PSCIG 1542 Sterile Products Packaging & Administration (Winter 2024) PDF

PSCIG 1542: Pharmaceutics II - Sterile Products Packaging and Administration Systems Objectives 1. Describe different container/packaging types used to package parenteral drug products; 2. Identify stability concerns for parenteral products in various packaging systems; 3. Describe influenc...

PSCIG 1542: Pharmaceutics II - Sterile Products Packaging and Administration Systems Objectives 1. Describe different container/packaging types used to package parenteral drug products; 2. Identify stability concerns for parenteral products in various packaging systems; 3. Describe influences of dosage form and formulation on drug product performance. References and Resources 3. Allen, LV. (2018) Chapter 15: Parenterals. In Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 11th ed. Philadelphia, PA: Wolters Kluwer. Available online at http://pharmacy.lwwhealthlibrary.com/books.aspx 4. Elder, D. (2018) Chapter 32: General Principles of Sterile Dosage Form Preparation; Chapter 34: Parenteral Preparations. In A Practical Guide to Contemporary Pharmacy Practice, 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins. 7. Ochoa, PS and Vega, JA. (2015) Concepts in Sterile Preparations and Aseptic Technique, 1st ed. Burlington, MA: Jones & Bartlett Learning, pp 1 - 15; 107 - 139. 77 PSCIG 1542: Pharmaceutics II - Sterile Products Standard Packaging Systems Ampules Glass containers that are hermetically sealed by fusion of the glass top, creating a closed-system which protects the drug product from environmental and atmospheric exposure. The system is disrupted by breaking off the top of the ampule, allowing accessing to the drug product. Once opened, the product is completely exposed to the environment. Advantages Disadvantages Hermetically sealed Broken glass (requires filtration) Single use (see video on Canvas: Ampules) 1. Clean the neck of the ampule with sterile 70% IPA and allow to dry 2. Always ensure that all liquid has been moved to the lower body of the ampule before opening by gently tapping on the counter or holding the tip and quickly flicking the ampule outward 3. Quickly snap the top of the ampule off. Finger placement may be indicated on some ampules by a colored dot. 4. Breaking of a glass ampule creates glass particles that must be removed from the solution using a filtered needle or filter straw to draw up the content of the ampule. a. Draw contents up with a filter needle/straw (draw up excess to prime a second needle and adjust volume) b. Change to a new needle c. Remove air bubbles by gently knocking against the side of the syringe with your knuckles d. Adjust the volume, catching any drips on an absorbent pad Vials / Bottles Glass or plastic closed-system containers having a rubber closure that allows for repeated penetration without removing or destroying the sealed system. Hermetically sealed containers meant to prevent environmental and/or atmospheric contamination. These containers are nonflexible. 78 PSCIG 1542: Pharmaceutics II - Sterile Products Advantages Disadvantages Multi-use Non-vented (requires pressure equilibration) Container-product interactions (stability) Working with vials and bottles (see videos on Canvas: Working with Vials & Reconstituting Vials): 1. Swab all rubber closures with a new sterile 70% isopropyl alcohol (IPA) swab and allow to dry 2. Insert needle bevel up, with slight added pressure to minimize risk of coring the vial septum 3. Equilibrate pressure: a. When removing solution first inject a volume of air slightly less than the volume being withdrawn to prevent vacuum formation b. When adding liquid, allow the vial to give back the same amount of air so the vial is not over-pressurized (avoids aspiration) c. Use a “see-saw” technique when trading air and liquid Bags Plastic closed-system containers having a rubber closure (port) meant for addition of drug that allows for repeated penetration without removing or destroying the sealed system. Most bags meant