COLLEGE OF STERILE PRODUCTS PHARMACY PHT 434 · Used for ready-to-use all parenterals Most expensive type of glass ... –Washing, Drying, Sterilization, Sealing methods •Product

COLLEGE OF PHARMACY

Dr. Mohammad Javed Ansari, Ph.D Contact info: [email protected]

STERILE PRODUCTS PHT 434

mailto:[email protected]

LECTURE OUTLINES • Objectives of the lecture is to learn about

• Parenteral Packaging systems such as • Ampoules,

• Vials,

• Bags,

• Prefilled syringes & cartridges

• Bottles.

• Parenteral Packaging materials such as • Glass

• Rubber

• Plastic.

• Drug product –packaging interactions.

• AMPOULES

• VIALS

• DUAL CHAMBER VIALS

• PREFILLED SYRINGES AND CARTRIDGES

• GLASS OR PLASTIC BOTTLES AND PLASTIC BAGS

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Parenteral Packaging systems

• AMPOULES

• A small cylindrical glass /

plastic container that is

sealed after filling single

dose of drug /water.

• Most commonly used for

supplying WFI.

• They are also used for

single dose small volume

parenterals.


• AMPOULES


• AMPOULES: Types of Ampoules

• “Rupture-disk" (VIBRAC)

• " One-Point Cut Ampoules" (OPC)

• These are named based on facilitator mechanisms for breaking ampoule safely to decrease percutaneous injuries and contamination of contents.

• “Rupture-disk" (VIBRAC): implies applying a ring of paint after the cure/tempera process of ampoule manufacture.

• It partially penetrates in the glass, causing fragility of the area of application.

• This fragility is located at the strangulation point of the ampoule (between the head and body of the ampoule).


• AMPOULES: Types

• Rupture-disk"

(VIBRAC)


• AMPOULES: Types

• " One-Point Cut Ampoules" (OPC)

• A small incision is made in the strangulation area of the ampoule.

• A small point of paint is placed a few millimeters above the incision.

• This point orients the correct opening position.


• AMPOULES

• How to Open Ampule?

• Ampules are opened by snapping off the glass top at the neck where a score line/point was pre-made during process of ampoule production.

The score line at neck does not always break where it is intended.

Hand injuries from ampoule opening are common.

Content contamination by glass fibers possible.

Cross infection through blood borne pathogens is likely.


• AMPOULES



https://www.youtube.com/watch?v=3l9p4VXVaOk

• AMPOULES


• Wash your hands thoroughly or use gel sanitizer.

• Hold ampoule upright and tap on neck /top.

• Firmly grasp the top portion of the ampule in your dominant hand, between the thumb and forefinger while grasp the bottom portion in your other hand.

• Apply firm but gentle pressure at the neck (Use gauze or a paper towel to protect your fingers), break it open by quickly snapping the neck away from your body.


• AMPOULES

• How to break any types of ampoule safely

• Use an ampule cutter and gauze to prevent injury.

– Cut the neck of ampule.

– Protect your self using gauze.

– Snap off the conical tip of ampule.


• AMPOULES

• Disposal of Ampoules

• When you have taken the medicine, discard remaining drug if any and all the pieces of the ampoule by wrapping in a tissue or paper.

• If the glass shatters instead of breaking cleanly, discard it entirely since the medicine may not be safe to use at this point due to contamination with glass fibers in the ampoule content.


• AMPOULES

• Aspiration of Ampoules

• Aspiration needles with micro-filters are used to avoid any glass residue in injection.


