Understanding the Changes to USP 661

By Stephen Doherty and Amtul Qamar

Confused about the revisions to USP <661>?  We can help.  In May 2016, the revision of USP General Chapter <661> with the new title “Plastic Packaging Systems and Their Material of Construction” took effect.  The revision represents a major change in the testing strategies related to plastic container systems.  The testing strategy has adapted to move from generic testing strategy to a more targeted testing strategy based on materials of construction and product use.  The chapter has also been separated into different components.  <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.  The release of the revised USP, along with the introduction of new chapters <1663> “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems” and <1664> “Assessment of Drug Product Leachable Associated with Pharmaceutical Packaging/Delivery Systems”, works to bring the USP <661> into allowing for a well characterized container closure system and ensuring that the chosen packing system does not adversely impact the pharmaceutical stored within.

In a departure from the general testing approach in the previous 661, the revision makes use of specific extraction solution and conditions, as well as varying extraction conditions (Table 1).  In addition, the testing strategy has become much more comprehensive.  Rather than relying on primarily colorimetric and gravimetric analysis, the new revisions make use of standard analytical instrumentation that is able to provide more specific and quantitative information (Tables 2 and 3).  These methods include Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) Spectroscopy, Total Organic Content (TOC), Inductively Coupled Plasma (ICP), and High Performance Liquid Chromatography (HPLC).

In <661.1> > Plastic Materials of Construction, the monograph calls out several specific materials of construction: 1. Polyethylene, 2. Polypropylene, 3. Polyolefin, 4. Polyvinyl chloride, 5. Polyethylene terephthalate, and 6.  Polyethylene terephthalate G specifying test and extraction methods for each material.  Each material includes a series of tests to understand the material and extracts from it.  These tests include Identification (FTIR, DSC) Physicochemical Tests (Absorbance, Acidity/alkalinity, TOC) Extractable Metals, and Plastic Additives, including phenolic and nonphenolic antioxidants.  Analysis for plasticized PVC also includes analysis for additives di(2-ethylhexyl) phthalate, N’N”-diacylenediamines, epoxdized soya oil, epoxidized linseed oil and residual vinyl chloride monomer.

In <661.2> Plastic Packaging Systems for Pharmaceutical Use”, the materials in the finished form are evaluated.  Physicochemical tests are performed with a water extraction at 121 ± 2 °C (reached in 20 – 30 minutes) for 30 ± 3 minutes.  If these conditions lead to deterioration of the container, heating at 100 ± 2 ^oC for 2 hours ± 10 minutes or 70 ± 2 ^oC for 24 ± 2 hours is recommended.  The solution is then analyzed for Physicochemical Tests (Absorbance, Acidity/alkalinity, TOC). In Polyethylene terephthalate and Polyethylene terephthalate G systems, evaluation of ethylene glycol and total terphthalyoyl moieies is also performed.

In its revised form, the <661> chapter lays out a much more useful methodology for the characterization of plastic packaging systems.  The incorporation of which requires the user to have a good understanding of the materials being used and provides more detailed and specific information related to compounds which may be migrating from the material.  The testing strategy moves closer in alignment with a more traditional extractable and leachable studies in that it is evaluating for the various polymer additives that may migrate from the system during use to allow for better evaluation of the potential impact of the system on the pharmaceutical product.

By working with our team of scientists, we can assist you in the development of an appropriate study design based on your material and intended application.

Table 1: Extraction Procedures

Extractions	Old Pchem	New Pchem	Solvent
	Conditions	Conditions
Extraction 1	70oC for 24 hours	Autoclave at 121oC for 30 minutes	Purified water
Ratio	20mL/120 cm2	1 unit (volume needed is 70 mL)
Extraction 2: Terephthaloyl Moieties in Polyethylene Terephthalate and Polyethylene Terephthalate G packaging systems	None	49 oC for 10 Days	50 % Alcohol
		49 oC for 10 Days	25 % alcohol
		49 oC for 10 Days	Purified water
		49 oC for 10 Days	n-Heptane

 

Table 2: Tests Required

Tests	Old Pchem	New Pchem	Comments
Non-volatile Residue	Yes	No	Extraction 1 solution was used in old pchem.
Residue on Ignition	Yes (if NVR above 5 mg)	No
Heavy Metals	Yes	No
Buffering Capacity	Yes	No
Absorbance  between 230-360 nm	No	Yes	Extraction 1 solution used in new Pchem
Acidity or Alkalinity	No	Yes
Total Organic Carbon (TOC)	No	Yes
Total Terephthaloyl Moieties in Terephthalate and Terephthalate G packaging systems	No	Yes	Extraction 2 solutions of 50 % alcohol, 25 % alcohol and n-heptane used in new pchem
Ethylene Glycol in Polyethylene Terephthalate and Polyethylene Terephthalate G packaging systems	No	yes	Extraction 2, purified water solution used in new pchem

 

 

 

 

Table 3.  Extractions Performed for Various Chemical Tests

	Tests Performed with This Extracting Solution
Extraction Solution	Polyethylene, Polypropylene, Polyolefin	Polyethylene terephthalate, and 5. Polyethylene terephthalate G	Plyvinylchloride
Water	Absorbance, Acidity/Alkalinity, TOC	Absorbance, Acidity/Alkalinity, TOC	Absorbance, Acidity/Alkalinity, TOC
Toluene	Phenolic antioxidants, nonphenolic antioxidants, amides, and stearates	–
Acid  (HCl) Solution	Extractable metals: Al, Cr, Ti, V, Zn, and Zrc	Extractable metals: Al, Ba, Co, Mn, Ti, and Znc	Extractable metals: Ba, Ca, Cd, Sn, and Znc
Alkali (NaOH) Solution	–	Extractable metals: Sb and Ge	–
Alcohol		Absorbance
Tetrahydrofuran	–	–	Absorbance

 

 

 

 

 

 

 

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