for administration have a second port consisting of a removable plug and interior, pierceable seal into which the administration tubing is inserted. These containers are flexible systems. (see video on Canvas: Infusion Bags) Advantages Disadvantages Flexible Plastic-product interactions 79 PSCIG 1542: Pharmaceutics II - Sterile Products For bags and vial, the labeled volume often indicates the volume to be withdrawn; come containers may be overfilled to ensure withdrawl of the total volume. Labeled Volume Excess Volume (mobile liquids) Excess Volume (viscous liquids) 0.5 0.10 0.12 1.0 0.10 0.15 2.0 0.15 0.25 5.0 0.30 0.50 10.0 0.50 0.70 20.0 0.60 0.90 30.0 0.80 1.20 50.0+ 2.00%+ 3.00%+ Syringes Modern day syringes are disposable units consisting of a plastic barrel and tip, plastic plunger rod with interior rubber tip. Syringes may be staked (integrated needle) or have either a slip tip or Leur-Lok tip for the attachment of a needle. Advantages Disadvantages Accurate measuring Plastic/rubber-product interactions Proprietary Systems Pre-Filled Syringes Pre-filled syringes comprise a large percentage of market growth due to the emergence of biotech products, trends towards self-administration of injectable products, and the ready availability of pre-sterilized, ready-to-fill syringes by contract syringe manufacturers. The majority of these devices are staked-needle systems (~75%). 80 PSCIG 1542: Pharmaceutics II - Sterile Products Typical Pre-Filled Syringe Examples: Depo-Provera™ Pegasys™ (peginterferon a-2a) Neulasta™ (pegfilgrastim) Abboject™ Heparin and Saline Flushes Enbrel™ (etanercept) Dual-Chambered Syringes Syringe system used for reconstitution of drug product or mixing of two incompatible liquids (long term stability) just prior to administration. Chambered glass or plastic vial consists of lyophilized powder (or liquid) in one segment and diluent (or second liquid) in another segment, separated by a rubber plug. Application of pressure onto the system causes release of the plug and mixing of the two compartments. 81 PSCIG 1542: Pharmaceutics II - Sterile Products Example Xyntha™ (antihemophilic factor in Lyoject™ system) Vial-to-Syringe Liquid Transfer Devices Needleless reconstitution systems available either as compounding supplies (devices only) on in drug product preparation kits. Examples: Trelstar™ Depot (triptorelin pamoate in Clin’N’Ject™ system) Kogenate™ (antihemophilic factor in Bio-Set™ system) 82 PSCIG 1542: Pharmaceutics II - Sterile Products Recothrom™ Reconstitution Kit http://www.hemostatsolutions.com/recothrom/Convenience Cartridge Systems, Pen Injectors, and Auto-Injectors System consists of a reusable injection device into which a pre-filled cartridge is inserted. The drug dose is pre-measured prior to injection. Pens and auto-injectors administer the dose automatically upon depression of a trigger (e.g. button) or applied pressure of the device against the skin. Examples: Sumatriptan succinate Lantus™ (insulin glargine in Opticlik™system) Humira™ (adalimumab) https://www.youtube.com/watch?v=vvITubaN9dg Epi-Pen (epinephrine) Insulins (various) 83 PSCIG 1542: Pharmaceutics II - Sterile Products Needle-Free Injectors Injection devices that use high pressure to deliver liquid or powder drugs ID, SQ, or IM. Although this is an anticipated growth area, especially given the inherent compliance with "sharps" regulations and safety issues, there are several drawbacks: High cost Pain, bruising, bleeding Examples: Pharmajet™ (device) Sumavel™ DosePro (sumatriptan) Comfort-In™ Injection System http://pharmajet.com Sumavel Dose Pro https://injectneedlefree.com/ Proprietary Bag Systems Quick connect systems or pre-mixed products for the rapid preparation of drug products. Systems may include a separate vial (drug) and bag (diluent; infusion solution) (e.g. ADD-Vantage), pre- mixed drug solutions (e.g. Galaxy Bag), or dual chambered IV bags in which drug and diluent are separated by a rubber/plastic divider to be removed just before preparation (e.g. Duplex