• AMPOULES

• Alternative methods of opening ampoules

• Inserting the conical tip of the ampoule inside the hollow cylindrical space of the barrel


https://www.youtube.com/watch?v=nbRfFS-3W-s

https://www.youtube.com/watch?v=Q-2mjsKHcqY



https://www.youtube.com/watch?v=Od5WShZIOoY


• Inserting the conical tip of the ampoule inside the hollow cylindrical space of the barrel


https://www.youtube.com/watch?v=zEGN3MSFxVQ

https://www.youtube.com/watch?v=Ic_K1HQLd0A

https://www.youtube.com/watch?v=dra8C-1Ewdc

• VIALS:


VIAL

CRIMPER

1-RUBBER CAP, 2-ALUMINIUM CLOSURE, 3-PLASTIC COVER

https://www.youtube.com/watch?v=L8ZOpZNOS8k

• VIALS:

• For single-dose or multi-dose use (contain

preservative).

• Product is easier to remove from vials than form

ampoules

• Eliminate the risk of glass particles contamination

during opening

The rubber stopper can become cored causing a

small bit of rubber to enter the solution especially in

multi-dose uses.


• Compare Ampoules & Vials:


Ampoules Vials

Single dose Single / multi dose

No Preservatives Preservative + (toxic)

Hermetically sealed Not hermetic

Protection from air or humidity

Air /humidity may permeate

Drugs more stable Drugs less stable

Difficult opening Easy opening

Risk of injury No risk of injury

Risk of glass contamination No risk of contamination

Container is not reusable Vials are reusable

• DUAL CHAMBER VIALS

• Pfizer’s Act-O-Vial system

• Pressing down on the plastic activator

• Displaces the center stopper

• Gravity forces the diluent of upper chamber into the dry powder in lower chamber

Suitable for unstable /

hydrolysable drugs.

Minimizes number of steps in

reconstitution of injection.

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• PREFILLED SYRINGES AND CARTRIDGES

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Single-dose medicine filled in

syringe with fixed needle.

Labeled properly

Or done individually

for particular patient

In hospitals.

Some medicine may be supplied in pre-filled for self

administration

Plastics / glass sometime

• PREFILLED SYRINGES

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• PREFILLED SYRINGES : PROS & CONS

Emergency drugs are available right away.

Ease of administration (less steps involved) .

Self administration is possible.

Reduction of medication error (right dose always)

Reduction of contamination (Assurance of sterility).

Less overfill required (economical for biopharmaceuticals)

Good control of controlled drugs (e.g. narcotics).

Component/material may have extractables and leachables.

Primary packaging materials / plastics may have an adverse

interaction with the drugs.

Silicone oil (used to lubricate the inner surface of glass pre-

filled syringe) is seen as an “essential evil / interctant.

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Parenteral Packaging systems PREFILLED DUAL CHAMBER SYRINGES

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Parenteral Packaging systems PREFILLED DUAL CHAMBER SYRINGES

The pre-filled, dual chamber syringe (DCS) features an

all-in-one delivery system that decreases the number of

steps required for reconstitution compared with vial kit

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Parenteral Packaging systems PARENTERAL INJECTABLE CARTIDGES

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Parenteral Packaging systems GLASS / PLASTIC BOTTLES & PLASTIC BAGS

• GLASS/PLASTIC BOTTLES & PLASTIC BAGS

• They are used for Large volume parenterals for IV administration.

• For the intermittent or continuous infusion of fluids or drugs.

• Need special administration devices to permit drug administration.

• CANULA SALINE SET

» DRIP CHAMBER

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Parenteral Packaging MATERIALS • Glass

– Types I, II, III and surface treatments

– Leachables

– Particulates

– Color (amber)

• Rubber

– Types: unsaturated and saturated elastomers

– Complexity of formulation

– Leachables

– Sorption

– Moisture vapor transmission

– Coring and other physical properties

• Plastic

– Types of polymer

– Leachables

– Air and moisture transmission

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Parenteral Packaging MATERIALS: Glass • Type I Highly resistant borosillicate glass

Very little, if any, alkali leachables

Used for ready-to-use all parenterals

Most expensive type of glass

• Type II Treated (sulfar dioxide) soda lime glass

Sodium sulfate forms on glass (looks like frost)

(reaction between H2SO4 and sodium ions)

Used for LVP bottles and acidic/neutral SVPs

• Type III Soda-lime glass

About 10x less resistant to alkali than type I

Used for dry powder SVPs

Cannot be terminally sterilized with final product

• NP Non parenteral glass

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Parenteral Packaging MATERIALS: Glass Interactions

• Adsorption: Insulin, albumin, epinephrine, atropin.

