IDENTIFYING THE BIGGEST RISKS – DURING MATERIAL TRANSFERS/PROCESS STEPS
Several factors must be carefully assessed to ensure safe handling, especially for production processes involving numerous material transfers and multiple processing steps, from handling of the pure active pharmaceutical ingredient (API) to the finished dosage form.
KEY MATERIAL & PROCESS CONSIDERATIONS
Material Health Based Exposure Limits (HBELs): The risk controls to be used when handling HPAPIs should be commensurate with the HBELs used (1).
Material Physical Properties: key considerations during handling of the API, drug product, and any associated intermediates include:
- Physical state: powders become more easily airborne than liquids, thus leading for potential exposure scenarios when not properly controlled.
- Particle size: smaller particles become very easily airborne and can remain as such for several hours (2).
Quantity & Concentration of API: Larger batch sizes often require more complex and expensive controls; handling of pure API requires a higher level of containment vs handling of a final blend within which the API has been significantly diluted within the formulation.
Duration & frequency of the process step(s): Processes requiring significant time to complete may result in higher airborne risks if they aren’t well controlled; the same may be true for shorter runs involving multiple processing steps. During filling of a liquid or injectable product, particle build-up may occur at the filling head over time (3).
Dosage Form – Injectable vs Oral: sterile products have an additional level of complexity, as evidenced by Annex 1 (Manufacture of sterile medicinal products) of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part I (1).
HIERARCHY OF RISK REDUCTION FOR PRODUCT AND WORKER EXPOSURE
Similarities exist when comparing the risks for preventing cross-contamination versus protecting workers from occupational exposure. These are well summarized within ISPE’s Risk MaPP document (2), with the most effective option being Elimination (e.g. removing process steps or transfers), and the least effective being open processing (exposed to potential cross-contamination). This aligns well with the NIOSH Hierarchy of Controls in Figure 1.
Risk reduction when handling HPAPI products is often via engineering controls, e.g., containing at the source through using isolators or other containment options. Residual risks are then addressed through administrative controls, e.g., procedures, training, etc. Personal Protective Equipment (PPE) are the least effective and should always be used only as a last resort, when no other options are possible.
To quantify the exposure risks related to the process equipment to be used, the recommended approach is to assess their particulate containment performance (ISPE, Safebridge).
Following this, residual risks must be managed by other engineering and/or administrative controls and PPE, or a combination thereof.
Several risk management tools are used within the pharmaceutical industry. ISPE and ICH have published guidelines which describe many practical risk assessment tools including Failure Mode and Effects Analysis (FMEA) (2, 6).
CONTRASTING CROSS-CONTAMINATION RISK ASSESSMENT VS OCCUPATIONAL RISK ASSESSMENT
Presented below are possible scenarios and associated high-level risk assessments for airborne transfer presented using an FMEA approach, whereby the Risk Priority Number (RPN) is the product of severity, occurrence, and detection. Consider the proposed scoring described within Figure 2. Consider a theoretical cross-contamination risk assessment for a multi-product shared facility with a ‘clean’ GMP corridor with positive differential pressure relative to material and personnel airlocks (MAL and PAL, respectively), which are in turn positive relative to the processing room (Figure 3):
Scenario 1: HPAPI with an Occupational Exposure Limit (OEL) of 1 µg/m3 and Acceptable Daily Exposure (ADE) of 10 µg/day, and process includes hand scooping of 5kg of pure API into a comil, for which no air monitoring has been performed, and operators are wearing PAPR with assigned protection factor of 1000 with full Tyvek suit.
Using the scoring system proposed above, the resulting FMEA is shown in Table 1.
By remediating as per the action described in Table 1, this will significantly reduce the airborne concentration, however the containment performance must be
verified accordingly (5).
The same scenario, although now for occupational risk is in Table 2.
Not surprisingly, the occupational risk is too high and open hand-scooping must be stopped immediately. By implementing the same recommended action as per the cross-contamination assessment above, the revised combined
assessment becomes:
Scenario 1 Revised: Risk Reduction implemented – containment implemented & performance validated using the ISPE methodology (5) (Table 3).
The risk level has been significantly reduced and is now acceptable; there may even be an opportunity to reduce PPE.
Scenario 2: Consider a similar facility in terms of design and differential pressures, except with a process room within a Grade C environment, for the transfer of a Safebridge Category 4 API (7) into a manufacturing vessel for an injectable product (prior to sterilization by filtration), whereby the API powder is added using contained transfer (Figure 4), however the OEL is 100 times lower than the validated containment performance; operators are wearing PAPR with assigned protection factor of 1000 with full Tyvek suit (Table 4).
For scenario 2, the assessed risk due to airborne transfer is considered comparable for both cross-contamination and occupational scenarios, due to the controls used combined with the FMEA scoring system; the resulting risk level is Medium, which must be remediated. One possible way to remediate would be to transfer the API powder into a solvent (WFI if possible) to make a slurry within an isolator. Once added to the solvent, the airborne concentration is significantly reduced, and the risk becomes acceptable (Table 5).
CONCLUSION
Handling HPAPI products can be risky business. Both Cross-contamination and occupational risks are often comparable and higher risk when processes are not well controlled and there is too much reliance on PPE; those which are well contained present lower risk. Although there may be some subjectivity involved when establishing the RPN scoring criteria and assessing risks, the scenarios presented above demonstrate how FMEA can be a useful risk management tool, possibly helping drive decision-making and investments, and ultimately lead to safer production techniques for both workers and patients.
Figure 1. Hierarchy of Controls (NIOSH) (4).
Figure 2. FMEA Scoring.
Figure 3. GMP Facility with clean shared corridor with pressure
cascade into Processing Room. Differential pressures are in parentheses.
Figure 4. Contained transfer of API.
Table 1.
Table 2.
Table 3.
Table 4.
Table 5.
REFERENCES AND NOTES:
- PIC/S. Guide to Good Manufacturing Practice for Medicinal Products Part I. 2023.
- ISPE. Risk-Based Manufacture of Pharmaceutical Products. 2nd ed., 2017
- Farris, John P, Safebridge Consultants. Assessing Risk and controlling Exposure to Potent Compounds during Pharmaceutical Packaging. 2010
- NIOSH website, from April 10, 2024, URL: https://www.cdc.gov/niosh/hierarchy-of-controls/about/index.html
- ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment. 2nd ed., 2012
- ICH. Quality Risk Management Q9(R1). Final version, adopted on 18 January 2023.
- Farris, John P; Ader, Allan; Ku, Robert H. Safebridge Consultants, Inc. History, implementation and evolution of the pharmaceutical hazard categorization and control system. Chemistry Today, Vol 24 No. 2, March/April 2006
- Axon, Martin W; Farris, John P; Mason, Justin. Handling highly potent active pharmaceutical ingredients – equipment containment performance. Chemistry Today, Vol 26 n 2, March-April 2008
