international by: prof. dr. anayanti arianto, apt. prof. dr ......the usp categorizes sterile...
TRANSCRIPT
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PRACTICAL
MANUAL
STERILE
DOSAGE FORM
TECHNOLOGY
Laboratory of Pharmaceutical
Dosage Form Technology
Fakulty of Pharmacy
University of Sumatera Utara
2019
INTERNATIONAL
CLASS
BY:
Prof. Dr.
Anayanti Arianto,
Apt.
Prof. Dr. Julia
Reveny, M.Si.,
Apt.
Prof. Dr.
Wiryanto, M.S.,
Apt.
Dra. Nazliniwaty,
M.Si., Apt.
Lia Laila,
S.Farm., M.Sc.,
Apt.
-
i
PRACTICAL MANUAL
STERILE DOSAGE FORM TECHNOLOGY
NAME :
STUDENT No. :
GROUP :
PROGRAMME : SI - INTERNATIONAL
By :
Prof. Dr. Anayanti Arianto, M.Si., Apt
Prof. Dr. Wiryanto, M.Si., Apt
Prof. Dr. Julia Reveny, M.Si., Apt
Dra. Nazliniwaty, M.Si., Apt
Lia Laila, S.Farm., M.Sc., Apt
LABORATORY OF PHARMACEUTICAL DOSAGE FORM TECHNOLOGY
FACULTY OF PHARMACY
UNIVERSITY OF SUMATERA UTARA
2019
-
ii
FOREWORD
Manual drug compounding period based on the hand skill which previously performed in drug
store had been passed a long time ago. It changes to technology and automatic production
machines period in pharmaceutical industry. Drug manufacture is no longer as simple as
compounding because pharmaceutical industry has to follow the steps and regulation based on
Good Manufacturing Practice (GMP) which include all the production and quality control
aspects. Following the changes in pharmaceutical industry, Sterile Dosage Form Laboratory
with available facility take effort to design continuosly the learning process, training and topic
in practical class based on the drug supply which become society need and requirement.
This practical manual is intended to be a guidance for students to conduct the Sterile Dosage
Form Practical Class. This practical manual is an excercise to plan and perform the Standard
Operational Procedure of sterilization and also excercise to plan and perform sterile product
manufacturing based on GMP procedure. It is expected that students will have competent
knowledge level, certain skill and ability in sterile product manufacturing.
Hopefully this practical manual can assist students to do practice, therefore the result can be
achieved according to the purpose.
Medan, February 2019
Laboratory of Pharmaceutical Dosage
Form Technology
Faculty of Pharmacy
University of Sumatera Utara
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iii
TABLE OF CONTENT
Cover ........................................................................................................................ i
Forewords ............................................................................................................... ii
Table of Content ..................................................................................................... iii
Rule of the laboratory........……………………………………………………..... iv
Tools SOP .............................................................................................................. v
Practical I : Production and Packaging of Large Volume Single
Dose Injection .................……………………………... 1
Practical II : Production And Packaging Of Small Volume Single
Dose Injection (Ampoule)..........………………………..... 15
Practical III : Production And Packaging Of Small Volume Multiple
Doses Injection (Vial)………........................................... 29
Practical IV : Production And Packaging Of Eye
Drop Product ………………………..................…….… 43
Practical V : Production And Packaging Of Eye
Ointment Product …………………….......................….. 56
Practical VI : Evaluation Of Sterile Products............……………....…… 69
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iv
PRACTICAL REQUIREMENTS
AND
RULE OF THE LABORATORY
Practical Requirements
1. Students that can take practical class should have finished the Sterile Dosage Form
course.
2. For every meeting, each student has to attend the Drug Manufacturing Plan discussion
which is prepared in the Main Manufacturing Procedure and Main Packaging
Procedure.
3. After finish each practical class, student is required to make written report as
Manufacturing Documents which is included: Main Manufacturing Procedure and
Batch Manufacturing Record. The reports are given before attend the Drug
Manufacturing Plan discussion for the next practical title.
4. Students that do not attend the plan discussion and do not hand over the practical
report will not be allowed to follow the next practical class.
5. The final marking (practical evaluation) is in the form of examination to make Main
Manufacturing Procedure.
Rule of the Laboratory
1. Attend 1 hour before practical class begin.
2. Wear suitable clothes according to the Faculty of Pharmacy requirements.
3. Wear laboratory coat with long sleeve, head cover, masker, and gloves.
4. Do not wear jewelry, accessories, or other source of contaminant during the practical
class..
5. It is not allowed to eat, drink, smoking and talking in the laboratory.
6. The required tools can be obtained from the laboratory using a tools record.
7. Before practical start, the tools have to be cleaned and wrapped, ready to be sterilized.
8. Broken glasswares, damage or missing tools should be replaced as soon as possible.
9. Prepare 2 piece of clean clothes, wool, glue, small scissor, and secondary packaging
include label and brochure for the related products.
