
 ND = not determined.
 Absorption
Following a single intravenous dose of Levofloxacin to healthy volunteers, the mean ± SD peak plasma
concentration attained was 6.2 ±1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0
mcg/mL after a 750 mg dose infused over 90 minutes.
 Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens.
Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage
regimen. The mean ± SD peak and trough plasma concentrations attained following multiple once-daily oral
dosage regimens were approximately 5.7 ± 1.4 and 0.5 ±0.2 mcg/mL after the 500 mg doses, and 8.6 ± 1.9
and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ± SD peak and trough plasma
concentrations attained following multiple once-daily IV regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2
mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the 750 mg doses,
respectively.
 The plasma concentration profile of Levofloxacin after IV administration is similar and comparable in extent of
exposure (AUC) to that observed for Levofloxacin tablets when equal doses (mg/mg) are administered.
Therefore, the oral and IV routes of administration can be considered interchangeable
 (see Figure 2 and Figure 3).
 Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg

 Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg
 Distribution
The mean volume of distribution of Levofloxacin generally ranges from 74 to 112 L after single and multiple
500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak
levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin
tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately
1 following multiple once-daily oral administration of 750 mg and 500 mg doses of Levofloxacin, respectively,
to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were
generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g
over a 24-hour period after a single 500 mg oral dose.
 In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma Levofloxacin concentrations,

Levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined
by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin
binding to serum proteins is independent of the drug concentration.
 Metabolism
Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its
enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as
unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was
recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in
feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-
oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant
pharmacological activity.
 Excretion
Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-
life of Levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of Levofloxacin
given orally or intravenously. The mean apparent total body clearance and renal clearance range from
approximately 144 to 226 mL/‌min and 96 to 142 mL/min, respectively. Renal clearance in excess of the
glomerular filtration rate suggests that tubular secretion of Levofloxacin occurs in addition to its glomerular
filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and
35% reduction in the Levofloxacin renal clearance, respectively, indicating that secretion of Levofloxacin
occurs in the renal proximal tubule.
 No Levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving
Levofloxacin.
 Geriatric
There are no significant differences in Levofloxacin pharmacokinetics between young and elderly subjects
when the subjects’ differences in creatinine clearance are taken into consideration. Following a 500 mg oral
dose of Levofloxacin to healthy elderly subjects (66 – 80 years of age), the mean terminal plasma elimination
half-life of Levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The
difference was attributable to the variation in renal function status of the subjects and was not believed to be
clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based
on age alone is not necessary.
 Pediatrics
The pharmacokinetics of Levofloxacin following a single 7 mg/kg intravenous dose were investigated in
pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared Levofloxacin faster
than adult patients, resulting in lower plasma exposures than adults for a given mg/kg dose. Subsequent
pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg
per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma
exposures (AUC0-24 and Cmax) to those observed in adult patients administered 500 mg of Levofloxacin once
every 24 hours.
 Gender
There are no significant differences in Levofloxacin pharmacokinetics between male and female subjects when
subjects’ differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of
Levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of Levofloxacin was
about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable
to the variation in renal function status of the male and female subjects and was not believed to be clinically
significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based
on gender alone is not necessary.
 Race
The effect of race on Levofloxacin pharmacokinetics was examined through a covariate analysis performed on
data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume
of distribution were not affected by the race of the subjects.
 Renal Impairment:
Clearance of Levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in
adult patients with impaired renal function (creatinine clearance < 50 mL/min), requiring dosage adjustment
in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis
(CAPD) is effective in removal of Levofloxacin from the body, indicating that supplemental doses of
Levofloxacin are not required following hemodialysis or CAPD.

