Dawaflox - Forte DPS PD

Generic Name: Flucloxacillin powder for oral solution
Brand Name: Dawaflox - forte powder for oral solution
DAWA Limited Each 5ml after reconstitution contains: Flucloxacillin (as Sodium) 250mg
PHARMACEUTICAL DEVELOPMENT Pack Size: 60ml and 100ml
Page 1 of 20
DAWAFLOX - FORTE POWDER FOR ORAL SOLUTION
PHARMACEUTICAL DEVELOPMENT
Prepared by: J. Akinyi Approved by: W. Maina Authorized by: Dr. M. Kinyua
Product Development Officer Quality Control Manager Quality Assurance Manager
Signature Signature Signature
Date: Date: Date:

Page 2 of 20
TABLE OF CONTENTS:
SECTION PARTICULARS PAGE NUMBER(S)
1.0 Introduction 3
2.0 Formulation development 4-5
3.0 Components of the drug 6
4.0 Justification of the choice of excipients 7–9
5.0 Good manufacturing practices 10 – 11
6.0 Physico - chemical properties 12
7.0 Manufacturing process 13 – 15
8.0 Container closure system 16 – 17
9.0 Manufacturing process flow chart 18
10.0 Compatibility and product stability 19
11.0 Literature review and References 20
1.0 INTRODUCTION
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This product development contains information on the studies conducted to establish that the dosage form,
the formulation, the manufacturing process, the container closure system, microbiological attributes and
usage instructions are appropriate for the purpose of producing a high quality antibacterial agent. This
powder for oral solution is reconstituted with previously boiled and cooled water prior to administration. The
main objective of the study was to develop a pharmaceutically equivalent to the innovator which is stable
and cost effective. Powders for oral solution formulations have the following advantages over the other
dosage forms(tablets and capsules): Therapeutic agents can easily be administered orally to individuals
who have difficulty in swallowing, e.g. elderly patients and infants, the therapeutic agent is dissolved in the
formulation thus readily absorbed on and also taste-masking of bitter APIs and excipients can be readily
achieved.
2.0 FORMULATION DEVELOPMENT FOR DAWAFLOX - FORTE POWDER FOR ORAL SOLUTION
Dawaflox - forte powder for oral solution contains Flucloxacillin (as Sodium) as the Active
Pharmaceutical Ingredient (API), thus it is indicated for the treatment of bacterial infections caused by
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susceptible, usually gram-positive organisms. Dawaflox - forte powder for oral solution also contains in –
active ingredients (excipients). Excipients determine the stability of the final product during storage. All
excipients should be compatible with the API and other excipients i.e. excipients should have no
bioactivity, no reaction with the drug substance, no effect on the functions of other excipients, and no
support of microbiological growth in the product.
To develop a product with high quality, every detail was subjected to scrutiny to ensure cGMP
compliance, analytical method validation, stability studies, documentation, safety, health and
environmental control measures were observed, a variety of formulation trials were carried out, in -
process controls, quality control analysis on parameters such as the pH of the product, appearance,
specific gravity, microbial contamination and assay were carried out. The active pharmaceutical
ingredients, Flucloxacillin sodium was subjected to quality control studies .All the excipients used in this
formulation were also analyzed in the quality control laboratories before they were released for
production. Product optimization and scale up was done by preparing small trial batches of five litres,
twenty litres and finally one hundred litres. The stability of the finished product was determined by
conducting accelerated stability studies in the stability chamber at set storage conditions: temperature of
40°C ± 2°C and relative humidity of 75% ± 5% for a period of six months in the order of: initial,2nd,4th ,
and 6th month respectively. The real time stability studies were also conducted at the
initial,3rd ,6th ,9th ,12th ,18th,24th and 36th month respectively at storage conditions of 30ºC ± 2ºC
temperature and 65% ± 5% relative humidity. From the stability studies, Dawaflox - forte powder for oral
solution was stable throughout the study period. The packaging materials used also did not show any
interference with the product. This was done with reference to:
1. ICH Guidelines: Q6A and Q6B
2. ICH Q8 guidelines: Pharmaceutical Development
3. ICH Q9 guidelines: Quality Risk Management
Page 5 of 20
3.0 COMPONENTS OF THE PRODUCT

