Sterile Dosage Forms and Technology

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Learning Outcomes
Sterile Dosage Forms
01
and calculation

02 Preformulation

03 Formulation

Sterility Test and

04
pyrogenetic test
 Class Rules
Time Evaluation
1 SKS Theory : 50/45 minutes Mid exam : 35%
2 SKS Practice : 2 x 160/145 minutes Final exam : 35%
200 minutes practice lab Task + soft skill (include quiz) : 30%
120/90 minutes yaitu pre dan post practice
UP I : 30%
Late maximum : 10 minutes? UP II : 35%
UP III : 35%
No eat and snacking, No SLEEP!
Keep the camera ON during class Final score : ((NT X SKS) + (NP X SKS))/Total SKS
Drink is allowed

Keep the class comfortable for everyone

Pro active!!
 References
Armstrong, N.A., and James, K.C., 1996, Pharmaceutical Experimental Design and
Interpretation. Taylor and Francis, Bristol.

Aulton,M.E., 1988, The Science of Dosageform Design, Churchil Livingstone, Edinburgh.

Avis, K.E., Lachman, L, and Lieberbamn, H.A., 2000, Pharmaceutical Dosageform :

Parenteral, Tablet, Disperse System, vol I, II, III, Marcel dekker Inc., New York.

Banker, G.S. and Rhodes, C.T. 2002, Modern Pharmaceutics, 3rd. Ed., MNarcel-Dekker Inc.,
New York.

Gennaro A.R, 2013, Remington : :The Sience and Practice of Pharmacy, 22nd Ed., Mack
Publ. Co., Pensylvania.

Lachman, 1986, The Theory and Practice of Industrial Pharmacy, 2nd, Ed., Lea & Febiger,
Philadelphia.
Sterile dosage Forms
Q Q
Sterile? Sterilization? Dosage form of sterile

Q product?

How to make sterile dosage

Q
Q forms?

Administration?
Why should be sterile?

Q
How to make sure the
sterility?
Q
Production facility?
 Sterile Products
01 Sterile 02 Why? 03 So, why?? 04 What?
Free of viable Injected through the skin
As first line of body - Starting material
microorganism or mucous membranes
defense - Production facility
into internal body
compartments - Manufacturing
Absolute condition process
(Relative - Person
connotation and
probability) of a total
destruction or
elimination of all
living microorganism
REMEMBER SAL!
06 Administration 05 How?
- Biovalaibility Sterilization ?
- Fast effect
- Targeted
Sterile
Dosage Forms Administration
Dosage - Small volume injection - Intravenous
Water or non water based - Intraspinal

Forms Oil
Suspension
Reconstitution powder
-
-
-
Intramuscular
Subcutaneous
Intradermal
- Ophthalmic preparation
- Large volume injection
Water based

- Semisolid
Ointment
Cream
Gel

- Ophthalmic preparation

- Solid
Pellets
Implantation tablet
 Administration route
Intravascular Nonvascular injection

Absorption, passive diffusion

Absorption affected by :
Isotonic
1. PSD
2. Blood supply
3. Movement of tissue
4. Physicochemical properties
Has lipophilic and hydrophilic properties (Why?) 5. Dosage forms

Solution Solution
Suspension (particle size?, %) Suspension 5%
Emulsion
ACHTUNG!! Blockage of fine capillaries
 Nonvascular
Intramuscular, Intracutaneous Intraspinal
Subcutaneous

Solution
Suspension Less than 0.2 mL tissue
10 mL or less
Emulsion volume
Solid pellets

Intramuscular < 2 mL Absorption slow  lack of Absorption?

