The document discusses manufacturing techniques for parenteral dosage forms. It covers the key steps which are: 1) Cleaning equipment and containers, collecting ingredients, and preparing the product under aseptic conditions 2) Filtering the preparation to remove particles 3) Filling the filtered preparation into final containers such as ampoules and vials 4) Sealing the filled containers immediately 5) Sterilizing the sealed containers by autoclaving or dry heat to make the products sterile and ready for use.

1. Manufacturing
Techniques
PARENTERAL DOSAGE
FORM
1
 Formula
 Equipment
 Process
 Quality
control

2. PARENTERAL PRODUCTS
Parenteral preparations are sterile,
pyrogen-free liquids (solutions, emulsions,
or suspensions) or solid dosage forms
containing one or more active ingredients,
packaged in either single-dose or multidose
containers.
They are intended for administration by
injection, infusion, or implantation into the
body.
2

3. Classifications
Based on volume
1. Small Volume Parenteral
( = or <100ml)
Solutions
Suspensions
Emulsions
Dry powders for reconstitution
as solutions
Dry powders for reconstitution
as suspension
2. Large Volume Parenteral
(>100ml)
Hyperalimentation solution
Cardioplegic solution
Peritoneal dialysis solution
Irrigation solution
3

4. FORMULATION
VEHICLES
EXIPIENTS
ANTI MICROBIAL
ANTI OXIDANTS
BUFFERS
TONICITY MODIFIERS
SUSPENDING AGENTS
FLOCCULATING AGENTS
WETTING AGENTS
EMULSIFIERS
MICELLANEOUS
4

5. 1. VEHICLES
AQUEOUS VEHICLES
Water for injection (WFI)
Sterile water for injection (SWFI)
Bacteriostatic sterile water for injection
(BWFI)
Sodium Chloride injection
Bacteriostatic Sodium Chloride injection
NON AQUEOUES VEHICLES
1. WATER MISCIBLE
Agents like Ethanol, Glycerine and Propylene
glycol are used with water for injection to
promote the solubility and stability.
2. WATER IMMISCIBLE
Fixed oils- corn oil, olive oil, arachis oil, almond
oil, soya oil, poppyseed oil, sesame oil,
cottonseed oil, peanut oil, castor oil
•Ethyl oleate
•Isopropyl myristate
•Benzyl benzoate
5

6. 2. Antimicrobial Agents
Antimicrobial agents or preservatives are added to multiple dose containers to
prevent the growth of microorganisms.
Properties of antimicrobial agents used
• Compatible with other ingredients used.
• Non-toxic. Non-irritant and inert.
• Should not be absorbed by rubber or plastic closure.
• Should be thermostable.
Examples: Quaternary ammonium compounds, Phenyl mercuric nitrate,
Phenol, cresol and chlorobutanol, Benzyl alcohol, A combination of methyl
parabens and propyl parabens
6

7. 3. Antioxidants
Prevents oxidative degradation of active ingredient by:-
 Undergoing oxidation in place of API.
 Blocks an oxidative chain reaction
 Prevent oxidation by forming a complex.
Example:
Reducing agents: ascorbic acid, sodium bisulphite, sodium metabisulphite.
Blocking agent: ascorbic acid esters, butyl hydroxy toluene (BHT),
tocopherols.
Chelating agents: ethylenediamine tetra acetic acid (EDTA)
7

8. 4. Buffering agent
They prevent degradation of API due to change in pH  by maintaining
desired pH.
Buffers selected should not affect the pharmacological activity and solubility
of drug.
The most ideal pH of parenteral preparation is  7.4
Example:- acetate buffer, acetic acid buffer, benzoate buffer, sodium
bicarbonate buffer.
8

9. 5. Surfactants / solubilizers
These are used to increase the solubility (wetting property) of the drug
or to disperse water insoluble drug.
Examples:
Propylene glycol, povidone, polysorbate 80, PEG 30, glycerine, dioctyl sodium
sulphosuccinate (DOSS)
9