Page 6 of 20
SR.NO. NAME PURPOSE QUANTITY

1.0 Flucloxacillin (as Sodium) Active pharmaceutical 250.0mg/5ml
Ingredient
C19H16ClFN3NaO5S,H2O 493.9
2.0 EXCIPIENTS PURPOSE QUANTITY
i Pineapple powder Flavoring agent 20.00mg/5ml

ii Golden yellow Coloring agent 0.40mg/5ml
iii Sodium benzoate Preservative 3.00mg/5ml
iv Sodium citrate anhydrous Buffering agent 16.00mg/5ml
v Sodium CMC Viscosity modifier 6.00mg/5ml
vi Sodium chloride Buffering agent 6.00mg/5ml
vii Sucrose Sweetening agent 1926.00mg/5ml
3.0 No overages were added
The API (Flucloxacillin sodium) used in the manufacture of Dawaflox - forte powder for oral solution was
from a pre - qualified supplier.
4.0 JUSTIFICATION OF THE USE AND CHOICE OF EXCIPIENTS

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4.1 PINEAPPLE POWDER

White to off-white amorphous powder, a characteristic odour of ripe pineapple, slightly soluble in water,
freely soluble in alcohol and in methanol. It dissolves in dilute solutions of alkali hydroxides.
Application
As a flavoring agent
Unfortunately the vast majority of drugs in solution are unpalatable and therefore, the addition of flavours is
often required to mask the taste of the drug substance. It was used to produce a palatable formulation of
Dawaflox - forte powder for oral solution.
4.2 GOLDEN YELLOW
A bright orange coloured amorphous powder, soluble in water, dilute acids and alkalis.
Application
As a colouring agent
Colouring agents are pharmaceutical ingredients that impart the preferred colour to the formulation. Golden
yellow colour was used as an in – active ingredient to enhance the visual appeal of the product, as well as
to assist in identification of the product.
4.3 SODIUM BENZOATE
A white, crystalline or granular powder or flakes, slightly hygroscopic, freely soluble in water, sparingly
soluble in alcohol (90 per cent V/V).
Application
As a preservative
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Sodium benzoate is a chemical agent that is capable of reducing the number of viable microorganisms in a
formulation to a level that is safe for its designated use and will maintain the numbers of viable
microorganisms at or below a level for the use / shelf-life of the product, hence its use as a preservative in
this product.
4.4 SODIUM CITRATE ANHYDROUS
A white, crystalline powder or white, granular crystals, freely soluble in water, practically insoluble in
alcohol.
Application
As a Buffering agent
The stability of many pharmaceutical substances can be strongly dependent on the degree of acidity or
basicity to which they are exposed and that a change in pH can cause significant changes in the rate of
degradation reactions. Sodium citrate as an alkalizer has the adequate capacity in the desired pH range of
this product (4.0 and 7.0) after reconstitution. It is also biologically safe and has no effect on the stability of
the product.
4.5 SODIUM CMC
A white or almost white, granular powder, hygroscopic after drying, practically insoluble in acetone, in
ethanol and in toluene. It is easily dispersed in water giving colloidal solutions.
Application
As a viscosity modifier
The administration of oral solutions to patients is usually performed using a syringe, a small measuring cup
or a 5ml teaspoon. The thickness of the formulation must be sufficiently controlled in order to ensure the
accurate measurement of the volume to be dispensed. Sodium CMC was used to increase the viscosity of
4.6 SODIUM CHLORIDE
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A white, crystalline powder or colourless crystals or white pearls, freely soluble in water, practically
insoluble in ethanol.
Application
As a Buffering agent
As an acidifier, sodium chloride was used in this formulation in order to maintain the pH of this product
within the range of 4.0 and 7.0 after reconstitution.
Sodium chloride was also used to improve the palatability of this product as an added advantage.
4.7 SUCROSE
White or almost white, crystalline powder, or lustrous, colourless or white or almost white crystals, very
soluble in water, slightly soluble in ethanol (96 per cent) and practically insoluble in anhydrous ethanol.
Application
As a sweetening agent
Sweetening agents are used in formulations designed for oral administration specifically to increase the
palatability of the therapeutic agent. Sucrose was used as the major sweetening agent in this formulation.
N/B – Full quality control analysis was done as per the set specifications for Dawaflox - forte powder for
oral solution and all other excipients mentioned above before they were approved for production.
5.0 GOOD MANUFACTURING PRACTICES (GMP)