Subcutaneous < 1 mL blood vessels

Hypertonic for rapid Example? Example?

absorption
 Ophthalmic preparation
Location Dosage forms (conventional) Dosage form (new)

External surfaces (topical) Solution Gel

Inside (intraocular) Suspension Gel forming solution

Adjacent (periocular) Ointment Ocular inserts

Intravitreal injection

Implants
Specification
Example Text :
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 Calculation of tonicity
1 2

3
 Thermal
Physical
Non
Thermal
Sterilization
technique
Gas
sterilization
Chemical
Surface
disinfection
 Manufacturing Process of Sterile Products
CPOB 2012

Isolator
technology and Terminal vs Building and
Principle
Blow, Fill and Aseptic process facility
seal tech

Personnel Equipment Sanitation Waters

Processing
 Principle
Special req  minimize risks contamination of micro, particulate and pyrogen, depends on sktll, training and personnel

General Grade A:
• Airlocks The local zone for high risk operations.
• Preparation in separate area Provided by a laminar air flow work station
• In operation and at rest states (air speed in a range of 0.36 – 0.54 m/s
(guidance value) at the working position. The
maintenance of laminarity should be
demonstrated and validated.

Grade B: For aseptic preparation and filling,

this is the background environment for Grade
A zone.

Grade C and D: Clean areas for carrying out

less critical stages in processing of sterile
products.
Clean rooms and clean air device classification Clean rooms and clean air device monitoring

• Routinely monitored
• Class A  during critical process
• Class B  frequency less than A
• C and D areas  accordance with priciples of quality risk
management

• Aseptic operation : settle plates, volumetric air, surface

sampling (swab and contact plates)
 Isolator Technology Blow/Fill/Seal Technology

• Minimize human interventions  decrease in

the risk of microbiological contamination
• The transfer of materials into and out of the unit
is one of the greatest potential sources of
contamination
 Terminally Sterilized Products
• Preparation of components and most products should
be done in at least a Grade D. Where there is unusual
risk  Grade C
• Filling of products for  Grade C. Where the product is
at unusual risk  Grade A zone
Aseptic Products
• Components after washing Grade D
• Handling of sterile starting materials and components,
unless subjected to sterilization or filtration  Grade A
environment with Grade B background.
• Preparation of solutions which are to be sterile filtered 
Grade C
• Handling and filling of aseptically  Grade A
environment with a Grade B background
• Transfer of partially closed containers, as used in
freeze drying  Grade A with Grade B background
• Preparation and filling of sterile ointments, creams,
suspensions and emulsions should be done in a Grade A
with a Grade B background,
Building and Facility

• Can be observed from outside

• Surfaces should be smooth, impervious

and unbroken

• No un-cleanable recesses and a minimum

of projecting ledges, shelves, cupboards
and equipment

• Sinks and drains should be prohibited in

Grade A/B areas

• Changing room should be for personnel only

• Airlock doors should not be opened

simultaneously, pressure differential of 10 - 15
pascals
 Personnel

• Minimum number Clothing A B C D

Hair cover V V
• Selected Beard cover V V
Face mask
• Receive regular training Headgear V V
Coverall Single or two-piece The clothing V
• Outdoor clothing and regular working trouser should shed
clothes should not be brought into suit, gathered at the virtually no
changing rooms leading to Grade B and C wrists and with a fibres or
high neck, particulate
rooms
matter

• Gloves should be regularly disinfected

Gloves V V
• Masks and gloves should be changed at least Booties V V V V
at every working session

• Wristwatches, make-up and jewellery

should not be worn in clean areas.
 Equipment
• Conveyor belt should not pass through a
partition between a Grade A or B area
and a processing area of lower air
cleanliness
• Equipment used can be effectively sterilized
• Equipment and services  operations,
maintenance and repairs can be carried out
outside the clean area
• All equipment should be subject to validation
and planned maintenance; their return to use
following maintenance should be approved
and recorded
Sanitation
• Accordance with a written programme.
• More than one type disinfectant . In Grades A
and B areas  should be sterilized prior to
use
• UV light should not be used as a substitute
• Levels (limits) of detection of microbiological
contamination should be established for alert
and action purposes, and for monitoring the
trends in air quality in the facility
 Water
• Controlled , as a starting material
• WFI produced either by distillation or other
• WFI  produced, stored and distributed in a
manner which prevents microbial growth
• WFI  stored in clean, sterile, non-reactive,
nonabsorptive, non-additive containers and
protected from contamination
• Water sources, water treatment equipment
and treated water should be monitored
regularly
• Recording devices should be used to
monitor storage temperature
Processing
• Microbiological origin  different areas,
except vaccines consisting of dead
organisms or of bacterial extracts after
validated inactivation and validated cleaning
procedures
• Validation of aseptic  include (media fill),
three consecutive satisfactory simulation tests
per shift
• Microbiological contamination of starting
materials should be minimal
• Containers and materials liable to generate
particles should be minimized and avoided
completely
• The bioburden should be monitored before
sterilization
 Practice Steril A
Topic 1 Topic 2 Topic 3

