1.

PARENTERAL PRODUCTS
 PARENTERALS :
1. SMALL VOLUME PARENTERAL
(SMP)/ INJECTION
2. LARGE VOLUME PARENTERAL
(LVP)/ INFUS
 SVP - solutions LVP
Volume < 100 ml  100 ml

Packaging single dose (ampul) Vial >10 mL, flacon, collabsible

multiple dose (vial) bag
pH & tonicity Isotonic, isohydric (im, iv, isotonic, iso-osmoles, and
sc, intra dermal), iv : if it isohydric
is possible

Preservative (-) single dose (-)

(+) multiple dose
Buffer If it is needed (-)

Pyrogen Not necessarily Pyrogen Pyrogen free

free
Particulate > 50m-negative : FI IV > 50m-negative : FI IV(no
Matter (no visual particles), visual particles),
(particles/ml)  25m: <xxx  25m: < xx
 10m: <xxx  10m: < xx
 ROUTES USUAL VOLUME (mL)

Small Volume Parenterals

Subcutaneous 0,5-2
Intramuscular 0,5-2
Intravenous 1-100
Large Volume Parenterals
≥ 101 (infusion unit)
Other parenteral routes
Intra arterial 2-20
Intrathecal/intraspinal 1-4
Intraepidural 6-30
Intracardial 0,2-1
Intrapleural 2-30

Diagnostic testing, intradermal 0,005

 Tonicity calculation:

Calculation methods :

1. Freezing point depression (Tf)

2. Sodium chloride equivalent
3. Liso
 Liso method
 Liso value can be used to predict the freezing depression
of drug solution
Tf = Liso . C
 Liso value can be used to predict the NaCl equivalentof
drug solution
E = 17. Liso / MW
 Liso
Ion type Example
value
Sucrose, dextrose,
Non-electrolyte 1.9
gliserin
Weak electrolyte 2.0 Boric acid, citric acid
Divalent-divalent electrolyte 2.0 MgSO4, ZnSO4
Univalent-univalent electrolyte 3.4 NaCl, AgNO3
Atropin sulfate,
Univalent-divalent electrolyte 4.3
Na2CO3
Divalent-univalent electrolyte 4.8 CaCl2, Ca-gluconate
Univalent-trivalent electrolyte 5.2 Na-citrate, K-citrate
Trivalent-univalent electrolyte 6.0 AlCl3, FeCl3
Tetraborate 7.6 Na-borate, K-borate
 No Ingredients Concentration
1 Anthazoline HCl 2.5 mg/ml
2 NaH2PO4 5.9 mg
3 Na2HPO4 0,392 mmol
4 Benzalkonium chloride 0,01%
5 Aqua p.i. Ad. 10 ml
How much is NaCl needed?
Calculate using NaCl equivalent method

Mr. NaH2PO4 119,98

Mr. Na2HPO4 141,96
Mr. Anthazoline HCl 301.8
Mr. Benzalkonium chloride 360
Ingredients Concentration, Equivalent of NaCl (E)
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
 Question 2

Ingredients Concentration, Freezing Point Deprsn (ΔTf)

0,5% 1,0% 2,0% 3,0% 5,0%

Anthazoline HCl 0,073° 0,13° 0,24° - -
Benzalkonium chloride
Ingredients
0,048° Concentration,
0,09° Equivalent
0,17°
of NaCl (E)
0,24° 0,38°
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
1. How much is NaCl needed?
Calculate using freezing point depression method!

2. Calculate the pH of the formulation! pKa1 2,15

pKa2 7,09
pKa3 12,32
 Tonicity & osmolarity FOR INFUS
 Calculate both osmolarity and tonicity
mOsmole/L = [(g/L)/MW] x 1000 x ion numbers
 For electrolyte : calculate mEq

mEq/L = [(g/L)/MW] x 1000 x valence

 HIPERTONIC/HIPEROSMOLE ??
Use with local anesthetics for im, sc, id.
Injected to vena cava
Dilute with water for injection/infus
Slow injection / infus
1. Anti-oxidant
2. Buffer
3. Preservative
 Oxidation reaction
1. Add antioxidant: pH activity of the antioxidant at the
pH target of the product with maximum solubility and
stability of API (HOPE 670-672)

2. Container: light resistance container

3. Bubble N2 in the WFI &/product

4. Pack as single dose with minimum air space

Oxidation reaction
 Hidrolysis reaction
1. pH adjustment with buffer if required

2. Use minimum amount of water as the solvent:

a. Use solvent mixture
 be aware with final tonicity of the product
and solubility of API
b. Disperse in vegetable oil and prepare O/W
emulsion

3. Reconstituted injection
 Preservative
1. Multiple dose:
to prevent microbial
contamination after opening the
closure
Labelling:
Discard within 30 days from
opening the closure
After opening however, the
preservative can only ensure
the drops are safe for the eye for a
period of 28 days.

2. The selection of preservative:

pH activity for preservative = pH of dosage form
 Preservative
Interaction of preservatives with solvent, surfactant etc !!!

Which product needs a preservative(s)?

