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HPAPIs at Metrics

Developing and manufacturing a complex novel oral solid dose product requires highly focused, niche expertise. At Metrics, we specialize in novel OSD development and manufacturing and have ample experience in handling highly potent compounds.

Classifying HPAPIs
  • Before defining the specific handling controls and/or containment levels, an HPAPI must be evaluated to determine its occupational exposure band (OEB) or occupational hazard class (OHC).
  • The most common method of classifying an HPAPI relies on a systematic control banding strategy to categorize the compound based on its OEL and other recognized health hazards (acute toxicity, reproductive toxicity, teratogenicity, genotoxicity, carcinogenicity, specific organ toxicity from single dose and repeated dose studies, and respiratory and skin sensitization).
  • Once an OEL and adverse health hazards are determined, the HPAPI is then assigned to the appropriate OEB or OHC band.  Most CDMOs use either a 4- or 5-band system to classify their HPAPIs.
  • Metrics currently uses a 5-band system, where compounds placed in an OHC band 3A, 3B and 4 are considered highly potent and demand special handling and isolation practices. An example of an OEB/OHC control table is shown in Table 1. Information in Table 1 includes the OEB/OHC band, OEL in µg/m3, and recommended hazard controls.
  • Any time more information becomes available from preclinical toxicology or clinical study in humans, the OEB/OHC for an HPAPI can change from where it was initially assessed. Sometimes an HPAPI will be found to be less potent than initially determined, which reduces containment burden and the associated processing costs.
  • Other times the OEB/OHC category of a compound can change from where it was initially assessed and ends up to be more potent and will dramatically increase the containment and cost burden and associated processing costs because retro-fitting of containment systems to an existing unit operation.
Example Occupational Exposure Banding and Control Table

OEB/OHC

OEL (µg/m3)

Recommended Controls

1

> 500

Open handling is acceptable for powders. Good handling techniques to minimize dust generation. No special containment technology is required. General room ventilation is acceptable. Conventional open equipment with LEV. No recirculation of air is permitted into non-production spaces. Dry floor sweeping or use of compressed air is prohibited.

2

< 500 - 10

Minimize open handling of powders. Containment should be used to minimize high-energy dust generation operations (milling, sifting, etc.). Good handling techniques to reduce dust generation. Open face containment devices are acceptable. No recirculation of air is permitted into non-production workspaces. Dry floor sweeping and compressed air is prohibited. Use HEPA filtered vacuums when feasible.

3A

< 10 - 1

Open handling is limited to small quantities (grams). No open handling is preferred. Good powder handling techniques to reduce dust generation. Use containment technologies to reduce dust exposures. Airlocks (MALs & PALs) and means of decontamination required to prevent migration of dust to uncontrolled areas. Dry floor sweeping and compressed air is prohibited. Single pass air with HEPA filtration. Any LEV must be HEPA filtered prior to discharge from the building. Transfer powders using direct coupling and closed systems. Appropriate RPE is required if dust levels are above the OEL.

3B

< 1 – 0.1

No open powder handling. Use totally enclosed material transfer systems. Totally enclosed processes and equipment; direct coupling transfers with SBVs; isolation technology as required. No recirculation of air is allowed and must be HEPA filtered prior to discharge. Airlocks (MALs & PALs) and means of decontamination required to prevent migration of dust to uncontrolled areas. Dry floor cleaning is prohibited. Use HEPA filtered vacuums to clean up all powder. RPE is required unless IH data specifies otherwise. CIP systems recommended when feasible. Safe change filters (BIBO) for all ventilation systems is preferred.

4

< 0.1

No open handling is permitted. Full containment technology is required. Dispensing isolators are required. Totally enclosed processes and material transport systems are required. Process steps & equipment should be combined to minimize transfer points/handling. Airlocks (MALs & PALs) and means of decontamination required to prevent migration of dust to uncontrolled areas. No recirculation of air is allowed & must be HEPA filtered prior to discharge from the building. Safe change filters (BIBO) for all ventilation systems is preferred. Appropriate RPE is mandatory.
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Introducing new HPAPI products at Metrics

Important containment considerations

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