Industrial pharmacy
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KOMUNITAS BLOGGER UNIVERSITAS SRIWIJAYA
PRODUCTION OF PARENTERALS A. Cleaning 1. Containers Containers and equipments
coming in contact with parenterals should be cleaned meticulously. New and unused
containers and equipment will be contaminated with such debris as dust, fibers, chemical
films and other materials arising from the atmosphere, cartons, manufacturing process and
human hands. Characteristics of Machinery for Cleaning: Ø Liquid or air treatment
should strike the bottom of the inside of the inverted container, spread in all directions, and
smoothly flow down the walls and out the opening with a sweeping action. *Pressure of jet
stream should cause only minimal splashing and turbulence. *Splashing prevents cleaning of
all areas *Turbulence may redeposit loosened debris Ø Container must receive a
concurrent outside rinse Ø Cycle of treatment should be a sequence of alternating
very hot and cool treatments to dissolve contaminants. Final rinse should be WFI (water for
injection) *Thermal shock aid (by expansion and contraction) in loosening of debris that
adhere to container wall Ø All metal parts coming in contact with container or
treatments should be made of stainless steel or a noncorroding and noncontaminating
material Treatment Cycle Ø Loose debris removed by vigorous rinsing with water
Ø Thermal shock treatment Ø Air rinse for new containers (if only loose debris
are present) Ø Use only new containers for parenterals. 2. Rubber closures Ø
Gentle agitation in a hot solution of a mild water softener or detergent (0.5% sodium
pyrophosphate) Ø Remove from solution and rinse several times with WFI *Rinsing is
done in a manner that will flush away loosened debris Ø Final rinsing with WFI
*cleaning and final rinsing must remove pyrogens since autoclaving does not remove
pyrogens Ø Sterilize by autoclaving Ø Store in closed containers until ready
for use *If closures are immersed during autoclaving, drain-off solution before storage to
reduce hydration of the rubber Ø Vacuum dry at 100o if necessary 3. Equipment
Ø Disassembled Ø Surfaces scrubbed with a stiff brush, using an effective
detergent *Especially joints, crevices, screw threads and other structures were debris is apt
to collect Ø Thorough rinsing with distilled water 4. Glassware Ø Use
dichromate cleaning solution Ø Wrap in parchment paper and secure with autoclave
tape Ø Sterilize by autoclave 5. Rubber tubing Ø Soak in 10% NaOH for 24
hours Ø Rinse thoroughly and boil in 1% HCL for 1 hour Ø Rinse several
times with water Ø Final rinsing with WFI Ø Sterilize by autoclave *Rubber
tubing must be left wet when preparing for sterilization by autoclaving Because of the
relatively porous nature of rubber compound and difficulty in removing all traces of chemicals
from previous use, it is inadvisably to reuse rubber or polymeric tubing. B. Compounding
Ø All measurements should be accurate and checked by a second qualified person
*liquids are prepared by weight since weighings are more accurate than volume and no
consideration on temperature has to be made. Ø Equipment should be dry and sterile
Ø Follow established order of mixing Ø For parenteral suspensions and
emulsion: maintain proper reduction of particle size under aseptic conditions Ø
Distilled water as solvent/vehicle should be kept and stores at 60-80oC and used within 24
hours C. Filtering Mechanisms of action of filters Ø Sieving or screening *Particles
are retained on the surface of the filter Ø Entrapment or impaction *particles smaller
than the pores become lodged in a turn or impacted on the surface of the passageway
Ø Electrostatic attraction *Particles opposite in charge to that of the surface of the
filter pore are held or adsorbed to the surface Membrane filters Ø used exclusively for
parenterals because of their particle-retention effectiveness, nonshedding property,
nonreactivity and disposable characteristics Ø Ex: Cellulose ester, Nylon,
Polysulfone, Polycarbonate, Polyvinylidene difluoride, Polytetrafluoroethylene (Teflon)
Ø Other filters used: asbestos, sintered glass (bacterial filters), unglazed porcelain,
kieselguhr Factors in filter selection Ø Flow rate required Ø Loss of vehicle by
evaporation or absorption Ø Interaction with the solution Ø Cleanability
Polishing Ø Filtering to remove particles 2-3 microns in size Cold sterilization
Ø Filtering to remove particles 0.2-0.3 microns in size Ø Eliminates
microorganism = bacterial filtration D. Filling Ø Must be done with minimum exposure
time Ø Fill under a blanket of HEPA-filtered laminar-flow air Ø Flow air while
filling until sealing Ø Employ aseptic technique Ø For smaller volumes of
liquid: use hypodermic syringe Ø For large volumes of liquid: use liquid filters with
multiple filling units Ø To speed up filling: use gravity, vacuum or pressure pumps
Allowable excess by USP (to permit withdrawal and administration of labelled amount)
Liquids: Ø For 1mL: mobile 0.1mL; viscous 0.15mL Ø For 10mL: mobile
0.5mL; viscous 0.7mL Ø For > 50mL: mobile 2%; viscous 3% Solids: Ø For
single dose containers: 1-3% Ø For multiple dose containers: 5-8% E. Sealing For
ampules – fusion method (melting a portion of the glass neck) 1. Tip Sealing Ø
melting enough glass at the tip of the neck of an ampule to form a bead and close the
opening Ø rotating the ampule on a single flame to heat evenly on all sides *leaker
– an incomplete sealed ampule 2. Pull Sealing Ø heating the neck of ampule
below the tip, leaving enough of the tip for grasping with foreceps Ø ampule is rotated
in a single flame when glass has softened, the tip is grasped firmly and pulled quickly away
from the body which continues to rotate thus, the small capillary tube formed is twisted close
Ø slower but seals are more sure Ø applied to ampoules with wide opening
e.g. powder ampoules For vial/bottles – manual or mechanical sealing with rubber
stoppers then crimped with aluminium caps or seals For plastic bags/bottles – blowfill-seal aseptic packaging technique Steps: Ø formation of container Ø filling
with metered amount of solution Ø formation or application of seal Advantages:
Ø economical Ø high quality products Ø rapid (9-19 sec) F.