 Hepatic Impairment
Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent
of Levofloxacin metabolism, the pharmacokinetics of Levofloxacin are not expected to be affected by hepatic
impairment.
 Bacterial Infection:
The pharmacokinetics of Levofloxacin in patients with serious community-acquired bacterial infections are
comparable to those observed in healthy subjects.
 TOXICOLOGY:
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
 In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary
administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the highest recommended
human dose (750 mg) based upon relative body surface area.
 Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino
(Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of
this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the
highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison,
dermal levofloxacin concentrations in human subjects receiving 750 mg of LEVAQUIN® averaged
approximately 11.8 mcg/g at Cmax.
 Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium
and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat
unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in the in
vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.
 Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as
360 mg/kg/day, corresponding to 4.2 times the highest recommended human dose based upon relative
body surface area and intravenous doses as high as 100 mg/kg/day, corresponding to 1.2 times the highest
recommended human dose based upon relative body surface area.
Use In Specific Populations

Pregnancy
Pregnancy Category C
 Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4
times the highest recommended human dose based upon relative body surface area, or at intravenous
doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based
upon relative body surface area.
 The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality.
No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds
to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed
intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose
based upon relative body surface area.
 There are, however, no adequate and well-controlled studies in pregnant women. LEVAQUIN® should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
 Based on data on other fluoroquinolones and very limited data on LEVOFLOXACIN, it can be presumed that
levofloxacin will be excreted in human milk.
 Because of the potential for serious adverse reactions from LEVOFLOXACIN in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
 Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several
species.
 Pharmacokinetics following intravenous administration
 The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric
patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult
patients resulting in lower plasma exposures than adults for a given mg/kg dose.
Inhalational Anthrax (Post-Exposure)

 Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-
exposure).
 The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate.
 The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied.
Plague
 Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including
pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague.
Efficacy studies of LEVOFLOXACIN could not be conducted in humans with pneumonic plague for ethical and
feasibility reasons.
 Efficacy &Preclinical Safety Data:
 Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity,
repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.
 Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on
fetuses was delayed maturation as a result of maternal toxicity.
 Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome
aberrations in Chinese hamster lung cells in vitro.
 These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid
exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.
 Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses.
 Levofloxacin did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour
development in a photocarcinogenity study.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats
and dogs. These findings were more marked in young animals.
 Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome
aberrations in Chinese hamster lung cells in vitro.
 These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid
exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.
 Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses.
 Levofloxacin did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour
development in a photocarcinogenity study.

In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in
rats and dogs. These findings were more marked in young animals.

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Dossier Le-One Tab.

LEVOFLOXACIN(LE-ONE) TABLETS 500MG

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I. Section One: General Information

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ADMINISTRATIVE DATA AND

Noted: Afghan business partner will submit this Letter Locally

2. A Completed and Signed Application Form

Noted: Letter of Authorization - Attached

a) A copy of “Manufacturing License”*(issued by the competent authority in the country

d) A copy of “GMP Certificate” of the manufacture*

5. Product Labeling Requirement

Check-List for Unit Carton:

------ Draft Copy Attached------

------ Draft Copy Attached------

Parameters of Patient Information Leaflet(PIL)

------ Draft Copy Attached------

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2-) Properties of Active

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3-)Site(s) of Manufacture- Active

Route(s) of Synthesis of Active Pharmaceutical Ingredient (s)

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 European pharmacopeia, provide a European certificate of suitability together with a

4-)Specification for the Active

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5-) Batch Analysis

6-) Container Closure System

 Provide a description of the container closure system(s), including the identity of

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7-) Stability Testing of the Active

Study Storage Condition Relative humidity Minimum time

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The information on the Finished Pharmaceutical Products (FPP) should be submitted

1. Description of the Finished Pharmaceutical Product

Product Name LE-ONE 500mg Tablets

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S# Ingredient Functions Quality Qty/Unit(Tab.) Qty/Batch 5000

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- Comparative dissolution of the batch used in pharmacokinetic or bioequivalence studiescompared with an

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P3.1: Information on development studies:

N/A as product is generic formulation

P3.2: COMPONENTS OF THE DRUG PRODUCT

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S# Name of excipients Functions Qty/Unit(Tab.) Specifications

*Will not appear in the final product

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P3.3.1 Formulation Development

1. Producing an optimal formula and process.

4.0 A Systematic Approach:

A Systematic approach to LE-ONE (Levofloxacin-as Hemihydrate) 500 mg Tablets. design and

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 TRAIL BATCHES FOR LEVOFLOXACIN (AS HEMIHYDRATE) 500 mg TABLETS

 Comparative Dissolution Report

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Test product: LE-ONE 500MG TABLETS

Reference product: TANAVIC 500 mg TABLET