Parenterals product requiring sterile packaging: Production procedure (Part – II) Containers and Closures and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Parenterals product requiring sterile packaging: Production procedure (Part – II) Containers and Closures and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Containers and Closures: Injectable formulations are packaged into containers made of glass or plastic. Container systems include ampoules, vials, syringes, cartridges, bottles, and bags. Ampoules are all glass, whereas bags are all plastic. The other containers can be composed of glass or plastic and must include rubber materials, such as rubber stoppers for vials and bottles and rubber plungers and rubber seals for syringes and cartridges. Irrigation solutions are packaged in glass bottles with aluminum screw caps.

Container types:

Glass – Glass is employed as the container material of choice for most SVIs. It is composed, principally, of silicon dioxide, with varying amounts of other oxides, such as sodium, potassium, calcium, magnesium, aluminum, boron, and iron. The basic structural network of glass is formed by the silicon oxide tetrahedron.

Types – The USP provides a classification of glass:

• Type I, a borosilicate glass ;
• Type II, a soda-lime treated glass;
• Type III, a soda-lime glass; and
• NP, a soda-lime glass not suitable for containers for parenterals.

Type I glass is composed, principally, of silicon dioxide (~81%) and boric oxide (~13%), with low levels of the non-networkforming oxides, such as sodium and aluminum oxides. It is a chemically resistant glass (low leachability), also having a low thermal coefficient of expansion (CoE) ( 32.5 x 10 7 cm/cm-°C for 33 expansion glass; 51.0 x 10-7 cm/cm-°C for 51 expansion glass). In comparison, soda-lime glass has a thermal CoE of expansion of 8.36 x 10-5/cm/cm-°C. The lower the thermal CoE, the more dimensionally stable the glass against thermal expansion stress that can result in cracking.

Types II and III glass compounds are composed of relatively high proportions of sodium oxide (~14%) and calcium oxide (~8%). This makes the glass chemically less resistant. Both types melt at a lower temperature, are easier to mold into various shapes, and have a higher thermal coefficient of expansion. Although there is no one standard formulation for glass among manufacturers of these USP type categories, Type II glass has a lower concentration of the migratory oxides than Type III. In addition, Type II has been treated under controlled temperature and humidity conditions, with sulfur dioxide or other dealkalizers to neutralize the interior surface of the container. Although it remains intact, this surface increases substantially the chemical resistance of the glass. However, repeated exposures to sterilization and alkaline detergents break down this dealkalized surface and expose the underlying soda-lime compound.

The glass types are determined from the results of two USP tests: the Powdered Glass Test and the Water Attack Test.

Glass can be the source/cause of leachables/ extractables, particulates (glass delamination or glass lamellae formation), adsorption of formulation components, especially proteins, and cracks/scratches.

Leachables/ExtractablesIf the product is sensitive to the presence of ions, such as boron, sodium, potassium, calcium, iron, and magnesium, great care must be taken in selecting the appropriate glass container, as these ions may leach from the glass container and interact with the product, reducing chemical stability, inducing formation of particulate, or altering pH of solution. The following rules apply with respect to glass leachables:

  • Relatively low levels of leachable at pH 4-8.
  • Relatively high levels of leachable at pH > 9.
  • Major extractables are silicon and sodium.
  • Minor extractables include potassium, barium, calcium, and aluminum.
  • Trace extractables include iron, magnesium, and zinc.
  • Treated glass gives less extractables, if pH < 8.

