Guidance 126 – Establishing Reevaluation Intervals for API Intermediates Pharmaceuticals quality assurance & validation procedures GMPSOP

Introduction

This document provides guidance for establishing re-evaluation intervals for API Intermediates that are stored dry or wet in drums or intermediate bulk containers (IBC). Wet intermediates include solvent wet, water wet, intermediates in solution (liquid) and intermediates in suspension. API Intermediates for Sale require stability studies and are outside the scope of this guidance document. Intermediates for Biological Products are also out of scope of this document.

Practice

This document is intended to provide risk based guidance for the determination of re-evaluation intervals for API Intermediates. For API Intermediates that have a higher risk for degradation or for the proliferation of microbial organisms, hold time studies or microbiological proliferation studies can be used to support the determination of re-evaluation intervals.

Dry intermediates or intermediates that are stored as oils that are considered stable through appropriate scientific judgment or literature search, through experience during development activities, or through consistent historical data gathered during routine manufacturing can use the “one year” default re-evaluation interval.
Wet intermediates (Intermediates in solution, suspension, or wet cake) have a greater risk than dry intermediates for chemical degradation and/or microbial contamination. Microbiological concern is reduced if the material is wet with, dissolved in or suspended in an organic solvent as it is generally accepted that organic solvents impede the proliferation of organisms. Appendix I and II list risk assessment information for determining a re-evaluation period for wet intermediates relative to potential microbial proliferation.

Discussion and Recommendations

Intermediates that are stored wet have a greater potential for chemical degradation. If these wet intermediates are stored refrigerated or stored under nitrogen the potential chemical degradation process can be slowed. To support a storage time beyond 3 months, hold time studies should be considered.

Since analytical test methods for the evaluation of intermediates are typically not stability indicating the primary method of assessing chemical degradation is to process the intermediate forward, monitor subsequent processing, and test the final API for impurities. This activity can be performed retrospectively or prospectively.

See Appendix III for guidance on intermediate hold time studies to test the impact of any potential chemical degradation on the final API. Also intermediates that are stored wet have a greater potential for the proliferation of microbiological organisms. In addition to the risk of these microorganisms moving forward into the final API and subsequent Drug Product, there is the potential risk of by-products associated with microbial growth (endotoxins, exotoxins and other metabolites) also ending up in the final Drug Product. In assessing the microbial risk of storing wet intermediates there are two key risk components to consider.

The first component is severity which is determined based on the dosage form that will ultimately be manufactured from the API made from the wet intermediate. The second component is probability for microbial proliferation which is based on the manufacturing process and the storage conditions of the wet intermediate. The process for determining the risk band and ultimately a proposal for a re-evaluation interval relative to microbial proliferation is shown in Appendix I an II.

Risk Component One

The lowest severity factor “1” is for oral dry products or oral or topical non-aqueous liquid or semi-solid products. The severity factor is low for these products due to their typical low water activity which precludes further microbial proliferation. Severity factor “2” is for aqueous liquid or semi-solid oral and topical products, otic products, ophthalmic products, and inhalant products. The severity factor is intermediate because there is the potential for a higher water activity which could allow for microorganisms to grow. The final Severity factor “3” is for injectable products. This severity factor is high because this dosage form potentially presents the most risk to the patient as a result of microbial proliferation.

Risk Component Two

The primary consideration for determining the probability factor for the risk of microbial proliferation is to evaluate the characteristics of the wet intermediate. Appendix II lists characteristics that determine whether conditions are unfavourable or favourable for microbial growth. If the conditions are unfavourable for microbial growth than the probability factor is “1” or low. If the conditions are favourable for microbial growth than the probability factor is “8” or high. There is however various considerations that alone or in combination can be used to reduce this high probability factor and generate an adjusted probability factor. These probability reduction considerations are also listed in Appendix I.

Risk Based Re-evaluation Interval

Using the severity factor and the probability factor (or adjusted probability factor) a risk band can be determined using the risk matrix in Appendix I. This risk band can be used to propose a risk based re-evaluation interval relative to microbial proliferation. To support re-evaluation intervals beyond those suggested in Appendix I a microbial proliferation study should be considered. See Appendix IV for guidance on performing a microbial proliferation study.