• Filomena • Nada • Selvina

• Fika • Rifa • Afifah
• Erika • Herlinda • Luly
• Shinta • Tri Dewi • Denanda
 Practice

Before Spec Olopatadin ISDN Dexametha

Olopatadine eye drop autoclave e eye drop Injection sone
suspension
eye drop
ISDN Injection Assay (%) 90-115% 101 105 102

Impurity (%) NMT 1.0% BDL BDL BDL

Dexamethasone
suspension eye drop After Spec Olopatadin ISDN Dexametha
autoclave e eye drop Injection sone
suspension
eye drop
Assay (%) 90-115% 100 103 103

Impurity (%) NMT 1.0% BDL 1.2% BDL

 Practice Sterile B
Topic 1 Topic 2 Topic 3
Anggun Larasati Kharisma Bunga Reni Rahayu
Arif Bayu Lia Marliani Riris L
Ayu Febrina Lina Afiatul Sabrina Salsabila
Cami Cahyati Muhammad Rifqi Sivana
Danang Setyo Nita Maulida Sri wahyu
Deby Srianto Nova Parlindani Susmaeni
Dinda Bhestari Pieter Tanti Lestari
Dini Laraswati Puji Priatna Tiat Minarti
Diyah L Putri Oktaviani Vianica
Henny Duita Rendy Yanti

Task : individu (per org), bukan kelompok

 Practice

Before Spec Olopatadin ISDN Dexametha

Olopatadine eye drop autoclave e eye drop Injection sone
suspension
eye drop
ISDN Injection Assay (%) 90-115% 101 105 102

Impurity (%) NMT 1.0% BDL BDL BDL

Dexamethasone
suspension eye drop After Spec Olopatadin ISDN Dexametha
autoclave e eye drop Injection sone
suspension
eye drop
Assay (%) 90-115% 100 103 80

Impurity (%) NMT 1.0% BDL 1.2% BDL

1. Tipe sterilisasi
2. Jalur personalia dan barang
3. Jelaskan tiap step nya

Step Class Reason

Weighing
Mixing
Filling
Sterilization
Weighing Preparation Mixing Filling Sealing
Sterile
Dosage Forms Administration
Dosage - Small volume injection - Intravenous
Water or non water based - Intraspinal

Forms Oil
Suspension
Reconstitution powder
-
-
-
Intramuscular
Subcutaneous
Intradermal
- Ophthalmic preparation
- Large volume injection
Water based

- Semisolid
Ointment
Cream
Gel

- Ophthalmic preparation

- Solid
Pellets
Implantation tablet
STEP PREFORMULATION
1. Physicochemical properties
1.Preformulation 2. Pharmacology & Pharmacokinetics
3. Supplier
2.Formulation trial Lab Scale 4. Cost
5. Compatibility with excipient
3.Pilot Scale 6. Market
4.Production FORMULATION
1. Hypothesis
2. Excipient selection (quality and
quantity)
Formulation process is same, the different only req for sterile
3. Process optimization
and ‘place’ for manufacturing process & grade starting
material
Basic in formulation :
1. Dose
2. Goal of treatment
Material should be able to sterilize 3. Route of adm
1. Starting material  aseptic without filtration 4. Patient
2. Bulk of finished product  aseptic with filtration
3. Finished product (in final prim pack)  terminal sterilization
 Physicochemical properties

Organoleptic Solubility Polimorphisme pH Stability

Color Kp Qty Ion/salt condition Hydrolysis

Taste Kow Stability Absorption Oxidation
Odour Absorption Amorphous pH FP Photolysis
Dissolution /Crystalline Heat
Solubility pH stab
Storage
Excipient
Manufacturing
process
Primary
packaging
 Excipient

Solvent Solutes

• Aqueous • Antioxidant
• Non aqueous • Buffer
• Miscible w/ water • Tonicity agent
• Immiscible w/water • Preservative
• Solubilizer
 Solvent
When we are using aq or no aq?
Req for non aq?