1. Oral/topical non-sterile product 
2. Sterile product :

 multiple dose injection/drops 

(To maintain sterility during in use)

 single dose injection/drops x

 infus x 18
 CLEAN ROOM AND CLEAN AIR DEVICE
CLASSIFICATION

Grade A Grade B
• High risk activities
• Aseptics preparation & filling
• Background of grade A
• LAF

Kelas C
• Lower risk of sterile product Grade D
preparation
• Lower risk of sterile
product preparation
 PharmaTech

Definition of Conditions

as built at rest in operation

air air air

22
 Room criteria :“white area” and “gray area”
Clean rooms and clean air devices should be classified in accordance with EN ISO
14644-1; PIC/s PE 009-9 (Annexes-1) 2009

At rest In operation
Maximum permitted number of particles/m³
Grade equal to or greater than the tabulated size

0,5 µm 5 µm 0,5 µm 5 µm
A 3520 20 3520 20
B 3520 29 352000 2900
C 352000 2900 3520000 29000
D 3520000 29000 Not defined Not defined

For the “at rest” state should be achieved in the unmanned state after a short
“clean up” period of 15–20 minutes (guidance value), after completion of
operations.
 Recommended limits for microbiological
monitoring of clean areas during operation:
Recommended limits for microbial contamination (a)
Settle plates
Grade Contact plates Glove print
Air sample (diam. 90 mm),
(diam. 55 mm), 5 fingers
cfu/m³ cfu/4 hours (b)
cfu/plate cfu/glove

A <1 <1 <1 <1

B 10 5 5 5
C 100 50 25 -
D 200 100 50 -

Notes:
(a) These are average values.
(b) Individual settle plates may be exposed for less than 4 hours.
(c) In order to reach the B, C and D air grades, the Particles
number of air changes should be related to the size of Temperature
the room and the equipment and personnel present in Pressure
the room. The air system should be provided with Humidity
 ROOM CRITERIAS FOR
ASEPTIC PREPARATION

Required standard
before terminal
Procedure sterilization
Handling of sterile starting
materials
Grade A with
Preparation and filling of Grade B
ointment, creams,
suspensions, and emulsions
background
Filtration and filling of filter
(LAF)
sterilized product
 SVP
C/Mixing room A/B room: LAF

1. Dissolve active 2. Dissolve excipients in

ingredient in water and mixed up
WFI
Mix 1 & 2

Check pH/adjust pH if required

Add volume, minimize particulate matter

(0.45 m pre-filter; 0.22 m filter)

Filling C/A Room local Bacterial membrane filtration

Autoclave  0.1-0.22 m
Aseptically filling (A with B Room
Background)
 LVP
Mixing room LAF

1. Dissolve active 2. Dissolve isotonic adjusting agent if

ingredients in WFI required

Mix up 1 & 2, Check pH/adjust pH if required, add volume

Depyrogenization

Check endotoxin content

Minimize particulate matter using 0.45m prefilter & 0.22 m filter

Filling in C/A Room Aseptically filling (Class A, monitoring

local with media fills)
Autoclave Not applicable for industrial production
 Metronidazole infusion

API Monograph
Metronidazole infusion
 STERILIZATION METHOD

- Powder : melting point with decomposition?

- Heat stability in solution

AUTOCLAVE STERILIZATION only for solution

containing water!!!!!

Photodegraded drugs : amber glass vial/ampoule

 LVP:
 Make WATER FOR INJECTION: aquabidest and
eliminate pyrogen by positive charge membrane
filtration
 Rinse double filters, filtration using 0.45
m and 0,22 m and use pyrogen free containers

 To anticipate the reduction of drug concentration

due to retension on the filter = add 10%
 Evaluation:
1. pH
2. Clarity
3. Packaging integrity
4. Pyrogen content
5. Sterility test
6. Particulate matter
7. Concentration of drugs etc

 While waiting for final sterilization, do product

evaluation provided in the lab (OSCE’s methods)
 Labelling
 Label must not cover all the packaging surface to
leave a room for observing the content
 Registered name followed by generic name of the
drug, using the same font but 80% size
 Nett ……mL or gram
 Composition: every 1 mL contains: active ingredient
…… milligram
 Batch No., Registration no., Exp. date,
manufacturing date, use before:
 Logo: Awas obat keras (K)
 Nama Pabrik dan alamat.
 Brosur, kardus
• Brosur: indikasi dan kontraindikasi
diterangkan lebih lengkap, tanpa no.
batch.
• Kardus: isi sama spt etiket. I & KI
bisa tidak dijelaskan secara lengkap,
diberi keterangan: Keterangan
lengkap lihat brosur di dalam.
 Penomoran
• DKL 00009315521A1
• No. registrasi: 15 digit

1 : D = dagang, G= Generik
2 : K = keras, T = bebas terbatas, B= bebas, P = psichotropik
3 : L = dalam negeri, A = PMA
4 & 5 : tahun registrasi
6,7,8 : no pendaftaran di POM
9, 10, 11, 12, 13 : jenis obat
14 & 15 kode pabrik: menyatakan isi/komposisi
14 : Huruf A
15 : angka 1