10. 6. Chelating agents
These inactivate heavy metals such as copper, iron, lead, mercury, chromium
etc. by forming complexes.
Examples: EDTA ( ethylene diamine tetra acetic acid) and its salts.
Sodium or potassium salt of citric acid .
7. Tonicity modifiers
Parenteral need to be isotonic with body fluids .
Depends on the amount and nature of solute present in it.
Tonicity adjustment is done by 0.9% NaCl , 2.0% Boric acid, 5.0% Dextrose.
10

11. 8. FLOCCULATING AGENTS
Typical flocculating agents used in injectable suspensions include:
SURFACTANTS: Polysorbate 20, Polysorbate40, Polysorbate 80, Pluronic F-
68, Sorbitan trioleate
HYDROPHILIC COLLOIDS: Sodium CMC, Gelatin, Methylcellulose,
Polyvinylpyrrolidone
ELECTROLYTES: Potassium/Sodium chloride, Potassium/Sodium citrate,
Potassium/Sodium acetate
11

12. 9. WETTING AGENTS
Added to facilitate dispersion
Surfactants with HLB value in the range 7 to 9 show maximum wetting
efficiency
Usual concentration of surfactant varies from 0.05% - 0.5% depending on
the solid content of the suspension
Example-polysorbate 80, polysorbate 20, lecithin
12

13. 10.EMULSIFIERS
The oils have hydrophobic surface. For their dispersion in aqueous system,
suitable emulsifying agents are essential.
eg. Natural lecithin :- advantage -it is metabolized in the same way as fat
and is not excreted via kidneys, as are many synthetic agents.
Poloxamers are also promising emulsifiers for parenteral emulsions.
Cholesterol is sometimes added to increase stability of emulsions.
13

14. EQUIPMENT
14

15. The following equipment's is recommended(as
per schedule-M):
Manufacturing area: -
1. Storage equipment for ampoules, vials
bottles and closures.
2. Washing and drying equipment.
3. Dust proof storage cabinet
4. Water still.
5. Mixing and preparation tanks or other
containers.
6. Mixing equipment where necessary.
7. Filtering equipment.
8. Hot air sterilizer/ Moist heat
Aseptic filling and sealing rooms –
9. Benches for filling and sealing.
10.Bacteriological filters.
11.Filling and sealing unit under laminar
flow work station.
General Room : –
12.Inspection table.
13.Leak testing table.
14.Labeling and packing benches.
15.Storage of equipment including cold
storage and refrigerators if necessary.
15

16. 16
Sterile Garment Cabinet
Horizontal Laminar
flow cabinet HVAC system

17. 17
Ampules washing sterilizing filling
and sealing machine
Vials filling and sealing
machine

18. Layout of parenteral manufacturing area
18

19. 19

20. Pilot Plant Space requirements for Parenteral
20

21. Clean room
21
WHO
(GMP)
United States
(customary)
ISO European
Commission
Grade A Class 100 ISO 5 Grade A
Grade B Class 1000 ISO 6 Grade B
Grade C Class 10 000 ISO 7 Grade C
Grade D Class 100 000 ISO 8 Grade D
An area with defined
environmental control of
particulate and microbial
contamination,
constructed and used in
such a way as to reduce
the introduction,
generation and retention
of contaminants within the
area. GRADE “A”: The local zone for high risk operations. eg. Filling zone,
stopper bowls, open ampules and vials.
GRADE “B”: In case of aseptic preparation and filling, the back
ground environment for grade “A” zone.
GRADE “C” &”D”: Clean areas for carrying out less critical stages

22. 22
(1)Class 100,000 Particle count not to
exceed a total of 100,000 particles per
cubic foot of a size 0.5μ and larger or
700 particles per foot of size 5.0μ and
larger.
(2) Class 10,000 Particle count not to
exceed a total or 10,000 particles per
cubic foot of a size 0.5μ and larger or
65-70 particles per cubic foot of a size
5.0μ and larger.
(3)Class 1,000 Particles count not to
exceed a total of 1000 particles per
cubic foot of a size 0.5μ and larger or 10
particles per cubic foot of a size 5.0μ
and larger.
(4)Class 100 Particles count not to exceed
a total of 100 particles per cubic foot of
a size 0.5μ and larger
The class is directly related to the number of particles per cubic foot of air
equal to or greater than 0.5 micron.