Aqueous Non Aqueous

• WFI • ɳ, ρ, polarity, stability,
• Conductivity solvent act, toxicity
• Distilation/RO • Miscible : e.g?
• Sterile? • Immiscible : e.g?
• Free from pyrogen?
 Antioxidant
When we are using antioxidant?
Wadah tertutup rapat dan kedap
Stability Hampa udara
Oxygen in trapped air at prim pack Inert gas
Low temp
Oxidizing agent
Enzyme
Added antioxidant

Reducing Chelating
Blocking agent Synergist
agent agent
• Oxidized first • H • Increasing • Complex with
merusak effectiveness catalyst
radikal of
antioxidants
 Buffer
When we are using buffer?

To maintain Select : pKa,

Stability
req pH conc, β

Why can be altered?

Dissolving gases and

Dissolving glass Release from vapor fr air space
constituent rubber/plastic entrapped or diffusion
through closure
 Tonicity agent
Why sterile dosage forms (esp injection) should have tonicity req?
If hypertonic  pain, then? Ion type Liso value Example
1. + anesthetic local
2. Vena cava Non-electrolyte 1,9 Sucrose, dextrose, gliserin
3. Dilution Weak electrolyte 2,0 Boric acid, citric acid
4. Slowly
Divalent-divalent electrolyte 2,0 MgSO4, ZnSO4

1. Diff at freezing point (∆Tf)  0.52º Univalent-univalent electrolyte 3,4 NaCl, AgNO3
2. E NaCl  0.9% NaCl Univalent-divalent electrolyte 4,3 Atropin sulfate, Na2CO3
3. Liso
Divalent-univalent electrolyte 4,8 CaCl2, Ca-gluconate

Univalent-trivalent electrolyte 5,2 Na-citrate, K-citrate

∆Tf = Liso x C
C  molar Trivalent-univalent electrolyte 6,0 AlCl3, FeCl3
E = (17 x Liso)/MW
Tetraborate 7,6 Na-borate, K-borate

Osmolarity = mmol/L mEq = (mass in mg x valence)/MW

Osmolality = mmol/kg  275-295
+ 2-
Na2HPO4  2Na + HPO4
Valence 3
 Example
Ingredients C C E
Anthazoline HCl 2.5 mg/ml = 250mg/100 mL = 0.25 gr/100 mL =0.25%0.25
NaH2PO4 5.9 mg (17 x 3.4)/119.98 = 0.48
Na2HPO4 0.392 mmol (17 x 4.3)141.96 = 0.51
Benzalkonium chloride 0.01% 0.01% 0.18
Aqua p.i. Ad. 10 ml =0.25+0.48+0.51+0.18
= 1.42
Mr. NaH2PO4 119.98 NaH2PO4  Na+ + H2PO4-
Mr. Na2HPO4 141.96 Na2HPO4  2Na+ + HPO42-
Mr. Anthazoline HCl 301.8
Mr. Benzalkonium chloride 360

Concentration, Equivalent of NaCl (E)

Ingredients
0.5% 1.0% 2.0% 3.0% 5.0%

Anthazoline HCl 0.25 0.23 0.21 - -

Benzalkonium chloride 0.18 0.16 0.15 0.14 0.13
 Preservative
When we are using preservative?

