2.2      Model risk assessment process

The risks associated with a propensity for leaching or potential leachables extracted from polymeric components can be weighted in alignment with user’s process understanding and experience. The BioPhorum model is presented here, which companies can adapt to their requirements (see Tables 1 and 2).

Table 1: Example leachables risk assessment model

2.2.1    Disposable component qualification per risk categorization

The overall leachables risk rating (LRR) is calculated as shown in Table 2.

Per the model, the overall leachables risk rating will be in the range of 1.0–9.0, allowing prioritization and translation into high, medium and low overall risk levels.

Once determined, the leachables risk level can be used to determine the testing requirements (i.e. a high risk level in one component in the process can prompt more in-depth testing, whereas another component with a lower risk may require a less comprehensive set of tests). Once the overall risk rating of the polymeric component of interest has been finalized and has been ranked as low, medium or high, the qualification requirements (such as those shown in Figure 4) should be established to fully qualify the disposable for its intended use.

For low-risk applications (LRR = 1.0–3.6), the minimum qualification requirements should be the meeting of relevant compendial test standards such as USP Class VI (also EP 3.1.9, if the component is silicone tubing).

For medium-risk applications (LRR = 3.7–6.2), supplier- provided extractables data (as per the BioPhorum Extractables Protocol) or in-house leachables simulation study data can be used to demonstrate risk control, where appropriate, for further evaluation in addition to the minimum qualification requirements.

For high-risk applications (LRR = 6.3–9.0), the minimum qualification requirements include those for medium- risk components as well as an additional, process- specific, leachables risk assessment. If the calculated per dose exposure level cannot be accepted from a safety perspective (based on a toxicological assessment of the extraction profile), a leachables study may be warranted to demonstrate risk control and/or establish the safety of the disposable component based on its leachables profile in the DP. This is only required in situations where extractables data from the supplier are either:

•         not available

•         do not correspond to current processing conditions in which the polymeric component in question is utilized.

If so, it will be necessary to generate extractables and/ or leachables data prior to proceeding with the next step in the qualification process.


It is recommended that leachables data be generated utilizing worst-case conditions applicable to the intended process step – specifically with respect to the polymeric component process usage parameters such as exposure temperature (ET), exposure duration (ED), etc. Guidance for execution of this leachables testing step, including recommended process simulation conditions and analytical methodology, is indicated in Sections 2 and 3 below.

Once an appropriate extractables data set is available, a DP-specific safety assessment based on production batch size and dosing regimen should be conducted to evaluate the patient safety aspects of extracted compounds (Ref. 5). If certain extractables are above the safety concern threshold (SCT) after an initial worst-case assessment has been conducted, a leachables study may be necessary.

Such a leachables study may include an examination of long-term leachables profile (e.g., product intermediate storage container) in order to fully qualify a high-risk component. Alternatively, another polymeric component with a different MOC may be considered for use.

The overall extractables profile of the SUS is used for a toxicological assessment of patient safety. If the calculated potential patient exposures of the potential leachables are lower than appropriate safety thresholds, e.g. threshold of toxicological concern (TTC), (based on ICH M7 guidelines, the standard reference at the time of preparing this guide), then the safety risk of the potential leachables from the material is considered to be acceptable with regard to patient safety, and no further leachables studies are required.

However, if the calculated potential patient exposures of the extractables are higher than the permissible daily exposure (PDE) for known compounds, or SCT for unidentified compounds, then the extractables should be positively identified (if not already achieved) and their toxicity profiles should be assessed. These high-risk components should be tested as per a leachables study plan, and a further safety risk assessment should be conducted based on the leachables profile.

If the toxicological risk assessment of extractables data determines that the maximum dosage of drug presents a safety risk, then a leachables study is necessary. The primary focus of the leachables testing will be to first determine the levels of these compounds in the process stream. The analytical methodology employed to detect and quantitate these compounds will be defined by the nature of the particular extractables compounds. Guidance for the design of such a leachables study can be found in Section 2.

Potential interactions between leachable compounds and the DS can be monitored through the stability monitoring program for that product.

The risk assessment model proposed (Tables 1 and 2) was applied to an example of a typical biologics manufacturing process as described in Appendix 3 (Ref. 6). The parameters used for the process and example assessment that are described in Appendix 4 were used to calculate the risk profile of different polymeric components used in the process. The calculated risk profile numbers identified “High”, “Medium”, and “Low” E/L risk classifications. For example, a sterilizing filter and a Bulk Drug Substance (BDS) storage bag were identified to have a high-risk classification for leaching, requiring an extractables profile to be obtained and evaluated further.

A toxicological evaluation of the extractables also needs to be completed for these two high-risk example components shown in Appendix 4. If the toxicological profile of the extractables represents an acceptable risk to patient safety then no further leachables studies are required and the extractables data can be used as part of the components’ qualification package. However, if the toxicological profile represents a risk with regards to patient safety, then conducting a leachables study as described in Section 2 may be deemed necessary. A leachables safety risk evaluation based on the leachables profile would also need to be completed. From this latter study, if the toxicological profile of the leachables is considered to represent an acceptable risk to patient safety, then the leachables data should be used as part of the qualification package. However, if the toxicological profile of the leachables presents an unacceptable risk to patient safety, then an alternate polymeric component (i.e. material change) with a lower risk profile or a non- polymeric component must be considered. Alternatively, process conditions may be modified in order to lower the risk profile, if feasible.