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It is an essential requirement in manufacture of pharmaceuticals that the manufacturer must comply with
the Good Manufacturing Practices. Considerable efforts were made in the production areas to establish
procedures and facilities that decreased the occurrence of any mishap in manufacture and packing that
might adversely affect the health of the public. Compliance with these procedures was monitored by
frequent internal and external audits. The main points covered in these procedures were as follows:
• The manufacturing premises were kept clean and designed to allow a product to be made in complete
isolation from any other product being made at the same time. This was to help reduce the cases of cross-
contaminations.
• Equipment were cleaned before use with all traces of the last product removed. This was well observed
by the in – process quality control personnel on the shop floor together with the production supervisors
in charge.
• The batch records detailed the product formula, and the manufacturing steps required to be followed in
preparation of this product. The operator entered appropriate information on the batch records during
manufacture, such as the identifying numbers of raw materials, the results of in-process checks etc. Once
manufacture was complete, these records were retained as they constituted a complete
record of the batch and must be readily accessible if required for either audit purposes or investigation of
any product complaints.
• Each batch of a product was given a unique identifying number which was written on the batch
manufacturing records and identified the product throughout manufacture and was then used as
the batch number on all labeling of product filled from the batch during packaging.
• Each raw material had to comply before use in production and also the bulk finished product had to
comply before packaging, with specifications that are set down for each product. Such specifications were
found in either the British Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia, or the
in - house specifications as is accepted by appropriate regulatory authorities such as the Pharmacy and
Poisons Board (PPB) and other drug regulatory authorities . Such specifications detailed the tests and
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analytical methods which had to be performed to confirm the identity; determine the concentration of active
drug; and ensure the absence of any undesirable contaminants prior to release of this product.
▪The standard operating procedures were available for all production processes.
All these GMP standards were followed in order to achieve Dawaflox - forte powder for oral solution of high
quality.
• Samples of each batch was retained for other references as well as for re - analysis to determine its shelf-
life.
6.0 PHYSICO - CHEMICAL PROPERTIES
Below are the parameters and their specifications that were used during the product development to
determine the product quality:
FINISHED PRODUCT
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TEST SPECIFICATIONS
Physical appearance A whitish coloured, free flowing granular powder yields orange coloured syrup
on reconstitution
Identification To pass test for the presence of Flucloxacillin Sodium
pH 4.0 to 7.0
Specific gravity 1.05 to 1.25
Assay :Content of
Flucloxacillin (as Sodium) Initial analysis = 90.0to 120.0% (225.0 – 300mg/5ml)
Stability after 7 days of reconstitution = 80.0 to 120.0% (200.0 – 300.0mg/5ml)
7.0 MANUFACTURING PROCESS
The manufacturing process for Dawaflox - forte powder for oral solution involved various steps namely
dispensing and transfer of the raw materials to the production area, sugar milling and drying, mixing of API
and the excipients, sampling for quality control analysis, powder filling, labeling and packing.
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7.1 DISPENSING
The raw materials were weighed one by one directly into the pre-labelled plastic raw material weighing bag
as per SOP WH/OPR/005 and each weight recorded in the BMR. This was verified by the in - process
quality control in charge.
7.2 SUGAR MILLING AND DRYING
Sugar was milled in the multi - mill machine and then dried in the fluid bed equipment machine at between
550C – 650C temperature.
7.3 MIXING OF API AND THE EXCIPIENTS
Sodium Benzoate, Sodium Citrate Anhydrous, Sodium CMC, Sodium Chloride, Pineapple Powder, Golden
Yellow and of sucrose were mixed together in a dry polythene bag. This mixture was transferred into a
double cone mixer whereby Flucloxacillin sodium and more sucrose were added and further mixed for 20
minutes. The remaining sugar was added and mixing continued for another 20minutes.
7.4 SAMPLING FOR QUALITY CONTROL ANALYSIS
The sample was then collected for quality control analysis as the bulk product awaited approval after the
analysis report. At this stage, the parameters that were checked in Quality Control were: moisture content,
colour of the sample, pH of the reconstituted syrup, specific gravity and the assay of the API present in
QUALITY CONTROL CHECKS ON THE INTERMEDIATE BULK PRODUCT:
Intermediate products were kept under appropriate conditions awaiting the analysis results. The analysis
was done as per the specifications / test procedures shown below:
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TEST PROCEDURES
TEST SPECIFICATIONS
A whitish coloured, free This was done by visual examination. The sample
Physical Appearance flowing granular powder was to be : whitish coloured, free flowing granular
yields orange coloured powder yields orange coloured syrup on reconstitution
syrup on reconstitution
pH 4.0 to 7.0 This was done by measuring the pH of the
reconstituted syrup using a well calibrated pH meter
Moisture content Not more than 1.5% This was done by measuring the moisture content of
the dry powder using a moisture analyzer
Specific gravity 1.05 to 1.25 This was done by taking the weight of an empty
pycnometer = A, Taking the weight of the pycnometer
filled with water = B using the same pycnometer, the
pycnometer was then filled with the sample under
study and weighed = C
Formula: (C – A)
(B – A)
Assay :Content of
Flucloxacillin 90.0to 120.0% (225.0 – As per the BP 2012 analytical method
(as Sodium) 300mg/5ml)
7.5 POWDER FILLING/PACKING STEP (PROCESS)