Delamination—Delamination, or glass particulate formation, is caused by chemical attack on the glass matrix by the formulation solution, resulting in weakening of the glass and eventual dislodgement of flakes from the glass surface. These fragments can be subvisible in size and, thus, difficult to detect. Delamination is of particular concern in tubing vials, and susceptibility may be driven by many of the same heat history factors that influence alkali leaching potential (as measured by compendial methods as a pH shift), although measures to reduce alkali leaching (ammonium sulfate treatment) may be completely ineffective in reducing delamination susceptibility. In some cases, delamination may be reduced or eliminated by careful control of process parameters during the glass forming processes; lower heat levels during the conversion process may be critical. Ammonium sulfate-treated glass containers are also known to be more susceptible to delamination. Although compendial chemical resistance testing may be predictive of delamination potential. For sterile-fill applications, it is recommended that the glass containers be filled with formulation placebo (all components except the unstable API) at the pH release limit(s) for the product and be challenged with a single autoclave cycle or an accelerated aging study at 55°C for at least 4 weeks, followed by filtration and microscopic examination for glass particles.

AdsorptionAdsorption of drug to solution contact surfaces and consequent loss of potency of delivered solution is a primary concern of container/solution compatibility and must be rigorously and formally evaluated during solution/container evaluation and stability studies. Glass containers are fairly inert surfaces, for most small drug products at relatively high concentrations, but pose a higher risk for therapeutic proteins and other smaller drug products formulated at low concentrations. Since adsorption is a surface phenomenon, increasing the surface area to volume ratio increases the risk of losses due to adsorption. Thus, small volume products carry higher risk for loss of potency due to adsorption and should be carefully evaluated for drug loss.

Cracks and ScratchesSmall cracks and scratches on glass containers can best be minimized by implementation of quality agreements between parenteral product manufacturers and glass container manufacturers. Not only does the glass container manufacturer need strict control procedures to minimize cracks and scratches from the time the container is formed until it reaches the finished product manufacturer, but there also needs to be high quality, 100% inspection practices by both glass and final product manufacturers. Also, local quality inspection procedures and practices need to have clearly understood definitions and a library of examples for what is defined as a crack and scratch. Cracks are considered unacceptable, whereas scratches are more of an esthetic indication of product elegance.

Rubber Closures:

Table 1 – Examples of ingredients found in rubber closures

Ingredients Examples
Elastomer Natural rubber (latex)

Butyl rubber

Neoprene

Vulcanizing (curing agent) Sulfur
Peroxides
Accelerator Zinc dibutyldithiocarbamate
Activator Zinc oxide

Stearic acid

Antioxidant Dilauryl thiodipropionate
Plasticizer/lubricant Paraffinic oil

Silicone oil

Fillers Carbon black

Clay
Barium sulfate

Pigments Inorganic oxides

Carbon black

Rubber closures are composed of multiple ingredients plasticized and mixed together at an elevated temperature on milling machines. The physical properties considered in the selection of a particular formulation include elasticity, hardness, tendency to fragment, and permeability to vapor transfer. Slotted closures are used on freeze-dried products to permit the escape of water vapor, since they are inserted only partway into the neck of the vial until completion of the drying phase of the cycle. The plunger type of rubber is used to seal one end of a syringe or cartridge. Rubber closures must be ‘slippery’ to move easily through a rubber closure hopper and other stainless steel passages, until they are fitted onto the filled vials. Traditionally, rubber materials are ‘siliconized’ (silicone oil or emulsion applied onto the rubber) to produce such lubrication. However, advances in rubber closure technologies have introduced closures that do not require siliconization, due to a special polymer coating applied to the outer surface of the closure. Examples are the Daikyo/West closures (Flurotec) and the Helvoet (Omniflex) closures.

Plastic: Thermoplastic polymers have been established as packaging materials for sterile preparations, such as large-volume parenterals, ophthalmic solutions, and, increasingly, small- volume parenterals. For such use to be acceptable, a thorough understanding of the characteristics, potential problems, and advantages for use must be developed. Three principal problem areas exist in using these materials:

  • Permeation of vapors and other molecules in either direction through the wall of the plastic container;
  • Leaching of constituents from the plastic into the product; and
  • Sorption (absorption and/or adsorption) of drug molecules or ions on the plastic material.