10. Keep silent and keep clean during the practical class.
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v
STANDARD OPERATING PROCEDURE FOR STERILIZATION
OF TOOLS AND CONTAINERS
No. Tools/Materials Sterilization
method
Temperature and
Time
Sterilization
time
1 Beaker glass Oven 170°C 30 min
2 Erlenmeyer Oven 170°C 30 min
3 Measuring cylinder Oven 170°C 30 min
4 Watch glass Oven 170°C 30 min
5 Glass rod Oven 170°C 30 min
6 Funnel + filter paper Autoklaf 121°C 15 min
7 Vial + aluminium
closure Oven 170°C 30 min
8 Bottle + aluminium
closure Oven 170°C 30 min
9 Rubber closure Autoklaf 121°C 15 min
10 Ampoule Oven 170°C 30 min
11 Tube + closure Autoklaf 121°C 15 min
12 Eye drop bottle Autoklaf 121°C 15 miin
13 Mortar and stamfer Oven 170°C 30 min
14 Sudip Autoklaf 121°C 15 min
15 Spatula Oven 170°C 30 min
16 Distilled water Autoklaf 121°C 15 min
1. Tools or containers are cleaned.
2. Tools and container are wrapped with paper.
3. Wrapped tools or containers are placed in to the sterilization apparatus according to the
table, count the sterilization time starting from the required temperature.
4. After the sterilization process is finished, turn off the apparatus, take out the sterilized
tools or container.
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Practical Manual of Sterile Dosage Form Technology 1
PRACTICAL I
I. TOPIC : PRODUCTION AND PACKAGING OF LARGE VOLUME
SINGLE DOSE INJECTION
II. AIM : to produce, pack and sterilize large volume single dose injection
III. R/
IV. THEORY
An injection is a preparation intended for parenteral administration and/or for
constituting or diluting a parenteral article prior to administration. It is administered
through the skin or other external boundary tissue, rather than through the alimentary
canal, so that therapeutic substances, using gravity or force, can gain direct entry to a
blood vessel, organ, tissue, or lesion.
The USP categorizes sterile preparations for parenteral use according to the physical
state of the product as follows:
1. Liquid preparations that are drug substances or solutions thereof, for example,
[drug] injection.
2. Dry solids that, upon the addition of suitable vehicles, yield solutions conforming
in all respects to the requirements for injections, for example, [drug] for injection.
3. Liquid preparations of drug substances dissolved or dispersed in a suitable
emulsion medium, for example, [drug] injectable emulsion.
4. Liquid preparations of solids suspended in a suitable liquid medium, for example,
[drug] injectable suspension.
5. Dry solids that, upon the addition of suitable vehicles, yield preparations
conforming in all respects to the requirements for injectable suspensions, for
example, [drug] for injectable suspension.
Depending on the volume of injection in a package, the USP further designates
injection, as either
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Practical Manual of Sterile Dosage Form Technology 2
(i) Small-volume injections or
(ii) Large-volume intravenous (IV) solutions.
The term small-volume injection applies to an injection that is packaged in
containers labelled as containing 100 mL or less. The large-volume IV solution
applies to a single-dose injection that is intended for IV use and is packaged in
containers labelled as containing more than 100 mL.
The term sterilization, as applied to pharmaceutical preparations, means destruction
of all living organisms and their spores or their complete removal from the
preparation. Five general methods are used to sterilize pharmaceutical products:
1. Steam
2. Dry heat
3. Filtration
4. Gas
5. Ionizing radiation
In every container, the volume of injection should excess the volume stated on the
label to fulfil the uniformity of volume. The suggested additional volumes are listed
in Table 1.
Table 1. Suggested additional volume
Volume stated in label Additional volume
Non viscous liquid (ml) Viscous liquid (ml)
0,5 ml
1,0 ml
2,0 ml
5,0 ml
10,0 ml
20,0 ml
30,0 ml
50,0 ml or more
0,10
0,10
0,15
0,30
0,50
0,60
0,80
2 %
0,12
0,15
0,25
0,50
0,70
0,90
1,20
3%
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Practical Manual of Sterile Dosage Form Technology 3
V. PREPARATION
a. Ingredients
b. Vehicle
c. Container (primary packaging)
d. Tools
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Practical Manual of Sterile Dosage Form Technology 4
e. Materials
f. Calculation
1. Number of products that will be produced
2. Amount of materials that are needed
No. Name of tools Number Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 5
3. Tonicity calculation
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Practical Manual of Sterile Dosage Form Technology 6
VI. PRODUCTION
Procedure:
VII. PACKAGING
a. Where does the packaging process take place? Give the reason.
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Practical Manual of Sterile Dosage Form Technology 7
b. Write down the Label/Brochure needed for the product
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Practical Manual of Sterile Dosage Form Technology 8
VIII. REFERENCES
------------------------------------------------------------------------------------------------------------
Questions
1. Why do the large volume injections should be pyrogen free?
2. What is the function of carbon absorbent addition in the production of large
volume injection products?