This was done after the quality control analysis report issue. The report showed that the bulk product
sample had passed all specifications and was released for filling.
Complete finished product analysis was done as per the set specifications (page 12) before it was released
for packing. This was to confirm if the product met the set quality control specifications.
Packaging is defined as the process that a bulk material must undergo to become a finished product. This
was done by competent personnel with practical experience and the awareness of the principles of GMP
involved in packing the pharmaceutical products. The personnel were dressed in clean factory attires
including the head caps, face masks and hand gloves. This was to prevent any kind of contaminations that
could be caused by the personnel.
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8.0 CONTAINER CLOSURE SYSTEM

Dawaflox - forte powder for oral solution was filled in 60ml and 100ml amber coloured glass bottles as
primary packing materials.
Packaging is defined as the collection of different components which surround the pharmaceutical product
from the time of production until its use. The packaging materials should not interact physically or
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chemically with the product in any manner to alter the strength, quality, or purity beyond the official
requirements under the ordinary or customary conditions of handling shipment, storage and use.
All the packaging materials were subjected to quality control tests before they were approved for packing.
These tests were:
1. Visual inspection – to check for any damages and to compare with the approved standards
2. Dimensional tests
3. Physical tests
Importance of packaging
• To protect against all adverse external influences that can alter the properties of the product.
• To protect against biological contamination.
• To protect against physical damage.
• To carry the correct information and identification of the product.
• As a tamper evident / Child resistance/ Anti counterfeiting.
Functions of packaging
1) Containment
The containment of the product is the most fundamental function of packaging for medicinal products. The
design of high-quality packaging must take into account both the needs of the product and of the
manufacturing and distribution system. This requires the packaging: not to leak, nor allow diffusion and
permeation of the product, to be strong enough to hold the contents when subjected to normal handling and
not to be altered by the ingredients of the formulation in its final dosage form.
2) Protection
The packaging must protect the product against all adverse external influences that may affect its quality or
potency, such as: light, oxygen and biological contamination.
Factors that led to the choice of amber coloured glass bottles as the primary packaging material for
Dawaflox - forte powder for oral solution syrup:
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1. Physical degradation – it can preserve all the physical properties of the dosage form
2. Chemical degradation – it can not alter the physico chemical/biological entities of the product
3. Mechanical properties – it is strong enough to hold the contents during handling
4. Presentation – it is presentable and attractive
The active pharmaceutical ingredient should remain within its specification limits over the shelf-life of the
pharmaceutical product. The question of whether a packaging will provide the required protection for the
pharmaceutical product and the required stability over a certain time period can only be answered by
means of real-time stability studies. Such studies must evaluate the changes in the quality of the product, in
contact with its packaging, during a period equivalent to its intended shelf-life. For this reason, the final
decision for the choice of the primary packaging material for Dawaflox - forte powder for oral solution was
based on stability studies conducted on this product. It was confirmed after the real time stability studies
that the kind of packaging material used for Dawaflox - forte powder for oral solution cannot alter its quality.
9.0 FLOW CHART
Approved Raw Materials/ Packaging Materials
Raw Materials Dispensing
Sugar milling and drying & mixing of API and the excipients
Intermediate product sampling for quality control analysis

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Packing into unit cartons then into shipper cartons
Finished Goods Store
10.0 COMPATIBILITY AND PRODUCT STABILITY

The Real time and Accelerated stability studies conducted for Dawaflox - forte powder for oral SOLUTION
indicated that the shelf life of 3 years was appropriate for it. No incompatibilities were identified between the
active pharmaceutical ingredient, excipients and packaging materials.
The average stability study data provided for three consecutive trial batches:
Accelerated stability studies - for 6 months and real time stability studies - for 3years.
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ACCELERATED STABILITY REAL TIME STABILITY

STUDIES STUDIES
STORAGE CONDITIONS: STORAGE CONDITIONS:
PARAMETERS Temperature: 40oC + 2oC Temperature: 30oC + 2oC
STUDIED SPECIFICATIONS Relative Humidity: 75% + 5% Relative Humidity: 65% + 5%
A whitish coloured, free A whitish coloured, free
A whitish coloured, free flowing flowing granular powder flowing granular powder
granular powder yields orange yields orange coloured syrup yields orange coloured syrup
APPEARANCE coloured syrup on reconstitution on reconstitution on reconstitution
pH
4.0 – 7.0 Min 5.37 Max 5.62 Min 5.28 Max 5.53
SPECIFIC
GRAVITY
1.05 to 1.25 Min 1.120 Max 1.144 Min 1.120 Max 1.163
ASSAY: Content
of Flucloxacillin Initial analysis: 90.0 to 120.0% Min 100.47% Max 106.42% Min 99.23% Max 106.42%
(as sodium) Analysis after 7 days of
reconstitution: 80.0 to 120.0% Min 97.66% Max 102.63% Min 96.27% Max 102.63%
NOTE: Min – Minimum and Max – Maximum.
11.0 LITERATURE REVIEW