23. 23
AIR CLASSIFICATION
US cGMP:
AIRBORNE
PARTICULATE
CLASSIFICATION
• European standards
• GMP India

24. PROCESS
24

25. PROCESSING OF PARENTERALS
Steps invoved:
1. Cleaning of
containers,
closures and
equipments
2. Collection
of materials
3. Preparation
of parenteral
products
4. filtration
5. Filling the
preparation in
final
containers
6. Sealing the
containers
7. Sterilization
8. Evaluation
of parenteral
preparation
9. labeling and
packaging
25

26. Cleaning of containers, closures and equipment
All the containers ,closures and equipment
required during the preparation of parenteral products are thoroughly
cleaned
with detergent and tap water
followed by clean distilled water
finally rinsed with water for injection.
Rubber closures are washed with
hot solution of 0.5 % sodium pyrophosphate in water.
 removed from the solution, washed with water
 rinsed with filtered water for injection
26

27. Collection of materials
Required quantity of ingredients for formulation
are weighed and collected in the preparation room.
The raw materials  should be pure.
Water for injection free from pyrogens and microorganisms
 The pharmacist should decide the order of mixing and exact method of
preparation to be followed before preparing the parenteral products .
 The parenteral preparation must be prepared under strict aseptic
conditions.
The ingredients are accurately weighed separately and dissolved in the
vehicle as per method of preparation to be followed.
Preparation of parenteral product
27

28. • The parenteral solutions –
passed through bacteria proof filter - filter
candle, membrane filter and sintered glass
filters.
objective  clarify the solution
by removing foreign particles .
• Filtration should be done under strict
aseptic condition to avoid
contamination of filtered solution,
before it is finally transferred into final
container and sealed.
Filtration
28

29. Filling the preparation in final containers
On small scale --manually by using hypodermic syringe and needle .
On the large scale -- automatic filling machine.
Sterile Powders -- by individual weighing or by using automatic or semi
automatic devices.
The filtered product is filled into final container
ampoules vials transfusion bottles
single dose multidose transfusion fluids
29

30. Sealing the containers
Sealing should be done immediately after filling .
 Ampoules
Small scale by rotating the neck of the ampoule in the flame of Bunsen burner.
Sealing of ampoules are done by melting of the portion of the glass neck. There
are two types of sealing:-
Pull –seals
Tip-seals (bead –seals)
Large scale ampoule sealing machine is used.
 The vials and transfusion bottles are sealed by
Closing its opening with rubber closures .
The rubber closures are held in place by crimping the aluminum caps
which is done manually or by mechanical means.
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31. Sterilization
The parenteral preparations should be immediately sterilized after
sealing in its final containers.
Thermostable medicament
sterilized by –
autoclaving at the temperature of
115°Cto 116°C for 30 minutes or
121°C for 20 minutes or
in hot air oven at 160°C for 2hours.
Thermolabile preparations
are sterilised by filtration through a
suitable bacteria proof filters. The
process of filtration, filling and
sealing are done under aseptic
conditions.
31

32. Evaluation of parenteral preparations
Finished parenteral products are subjected to the
following tests in order to maintain quality
A)Sterility Test
B) Clarity Test
C) Leakage Test
D) Pyrogen Test
E) Assay
32

33. Labelling and packaging
• After evaluation of the parenteral preparation, the ampoules, vials
and transfusion bottles are properly labelled and packed.
• The label should state:-
a) Name of the preparation
b) Quantity of the preparation
c) Mfg. Lic .no.
d) Batch no.
e) Date of manufacture
f) Date of expiry
g) Storage condition
h) Retail price
i) Manufacturer's address
33

34. Blow-fill-seal (BFS) technology
Blow-fill-seal (BFS) technology is an automated process by which containers
are formed, filled, and sealed in a continuous operation.
The products can be sterile filled, which makes BFS a cost - effective
alternative for aseptic filling.
It reduced human intervention.
34

35. QUALITY CONTROL
37

36. 1. Leakage Test
 Leakage test is employed to test the package integrity.
 Package integrity reflects its ability to keep the product within and prevent
potential contamination from entering. Leakage test can be done by dye bath
test.
38
 Performed by immersing the ampules in a vacuum chamber containing dye.
(1% methylene blue)
 A vacuum is created for about 15 to 30 min.
 The vacuum will create high pressure on the weak points on the ampoule
seal and will also assist the passage of the dye into the leaking ampoule.
Detection: if solution appears blue  it confirms leakage

