Small Volume Parenteral : Sterile, pyrogen free injectable

product which are packaged in volume s up to 100 ml

(Avis et al. 1984).
SVP product can be classified into one or more of the
following categories :

a. Pharmaceutical product (solution, suspension, emulsion, freeze dried

product for reconstitution or powder for constitution).
b. Biological product (vaccines, toxoid, biological extracts).
c. Diagnostic agent are used to diagnose clinical condition (x-ray contrast
media, dyes)
d. Allergenic extracts
e. Radiopharmaceutical products
f. Dental product (local anesthetics)
Market Inventory and Projected Sales. A combination
of product inventory and projected sales determine
in large measure when and how much the
product is to be made by a production department.

Planning and scheduling activities are the key to

the successful production of small volume
parenterals.
Materials Management

This group of personnel is responsible for providing

the materials necessary to manufacture the product.

Materials management personnel coordinate the

activities :

chemical stock, package component warehouse,

printing, and purchasing so that there are sufficient
supplies of chemicals, package components, and
printed components to keep up with the needs of
production, and makes certain that these supplies are
available in a timely manner.
Personnel Management

The key factor in the large-scale manufacturing of high-

quality products is a properly motivated production staff .

Documentation Control

Documentation is the control and verification of the critical

activities in a pharmaceutical process production and
control cycle.
The elements of good documentation include
the following:

a.Master file
b.Batch records
c.Process logs
d.Material Iogs
e. Distribution records
f. ComPlaint files
g.Retained sample storage area records
h.Return good records
The master file is a perpetual record of the
production and control cycles on all batches of a
particular product.

The batch record is the complete record of the

manufacture, control, and distributiott of a single
batch of a product.

Process logs are written verification by a

responsible person that the facilities and equipment
used during a pharmaceutical process have been
cleaned, maintained,calibrated, and/or operated in
an acceptable manner.
Material logs are a verification that the raw materials used in a
pharmaceutical process are acceptable

Distribution records are maintained so that the manufacturer can

determine the location of all manufactured products at all times.

In addition, a complaint file is maintained as a backup to in-house

monitoring of product performance. Complaint files include
inquiries or complaints on product and,/or package defects or
adverse product reactions.

A retained sample storage area is maintained as a comparative

reference source to assist in the reply to product inquiries and
complaints.

The returned goods record is a record of products returned to the

manufacturer as a result of complaints or products exceeding their
shelf life before being consumed. In any case, returned goods are
an important indicator of product market demand and acceptance
of a product.
The majority of formulation fall into three
pharmaceutical products :

I. Solution
II. Suspensions/dispersions
III. Solid for constitution

Sterile solution is the most common small volume

parenteral dosage forms.
Composition of a sterile solution :

a. Soluble drug
b. Osmotic pressure adjusters (sodium chloride or mannitol)
c. Bacteriostatic agents (required for multiple dose
containers such as benzyl alcohol)
d. Buffering agents (phosphates, acetate and citrate salt)
e. pH adjusters (such as sodium hydroxide and hydrochloric
acid)
f. Antioxidants (such as bisulfite, ascorbate and citrate )
g. Chelating agent (EDTA)
Dosage
10 mg Soluble drug Active drug
8,3 mg Sodium phosphate Buffering agent
mono basic
11,29 mg Sodium phosphate Buffering agent
dibasic
9,0 mg Benzyl alcohol Parenteral
preservative
Qs pH 6,8 - 7 Sodium hydroxide pH adjuster
Ad 1 ml Water for injection Solvent

The soluble drug is heat labile, cannot be terminally sterilized via

autoclaving
Figure I : operation I – Nonsterile Formulation

I.Place WFI (in excess of 10 % of the final volume) into stainless

steel tank
II. Heat WFI (121 °C – 20 min), cool to 60 °C
III.Remove and place WFI (30 %) in separate container, save for final
volume adjustment
IV. Dissolve with stirring the buffering agent with remaining WFI (60
°C)
V. Allow the solution to cool (at room temperature 25 – 30 °C),
dissolve active drug and preservative, check the pH of the solution,
if required, adjust with 1 N sodium hydroxide solution
VI. Bring the bulk to final volume with WFI and mix well.
Figure I : operation II – Sterilization

I. Sterilize the bulk solution by filtration method

II. Collect the sterile filtrate

Figure I : operation III– Sterile Subdivision

I. Aseptically subdivide the sterile bulk into appropriate sterile

container
II. Aseptically apply sterilized closure systems to the container and
seal
III. Inspect for sterility and volume fill check during filling operation
IV. Inspect all units for defect and particulate matter
V. Submit samples to the quality control laboratory for release
assays
The blue zone (Dan Buettner, 2008)
Figure 2 : operation I – nonsterile formulation of the
vehicle

I.Place WFI (in excess of 10 % of the final volume)

into stainless steel tank
II. Heat WFI (121 °C – 20 min), cool to 60 °C
III.Remove and place WFI (30 %) in separate
container, save for final volume adjustment
IV.Dissolve with stirring the buffering agent with
remaining WFI (60 °C)
V.Seal the tank for autoclaving
Figure 2. Operation II thermal sterilization of the vehicle

Autoclave both of the vessel from operation I for 30 min at 121 °C

Figure 2. Operation III – aseptic formulation of the active and

preservative

I. Cool the sterile vessel from OP II to room temperature,

aseptically add and dissolve active drug and preservative
II. Aseptically check and adjust the pH 6,8 – 7 if required
III. Aseptically bring the bulk to final volume with WFI

Figure 2. operation IV – Filtration

Figure 2. operation V – sterile subdivision

Formulation for a sterile injectable suspension

Dosage
800 mg Insoluble drug Active drug
O,2 mg Polysorbate 80 USP Surface active agent
6,67 mg Sodium Chloride USP Tonicity adjuster
5,0 mg Sodium Carboxymethyl Viscosity building
cellulose agent
9,0 Benzyl alcohol Parenteral
preservative
Ad 1 ml Water for injection Solvent
Sterile suspensions for injection are more
complicated in composition than a sterile solutions.
Consequently, they are more difficult to process and
sterilize than solutions.

Solid active ingredient may be sterilized prior to

compounding into a suspensions in a numer of
ways , dry heat, autoclave, radiation, sterile
precipitation or crystallization.
Dry heat sterilization ; low melting point , heat
sensitivity of active drug.

Autoclaving of suspensions : increased solubility

of active drug , induce degradation and
recrystallization when is cooled.

Alter the crystal form , habits, or sizes of solid drug

Ethylene oxide : residuals of toxic gas, react with

the active drug
Radiation : radiation energy can break chemical bonds
and or form a new one.

The most practical method of preparing a sterile solid

for suspension : sterile crystallization and
precipitation .

Active drug dissolve in a solvent (organic solvent and

co-solvent), then sterilized by filtration through a
sterilizing membran with porosity 0,2 mikron or less,

Collected in a sterile vessel containing a sterile liquid

in which the dug is insoluble.

The active drug precipitates as crystalline or

amorphous mass.
Some sterile solids may have to be aseptically milled
to reduce particle size or break up hard aggregates of
solid if the crystallizing or precipitation pro
cess does not produce a uniform particle size