FLUCLOXACILLIN SODIUM
Flucloxacillin is indicated for the treatment of infections due to Gram-positive organisms, including
infections caused by β-lactamase producing staphylococci.It is also indicated in skin and soft tissue
infections e.g. boils abscesses, carbuncles, furunculosis, cellulitis, infected wounds, infected burns,
protection of skin grafts, and impetigo.
Infected skin conditions: e.g. ulcer, eczema and acne.
Page 20 of 20
Respiratory tract infections: Pneumonia, lung abscess, emphysema, sinusitis, pharyngitis, tonsillitis, quinsy,
otitis media and externa.
DOSAGE AND ADMINISTRATION:
Recommended dose is as shown below:-
Oral: To be taken at least 30 minutes before food.
Adults: 250–500 mg every 6 hours.
2–10 years: 125 – 250mg every 6 hours.
Children under 2 years: 62.5mg – 125mg every 6 hours.
REFERENCES:
1. Martindale: The complete drug reference; 34th Edition
2. British pharmacopoeia 2012
3. USP 30 – NF25
4. Remington: The science and study of pharmacy,21st Edition
5. Handbook of Pharmaceutical Excipients, Fifth Edition
6. PPB pharmaceutical product development guidelines
7. www.wikipedia.com

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Generic Name: Flucloxacillin powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

Product Development Officer Quality Control Manager Quality Assurance Manager

Signature Signature Signature

Date: Date: Date:

Brand Name: Dawaflox - forte powder for oral solution

SECTION PARTICULARS PAGE NUMBER(S)

2.0 Formulation development 4-5

3.0 Components of the drug 6

4.0 Justification of the choice of excipients 7–9

5.0 Good manufacturing practices 10 – 11

6.0 Physico - chemical properties 12

7.0 Manufacturing process 13 – 15

8.0 Container closure system 16 – 17

9.0 Manufacturing process flow chart 18

10.0 Compatibility and product stability 19

11.0 Literature review and References 20

Brand Name: Dawaflox - forte powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

3.0 COMPONENTS OF THE PRODUCT

Brand Name: Dawaflox - forte powder for oral solution

SR.NO. NAME PURPOSE QUANTITY

i Pineapple powder Flavoring agent 20.00mg/5ml

4.0 JUSTIFICATION OF THE USE AND CHOICE OF EXCIPIENTS

Brand Name: Dawaflox - forte powder for oral solution

4.1 PINEAPPLE POWDER

Brand Name: Dawaflox - forte powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

5.0 GOOD MANUFACTURING PRACTICES (GMP)

Brand Name: Dawaflox - forte powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

6.0 PHYSICO - CHEMICAL PROPERTIES

Brand Name: Dawaflox - forte powder for oral solution

7.0 MANUFACTURING PROCESS

Brand Name: Dawaflox - forte powder for oral solution

7.2 SUGAR MILLING AND DRYING

7.3 MIXING OF API AND THE EXCIPIENTS

7.4 SAMPLING FOR QUALITY CONTROL ANALYSIS

QUALITY CONTROL CHECKS ON THE INTERMEDIATE BULK PRODUCT:

Brand Name: Dawaflox - forte powder for oral solution

7.5 POWDER FILLING/PACKING STEP (PROCESS)

Brand Name: Dawaflox - forte powder for oral solution

8.0 CONTAINER CLOSURE SYSTEM

Brand Name: Dawaflox - forte powder for oral solution

Brand Name: Dawaflox - forte powder for oral solution

9.0 FLOW CHART

Approved Raw Materials/ Packaging Materials

Raw Materials Dispensing

Intermediate product sampling for quality control analysis

Brand Name: Dawaflox - forte powder for oral solution

Packing into unit cartons then into shipper cartons

Finished Goods Store

10.0 COMPATIBILITY AND PRODUCT STABILITY

Brand Name: Dawaflox - forte powder for oral solution

ACCELERATED STABILITY REAL TIME STABILITY

NOTE: Min – Minimum and Max – Maximum.

11.0 LITERATURE REVIEW

Brand Name: Dawaflox - forte powder for oral solution

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