John Iannone, Director, Extractables & Leachables (John.Iannone@amriglobal.com)
Brandon Zurawlow, Associate Director, Container Qualification & CCIT (Brandon.Zurawlow@amriglobal.com)
May, 2017

Recently, USP published a new notice that it intends to revise the following General Chapters:

  • <659> Packaging and Storage Requirement
  • <661> Plastic Packaging Systems and Their Materials of Construction;
  • <661.1> Plastic Materials of Construction;
  • <661.2> Plastic Packaging Systems for Pharmaceutical Use.

Initially effective May 1st, 2016, General Chapters <661.1> and <661.2> were introduced to provide more robust chemical characterization of plastic materials and package systems compared to the methods it replaced, while simultaneously providing testing options for newer polymeric materials being used in industry, such as Cyclic Olefins.

For 2017, the chapters are being revised to provide a three-year implementation period of the requirements stated in <661.1> and <661.2>, and to reinstate requirements previously expressed in General Chapter <661> during this three-year period for plastic packaging material and systems.  The new date in which one must be compliance with General Chapters <661.1> and <661.2> will be May 1, 2020, with a key note being that all systems qualified using General Chapter<661> during the implementation period shall require retesting to new standards before the final effective date of May 1, 2020.

In other words, a key revision to these chapters is the removal of the clause that effectively “grandfathers” currently filed package systems that have been approved by a regulatory body. With the introduction of the implementation period, there shall be an expectation that any package included in a filing will be updated with <661.1> and <661.2> test results by May 1st, 2020.

Given these considerations, the postponement of the required compliance date provides additional time for the pharmaceutical industry to adopt the requirements in General Chapters <661.1> and <661.2>, but careful strategizing and risk mitigation will likely lead pharmaceutical companies towards integration and adoption now as opposed to later. This activity includes extractable/ leachable based safety assessments, as well as biological reactivity testing and Toxicological risk assessments, which AMRI’s skilled scientists have been expertly supporting for our customers.

In fact, AMRI strongly encourages drug product companies to plan accordingly with regards to early adoption of the requirements in General Chapters <661.1> and <661.2>, a position supported by USP for various critical reasons.

First, by May 1, 2020, all plastic packaging materials and systems will have to meet the requirements of General Chapters <661.1> and <661.2>, which means pharmaceutical companies eventually will need to perform these tests, even if the plastic packaging materials and systems meet the requirements in reinstated General Chapter <661> during this three year period.   Further, the USP has clearly indicated that packaging materials and systems in compliance with these requirements of General Chapters <661.1> and <661.2> before May 1, 2020 will not need to perform any additional work to be in conformance with the USP–NF. Essentially, early adopters save both time and the associated cost with retesting existing materials, as well mitigate certain risks.

A second key benefit to early adoption comes from a liability perspective.  The goal of General Chapters <661.1> and <661.2> is to improve product safety by introducing more robust, sensitive, and relevant test methodologies when compared to the outgoing General Chapter <661>. The antiquated methodologies of the old <661> do not yield any indication of the potential chemical safety risks originating from packaging materials and systems, and therefore do not adequately evaluate their safety. In stark comparison, General Chapters <661.1> and <661.2> rely on sound scientific practices intended to thoroughly assess such chemical concerns.  Therefore, it poses a potential risk and definite uncertainty to pharmaceutical companies that choose to run the more antiquated methods now, only to retest by the more informative and robust <661.1> and <661.2> methods within the short time post-filing.   Early adoption mitigates risk and uncertainty, ultimately preventing potentially serious consequences, such as discovery of material failure and drug product recalls due to unsuitable packaging use.

Third, for companies with multiple drug products on the market, we also recommend to take early steps to adopt General Chapters <661.1> and <661.2> for both old and new plastic materials and packaging systems.  One of the critical changes for this revision is to remove the current exemption to General Chapter <661.1> and <661.2> for plastic materials and packaging systems previously approved by a regulatory authority.  In another words, regulatory authority will expect companies to perform risk assessment on all plastic materials and packaging systems on the market previously approved based on old General Chapter <661>, and provide evidence that these plastic materials and packaging systems for pharmaceutical use meet the requirements of General Chapters <661.1> and <661.2> after May 1, 2020. Early adoption of General Chapters <661.1> and <661.2> on these in-use plastic materials and packaging systems provides sufficient time to find alternative vendors if existing plastic materials and packaging systems do not meet new requirements.

Lastly, compliance with General Chapter <661> alone is not adequate for high risk dosage forms, such as parenteral, opthalmic, and inhalation products, as specified FDA Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, and USP <1664>.  Typically, extensive extractable and leachable studies, concurrent with a toxicological assessment of chemical profiles, are already required for these packaging systems due to their route of administration.  It will be prudent to incorporate the requirements of General Chapters <661.1> and <661.2> testing in the already required Extractable and Leachable Studies so that one does not need to circle back and do more testing in time for 2020!

To proactively meet the requirements of the revised chapters USP <661.1> and <661.2> yields significant benefits with respect to overall qualification cost, time, financial risk, and ultimately risk to patient safety, while also helping to ensure a smooth drug product launch and a reliable supply chain system. For these reasons, early adoption is strongly recommended for plastic packaging materials and systems for pharmaceutical use. At the time of this writing, our continuous client sample submissions support this rationale, with test requests showing signs of a strong trend toward early adoption