Transcript Lecture 5 hana

Sterile preparation
Facilities and Equipment
Ampules or Vials
Syringes and Needles
IV Bag
 Backaging Facilities
 Generally, vials comprise about 50% of small volume
injectable packaging, syringes 30% and ampoules 10%,
and cartridges and bottles/bags filling the rest.
o The advantages involve user convenience, marketing
strategy, handling during production and distribution,
volume considerations, and compatibility with the
product.
o The disadvantage with all these packaging systems is
the potential reactivity between the drug and other
ingredients in the formulation (e.g., antimicrobial
preservatives) and the packaging components.
 Selection of the packaging system not only depends on
compatibility
with
the
product
formulation
and
the
convenience to the consumer, but also on the integrity of
the container/closure interface to ensure maintenance of
sterility throughout the shelf-life of the product.
 Container/closure
integrity
testing
has
received significant attention and usually is
an integral part of the regulatory submission
and
subsequent
regulatory
good
manufacturing practice (GMP) inspections.
Ampoules
 The glass-sealed ampoules were the most popular
primary packaging system for small volume injectable
products.
 The ampoules offer only one type of material (glass) to
worry about potential interactions with the drug product
compared with other packaging systems that contain both
glass or plastic and rubber.
 Disadvantages of glass amp.
 The assurance of the integrity of
the sealing
 The problem of glass particles
entering the solution when the
ampoule is broken to remove the
drug product.
 Glass ampoules are Type I tubing glass in sizes ranging
from 1 to 50 mL.
 After solution is filled into the top opening of the ampoule,
the glass is heat sealed by one of two techniques:1. Tip sealing has the open flame directed toward the top
of the ampoule that melts and seals itself while the
ampoule is rotating on the sealing machine.
2. Pull sealing has the open flame directed at the middle of
the portion of the ampoule above the neck where the
glass is melted while rotating and the top portion is
physically removed during rotation.
 Thus the tip-sealed ampoule has a longer section above
the neck while the pull-sealed ampoule has a more blunt.
Vials
The most common packaging for liquid and freeze-dried
injectable is the glass vial.
Plastic vials have made some access as marketed packages
for cancer drugs. Plastic vials are made of cyclic olefin
polymer (COP) or cyclic olefin copolymer (COC). The
appearance of a plastic vial looks identical to a glass vial.
 Why plastic vials have not become as commonplace
as glass vials?
• The ease of introducing the container into a classified
(ISO 5) aseptic environment.
• Glass vials are sterilized and depyrogenated in dry
heat tunnels that convey the vials into the aseptic
environment without the need for manual transfer.
 Plastic vials are presterilized (typically irradiation) at the
vial and the finished product needs to solve how to
aseptically
transfer
plastic
vials
into
the
aseptic
environment.
 This is not an easy solution, especially compared to the
convenient way glass vials are introduced via the dry
heat tunnels.
Two other potential disadvantages of plastic vials are:
1. Challenges in handling and movement of much lighter
weight containers compared with glass along conveyer
systems on high-speed filling lines, with smaller vials (1-5
mL) especially difficult to process.
2. Concerns about potential interactions with the drug
product (absorption, adsorption, migration, leachable)
especially over a two to three year shelf-life.
 Vial openings are 13, 20, or 28 mm.
Syringes
Syringes are very popular delivery systems.
They are used either as: Empty sterile container systems
where solutions are withdrawn
from
vials
into
the
empty
syringe prior to injection
 Prefilled syringes can be presterilized by the empty syringe
or can be cleaned and sterilized by the finished product.
Other options regarding syringe size, components, formats,
treatment of rubber materials, and manufacturing methods.
 Primary reasons for prefilled syringe popularity:1- The emergence of biotechnology and the need to eliminate
overfill (reduced waste) of expensive biomolecules
compared with vials and other containers.
2- Vaccines, antithrombotics, and various home health care
products such as growth hormone and treatments for
rheumatoid arthritis and multiple sclerosis are much
more conveniently used and administered using
prefilled syringes.
3- The syringe processing with lower costs and high-speed
filling equipment.
4- Elimination of dosage errors because unlike vials, syringes
contain the exact amount of deliverable dose needed.
5- Ease of administration because of elimination of several
steps required before injection of a drug contained in a
vial.
6- Because fewer operations are required, sterility assurance
is increased.
7- More convenient for health care professionals and end
users; easier for home use; easier in emergency
situations.
8- Reduction of medication errors and better dose accuracy.
9- Lower injection costs-less preparation, fewer materials,
easy storage, and disposal.
 Syringe barrels can either be
glass or plastic while syringe
plunger rods are usually plastic.
 Plastic polymers for the syringe
barrel include polypropylene,
polyethylene, and polycarbonate.
 Syringes with needles may also have needle protectors to
avoid potential dangers of accidental needle sticks post
administration.
 Such protectors either can be part of the assembly
or can be assembled during the finishing process.
