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The purpose of this chapter of the USP is to provide standards for plastic materials and components used to package medical articles, such as pharmaceuticals, biologics, dietary supplements, and devices. Plastics are composed of a mixture of homologous polymers, having a range of molecular weights. Plastics may contain other substances such as residues form the polymerization process, plasticizers, stabilizers, antioxidants, pigments, and lubricants. Factors such as plastic composition, processing and cleaning procedures, surface treatment, contacting media, inks, adhesives, absorption and permeability of preservatives, and conditions of storage may affect the suitability of a plastic for a specific use. Extraction/leachable tests are designed to characterize the extracted components and identify possible migrants. The degree or extent of testing for extractables of the component is dependent on the intended use and the degree of risk to adversely impact the efficacy of the compendial article (drug, biologic, dietary supplement, or device).
The process of manufacturing a packaged therapeutic product is complex. Considering the packaging system specifically, packaging systems typically consist of components that are individually manufactured from plastic materials of construction. These individual plastic materials of construction are initially generated from reagents that are reacted to produce a base polymer,which is then compounded with various additives to produce a base resin. Individual base resins either are materials of construction themselves or may be combined with additional additives and processing aids to form a plastic material of construction. Testing of these plastic materials of construction to establish that they are well characterized and suitable for use, specifically considering safety, in packaging systems is within the scope of this series of chapters and is addressed in Plastic Materials of Construction <661.1>.
Below provides guidance on the appropriate application of the chemical tests. For aqueous-based oral drug products that contain cosolvents (or if, for any reason, it may be expected to extract greater amounts of substances from plastic packaging components than water), additional extractable information may be needed to address safety issues.
Extractions
Physicochemical testing of the plastic material requires that it be extracted or dissolved. Different tests are facilitated by various extraction methods. Table 3 describes the extracts that are generated and the tests that are performed on those extracts. Subsequent discussions address methods for producing the extracts. Note that these extracts may be used for tests other than the physicochemical tests.
Table 1. Extractions Performed for Various Chemical Tests
| Tests Performed On Plastic Using The Specified Extracting Solution | ||||
| Extraction | Extracting Solution | Polyethylene, Cyclic Olefin, And Polypropylene | Polyethylene Terephthalate And Polyethylene Terephthalate G | Plasticized Polyvinyl Chloride |
| S1 | Water | Absorbance, Acidity/alkalinity, Total Organic Carbon | Absorbance, Acidity/alkalinity, Total Organic Carbon | Absorbance, Acidity/alkalinity, Total Organic Carbon |
| S2 | Toluene | Phenolic Antioxidants, Non-phenolic Antioxidants, Amides, And Stearatesa | N/A | N/A |
| S3 | Acid | Extractable Metals: Al, As, Cd, Co, Cr,b Hg, Ni, Pb, Ti, V, Zn, And Zrc |
Extractable Metals: Al, Sb, As, Ba, Cd, Co, Ge, Hg, Mn, Ni, Pb, Ti, V, And Zn |
Extractable Metals: As, Ba, Ca, Cd, Co, Hg, Ni, Pb, Sn, V, And Zn |
| S4 | Alkali | N/A | Extractable Metals: Sb And Ge |
N/A |
| S5 | Alcohol | N/A | Absorbance | N/A |
a Although this extract is suitable for use with these specific ingredient methods, such an extract could be useful for other tests designed to establish a material’s composition.
b For nonplasticized polyethylene only.
c Not applicable for cyclic olefins.
Extractable Metals
The Extractable Metals testing described in this chapter is required for all plastic materials of construction used in packaging systems, regardless of whether the material is specified in this chapter. Specifically, all materials must be tested for those extractable metals listed and any other metals that are relevant in the sense that their presence in the test material is known or can be reasonably anticipated.
Plastic materials used in packaging systems for medical articles do not dissolve under the conditions of use. Rather, substances derived from packaging systems accumulate in the packaged articles by the process of leaching (extraction). Thus, the appropriate and relevant sample-preparation process for assessing metals in a packaging system’s materials of construction is extraction, as opposed to complete digestion, of the plastic material. Solution S3 (acidic extraction) and Solution S4 (alkaline extraction) prepared for Physicochemical Tests are the material extracts that are tested for extractable metals.
Instrumentation and methods are those specified in Elemental Impurities—Procedures <233> and include an inductively coupled plasma–atomic emission spectrometer and an inductively coupled plasma–mass spectrometer (see Atomic Absorption Spectroscopy <852>), as directed.
Extractable Metals Performed for Various Chemical Tests
Extractable Metals: (Polyethylene)
Aluminum: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Arsenic: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cadmium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Lead: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Mercury: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cobalt: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Nickel: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Chromium: Solution S3 contains NMT 0.02 mg/L (ppm), corresponding to 0.05 μg/g.
Titanium: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Vanadium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Zinc: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Zirconium: Solution S3 contains NMT 0.04 mg/L (ppm), corresponding to 1 μg/g.
Extractable Metals: (Cyclic Olefins)
Aluminum: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Arsenic: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cadmium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Lead: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Mercury: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cobalt: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Nickel: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Vanadium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Titanium: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Zinc: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Extractable Metals: (Polypropylene)
Aluminum: Solution S3 (see Table 3) contains NMT 0.4 mg/L (ppm), corresponding to 1 ug/g
Arsenic: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cadmium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Lead: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Mercury: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cobalt: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Nickel: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Vanadium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Chromium: Solution S3 contains NMT 0.02 mg/L (ppm), corresponding to 0.05 μg/g.
Titanium: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Zinc: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Extractable Metals: (Polyethylene Terephthalate and Polyethylene Teraphthalate G)
Aluminum: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Arsenic: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cadmium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g
Lead: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Mercury: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cobalt: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025ug/g.
Nickel: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025ug/g.
Vanadium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Barium: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 ug/g.
Antimony: Solution S4 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Germanium: Solution S4 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Manganese: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Titanium: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 0.1 μg/g.
Zinc: Solution S3 contains NMT 0.4 mg/L (ppm), corresponding to 1 μg/g.
Extractable Metals: Poly(Vinyl Chloride)
Arsenic: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Cadmium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g
Lead: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Mercury: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g..
Cobalt: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Nickel: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Vanadium: Report the measured value in Solution S3 at values above 0.01 mg/L (ppm), corresponding to 0.025 ug/g. If the measured values are below these values, report the result as less than 0.01 mg/L (ppm), corresponding to less than 0.025 ug/g.
Barium: Solution S3 contains NMT 0.25 mg/L (ppm), corresponding to 5 μg/g.
Calcium: Solution S3 contains NMT 35 mg/L (ppm), corresponding to 0.07 weight %.
Tin: Solution S3 contains NMT 1 mg/L (ppm), corresponding to 20 μg/g.
Zinc: Solution S3 contains NMT 100 mg/L (ppm), corresponding to 0.2 weight %.