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Practical Manual of Sterile Dosage Form Technology 9
MAIN PRODUCTION PROCEDURE
BATCH PRODUCTION RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Bacth
volume:
Type:
Container:
Date :
Start time :
Finish time:
I. Ingredients :
Volume of 1 batch = .............. containing :
II. Specification
A. Description :
B. Materials :
C. Primary container
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Practical Manual of Sterile Dosage Form Technology 10
III. Weighing
No
.
Name of
material
Amount needed Amount weighted Signature
IV. Tools
No. Name of tool Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 11
V. Production
Procedure Signature
1
2
3
4
5
6
. . . . .. .
. . . . . .
. . . .. . .
. . . . . .
. . .. . . .
. . .. . . .
VI. Filling
VII. Sterilization
VIII. Reconciliation
Reconciliation Checked by : Approved by :
Theoretical result :
Real result :
Deviation : %
Result range l : 97,0-100,5%
Production Supervisor
Date :
Production Manager
Date:
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Practical Manual of Sterile Dosage Form Technology 12
MAIN PACKAGING PROCEDURE
BATCH PACKAGING RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
Packaging and Labelling
1. Labelling on the primary container
2. Labelling on the box
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Practical Manual of Sterile Dosage Form Technology 13
3. Brochure preparation
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Practical Manual of Sterile Dosage Form Technology 14
4. Final packaging :
� Pack the labelled bottle with brochure in to wrapped box.
� Pack the filled wrapped box in to Master Box
� Label Master Box with outside label
� Label with QUARANTINE
� Theoretical result :
� Real result :
� % from theoretical result :
� Result range 99,5 – 100% from theoretical result
� If the real result is out of the range, do “failure investigation” and give
explanation below
� Explanation :
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Practical Manual of Sterile Dosage Form Technology 15
PRACTICAL II
I. TOPIC : PRODUCTION AND PACKAGING OF SMALL VOLUME
SINGLE DOSE INJECTION (AMPOULE)
II. AIM : to produce, pack and sterilize small volume single dose injection
III. R/
IV. THEORY
An injection is a preparation intended for parenteral administration and/or for
constituting or diluting a parenteral article prior to administration. It is administered
through the skin or other external boundary tissue, rather than through the alimentary
canal, so that therapeutic substances, using gravity or force, can gain direct entry to a
blood vessel, organ, tissue, or lesion.
The USP categorizes sterile preparations for parenteral use according to the physical
state of the product as follows:
1. Liquid preparations that are drug substances or solutions thereof, for example,
[drug] injection.
2. Dry solids that, upon the addition of suitable vehicles, yield solutions conforming
in all respects to the requirements for injections, for example, [drug] for injection.
3. Liquid preparations of drug substances dissolved or dispersed in a suitable
emulsion medium, for example, [drug] injectable emulsion.
4. Liquid preparations of solids suspended in a suitable liquid medium, for example,
[drug] injectable suspension.
5. Dry solids that, upon the addition of suitable vehicles, yield preparations
conforming in all respects to the requirements for injectable suspensions, for
example, [drug] for injectable suspension.
Depending on the volume of injection in a package, the USP further designates
injection, as either
(i) small-volume injections or
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Practical Manual of Sterile Dosage Form Technology 16
(ii) large-volume intravenous (IV) solutions.
Generally, injection products are produced to be given by venous (intra-venous;IV),
muscle (intra-muscular;IM), dermal (intra-dermal;ID), or under the skin
(subcutaneous; SC). However, a lot of products are injected through specific organ
such as heart, artery, ocular and so on.
In the injections manufacturing, the suitable excipients can be added to increase
stability or activity, except it is stated in each monograph. Additional excipients
should not be dangerous in the used amount and should not affect the therapeutic nor
respond to the test and assay. The excipients are included vehicle, solubilizing agent,
buffer, preservatives, anti-oxidants, inert gas, surfactants, complexion and chelating
agents.
To protect easily oxidized drugs, then it is recommended to add an anti-oxidant to
maintain the drug stability. Some of anti-oxidants that can be used as excipients in
injectable drug are listed in Table 2.
Table 2. Anti-oxidants used as injectable drug excipients
Anti-oxidant Used concentration (%)
Ascorbic acid
Butyl hydroxyanisole
Cystein
Monothioglycerol
Sodium bisulphite
Sodium metabisulphite
Thiourea
Tocopherol
0.01- 0.5
0.005 – 0.02
0.1- 0.5
0.1 – 1.0
0.1 – 1.0
0.1 – 1.0
0.005
0.05 – 0.5
V. PREPARATION
a. Ingredients
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Practical Manual of Sterile Dosage Form Technology 17
b. Vehicle
c. Container (primary packaging)
d. Tools
No. Name of tools Number Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 18
e. Materials
f. Calculation
1. Number of products that will be produced
2. Amount of materials that are needed
3. Tonicity calculation
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Practical Manual of Sterile Dosage Form Technology 19
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Practical Manual of Sterile Dosage Form Technology 20
VI. PRODUCTION
Procedure:
VII. PACKAGING
a. Where does the packaging process take place? give the reason.