Sterilization Ø To destroy microorganisms and their spores Ø Methods:
steam, dry heat, gas, ionizing radiation, bacterial filtration, tyndallization 1. Steam Ø
Saturated steam under pressure (autoclave) Ø Most common and most effective
Ø 121oC, 15-30 mins, 15 psi Ø MOA: coagulation of cellular protein Ø
Application: aq. solutions containing heat-stable substances 2. Dry heat Ø Employs
oven heated by gas or electricity Ø 160-170 oC, 2-4 hrs, (can lower temp and
increase time or vice versa) Ø MOA: oxidation Ø Application: non-aq.
solutions with heat-stable substances 3. Gas Ø Employs ethylene or propylene oxide
Ø MOA: alkylation of essential metabolites thus affecting reproduction of
microorganisms Ø Application: Dry materials e.g., medical and hospital supplies 4.
Ionizing radiation Ø Employs increased energy radiation emitted by radioactive
isotopes like cobalt 60 or produced by mechanical electron accelerators Ø MOA:
adverse effect on DNA or nucleis acid synthesis or metabolism resulting to lethal mutation
and reproductive stoppage Ø Application: aq. or non-aq. injections with heat-labile
substances 5. Bacterial filtration Ø MOA: physical removal Ø Application: aq.
solution with heat-labile substances 6. Tyndallization Ø Intermittent steam sterilization
exposing material to 100 oC for 30 mins or 80 oC for 1hr to 3 days Ø Application:
heat-labile substances Validating effectiveness of Sterilization Method Ø Biological
indicator Ø Recording thermocouples (a physical parameter indicator) Ø
Color-change and Melting indicators (gives visual indication that a package or truckload has
undergone sterilization) *Freeze-Drying (Lyophilization) Ø Process of drying in which
water is sublimed from the product after it is frozen Ø Adv: preparations are more
stable and more rapidly soluble; dispersions are stabilized throughout shelf-life; products
subject to oxidation have enhanced stability because process is carried out in vacuum IV.
QC Quality Control QUALITY CONTROL TESTS STERILITY TEST Two Basic Methods for
Sterility Testing: · Direct-inoculation: Direct introduction of product test samples into
culture media · Membrane Filtration: Filtering test samples through membrane filters,
washing the filters with fluid, and transferring the membrane aseptically to a culture media
Culture Media: Soybean-Casein Digest Medium (incubated at 20-25 oC) Intended for
anaerobic bacteria, however, it also detects aerobic bacteria. Fluid Thioglycollate Medium
(incubated at 30-35 oC) Suitable for the culture of both fungi and aerobic bacteria.
Incubation: Membrane filtration: 7days Direct-inoculation: 7-14 days *Growth Promotion Test
is done to check whether the media used in the sterility testing is suitable for growth of
microorganisms. This is done by inoculating different species of microorganisms (quantity:
100 colony-forming units) in separate media preparations and incubating it for 3 days
(bacteria) or 5 days (fungi). *Species of Bacteria Used as Biological Indicators Method of
Sterilization Species Moist Heat B. stearothermophilus Dry Heat B. subtilis Ethylene oxide B.
