Parenteral production

Parenteral Production
Department of Pharmaceutics | Sagar savale
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
Mobile No. +91 9960885333
Email: avengersagar16@gmail.com
2/27/2017Sagar Kishor Savale 1

Parenteral Route
 It is an route of administration other than the oral route, this route of administration bypasses
the alimentary canal.
 It includes, I.V., I. M., Subcutaneous route for parenteral administration.

Advantages
 Quick onset of action and site specific or targeted activity.
 It can prevent problem of first pass metabolism or presystolic metabolism.
 Useful for unconscious or vomiting or diarrhea patients.
 Duration of action can be prolonged by modifying formulation.
 Suitable for the drugs which are inactivated in GIT or HCl (GI fluid).

Dis-Advantages
 Injections may cause pain at the site of injection.
 Only trained person is required.
 If given by wrong route, difficult to control adverse effect.
 Difficult to save patient if overdose.

Types of Parenteral
Based on types of packaging
• Single dose units: ampoules, infusions and prefilled disposable syringes.
• Multiple dose units: multiple dose vials.

Based on the production and control
• Small volume parenterals: volume < 100 ml, single used, no preservative.
• Large volume parenterals: volume ≥ 100 ml, multiple used, add preservatives.

Based on clinical use
• Solutions for irrigation
• Ophthalmic solution
• Dialysis solution
• Diagnostic agent
• Allergenic extracts
• Implants

Based on physical state of product
• Sterile solutions
• Sterile suspensions
• Sterile emulsions
• Sterile solids

Route of Administration

Subcutaneous (Hypodermis) injection: Below the skin.
Intramuscular injection: Inside the large muscles.
Intravenous injection: inside the veins to blood stream.

Intra-arterial injection: Inside the arteries.
Intracardiac injection: Inside the Harte veins or cardiac veins.
Intrathecal injection: Inside the spinal cord.

Intracisternal injection: Inside the one or two cervical nerve.
Intra-articular injection: Inside the articular ends of joints and bones.
Intracerebral injection: Inside the cerebrum.

Official Types of Injections
Injection: e.g. Insulin Injection USP.
For Injection: e.g. Cefuroxime Injection USP.
Injectable Emulsions: e.g. Propofol USP.

Injectable Suspension: e.g. Methyl Prednisolone Acetate Suspension USP.
For Injectable Suspension: e.g. Imipenem and Cilastatin Injectable Suspension USP.

Requirements of Parenteral Preparations
 Stability
 Sterility
 Free from Pyrogens and Free from foreign particles

 Isotonicity
 Specific gravity
 Chemical purity

Preformulation Factors
 pH /pka
 Solubility
 Thermal/heat effect
 Dissociation constant
 Compatibility studies: FTIR / DSC / TLC/ HPLC
 Oxidation & reduction
 particle size

Formulation of Parenteral Products
1.The active drug
2.Vehicles
• Aqueous vehicle (e.g. water for injection, water for injection free from CO2 ).
• Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil).

Water for
injection
• Not sterilized and pyrogen
free
• It is intended to be used
within 24 hours after
collection
• Total solid contents not more
than 1 mg/100 ml
Sterile water for
injection
• It must be pyrogen free
• endotoxin level is not more
than 0.25 USP
• single dose containers not
larger than 1 liter
Bacteriostatic
water for injection
• One or more suitable
antimicrobial agents
• It is packaged in prefilled
syringes or in vials
• Not more than 30 ml of the
water
• Bacteriostatic agents such as
benzyl alcohol may cause
gasping syndrome
(multiorgan failure)).

Department of Pharmaceutics | Sagar savaleChloride
Test
Calcium
Test
Heavy
Metal Test
Sulphate
Test
Ammonia
test

3.Adjuvants
 Solubilizing agents (e.g. Tweens & polysorbates).
 Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol).
 Buffering agents (e.g. citric acid, sodium citrate).
 Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol).