-
Practical Manual of Sterile Dosage Form Technology 21
b. Write down the Label/Brochure needed for the product
-
Practical Manual of Sterile Dosage Form Technology 22
VIII. REFERENCES
------------------------------------------------------------------------------------------------------------
Questions
1. Give another method of sterilization for small volume injectable drug in
ampoule.
2. How to produce air free water for injection?
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Practical Manual of Sterile Dosage Form Technology 23
MAIN PRODUCTION PROCEDURE
BATCH PRODUCTION RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
I. Ingredients :
Volume of 1 batch = .............. containing:
II. Specification
A. Description :
B. Materials :
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Practical Manual of Sterile Dosage Form Technology 24
C. Primary container
III. Weighing
No
.
Name of
material
Amount needed Amount weighted Signature
IV. Tools
No. Name of tool Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 25
V. Production
Procedure Signature
1
2
3
4
5
6
. . . . .. .
. . . . . .
. . . .. . .
. . . . . .
. . .. . . .
. . .. . . .
VI. Filling
VII. Sterilization
VIII. Reconciliation
Reconciliation Checked by : Approved by :
Theoretical result :
Real result :
Deviation : %
Result range l : 97,0-100,5%
Production Supervisor
Date :
Production Manager
Date:
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Practical Manual of Sterile Dosage Form Technology 26
MAIN PACKAGING PROCEDURE
BATCH PACKAGING RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
Packaging and Labelling
1. Labelling on the primary container
2. Labelling on the box
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Practical Manual of Sterile Dosage Form Technology 27
3. Brochure preparation
-
Practical Manual of Sterile Dosage Form Technology 28
4. Final packaging :
� Pack the labelled bottle with brochure in to wrapped box.
� Pack the filled wrapped box in to Master Box
� Label Master Box with outside label
� Label with QUARANTINE
� Theoretical result :
� Real result :
� % from theoretical result :
� Result range 99,5 – 100% from theoretical result
� If the real result is out of the range, do “failure investigation” and give
explanation below
� Explanation :
-
Practical Manual of Sterile Dosage Form Technology 29
PRACTICAL III
I. TOPIC : PRODUCTION AND PACKAGING OF SMALL VOLUME
MULTIPLE DOSES INJECTION (VIAL)
II. AIM : to produce, pack and sterilize small volume multiple doses injection
III. R/
IV. THEORY
An injection is a preparation intended for parenteral administration and/or for
constituting or diluting a parenteral article prior to administration. It is administered
through the skin or other external boundary tissue, rather than through the alimentary
canal, so that therapeutic substances, using gravity or force, can gain direct entry to a
blood vessel, organ, tissue, or lesion.
The USP categorizes sterile preparations for parenteral use according to the physical
state of the product as follows:
1. Liquid preparations that are drug substances or solutions thereof, for example,
[drug] injection.
2. Dry solids that, upon the addition of suitable vehicles, yield solutions conforming
in all respects to the requirements for injections, for example, [drug] for injection.
3. Liquid preparations of drug substances dissolved or dispersed in a suitable
emulsion medium, for example, [drug] injectable emulsion.
4. Liquid preparations of solids suspended in a suitable liquid medium, for example,
[drug] injectable suspension.
5. Dry solids that, upon the addition of suitable vehicles, yield preparations
conforming in all respects to the requirements for injectable suspensions, for
example, [drug] for injectable suspension.
Depending on the volume of injection in a package, the USP further designates
injection, as either
(iii) small-volume injections or
-
Practical Manual of Sterile Dosage Form Technology 30
(iv) large-volume intravenous (IV) solutions.
Parenteral dosage form can be packed in single or multiple doses. Product packed in
multiple dose containers such as vial should contains preservative to prevent the
growth of microorganisms which probably enter in to the container when it is used.
However, there is a limitation of preservatives which not all of them compatible with
the active drug. As example, benzyl alcohol is not compatible with sodium succinate
chloramphenicol and paraben group and phenol are not compatible with
nitrofuranthoin, amphotericin B and erytromycin. It is very important to choose
suitable preservative that compatible with the active drug. The preservatives also
should be compatible with the container and the closure of the product.
Some of preservatives in parenteral product are listed in Table 3.