stearothermophilus Radiation B. pumilus, B. stearothermophilus, B. subtilis *Species of
highly resistant bacterial spores included in the materials being sterilized to validate whether
the sterilization process is sufficient enough to kill these microorganisms. PYROGEN TEST
Evaluated by a qualitative response test in rabbits (Reason: they show a physiologic
response to pyrogenic substances similar to man) through: A. Pyrogen Test (Introduced by
Seibert in 1923) Requirements: · Healthy, mature rabbits Test Procedure: · 3
rabbits receive 10 mL solution/kg body (via ear vein) administer within 10 minutes. ·
The rectal temperature recorded 1, 2, and 3 hr after injection. · Limit: Temperature
rise for any one rabbit is 0.6 0C and the total for three is 1.4 0C. · If the limit is
exceeded: Expand the test to include five additional rabbits. The requirement for absence of
pyrogen states that no more than three rabbits each exhibit a temperature rise of less than
0.6 oC and the total temperature rise for all eight rabbits is 3.7 0C or less. ·
Disadvantage: Not all injections can be subjected to this test since some medicinal agent
may have physiological effect on the test animal such that any fever response would be
masked. B. Bacterial Endotoxin Test (since USP21/NF15) Requirements: · Aqueous
extract of the circulating amebocytes of the horseshoe crab, Limulus polyphemus, called
Limulus Amebocyte-Lysate (Reason: causes gel-clot formation if pyrogen is present above a
limiting concentration). Test Procedure: · An aqueous sample is mixed with LAL and
incubated at 37 oC. · The endpoint is determined spectrometrically by an increased
turbidity due to gel formation. · The procedure requires a USP Reference Standard
(defined potency of 10,000 USP Endotoxin Units per vial, endotoxin obtained from E. coli)
· Advantage: The presence of pyrogens may be detected in drugs that have definite
physiological effects and for which the classic rabbit response could not be used. Simpler,
more rapid, and of greater sensitivity. · Disadvantage: Can only detect gramnegative bacteria. To provide standardization, the USP established reference endotoxin
against which lots of the lysate are standardized. Thus, the sensitivity of the lysate is given in
terms of endotoxin units (EU). Most injections now have been given limits in terms of EU, i.e.
Bacteriostatic Sodium Chloride Injection, 1.0 EU/mL. PARTICULATE EVALUATION
· Basis of evaluation: 5 µm (Reason: Erythrocytes have a diameter of 4.5
µm) · All of the product should be inspected by human inspectors under good
light, baffled against reflection into the eye and against black-and-white background. o Any
container which visible particle can be seen is discarded. Limitation: o Size of the particles
that can be seen (visible in unaided eye: 50 µm) o Variation of visual acuity from
inspector to inspector o Emotional state o Eye strain o Fatigue · For assessment of
particulate matter below visible size: Application: All Large-volume Injection(LVI) for single
use and small-volume injections(SVI), excluding IM and SC injections. Test Procedure: Light
Obscuration (Stage 1) · Equipment used to count and measure the size of particles
by means of a shadow cast by the particle as it passes through a high-intensity light beam
(Suppliers: Climet, HIAC/Royco) · If the limit is exceeded: Subject to Stage 2.
Microscopic (Stage 2) · Procedure: filter the measured sample through membrane
filter (under ultraclean condition) and counting the particles on the surface of the filter
· Microscope and oblique light at 100x magnification Subvisible Particulate Matter
Limits in USP Injections Light Obscuration Particle Count Test >10 µm >25
µm SVIs 6000 600/container LVIs 25 3/mL Microscopic Particle Count Test >10
µm >25 µm SVIs 3000 300/container LVIs 12 2/mL LEAKER TEST
Application: For ampules sealed by fusion Test Procedure Produce a negative pressure
within an incompletely sealed ampul (submerged entirely in deeply colored solution, i.e.
methylene blue solution). All leakers are discarded. Factors to Assure Container-Closure
Sealing Integrity o Developing specifications for the fit of the closure in the neck of the
container o Physical characteristics of the closure o Need for lubrication of the closure o
Capping pressure ***vials and bottles are not subjected to leaker test because the sealing
material (rubber stopper) is not rigid. SAFETY TEST Conducted in animals to provide
additional assurance that the product does not have unexpected toxic properties. V.
PACKAGING AND LABELING USP Requirements for Packaging Ø The volume of
injection in a single dose container is that which is specified for parenteral administration at
one time and is limited to a volume of 1L. Ø Parenterals intended for intraspinal,
intracisternal or peridural administration are packaged only in single dose containers
Ø Multiple dose containers should contain no more than 30mL Ø Injections for
irrigation, hemofiltration or dialysis or for parenteral nutrition exempt from packaging
requirements Ø Injections for veterinary use are exempt from requirements
concerning the volume limitation of single and multiple dose containers. USP Labeling
Definition and Requirements for Injection Ø Labeling – all labels and other
written, printed, or graphic matter upon an immediate container or any package or wrapper in
which it is enclosed, with the exception of the outer shipping container Ø Label
– part of labelling upon the immediate container Ø Label – name of the
preparation, percentage content of drug, amt of active ing., volume off liquid to be added to
dry preparations, route of administration, storage, expiration date, name of manufacturer, lot
number Ø Container label should be arranged that a sufficient area of the container is
uncovered to allow inspection of contents DOWNLOAD