bags). Examples: Add-Vantage™ (Baxter) Minibag Plus (Baxter) https://www.youtube.com/watch?v=OLvpKYkT_24 Galaxy™ Bag (Abbott), frozen premix Duplex™ (BBraun) 84 PSCIG 1542: Pharmaceutics II - Sterile Products Autodose™ (TanMed) Chambered Mixing Containers (BBraun) Compounding Devices Syringes Syringes are frequently used to measure small volume and should be selected as follows: Do not measure 80% of the indicated volume of the syringe, especially for hazardous substances Choose the syringe closest in size to the measurement being made Syringes are often used to dispense individual doses. However, syringes used for the transfer of drug products (i.e. removal from a vial and immediate injection into an IV bag or patient) are not approved for the long term storage of drug products. Stability of the drug product may be a concern and should be thoroughly validated prior to preparing doses for long term (>24 hour) storage. Interactions between the drug product and the components of the syringe can cause loss of drug product via adsorption, leaching of plastics, etc. 85 PSCIG 1542: Pharmaceutics II - Sterile Products Thompson, CA. "No Syringe is Approved as a Standalone Storage Container, FDA Says." AJHP News (11/01/15). Available online at http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4260 Drugs Known to be Affected by Rubber Stopper Components Fentanyl Rocuronium Neostigmine Morphine Midazolam Methadone Atropine Hydromorphone Cisatracurium Remifentanil Needles Needle size is indicated by both gauge and needle length. The larger the gauge of the needle, the smaller the diameter of the shaft. Appropriate needle selection depends on the purpose (i.e. injection, site of injection, compounding). Be aware of drug stability issues in the presence of tungsten in some needles (e.g. epoetin). Route / Use Appropriate Size IV / IM 20 - 22G; 1/2" - 1 1/2" SQ 35 - 30G; 1/2" - 5/8" ID 25 - 28G; 3/8" - 5/8" Compounding Larger gauge to minimize damaging rubber closures (e.g. coring vials): 20 - 22G Smaller gauge to draw up volumes with ease, especially with viscous solutions and suspensions: 18G Needle length should be appropriate in order to fully enter container (vial, IV bag) Assembling the Needle and Syringe (see VIDEO on Canvas) 1. Syringes are made to connect with needles using either a friction type slip (“slip tip”) or Luer-Lock (threaded) mechanism 2. When opening needle and syringe packaging, peel the packaging apart. DO NOT “pop” the needle or syringe through the paper wrapping! Dead Space (see https://www.vaajournal.org/article/S1467-2987(21)00065-9/pdf) Syringes are "to deliver" volumetric instruments, in which a small residual volume always remains in the syringe tip (and needle) following injection of the measured volume. This is not a concern 86 PSCIG 1542: Pharmaceutics II - Sterile Products when using one syringe to draw up and inject a single solution. However, when multiple drug products are to be mixed together into a single syringe (to minimize patient discomfort) the "Dead Space" must be accounted for by: 1. Measuring each drug separately and the injecting into a new syringe that will be used for administration purposes 2. Adding a "priming volume" to each dose to account for the empty dead space in the new syringe (so that the product is not lost, resulting in a lower than prescribed dose). The dead space becomes significant only for small volume injections ( 9 Major: Na and Si Minor: K, Ba, Ca, Al Trace: Fe, Mg, Zn Treated glass produces fewer extractables (pH < 8) Glass can delaminate at pH < 4 (http://www.pharmtech.com/causes-and-implications- glass-delamination; http://www.fda.gov/Safety/Recalls/ucm227202.htm [epogen & procrit]) Glass-Formulation Interactions Ion exchange of metals (salt forms of Na, K, Mg, Ca, Al, Li) Dissolution of glass (phosphate and citrate buffers) Glass pitting (EDTA) Adsorption of drug to glass surface Precipitation (phosphate in presence of divalent cations) 94 PSCIG 1542: Pharmaceutics II - Sterile Products Plastic