• Delamination: Glass flake off in specific zones of the packaging product and contaminate the solution.

• Leaching: component of glass going slowly in the liquid formulations.(esp solutions).

• Extraction: leaching in extreme conditions (acid, base, temperature / sterilization).

• Extraction usually at pH > 9 ie. Alkali react with SiO2 and ultimately corrodes glass).

• Major extractable: Si and Na, Minor extractable: K, Ba, Ca, Al

• Acid attack: Generally resistant except with HF. Acids react with alkali metals of glass slowly.

• Alkali attack: Faster attack on glass backbone SiO2.

• Buffer attack: citrate, phosphate, tartrate also attack glass SiO2 causing delamination.

• Ion exchange of metal ions: like Na, K, Mg, Ca, Al, Li.

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• Factors Affecting Glass Extractables

• Container size and design

• Container processing

–Washing, Drying, Sterilization, Sealing methods

• Product composition

– Type of ions, Concentration, pH

• Storage of filled container

– Time/Temperature, Shipping, Light

Parenteral Packaging MATERIALS: Glass Interactions

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• Rubber is used as Closures (container-closure).

• Closures prevent ingress of contamination into a vial once a needle is inserted (by enabling resealing of the vial after the needle is withdrawn).

• Hence these are called elastomers.

• Used in vials and bottles closure, syringes and cartridge plungers, ports on plastic bags and IV administration sets.

• Two primary rubber types / elastomers are natural and synthetic

• Synthetic rubbers are strongly resistant to permeation by oxygen or to water vapors.

Parenteral Packaging MATERIALS: RUBBER

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• Rubber are very complicated with many components

• Many potential problems are associated with the use of rubber, especially closures.

• Elastomer Base material (e.g. natural, butyl, silicone)

• Curing Agent Forms cross-links (sulfur, zinc oxide (Vulcanizing) peroxide) to shape the rubber

• Accelerator Increase cure rate (e.g. 2-MCBT)

• Activator Increase efficiency of accelerator (e.g. zinc oxide, stearic acid)

• Antioxidant Resist aging (e.g. phenol)

• Plasticizers Aid shaping process

• Filler Modify hardness(e.g carbon black, limestone)

• Pigment Provide color

Parenteral Packaging MATERIALS: RUBBER composition

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Parenteral Packaging MATERIALS: RUBBER properties

Type Auto-

clavable Additives

Water Vapor

Permeation

Pot. React.

with product

Butyl yes Moderate Low Moderate

Natural yes High Moderate High

Neoprene yes High Moderate High

Polyisoprene yes High Moderate Moderate

Silicone yes Moderate Very high Low

• Closures that form part of the container-closure

system are an important component in the packaging

of sterile products.

• It maintain the sterility of parenteral pharmaceuticals

and prevent ingress of contamination

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• The pharmaceutical manufacturer should consider the following questions relating to product compatibility, in conjunction with the manufacturer of the closure:

• Is the product absorbed by the rubber?

• Does the rubber react with the product and leach out impurities?

• At which temperature range is both closure and product stable?

• What happens when the product and stopper are stored together over time?

Parenteral Packaging MATERIALS: RUBBER quality considerations

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• Physical Tests: Break force, Particulate matter, resistance to sterilization, Oxygen / Water vapor transmission, Container-seal tests (dye test, helium leak test).