 Chelating agents (e.g. EDTA).
 Suspending, emulsifying & wetting agents (e.g. MC, CMC).
 Tonicity factor (e.g. sodium chloride, dextrose).

Processing of parenteral preparation

Cleaning of
containers and
Equipment
Collection of
materials
Preparation of
parenteral products
Filtration
Filling the
preparation in final
container
Sealing the container Sterilization
Evaluation of the
parenteral
preparation
Labeling &
packaging

Lay out of Parenteral Manufacturing Area

S
T
O
C
K
R
O
O
M
COMPOUNDING
AREA
CLEAN UP
AREA
ASEPTIC
AREA
QUARANTINE
AREA
STERILIZATION
STORAGE
AND
TRANSPORT
PACKING
AND
LABELLING

Qualitative Layout of Parenteral Manufacturing
Function
Area
Square meter Percentage
Production 11,094 45.1
Warehouse 7,606 30.9
Utility 1,716 4.1
Quality control 1,716 7.0
Administration 1,018 4.1
Maintenance 1,014 4.5
Employee services 1,014 4.1
Security 39 0.9
Total 24,607 100.0

Parenteral
Manufacturing

Manufacturing of Parenteral product
(Lyophilized)

Zones As Per Gazzete of India
1st zones as per gazette of India
BLACK
GRAY
WHITE
 White zone: final step (filling of parenteral).
 Grey zone: weighing, dissolution & filtration.
 Black zone: storage, worst area from
contamination view point.

Environmental Control Zone Grouping

1st Zones As Per The C GMP:
• Zone 1: Exterior
• Zone 7: Filling line
• Zone 6: Filling area
• Zone 5: Weighing, mixing & transfer area
• Zone 4: Clean area
• Zone 3: General production
• Zone 2: Warehouse

Air Handling System (Central Air-Conditioning)

Airborne particulate classification for manufacture of sterile products

Types of operations to be carried out in the various grades for aseptic preparations

Types of operations to be carried out in the various grades for terminally sterilized products

Recommended limits for microbiological monitoring of clean areas “in
operation”

The air classification limits stated by USFDA

Critical Area

ISO 14644-1 Cleanroom Standards

• Biological indicators (BIs) are the most accepted means of monitoring the sterilization process
because they directly determine whether the most resistant microorganisms (e.g., Geobacillus
or Bacillus species) are present rather than merely determine whether the physical and
chemical conditions necessary for sterilization are met.
• Because spores used in BIs are more resistant and present in greater numbers than are the
common microbial contaminants found on patient care equipment, an inactivated BI indicates
that other potential pathogens in the load have also been killed.
Biological indicators (BIs)

Biological indicators (BIs)

• Biological indicators (BIs) are used for determination of Bacillus
species.
• BIs such as, ethylene oxide, ethylene chlorohydrin, ethylene hydroxide
and halogenated ethylenehydrine.
• BIs was determined by Z value and D Value.

Z value and D Value
 Z value is define as Temperature is required to higher death rate.
 D value is define as reduction of microbial population by 90 % of the factor 10.
 D value is 10 factor greater than Z value.
 e.g. D value is 121 ºc as the Z value is 10 ºc.

Sterile area: the area which are used to kill the all microorganisms.
Techniques
• Celerity study
• Sterility study
• Leakage study
• Pyrogen study
• LAL test
• Assay for content uniformity study

Aseptic area: the area which are used to kill the pathogenic microorganisms.
Techniques:
• HEPA filter integrity test
• Air flow pattern
• Air velocity study
• Heat sensitization study
• Heat distribution study

Quality Control of Parenteral Preparations

 Quality Assurance The planned and systematic activities implemented in a quality system so
that quality requirements for a product or service will be fulfilled.
 Quality Control is a procedure or set of procedures intended to ensure that a manufactured
product or performed service adheres to a defined set of quality criteria or meets the
requirements of the client or customer.