Preservatives Used concentration (%)
Benzalkonium chloride
Benzethonium chloride
Benzyl alcohol
Chlorobutanol
Chlorocresol
Cresol
Metacresol
Ester of p-hidroxy benzoate:
Butyl
Methyl
Propyl
Thimerosal
0,01
0,01
1,0 – 2,0
0,25 – 0,5
0,1 – 0,3
0,3 – 0,5
0,1 – 0,3
0,015
0,1 – 0,2
0,02 – 0,2
0,01
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Practical Manual of Sterile Dosage Form Technology 31
V. PREPARATION
a. Ingredients
b. Vehicle
c. Container (primary packaging)
d. Tools
-
Practical Manual of Sterile Dosage Form Technology 32
e. Materials
f. Calculation
1. Number of products that will be produced
No. Name of tools Number Sterilization method Signature
-
Practical Manual of Sterile Dosage Form Technology 33
2. Amount of materials that are needed
3. Tonicity calculation
-
Practical Manual of Sterile Dosage Form Technology 34
VI. PRODUCTION
Procedure:
VII. PACKAGING
a. Where does the packaging process take place? give the reason.
-
Practical Manual of Sterile Dosage Form Technology 35
b. Write down the Label/Brochure needed for the product
-
Practical Manual of Sterile Dosage Form Technology 36
VIII. REFERENCES
------------------------------------------------------------------------------------------------------------
Questions
1. What is the function of preservative in the production of multiple dose
injection in vial?
-
Practical Manual of Sterile Dosage Form Technology 37
MAIN PRODUCTION PROCEDURE
BATCH PRODUCTION RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
I. Ingredients :
Volume of 1 batch = .............. containing :
II. Specification
A. Description :
B. Materials :
C. Primary container
-
Practical Manual of Sterile Dosage Form Technology 38
III. Weighing
No
.
Name of
material
Amount needed Amount weighted Signature
IV. Tools
No. Name of tool Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 39
V. Production
Procedure Signature
1
2
3
4
5
6
. . . . .. .
. . . . . .
. . . .. . .
. . . . . .
. . .. . . .
. . .. . . .
VI. Filling
VII. Sterilization
VIII. Reconciliation
Reconciliation Checked by : Approved by :
Theoretical result :
Real result :
Deviation : %
Result range l : 97,0-100,5%
Production Supervisor
Date :
Production Manager
Date:
-
Practical Manual of Sterile Dosage Form Technology 40
MAIN PACKAGING PROCEDURE
BATCH PACKAGING RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
Packaging and Labelling
1. Labelling on the primary container
2. Labelling on the box
-
Practical Manual of Sterile Dosage Form Technology 41
3. Brochure preparation
-
Practical Manual of Sterile Dosage Form Technology 42
4. Final packaging :
� Pack the labelled bottle with brochure in to wrapped box.
� Pack the filled wrapped box in to Master Box
� Label Master Box with outside label
� Label with QUARANTINE
� Theoretical result :
� Real result :
� % from theoretical result :
� Result range 99,5 – 100% from theoretical result
� If the real result is out of the range, do “failure investigation” and give
explanation below
� Explanation :
-
Practical Manual of Sterile Dosage Form Technology 43
PRACTICAL IV
I. TOPIC : PRODUCTION AND PACKAGING OF EYE DROP
PRODUCT
II. AIM : to produce, pack and sterilize eye drop product
III. R/
IV. THEORY
Eye drop product or Guttae Opthalmicae is a sterile dosage form in solution
or suspension, used to the eye by drop the drug solution in the conjunctive
layer around the eye lid and eye ball.
Eye drops are used to treat allergy, infections due to bacteria or virus,
glaucoma, and other eye disease. Eye is continuously exposed to the air, dirt,
pollutant, allergen, bacteria and other foreign material, when the protection
mechanism is occurred, then it is required eye product in the form of solution,
suspension or ointment.
In eye drop solution manufacturing, the physicochemical characteristic
should be considered, include: clarity, tonicity, pH, and sterility. For
suspension form, particle size in the product should be small enough which
will not irritate or scratch the cornea of the eye.
The usage of excipients such as preservatives, anti-oxidant and to increase
viscosity should be carefully considered. Eye drop solution usually is
buffered in pH where the maximum stability of the contained active drug can
be achieved.
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Practical Manual of Sterile Dosage Form Technology 44
V. PREPARATION
a. Ingredients
b. Vehicle
c. Container (primary packaging)
d. Tools
-
Practical Manual of Sterile Dosage Form Technology 45
e. Materials
No. Name of tools Number Sterilization method Signature
-
Practical Manual of Sterile Dosage Form Technology 46
f. Calculation
1. Number of products that will be produced
2. Amount of materials that are needed
3. Tonicity calculation
-
Practical Manual of Sterile Dosage Form Technology 47
VI. PRODUCTION
Procedure:
VII. PACKAGING
a. Where does the packaging process take place? Give the reason.
-
Practical Manual of Sterile Dosage Form Technology 48
b. Write down the Label/Brochure needed for the product
-
Practical Manual of Sterile Dosage Form Technology 49
VIII. REFERENCES
------------------------------------------------------------------------------------------------------------
Questions
a. What is the function of preservatives addition in the manufacturing of eye
drop product?
b. How to select suitable preservatives for eye drop product?
c. Give another method of sterilization that can be done to produce eye drop
product.