• Chemical Tests: Extractables, Leachables, Silicone oil determination

• Biological tests: Bioburden, pyrogen test, Biocompatibility,

• Performance / Functionality tests : – Pressure to puncture (penetrability),

– Coring (fragmentation),

– Resealability (self-sealing capacity)

Parenteral Packaging MATERIALS: Quality tests of RUBBER

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• Performance / Functionality tests :

• Pressure to puncture (penetrability).

• Fill 10 suitable vials to the nominal volume with water.

• Fit the closures to be examined, and secure with alumimum cap.

• Using a new hypodermic needle for each closure, pierce the closure with the needle perpendicular to the surface.

• Requirement—The force for piercing is no greater than 10 N for each closure, determined with an accuracy of ± 0.25 N.


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• Resealability (self-sealing capacity):

• Fill 10 vials with water to the nominal volume.

• Fit the closures that are to be examined, and cap.

• Pierce each closure 10 times, at different sites.

• Immerse the 10 vials in a solution of 0.1% methylene blue, and apply external pressure of 27 kPa for 10 minutes.

• Restore to atmospheric pressure, leave all vials immersed for 30 minutes. Rinse the outside of the vials.

• Requirement— None of the vials contain any trace of blue solution.


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• Coring (Fragmentation):

• Closures for Liquid Preparations—

• Fill 12 clean vials with water to 4 mL less than the nominal capacity.

• Fit the closures to be examined, secure with aluminum cap, and allow to stand for 16 hours.

• Closures for Dry Preparations—

• Fit closures to be examined into 12 clean vials.

• Secure each with a cap.


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• Procedure—inject into each vial 1 mL of water while removing 1 mL of air.

• Repeat this procedure 4 times for each closure, piercing each time at a different site.

• Use a new needle for each closure, checking that it is not blunted during the test.

• Filter the total volume of liquid in all the vials through a single filter with a nominal pore size no greater than 0.5 µm.

• Count the rubber fragments (should be no more than 5) on the surface of the filter visible to the naked eye (≻ 0.5 µm).


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• Plastic is a relatively new material for parenteral packaging.

• As per an estimate, 60–70% of all prefilled syringes in Japanese market are plastic, rather than glass.

• Issues with glass breakage and delamination are main concern in the marketplace.

• Glass can break at any time: in production, when used within a device such as an auto-injector, or even when in use by the patient or caregiver.

• Silicone oil (Glass lubricant) cause problems such as the formation of protein/silicone aggregates, which may alter the integrity of the drug product.

Parenteral Packaging MATERIALS: PLASTICS AS PARENTERAL PACKAGING

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• Polymer or plastic resists breakage extremely well and is also inert and resistant to broad range of polar solvents, acids, and bases.

• Plastic offers significant design flexibility and increased dimensional precision.

• Flexible design and tight dimensional tolerances make these syringes compatible with various intravenous connectors , thus ensuring patient safety.

• Plastic is used to produce various types of parenteral containers such as syringes, cartridges, intravenous connectors, infusion sets, vials, and ampoules.


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• Polyvinyl Chloride – PVC

• Polypropylene – PP

• Ethyl Vinyl Acetate – EVA

Above common plastic polymers are not inert and can be subjected to degradation and oxidation.

Plastic-drug Interactions hinder its generalized use.

For example, diazepam, nitroglycerin, isosorbide dinitrate, and warfarin sodium, can all be absorbed by PVC.

The availability of these drugs is decreased when they are in plastic containers or administered through plastic infusion sets.


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Plastics/polymers could be scratch-sensitive

Moreover, oxygen permeability of polymers /plastics is typically inferior to glass

Hence plastic packaging options must be evaluated on a drug-by-drug basis.

If a product is moisture /oxygen-sensitive, proper care is used to select appropriate packaging systems.

Concerns are scratch sensitivity, inferior barrier against oxygen and water vapor, and limited long-term experience.


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COLLEGE OF STERILE PRODUCTS PHARMACY PHT 434 · Used for ready-to-use all parenterals Most expensive type of glass ... –Washing, Drying, Sterilization, Sealing methods •Product