 Needle stick prevention during manufacturing
be:-
can
 Manual (shield activated manually by the user although there
can be risk of accidental sticking),
 Active (automated needle shielding activated by user), or
 Passive (automated needle shielding without action by the
 The selecting and qualifying components of a syringe
include:-
 Container/closure integrity testing
 Plastic component extractable
 Sterilizability, especially if needle is part of the package to
be sterilized
 Siliconization of barrel and plunger (provide both lubricity
and inert drug-contact surfaces)
 Compatibility of product with syringe contact parts,
especially the rubber plunger
 Syringe needle gauges range from 21 to 32 gauge (G).
o It is important to note that some suspensions may not syringe
properly if the needle gauge is not carefully considered.
o The syringe quality control is the assurance of container/closure
integrity during and after filling and terminal sterilization
 Siliconization Issues with Syringes
 For syringes, the rubber plunger must move easily within the
syringe barrel with the “glide force” being the same throughout
the barrel (from distal to proximal end).
There are several concerns related to siliconization of
syringes.
 Syringe functionality involves forces both to: Initiate movement of the plunger rod within the syringe
barrel.
 Maintain movement of the plunger rod throughout barrel
to the end of the syringe.
Siliconization significantly facilitates both forces.
 But, excess silicone is a problem from a physical stability: Visible appearance of silicone droplets in the product.
 Protein interaction with these hydrophobic droplets.
 Reduction of the amount of silicone applied within the inner
surface area of the syringe.
However, sometimes not all the inner surface of the barrel
is coated with silicone.
 This will potentially lead to an effect called “chattering” where
the syringe barrel will “stick” and require greater force to
make it move again.
 Syringe siliconization raises the potential for protein aggregation.
 Syringes becoming more popular for use with biopharmaceutical
products because the plastic surface does not require silicone for
facile movement of the rubber plunger and plunger rod through
the plastic barrel.
NEEDLES
 Stainless steel needles have been used to penetrate the skin and
introduce a parenteral product inside the body.
 Needles are hollow devices composed of stainless steel or plastic.
 Needles are available in a wide variety of lengths, sizes, and shapes.
 Needle lengths range from 1/4 in to 6 in.
 Needle size is measured both in length (usually inches in the United
States; centimeters in the rest of the world) and gauge.
 Needle gauge includes both internal or inner diameter (ID) and
external or outer diameter (OD) of the needle.
 The larger the gauge, the smaller the diameter. For example, a 21 G
needle has an ID of 510 u m and an OD of 800 u m.
 The ID is important especially for dispersed system formulations
containing insoluble particles suspended in a vehicle and for highly
viscous formulations (usually viscosity greater than 4 centipoise).
 The smaller the ID, the potential greater difficulties encountered in
needles clogging due to bridging of particles or insufficient force per
unit area to eject viscous solutions.
 The OD is important for the reason of the potential degree of
discomfort, pain, and tissue irritation when the needle penetrates the
skin.
 The smallest possible gauge needle is always used as long as the
product can be easily ejected from the syringe or other delivery device
into the appropriate bodily location.
 For deep intramuscular (IM) injections, typically (and
unfortunately for the patient) a long (1.5–2 in) needle of a
typical gauge of 18 to 20 must be used.
 For subcutaneous (SC) injections requiring injection of
very small volumes of drug product, a short (1/4 to 1/2 in)
high gauge (27–33) needle can be used, causing a
minimal amount of pain or discomfort.
o Gauge ranges are 11 to 32 G in practice (there are
smaller and larger gauge sizes, with the largest gauge for
injection usually being no greater than 16G.
 Sixteen gauge needles have an OD of 0.065 in (1.65
mm) while 32G have an OD. of 0.009 in (0.20 mm).
Needle shape includes:o Regular, short bevel, intradermal,
and winged.
o The other end of the needle is
beveled,
o meaning that it forms a sharp tip to
maximize ease of insertion.
o Bevels can be standard or short
 The route of administration, type of therapy, and whether the patient is a
child or adult dictate the length and size of needle used.
 IV injections use 1 to 2 in, 15-25 G needles.
 IM injections use 1 to 2 in, 19-22 G needles.
 SC injections use 1/4 to 5/8 in, 24-25 G needles.
 Needle gauge for children rarely is larger than 22 G, usually 25 to 27 G
Bags
 Bags used for IV fluids include prefilled or empty containers that range
in size from 25 mL to greater than 1 L.
 Sizes that are 1 L or greater are often used in hospital settings for
delivery of total parenteral nutrition.
 Bags of all sizes are often used for ease of delivery and ease of
transport. However, maintaining identification of the bags can be a
problem.
 Printing on plastic bags is a challenge because of the flexibility of the
bag material and labels adhered to the bags can become difficult to
read.
 This was mostly resolved by the introduction of bar coding that allows
traceability of bags from filling to patient use.
 Compatibility issues between the bag polymer and the drug solution
have plagued the industry over the years.
 Polyvinyl chloride (PVC) was the polymer material of choice for many
years because of the important collapsibility characteristic of PVC.
However, PVC was notorious for leaching a plasticizer used to add
flexibility, that material being di(2-ethylhexyl) phthalate (DEHP