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Practical Manual of Sterile Dosage Form Technology 50
MAIN PRODUCTION PROCEDURE
BATCH PRODUCTION RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
I. Ingredients :
Volume of 1 batch = .............. containing :
II. Specification
A. Description :
B. Materials :
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Practical Manual of Sterile Dosage Form Technology 51
C. Primary container
III. Weighing
No
.
Name of
material
Amount needed Amount weighted Signature
IV. Tools
No. Name of tool Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 52
V. Production
Procedure Signature
1
2
3
4
5
6
. . . . .. .
. . . . . .
. . . .. . .
. . . . . .
. . .. . . .
. . .. . . .
VI. Filling
VII. Sterilization
VIII. Reconciliation
Reconciliation Checked by : Approved by :
Theoretical result :
Real result :
Deviation : %
Result range : 97,0-100,5%
Production Supervisor
Date :
Production Manager
Date:
-
Practical Manual of Sterile Dosage Form Technology 53
MAIN PACKAGING PROCEDURE
BATCH PACKAGING RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
Packaging and Labelling
1. Labelling on the primary container
2. Labelling on the box
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Practical Manual of Sterile Dosage Form Technology 54
3. Brochure preparation
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Practical Manual of Sterile Dosage Form Technology 55
4. Final packaging :
� Pack the labelled bottle with brochure in to wrapped box.
� Pack the filled wrapped box in to Master Box
� Label Master Box with outside label
� Label with QUARANTINE
� Theoretical result :
� Real result :
� % from theoretical result :
� Result range 99,5 – 100% from theoretical result
� If the real result is out of the range, do “failure investigation” and give
explanation below
� Explanation :
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Practical Manual of Sterile Dosage Form Technology 56
PRACTICAL V
I. TOPIC : PRODUCTION AND PACKAGING OF EYE OINTMENT
PRODUCT
II. AIM : to produce, pack and sterilize eye ointment product
III. R/
IV. THEORY
Eye ointment is a sterile ointment for eye treatment purpose using suitable ointment
base. It is different with the dermatological ointment, eye ointment should be sterile.
Eye ointment should fulfil the sterility test as states in the official compendia.
Therefore, eye ointment can be defined as semi solid dosage form which easily
applies for topical usage on skin or mucous membrane in the eye where the active
drug should be soluble or dispersed homogenise in the suitable ointment base.
Based on Pharmacopoeia, ointment base used as vehicle is divided in to 4 groups:
1. Hydrocarbon ointment base
2. Absorbed ointment base
3. Washable ointment base
4. Water soluble ointment base
The selection of ointment base is depended on several factors such as the desired
effect, physicochemical properties of the drug, bioavailability and stability of the
product.
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Practical Manual of Sterile Dosage Form Technology 57
V. PREPARATION
a. Ingredients
b. Vehicle
c. Container (primary packaging)
d. Tools
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e. Materials
No. Name of tools Number Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 59
f. Calculation
1. Number of products that will be produced
2. Amount of materials that are needed
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VI. PRODUCTION
Procedure:
VII. PACKAGING
a. Where does the packaging process take place? give the reason.
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Practical Manual of Sterile Dosage Form Technology 61
b. Write down the Label/Brochure needed for the product
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VIII. REFERENCES
------------------------------------------------------------------------------------------------------------
Questions
1. Give example of other ointment base according to the Martindale Extra
Pharmacopoeia.
2. Give another eye ointment available in the market which contain same active
ingredient with your product.
3. Why does this eye ointment do not require addition of preservative?
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Practical Manual of Sterile Dosage Form Technology 63
MAIN PRODUCTION PROCEDURE
BATCH PRODUCTION RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
I. Ingredients :
Volume of 1 batch = .............. containing :
II. Specification
A. Description :
B. Materials :
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C. Primary container
III. Weighing
No
.
Name of
material
Amount needed Amount weighted Signature
IV. Tools
No. Name of tool Sterilization method Signature
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Practical Manual of Sterile Dosage Form Technology 65
V. Production
Procedure Signature
1
2
3
4
5
6
. . . . .. .
. . . . . .
. . . .. . .
. . . . . .
. . .. . . .
. . .. . . .
VII. Filling
VIII. Sterilization
IX. Reconciliation
Reconciliation Checked by : Approved by :
Theoretical result :
Real result :
Deviation : %
Result range : 97,0-100,5%
Production Supervisor
Date :
Production Manager
Date:
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Practical Manual of Sterile Dosage Form Technology 66
MAIN PACKAGING PROCEDURE
BATCH PACKAGING RECORD
Name of company : …………………
Procedure/Record No. : …………………
Product
Code:
Name of
Product:
Batch
No.:
Batch
volume:
Type:
Container:
Date :
Start time :
Finish time:
Packaging and Labelling
1. Labelling on the primary container
2. Labelling on the box
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3. Brochure preparation
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Practical Manual of Sterile Dosage Form Technology 68
4. Final packaging :
� Pack the labelled bottle with brochure in to wrapped box.