One of the principle advantages of using plastic packaging materials is that they are not breakable, as is glass; also, there is a substantial weight reduction. The flexible bags of polyvinyl chloride or select polyolefins, currently in use for large-volume intravenous fluids, have the added advantage that no air interchange is required; the flexible wall simply collapses as the solution flows out of the bag. Most plastic materials have the disadvantage of not being as clear as glass, and, therefore, inspection of the contents is impeded.

Needles: Historically, 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 ¼ inch to 6 inches. Needle size is referred to as its gauge (G), or the outside diameter (OD) of the needle shaft. Gauge ranges are 11 to 32 G, with the largest gauge for injection usually being no greater than 16 G. 16 G needles have an OD of 0.065 inches (1.65 mm), whereas 32 G have an OD of 0.009 inches (0.20 mm). Needle shape includes regular, short bevel, intradermal, and winged. Needle shape is defined by one end of a needle enlarged to form a hub with a delivery device, such as a syringe, or other administration device. The other end of the needle is beveled, meaning it forms a sharp tip to maximize ease of insertion.

The route of administration, type of therapy, and whether the patient is a child or adult dictate the length and size of needle used.

  • Intravenous injections use 1–2 inch 15–25 G needles.
  • Intramuscular injections use 1–2 inch 19–22 G needles.
  • Subcutaneous injections use ¼ 5/8 inch 24–25 G needles.
  • Needle gauge for children rarely is larger than 22 G, usually 25–27G.
  • Winged needles are used for intermittent heparin therapy.
  • Many different types of therapies (e.g,. radiology, anesthesia, biopsy, cardiovascular, ophthalmic, transfusions, tracheotomy, etc.) have their own peculiar types of needle preferences.

Multiple Choice Questions:

1.Injectable formulations are packaged into containers made of

a)glass

b)plastic

c)both of these

d)none of these

2.Container systems for parenterals include

a)ampoules

b)vials

c)syringes

d)all of these

3.Ampoules are made up of

a)glass

b)plastic

c)aluminium

d)all of these

4.Bags are made up of

a)glass

b)plastic

c)aluminium

d)all of these

5.Irrigation solutions are packaged in

a)glass bottles

b)plastic bags

c)aluminium containers

d)all of these

6.Glass is composed, principally, of silicon dioxide with varying amounts of other oxides, such as

a)sodium

b)potassium

c)calcium

d)all of these

7.The basic structural network of glass is formed by the

a)silicon oxide tetrahedron

b)silicon oxide hexagon

c)silicon oxide trigonal

d)none of these

8.According to USP glass is classified into how many categories?

a)1

b)2

c)3

d)4

9.Which of the following is a borosilicate glass?

a)Type I

b)Type II

c)Type III

d)NP

10.Which of the following is a soda-lime treated glass?

a)Type I

b)Type II

c)Type III

d)NP

11.The glass types are determined from the results of which of the following USP tests?

a)Powdered Glass Test

b)Water Attack Test

c)Both of these

d)Pyrogen test

12.The following rules apply with respect to glass leachables

a)Relatively low levels of leachables at pH 4-8

b)Relatively high levels of leachables at pH > 9

c)Major extractables are silicon and sodium

d)All of these

13.Vulcanizing agent in rubber is

a)Zinc oxide

b)Sulfur

c)Neoprene

d)Carbon black

14.Activator in rubber is

a)Zinc oxide

b)Sulfur

c)Neoprene

d)Carbon black

15.Which of the following are used on freeze-dried products to permit the escape of water vapor?

a)Slotted closures

b)Plunger type closures

c)Both of these

d)None of these

Solutions:

  1. c)both of these
  2. d)all of these
  3. a)glass
  4. b)plastic
  5. a)glass bottles
  6. d)all of these
  7. a)silicon oxide tetrahedron
  8. d)4
  9. a)Type I
  10. b)Type II
  11. c)Both of these
  12. d)All of these
  13. b)Sulfur
  14. a)Zinc oxide
  15. a)Slotted closures

References:

  1. Remington Essential of Pharmaceutics, 1st edition 2013, page no. 504-508.

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