Aseptic

Remove
microorganism

Bacteriostatic or
killing process

Self Preservative : How to choose:

1. Extreme pH 1. Stability
2. Low water c 2. pH activity
3. Chelating agent containing formula 3. Spectrum
4. Surfactant containing formula
5. Component as preservative
 Solubilizer
When we are using solubilizer?
Wetting agent? Emulsifier? Suspending agent?
 Practice Steril A
Topic 1 Topic 2 Topic 3

• Selvina • Herlinda • Nada

• Afifah • Tri Dewi • Rifa
• Erika • Filomena • Luly
• Shinta • Fika • Denanda

Latanoprost eye drop 0.005%, 2.5 mL
Zink Sulphate eye drop 0.4%, 10 mL
Dexamethasone suspension eye drop
1 mg/mL, 10 mL
Practice
1. Indication, route adm, dose, patient information
(see brochure)
2. Physicochemical properties
3. Problem and conclusion  stability, tonicity,
packaging or other
4. Formula  material, Qty (%), function
5. Manufacturing process  step, class
6. Evaluation parameter
In PPT or PDF
 Metode Sterilisasi
Akhir
Waktu Filtrasi
Aseptis
Tanpa filtrasi

Panas basah
Panas
Panas kering

UV
Metode Radiasi
Ionizing
Etilen oksida

Filtrasi
 Preparation Sealing
Weighing Mixing B Filling
(A) (C)

Waktu A B C
Metode
Aseptis tanpa filtrasi A Class
Aseptis dengan filtrasi B Weighing C-A E-C E-C
Terminal sterilisasi C Preparation A C C
Mixing A C/A C
Metode
Filling A A C
Panas basah C
Sealing A A C
Panas kering A, C
Sterilization A A C
Radiasi UV -
Radiasi ionizing A
Etilene Oxide A
Filtrasi B
 Sterilisasi Panas
• Diutamakan

• Pencatatan : t, T dgn alat perekam tervalidasi (probe)

• Indikator biologi dan kimia tidak menggantikan

pengukuran fisis

• Loading pattern tervalidasi

• Semua cairan atau gas pendingin yg kontak 

disterilkan kec dpt dibuktikan bahwa wadah tidak
bocor

Lethal effectiveness of heat on microorganism dependes upon the degree of heat

• Exposure period
• Moisture present
• Sterilizing temperatures

Mechanism : coagulation of the protein of the living cell

Masukkan produk yang akan di sterilisasi kedalam chamber Autoclave dengan urutan sebagai
berikut. Pastikan penempatan Internal trolley sesuai dengan gambar berikut. Loading pattern
mengacu pada dokumen 0183/FQ-VAL/R
 Moist Heat
Substances : tidak terdegradasi pd suhu 121 dan keberadaan
‘moist’, sediaan mengandung air

(1)The thermal increment time : chamber and material ‘catch up’

(2) Hold period at maximum temperature  coolest spot sensor
(3) Cooling time

• Catat : T dan P  grafik

• Kesalahan pd sistem
atau siklus hrs terdeteksi
• Uap : tepat mutu (kimia,
mikro dan endotoksin)
dan tidak mengandung
zat tambahan dlm kadar
yg dpt mencemari
produk/peralatan
 Moist Heat
Air Displacement
Density steam < air
Gravity

Time and temp

121 deg C, 15 minutes or 132 deg C, 3 minutes
Lethal effect

Air steam mixture

Pressure control

Reduction of cycle time

• Pre-cycle vacuum
• Temperature
• Spray cooling water
 Moist Heat

More effective than dry heat

Need lower temperature Effectiveness Do not destroy pyrogens

 thermal capacity
Temperature Pyrogens

Sterility After
Wet condition
SAL condition

How about liquid finished product that already completely sealed?

 Dry Heat
Substances that resist degradation at temperature
approximately 140 deg C
Substances that not containing or degraded in the presence
of moist

Sterilizer types :
(1) Natural convection: Rise of hot air and fall of cool air :
blocked, diff 20ºC ZAQ
(2) Forced convection : Blower
(3) Tunnel unit with moving belt : glass bottle

(1)The thermal increment time : chamber and material ‘catch

up’
(2) Hold period at maximum temperature  coolest spot
sensor
(3) Cooling time
 Dry Heat
- Limited Substances for
+ Largely for glassware, metalware,
chemicals anh oil

Anhydrous state  dry

SAL
- equipment

Higher temp Effectively destroy pyrogens

• Cairan nonair atau serbuk kering

• Menyirkulasikan udara dalam chamber (P+)
+
• Jika proses sterilisasi ini juga ditujukan utk menghilangkan pyrogen, ‘challenge test’ harus dilakukan sbg
bagian dr validasi

Pyrogens? Sources of pyrogens? Temperature to destroy them?