In Process Quality Control Test
 Conductivity measurement
 Volume filled
 Temperature for heat sterilized product
 Environmental control tests
 Visual inspection

Environmental Control
 Traffic control
 Surface disinfection personnel
 Air control (HEPA filters)

Volume Filled
An injection container is filled with a volume in slight excess of the labeled size
Determination of filled volume:
 10 mL or more 1 container
 3-10 mL 3 containers
 Less than 3 mL 5 containers

Leakage Test
 visual inspection
 bubble test
 dye tests
 vacuum ionization test

Clarity Test
 Clarity test is carried out to check the particulate matter in the sample.
 It is practically impossible that every unit of lost is perfectly free from visible particulate matter
, that is ,from particles that are 30 to 40 micrometer and large in size.
USP limits for large volume infusions
Particle size Particle limit
10 mm (or) larger/ml 50
25 mm (or) larger/ml 5

Instrumental Methods
This is also called as the particle count method particle counting may be based on
any one of the following principles; change in
Electrical resistance
Light absorption
Light scattering

Leaker Test

Pyrogen Test
1. LAL TEST 2. RABBIT TEST

LAL Tester

Criteria For Limulus Test Result
LAL TUBE TEST SAMPLE/CONTROL RESULT
1 Negative control
(pyrogen free saline)
Should be -Ve
2 Positive control (pyrogen ) Should be +Ve
3 Positive internal control
(test sample tainted with exdotoxins)
Should be +Ve
4 Test Sample May be +ve or -Ve

Sterility Test

Methods For Testing
1. Membrane Filtration Method 2. Direct Inoculation Method

 MEDIA SUITABLE FOR STERILITY TESTS ARE:
i. FLUID THIOGLYCOLLATE MEDIUM
ii. SOYA-BEAN CASEIN DIGEST MEDIUM
WASH THE FILTERS WITH FLUIDS TO REMOVE
INHIBITORY PROPERTIES, CUTTING THE
MEMBRANES ASEPTICALLY INTO EQUAL
PARTS AND TRANSFERRING ONE OF THE
PARTS TO EACH TYPE OF CULTURE MEDIUM
USED.
THE MEDIAARE THEN INCUBATED UNDER
PRESCRIBED CONDITIONS.
Membrane Filtration
Method

Parenteral Preparation
Culture Medium
• This Method Is Only Used When
Membrane Filtration Is Not Possible The
Sample Is Inoculated Directly Into The
Media Or The Device Is Placed Directly
Into The Media.
• Result:
• If No Growth In The Media Then Test Is
Positive.
DirectInoculationMethod

Lyophilization or freeze drying
o Lyophilization or freeze drying is a process in which water is removed from a product after it is
frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor
without passing through a liquid phase.
o The process consists of three separate, unique, and interdependent processes;
Freezing,
Primary drying (sublimation), and
Secondary drying (desorption).

The advantages of Lyophilization
 Ease of processing a liquid, which simplifies aseptic handling.
 Enhanced stability of a dry powder.
 Removal of water without excessive heating of the product.
 Enhanced product stability in a dry state.
 Rapid and easy dissolution of reconstituted product.

Disadvantages of Lyophilization
 Increased handling and processing time.
 Need for sterile diluent upon reconstitution.
 Cost and complexity of equipment.

The Lyophilization process generally includes the following steps
 Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
 Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
 Filling into individual sterile containers and partially stoppering the containers under aseptic
conditions.
 Transporting the partially stoppered containers to the lyophilizer and loading into the chamber
under aseptic conditions.

 Freezing the solution by placing the partially stoppered containers on cooled shelves in a
freeze-drying chamber or pre-freezing in another chamber.
 Applying a vacuum to the chamber and heating the shelves in order to evaporate the water
from the frozen state.
 Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms
installed in the lyophilizers.

 There are many new parenteral products, including anti-infectives, biotechnology derived
products, and in-vitro diagnostics which are manufactured as lyophilized products.
 Additionally, inspections have disclosed potency, sterility and stability problems associated
with the manufacture and control of lyophilized products.

Parenteral production

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