� Pack the filled wrapped box in to Master Box
� Label Master Box with outside label
� Label with QUARANTINE
� Theoretical result :
� Real result :
� % from theoretical result :
� Result range 99,5 – 100% from theoretical result
� If the real result is out of the range, do “failure investigation” and give
explanation below
� Explanation :
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Practical Manual of Sterile Dosage Form Technology 69
PRACTICAL VI
I. TOPIC: EVALUATION OF STERILE PRODUCTS
II. AIM: To evaluate injection products, eye drop product and eye ointment
products.
III. EVALUATIONS OF STERILE PRODUCTS
1. Sterility Test
Based on Indonesian Pharmacopoeia, there are two methods that can be used to
test the sterility of sterile product:
a. Direct inoculation to culture medium
This evaluation include direct test of sample in growth media. The media
that can be used to perform this test such as liquid thioglycolate medium
(for aerob condition), alternative liquid thioglycolate medium (for anaerob
condition) and soybean-casein digest medium (for bacteria and fungus at
aerob condition).
Procedure:
1. Transfer the liquid from the container using sterile pipette or needle. .
2. Aseptically inoculate certain amount of the sample to the medium
flask.
3. Mix the sample with the medium without excess aeration.
4. Incubate the medium at least for 14 days
5. Observe the growth on the medium regularly during the incubation
period.
b. Membrane filtration
This method include liquid filtration trough sterile membrane by aseptic
technique, then the membrane is placed in the media and incubated for 7-14
days.
2. Pyrogenicity test
The pyrogenicity tests include:
a. Rabbit test
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Based on the temperature elevation (fever respond) on rabbit. .
b. LAL (Limulus amebocyte lysate) test
Based on the gel formation of amebocyte lysate originated form
Limulus polyphemus.
Tools and Materials:
- Pyrogen free syringe
- Pyrogen-free needles
- Pyrogen-free test tubes or vials
- Tube rack
- Incubator or oven
- Vortex tool
- LAL reagent
- Test sample or solution
- Universal indicator paper
Procedure:
a. Sample preparation
- All tools and materials used must be free of pyrogen.
- Use aseptic techniques during the experiment
- Test samples must be stored in the refrigerator at a temperature of 2-8 jamC
24 hours before use but must be frozen if not used in 24 hours.
- Test samples must have a pH range of 6-8. Test with universal indicator
paper.
b. Preparation of reagents
Limulus Amebocyte Lysate (LAL)
- Reconstitute lysate powder by adding 2 ml. Reagent water into the vial.
- Stir slowly for at least 30 seconds to dissolve the lysate powder. Do not shake
or vortex to avoid forming foam.
The reconstituted Lisate can be stored at -20˚C or below it for up to 1 week if
it is frozen immediately after reconstitution. Avoid repeated freezing and
search cycles.
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c. E. coli Endotoxin Standard
- Reconstitute the E.coli endotoxin standard to a concentration of 0.5 EU / ml
by adding 1 ml of LAL Reagent Water to the vial.
- Mix homogeneously at least 15 minutes with the vortex to obtain endotoxin
mother solution as a positive control.
- Standard endotoxin solutions can be stored at -20˚C or below for up to 15
days.
d. Test procedure
Each experiment must have positive control and negative control. LAL reagent
water can be used as a negative control.
1. Pipette 3 x 0.1 ml of LAL reagent each into a vial or pyrogen-free test tube.
Label or mark as negative controls, positive controls and samples.
2. Carefully add 0.1 ml of negative control solution, positive control and
sample into each vial or test tube that has been labeled above. Close the vial or
test tube and mix it homogeneously.
3. Place the entire vial or test tube into the tube rack to be incubated at 37˚ ±
1˚C in an oven or incubator for 1 hour.
4. After 1 hour, carefully remove the vial or test tube, turning each tube slowly
180˚. Check whether gel is formed or not.
a. A positive reaction if the gel is hard and does not move when the vial or tube
is reversed.
b. A negative reaction if no gel is formed also if there is only turbidity and
thick liquid
3. Visual evaluation
a. Clarity and colour
The product should be clear (no turbidity) and colourless, there is no
undissolved particle in the product.
b. Free of foreign material
The product should be free of foreign materials such as fibre or
undissolved drug material.
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The procedure to check the foreign material in the injection product based on the
Good Manufacturing Practice (GMP):
1. Take container with cleaned surface, then hold the neck of the bottle and
slowly reverse the bottle to avoid bubble occurrence. After that, twirl the
bottle slowly to swirl the liquid inside.