Plastics are made from a wide variety of polymers to form either flexible or rigid synthetic materials (depending on the additives used). Rigid plastics (e.g. polystyrene, PVC) have poor impact resistance. Other issues with plastics include: Leachates and extractables (e.g. dyes and plasticizers) Permeability to moisture and gases o Influenced by moisture, temperature, and properties of the plastic o Aqueous products may lose water (change in drug concentration) o Hydrophobic plastics promote permeation and sorbtion of oils Cracking - stress cracking in the presence of surfactants, vegetable oil, or mineral oil (e.g. polyethylene) Crazing - development of a fine network of surface cracks (e.g. polystyrene) Plastics Used in Parenteral Packaging and Administration Systems/Devices Note: PVC banned in Germany, France and Scandinavia. Use polyolefin or polyethylene/polypropylene mixtures. 95 PSCIG 1542: Pharmaceutics II - Sterile Products Characteristics of Different Pharmaceutically Relevant Plastics Requirement PVC LDPE HDPE PP EVA Drug compatibility – ++ ++ ++ + Moisture permeation –– ++ +++ ++ –– Heat sterilization + – ++ +++ –– Transparency ++ + –– + + Collapsibility +++ – – – ++ Disposability – ++ ++ ++ + Plastic Additives Additive Examples Additive Examples Antioxidants BHT Plasticizers Phthalates (30 - 40% added to PVC) Thioesters Phosphites Heat Metallic stearates Colorants Dyes stabilizers Epoxidized soybean oil Pigments (ultramarine blue) Barium benzoate Lubricants Fatty acid amides PE waxes Silicones Fluorocarbons Zinc stearates Rubber Rubber is prepared via the vulcanization (high temperature and pressure) of a plasticized mixture in molds. The polymer strands are cross-linked by a vulcanizing agent, assisted by an accelerator and activator. The mixture of chemical ingredients in the rubber formulation affect the hardness, elasticity, fragmentation properties, and permeability to vapor transfer of the final closure device (e.g. vial septa). If natural latex is used in the rubber it must be noted in a warning label on the packaging, due to the potential for allergic reactions. Rubber Formulation Use Examples Elastomers Base material Natural rubber (latex) Butyl rubber Silicone Neoprene Curing (Vulcanizing) Agents Forms crosslinks to shape the rubber Sulfur Peroxides 96 PSCIG 1542: Pharmaceutics II - Sterile Products Accelerators Increases cure rate 2-MCBT Zinc Dibutyldithiocarbamate Activators Increase efficiency of accelerators Zinc oxide Stearic acid Antioxidants Resist ageing Phenol Dilaurylthiopropionate Plasticizers Aid in the shaping process Paraffinic acid Silicone oil Fillers Modify hardness Carbon black Clay Barium sulfate Pigments Provide color Inorganic oxides Carbon black Rubber-Formulation Interactions Adsorption of drug to rubber surface Absorption of drug into rubber Permeation of drug through rubber Leaching of rubber extractables into the drug product STUDY GUIDE 1. Explain the proper use of an ampule. 2. Explain the proper method of removing volume from a vial or bottle. 3. Describe the characteristics of IV bags. 4. Identify two main types of syringes (e.g. staked and non-staked) and two main types of connectors (e.g. Luer and slip). 5. Identify different types of proprietary delivery systems (you do not need to know specific examples/brand names) 97 PSCIG 1542: Pharmaceutics II - Sterile Products 6. Explain how to use various packaging and instruments in compounding sterile products. a. Explain the proper use of syringes in measuring volume, including limitations b. Explain the proper use of needles i. Explain “dead space” and why it is important ii. Be able to calculate priming volume. c. Understand when filtration devices are necessary d. Understand the appropriate use of closed system transfer devices. 7. Explain the proper methods for attaching a tubing/administration set to an IV bag. 8. Identify components of packaging that can cause drug-product stability issues. a. List the main stability issues with respect to glass, plastic and rubber. 98