July 1, 2008: General Chapter <467>, Residual Solvents

July 1, 2008 will mark the effective date for FDA enforcement of USP <467> - Residual Solvents, which replaces <467> - Organic Volatile Impurities (OVIs), established in 1990.  Much discussion on the subject has taken place over the past several years and many revisions to the chapter have been made.  Several reasons exist for the difficulty in forming consensus concerning both the application of the chapter and subsequent implications across pharmaceutical companies large and small.  Technically the OVI chapter relied on non-optimal direct injection gas chromatography (GC) methods that were less than adequate for effectively analyzing actual product matrices and the list of OVIs included only seven toxic industry solvents.  Finally, applicability of the regulation was vague.  The new <467> Residual Solvent chapter literally applies to all compendial drug substances – not just drug products, but potentially everything from raw materials to excipients and byproducts.  Additionally, it includes three separate lists totaling 61 solvents covering three compound classes from low human toxicity to carcinogenicity; 59 of which were initially published in the International Committee on Harmonization (ICH) Q3C guideline for “Residual Solvents” in 1997. Interestingly, it was the industry itself that determined toxicity for in-use solvents prior to that document, and very importantly, unlike Q3C’s “guideline” status, <467> is a mandatory, enforceable FDA drug standard that applies to all products with a USP monograph.  However, it has been suggested recently that depending on the circumstances and potential safety exposures, it is possible that FDA inspectors might look beyond only those with USP monographs to other drug products.1,2

While USP <467> has been under revision the past several years, advancements have continued in a number of areas surrounding the technical aspects of the testing.  The 1990 OVI version of <467> contains analytical methods based on direct-injection GC.  These methods are tough on analyzers and, considering solubility attributes, were inappropriate for many drug matrices. The ICH guideline did not offer direction regarding analytical methodology so the new regulation was in need of some updating on the subject. Indeed, USP <467> provides detail for instrumental analysis for residual solvents.  An analytical “Identification, Control and Quantitation of Residual Solvents” section exists in <467> that presents recommended methods for GC-flame ionization detection (FID); methods that are far more appropriate technically.  Even more importantly, the guideline clearly gives latitude to pharmaceutical companies and instrument manufacturers to develop improved methods and procedures appropriate to certain specific applications.  Though some have been scrutinized for occasional deviations from the regulation, one area of advancement has come with the use of headspace introduction systems for GC.  One interesting study performed by Teledyne Tekmar Co. (Mason, OH) allows users to use a single method for residual solvents using 1,3-dimethyl-2-imidizole (DMI) as a dissolution matrix, extremely careful sample handling/introduction and very precisely controlled sample pathways to achieve excellent separation and identification of residual solvents (Fig. 1).3,4  This is the type of method development chapter <467> was designed

Fig. 1 – Residual Solvent separation using Tekmar HT3 introduction system and single method.3

to encourage and that is crucial for the increased likelihood of the regulation’s adoptability and adaptability.

Along with the development of more effective and versatile analytical methods comes the need to challenge both instrument and analyst for method appropriateness and robustness.  Each method should be evaluated using standard analytical criteria:

·        Selectivity

·        Linearity

·        LOD/LOQ

·        Repeatability

·        Accuracy, Precision and Repeatability (±20%)

·        Robustness

This requires, however, that manufacturers have access to high-quality, certified QC and calibration standards, either preparing or purchasing CRM standards that demonstrate/support the claims being made and the overall data quality.   Practically, there are technical challenges related to preparing standards with numerous volatile organic compounds.  Several decades ago the National Institute of Standards and Technology (NIST) published details of gravimetric preparations of standard reference materials (SRMs) using container vacuum and a series of transfer tubes for each compound but were limited to 12-14 compounds total.  Subsequently, techniques were developed to microgravimetrically weigh high-purity organic compounds into thin-walled capillary tubes which are then transferred into an evacuated container.5,6,7 Cryogenic preparations of standards are quite common these days when it is necessary to microgravimetrically prepare a series of compounds with very low vapor pressure.

Philosophically the process is critical if you are to use standards to validate or verify product and process quality. Since data provokes decisions, one must always have confidence in the data being generated.  Confidence can be high when validated processes and procedures are in place and supported by validated protocols, routine audits and adherence to GLPs.  Traceability is a “property of the result of a measurement or the value of a standard whereby it can be related, with stated uncertainty, to stated references, through an unbroken chain of comparisons.”8 The traceability should be to a nationally or internationally recognized body that can be considered the definitive source for that property. It is also the property of the result of a measurement or the value of a standard whereby it can be related, with stated uncertainty, to stated references, usually national or international standards, through an unbroken chain of comparisons.  Traceability is one important element though; appropriateness of methods, proper handling and storage, analyst training and process/procedure ruggedness are all critical, and it is important to understand all of the considerations that exist when preparing standards for use in USP <467> testing.   

 

References:

  1. Rios, Maribel, (2008) “Clearing the Air on the USP Residual Solvents Requirements,” Pharmaceutical Technology, Vol 32, No. 2, pp 42-50.
  1. “International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Drug Use (Q3C guideline, Impurities: Guideline for Residual Solvents).” Recommendation for adoption at Step 4 by the ICH Steering Committee, July 2007.
  1. Bertsch, Brian, (2005) “Developing One Universal Method for Residual Solvents Using the New Teledyne Tekmar HT3 Headspace Sample Introduction System.” Teledyne Tekmar Application Note, Doc. HT3-001.
  1. Wallace, Brian and Kancler, Julie, (2004) “One Universal Method for Residual Solvent Analysis in Pharmaceuticals Using a High Temperature Static Headspace Introduction System.” Teledyne Tekmar Application Note, Doc. 7000-021.
  1. Schmidt WP, Rook HL (1988) Anal Chem 55: 290-294.
  1. Rhoderick GC, Zielinski WL, Jr (1988) Anal Chem 60: 2454-2466.
  1. Rhoderick GC (1991) Anal Chem 341: 524-531.
  1. ISO Guide 30, Terms and definitions used in connection with reference materials., 1992.