 Ultraviolet Light
Aid : Air and surfaces

Mechanism
Passed matter
Energy liberated
Reactivity
Excitation and alteration activity of
essential atoms within molecules
microorganism or of their essential Maintenance
metabolites  dies or unable to Free from dust, grease and scratches 
reproduces emission intensity
 Ionizing Radiations

• UV  bukan utk sterilisasi finished product

Sources
Radioactives isotopes : Cobalt 60
Electrons  high v & E (cathode rays,
beta rays)
• Dosis radiasi harus terukur (dosimetri  diselipkan diantara
muatan dlm jumlah yg cukup)
• Indikator biologis dpt digunakan sbg tambahan

• Radiation-sensitive colour disks  dpt digunakan, tp bukan

+ and - indikator keberhasilan
Expensive
Higher and uniform output

Lethal action
Transfer of radiation beam
energy lethal mutation (direct,
indirect)
 Gas Sterilization

05
04
03 -

02 +

01 Plastic materials, rubber goods, optical

• Last option
• Kontak langsung antara gas dan mikroba : esensial
• Wajib menggunakan indikator biologis
• Catat : P, T, RH dan c gas
instruments, SS, parenteral administration se
Alkylating essential metabolite  reproductive
process  replacing an active H
Formaldehyde, sulfur dioxide, ethylene oxide,
beta-propiolactone
 Filtration
Pore size and
“Remove” Sieving or 0.22 µm and
integrity
principle screening 0.45 µm
checking

• Double filter

• Free asbes
+ -
Accumulate then stop • Integritas filter : bubble point, diffusive flow atau
pressure hold
Removing dirt particles
as well as Flow rate
microorganism- • Tidak digunakan lebih dr 2 hari kerja kec telah
Filling speed divalidasi

• Filter tidak memengaruhi mutu produk :

menyerap atau melepaskan
Filtration
 Filter Selection
PVDF PESU Nylon Cellulose
Parameter
5h 10 h 5h 10 h 5h 10 h 5h 10 h
Appearance
Assay
Impurity
Particulate matter
Osmolality

1. Compatibility
2. Size
3. Cost
 Bubble point test

BUBBLE POINT TEST AWAL/AKHIR

a. Siapkan sistem bubble point test sesuai dengan protap
b. Rangkaikan filter yang digunakan dibawah LAF dalam mesin filling
c. Catat no lot filter yang digunakan, lampirkan Certificate of Quality Filt
Parameter Filter 1 Filter 2
Merk Opticap XL 2 Durapore 0.22 µm Opticap XL 2 Durapore 0.22 µm
No Lot

a. Siapkan system filter integrity tester sesuai protap  IT4

b. Lakukan bubble point test terhadap filter dengan integrity tester dengan cara sebagai berikut:
a. Basahi dan bilas filter dengan WFi suhu 25±5 derajat Celsius sejumlah ± 1 L. Pasang perangkat integrity tester pada bagian atas capsule filter.
b. Input identitas filter kedalam uji filter integrity dan lampirkan Certificate of Quality filter pada batch record.
c. Input system uji filter integrity sebagai berikut:
d. Lakukan uji bubble point terhadap WFI. Lampirkan print out hasil uji
Diffusion Pressure = 2760 mBar
Minimum bubble point pressure = 3450 mBar
Maximum bubble point pressure = 5000 mBar
Gross leak = 7.6 mL/menit

Main Filter I Main Filter II Kriteria

Parameter
(Lot No: ) (Lot No: ) Penerimaan

Bubble point pressure awal WFI NLT 3450 mBar

Bubble point pressure akhir WFI NLT 3450 mBar

 Jaminan tingkat steril
Free of viable microorganism
Absolute condition (Relative connotation and probability) of a total destruction or elimination of all living
microorganism REMEMBER SAL!