37. 2. Clarity Test
Clarity testing is carried out to check the particulate matter in the
sample.
Detection: In this test transparent particles or white particles observed
against the black background and the black or dark particles observed
against the white background.
39
Acceptance criteria: As per USP,
LVP: NMT 25 particles/ mL (size of 10 or more than 10 µm) & NMT 3
particles/mL (size more than 25 µm)
SVP: 6,000 particles/ mL of size 10 µm or greater & NMT 600 particles/
mL greater than 25 µm.

38. 3. Particulate matter in injections
The preparations intended for parenteral use should be free from particulate
matter and should be clear when inspected visually.
Two methods are described by USP according to the filled volume of the
product to be tested.
Large Volume Parenteral (LVP's)
a filtration followed by
microscopical examination
procedure is used.
Small Volume Parenteral (SVP's)
a light obscuration based sensor
containing electronic liquid-borne
particle counter system is used.
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39. SPECIFICATIONS
Volume of
solution
Particle size ≥ 10 μm Particle size ≥25
μm
IP / BP SVP 3000 per container 300 per container
LVP 12 per ml 2 per ml
USP SVP NMT 10,000 particles
per container
NMT 1000 particles
per container
LVP NMT 50 particles per
ml
NMT 5 particles per
ml
41

40. 4. Pyrogen test.
♦ The LAL Assay is an in vitro assay used to detect the presence and concentration
of bacterial endotoxins in drugs and biological products.
♦ This test is based upon the gelling property of an enzyme, the limulus
amebocyte lysate extracted from the horse shoe crab, limulus polyphormus.
♦ The enzyme gels in the presence of bacterial endotoxin and the degree of
gelling is related to the amount of endotoxin present
A. Limulus Amebocyte Lysate (LAL) Test
42

41. The test is performed using stated amounts of volumes of products,
standard, positive control, negative control of endotoxin.
The tubes are incubated at 37±1o
C for 60 ±2 minutes. When the tubes are
inverted at 180o
C angle.
formation of firm gel confirms positive reaction.
 While formation of a viscous gel that doesn't maintain its integrity or
absence of a firm gel confirms negative reaction
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42. 44
This test basically involves the injection of sample solution which is to be
tested into Rabbits which are used as test animals through marginal ear
vein.
The Temperature sensing probe (Clinical Thermometer or similar probe) is
inserted into the rectal cavity of Rabbit at the depth of 7.5 cm, the test
solution must be warmed at 370 C prior to injection.
Then Rectal temperature is recorded at 1, 2, 3 hr subsequent to injection.
B. Rabbit Test
No. of rabbits Individual
temp rise (0C)
Temp rise in a
group (0C)
Test
3 rabbits 0.6 1.4 Passes
If the above
fails
3+5=8 rabbits
0.6 3.7 Passes
If above test not passes the sample is said to be pyrogenic

43. 5. Sterility test
Principle: if micro-organism are placed in a medium that provide optimum
condition of nutrition, moisture, pH, aeration, temperature, they can grow and
their presence will be indicated by the presence of turbidity in clear medium.
A number of culture media are used:
1. Thioglycolate liquid medium: used to support the growth of anaerobic
organisms. It is incubated for 7 days at 35 - 37o C
2. Soybean-casein liquid medium: to support the growth of aerobic
organisms. It is incubated for 7 days at 35 - 37o C.
45

44. Membrane Filtration
method
Filtration of sample through filter 0.45
µm whose effectiveness to retain micro-
organisms has been established.
After filtration completion the
membrane is cut into 2 halves
One half is transferred into soyabean
casein digest medium (aerobic bacteria
and fungi)
- Incubated at 20-25°---NLT
seven days.
Second half is transferred into
thioglycolate medium (anaerobic
bacteria)
- Incubated at 30-35°---NLT
seven days
Direct Transfer method
Transfer the quantity of the preparation
to be examined directly into the culture
medium so that the volume of the
product is not more than 10 percent of
the volume of the medium, unless
otherwise prescribed.
46

45. 47
Interpretation of results