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