SAL : probability of viable microorganism on the product after it has been sterilized

Validasi proses sterilisasi

1. Design alat dan proses
2. Konfirmasi reprodusibilitas data dari SAL

Kuantifikasi : Microbial death kinetics

1. D value
2. F value
3. Z value
 Microbial death kinetic
D value : t/dose utk menurunkan 1 decimal (90% atau 1 log) Z value : suhu (C/F) utk menurunkan 1 log pd D value
 Microbial death kinetic
F value Fo value : eq t, 121C
1. Kuantitatif utk menghitung t yang
dibutuhkan pd T lain
2. Terkait dgn killing effisiensi pd T lain
yg setara dgn 121C
3. Menghitung kontribusi heating dan
cooling fase thd lethal effect t 5 10 15 20 25 30
4. Menghitung lethal effect pd coolest
T 25 110 118 120 121 100
point

Dipengaruhi o/:
1. Karakteristik container : ukuran, geometric, heat transfer
coefficient
2. Product vol dan ɳ
3. Ukuran dan konfigurasi ‘load’ dlm sterilizer
 Tahapan validasi
Tentukan
Tentukan penterasi
Lakukan heat
panas kedalam Ulangi
pengujian distribution Evaluasi
Kualifikasi produk pd coolest proses
Pilih utk pd efek dr Monitoring
dan point dan hingga
indikator menentuka keadaan cycle : t, T, scr
pengeceka ‘suspected location’ didapt
biologi n D value kosong, load dan periodik
n sterilizer dmn heat hasil
dan Z identifikasi Fo
penetration sesuai
value coolest
‘slowest’
point

Pilih
sensitive
microbial Jika
Evaluasi
Air and growth Sterilisasi Tentukan >0.1% 
fasilitas Inkubasi
surfaces medium groeth Lakukan level Ulangi perlu
dan filled
microbial dan medium simulasi kontamina proses dilakukan
critical container
test microorga dan filter si review
area
nism kembali
‘challenge
’
 Indikator Biologi
• To monitor sterilizers
• Microbiological test system providing a defined
resistance to a specific sterilization process
• BI is the most resistance to the process
Pengujian : min 3 lot spore, prepared from different
spore crops. Pengujian :
1. Viable spore population assay
2. Resistance characteristic study (resistometer) : D,
Z, survival/Kill window
3. Carrier and prim pack material evaluation
4. Holding time assessment
5. Recovery protocol  7 days
6. Mail in protocols
 CPOB
• Indikator biologis dan kimiawi bukan utk pembuktian proses sterilisasi telah efektif, tapi menunjukan
kegagalan proses

• Penanganan indicator biologis scr ketat  mencemari area bersih

• Indikator kimia : pita atau lembaran adhesive, kartu bercak warna dll. Indikator tsb dapat berubah
warna krn reaksi kimia saat proses sterilisasi
 Practice Steril A
Topic 1 Topic 2 Topic 3

• Selvina • Herlinda • Nada

• Afifah • Tri Dewi • Rifa
• Erika • Filomena • Luly
• Shinta • Fika • Denanda
 Practice Sterile B
Group 1 Group 2 Group 3
Anggun Larasati Kharisma Bunga Reni Rahayu
Arif Bayu Lia Marliani Riris L
Ayu Febrina Lina Afiatul Sabrina Salsabila
Cami Cahyati Muhammad Rifqi Sivana
Danang Setyo Nita Maulida Sri wahyu

Group 4 Group 5 Group 6

Deby Srianto Nova Parlindani Susmaeni
Dinda Bhestari Pieter Tanti Lestari
Dini Laraswati Puji Priatna Tiat Minarti
Diyah L Putri Oktaviani Vianica
Henny Duita Rendy Yanti

Benadryl injection (Diphenhydramine
Injection 50 mg/mL, 1 mL)
Delvosteron (Proligestone 100 mg/mL,
20 mL, suspension for injection)
Velcade (Bortezomib 3.5 mg/vial,
reconstituent : 0.9% NaCl)
Practice
Buatlah manufacturing instruction
1. Formula
2. Hitung kebutuhan bahan untuk BS 1L
3. Stabilita : panas dan air
4. List peralatan yang digunakan dan preparasi
(sterilisasi)
5. Buat prosedur lengkap