2. The container is held horizontally approximately 10 cm under the source
of light. Check the liquid in the container at the black and white
background.
3. If the magnifying glass is used (3x), the container is held at the back of
the magnifying glass at the focus distance approximately 9 cm in front of
the black and white background.
4. The liquid in the container should be free from the presence of particle,
fibre, etc.
5. The container is checked for the physically damage (e.g: broken or
crack).
4. Volume uniformity test (Indonesian Pharmacopoeia, Second Edition)
Procedure:
- Take one or more container if the volume equal to or more than 10 ml, 3
containers or more if the volume more than 3 ml and less than 10 ml, 5
containers or more if the volume equal to or less than 3 ml.
- For the volume less than 10 ml, take the content of each of the container with
hypodermal syringe with capacity not more than 3 times of the measured
volume, connected with gauge no.21 with the length of needle not less than
2.5 cm.
- Remove air bubble from the syringe and needle; release the content of the
syringe without emptying the needle to the calibrated measuring cylinder.
- The content of injection product with volume 1 or 2 ml can be combined in
the same measuring cylinder but it is taken from the container with different
syringe.
- For the volume equal and more than 10 ml, the liquid can be directly poured
to the measuring cylinder.
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Practical Manual of Sterile Dosage Form Technology 73
- The injection volume should be not less than the volume stated on the label,
for the combined volume measurement then the injection volume should be
not less than the total volume of each volume stated on the label.
- For injection in multiple dose container which on the label is stated certain
amount of dose with certain volume, then the test is conducted using the
same procedure by using the same syringe number with the stated amount of
dose. Measured volume should not be less than the all dose volume.
5. pH evaluation
pH evaluation can be tested by:
� pH indicator paper
Paper is immersed in to the liquid of sample. The resulted colour is
compared to the standard colour of pH.
� pH meter
pH value is a value given by the suitable potentiometric device (pH
meter) which had been standardized with the standard buffer liquid. The
standard buffer should has the same condition with the solvent of the
product.
6. Minimum fill
This evaluation is conducted specifically for eye ointment.
Procedure:
a. Take sample as much as 10 containers which contain active
ingredient.
b. Remove all the labels that can affect the weight
c. Clean and dry the outside part of container with suitable method and
weigh one by one
d. Remove the content quantitatively from each container.
e. Cut the edge of the container, wash with suitable solvent if necessary
(be careful of the closure and other part of the container)
f. Dry and weigh each empty container with all the parts.
g. The difference between the weight is the net weight of the content.
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Practical Manual of Sterile Dosage Form Technology 74
h. The average of the net weights from 10 samples should not be less
that the weight stated on the label and none of the sample that the net
weight is less than 90% of the weight stated on label.
7. Label evaluation
The following requirements should be stated on the label of the product:
- Name of product
- Name of ingredients, amount, dose and concentration
- Exp. date
- Administration instruction
- Storage condition
- For infussion: the amount of ions in mEq per litre
- Other required information
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Practical Manual of Sterile Dosage Form Technology 75
EVALUATION PROCEDURE
BATCH EVALUATION RECORD
Name of Company : ......................................
Procedure/Record No. : ......................................
Specification
1. Organoleptic
Type of dosage form/
Name of Product
Batch No. Colour Odor Sign
Infussion/Anticoagulant
Vial
Ampoule
Eye drop
Eye ointment
2. pH
Type of dosage form/
Name of Product
Batch No. Theoretical
pH
Product pH Sign
Infussion/Anticoagulant
1.
2.
Vial
1.
2.
Ampoule
1.
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Practical Manual of Sterile Dosage Form Technology 76
2.
Eye drop
1.
2.
3. Volume uniformity
Type of dosage form/
Name of Product
Batch No. Volume
stated on
label
Volume
obtained
Sign
Infussion/Anticoagulant
1.
2.
Vial
1.
2.
Ampoule
1.
2.
3.
4.
5.
Eye drop
1.
2.
4. Clarity/ foreign material
Type of dosage form/
Name of Product
Batch No. Clarity Foreign
material
Sign
Infussion/Anticoagulant
1.
2.
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Practical Manual of Sterile Dosage Form Technology 77
Vial
1.
2.
Ampoule
1.
2.
Eye drop
1.
2.
5. Minimum fill
No. Type of dosage form/
Name of Product
Batch No. Net Weight
obtained (g)
Sign
Average weight
Weight stated on the label (g)
Calculation:
Net weight = The weight of content and container – empty container
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Practical Manual of Sterile Dosage Form Technology 78
6. Labelling
Type of dosage form/
Name of Product
Batch No. Label Signature
Infussion/Anticoagulant
Vial
Ampoule
Eye drop
Eye ointment
Reconciliation
Reconciliation Checked by : Approved by:
Conclusion:
Supervisor
Date :
Quality Control
Manager
Date:
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Practical Manual of Sterile Dosage Form Technology 79
Notes: