Figure 1
FMECA analysis and the Acceptable Risk Level estimation process
Table 1
Main characteristics of antineoplastic drugs evaluated in the FMECA study (data obtained from the Agenzia Italiana del Farmaco database)
| ID substance | Trade packaging | Volume packaging–liquid (mg/mL) | Reconstituted concentration–powder mg/mL) | Recommended dosage | Corrosive | Stability | Poorly soluble | Packaging |
|---|---|---|---|---|---|---|---|---|
| MITC | 10 mg to 40 mg | 0.5 or 1 | 10–20 mg/m2 | Immediate use | Glass | |||
| DC | 100 mg to 1 g | 1.4–2.0 or 2.8–4.0 | 200–250 mg/m2 | No information | Glass | |||
| RTX | 2 mg | 0.04–0.008 | 3 mg/m2 | Up to 12 h | Glass | |||
| FTM | 208 mg | 52 | 100 mg/m2 | Immediate use | Glass | |||
| DNR | 20 mg | 2 | 0.5–3 mg/kg. | Up to 24 h at 20–25 °C or 48 h at 2–8 °C | Glass | |||
| VNB | 10 mg | 1 | 3.7 mg/m2 | Up to 28 days at 2–8 °C | Glass | |||
| MP | 2 mg to 200 mg | 5 | 8–200 mg/m2 | Immediate use or up to 1.5 h at 20–25 °C | x | Glass | ||
| VNC | 1 mg to 5 mg | 1 | 0.4–1.4 mg/m2 | No information | Glass, PP+plastic | |||
| CP | 200 mg to 1 g | 20 | 12–240 mg/m2 | x | Type III glass | |||
| PMX | 100 mg to 1 g | 25 | 500 mg/m2 | Up to 24 h at 2–8 °C | Glass | |||
| TPT | 1 mg to 4 mg | 1 | 1.5 mg/m2 | Up to 24 h at 2–8 °C to 30 days at 25 °C | Glass | |||
| EPI | 5 mg to 200 mg | 2 | 60–135 mg/m2 | 24 h at 20–25 °C to 7–28 days | Amber glass | |||
| DXR | 10 mg to 200 mg | 2 | 1–2 | 50–75 mg/m2 | 24 h at 20–25 °C to 7 days at 25 °C | Glass | ||
| IRT | 20 mg to 1 g | 1.5–20 | 180 mg/m2–350 mg/m2 | 6 h at 20–25 °C to 24 h at 2–8 °C | PP, glass | |||
| PTX | 30 mg to 600 mg | 6 | 1–5 | 100 mg/m2–260 mg/m2 | x | 4 h at 25 °C to 7 days at 5 °C and 25 °C | Glass or glass+PP | |
| BSF | 60 mg | 6 | 0.8–3.2 mg/kg | x | 4 h at 20–25 °C to 12 h at 2–8 °C | Glass | ||
| Carbo Pt | 50 mg to 600 mg | 10 | 400 mg/m2 | 3 h at 15–35 °C to 24 h at 2–8 °C | Amber glass or PP | |||
| CisPt | 10 mg to 100 mg | 0.5–1 | 50–120 mg/m2 | 6 to 24 h at 20–25 °C | Amber glass or PP | |||
| DTX | 20 mg to 160 mg | 10–20 | 75 mg/m2 | 6 h under 25 °C to 3 days at 2–8 °C | x | Amber glass or glass | ||
| IDC | 5 mg and 10 mg | 1 | 12 mg/m2 | Up to 48 h at 2–8 °C or 24 h at 20–25 °C | Glass | |||
| MT | 2.5 mg to 0.5 g | 7.5–100 | 10–25 mg/m2 or 7.5–25 mg/week | Immediate use or temperature< 25 °C | Glass | |||
| 5-FU | 50 mg to 5 g | 40–50 | 200–600 mg/m2 or 12 mg/kg | x | 24 h at 25 °C to 48 h | Glass or aluminium with epoxy phenolic lacquer | ||
| CTB | 100 mg to 5 g | 20–100 | 100–200 mg/m2 | 24 h at <30 °C to 72 h at 2–8 °C | x | Glass | ||
| ETP | 50 mg to 1 g | 20–100 | 60–200 mg/m2 | 24 h at 20–25 °C to 96 h | Amber glass | |||
| OxaliPt | 50 mg to 250 mg | 5 | 85 mg/m2 | up to 48 h at 2–8 °C or 6–24 h at 25 °C | Glass | |||
| VNR | 10 mg to 80 mg | 10 or 20–80 | 25–80 mg/m2 | up to 24 h at 2–8 °C or 25 °C | Glass or PVC/PVDC/aluminium |
[i] 5-FU – 5-fluorouracil; BSF – busulfan; CarboPt – carboplatin; CisPt – cisplatin; CP – cyclophosphamide; CTB – cytarabine; DC – dacarbazine; DNR – daunorubicin; DTX – docetaxel; DXR – doxorubicin; EPI – epirubicin; ETP – etoposide; FTM – fotemustine; GEM – gemcitabine; IDC – idarubicine; IP – iphosfamide; IRT – irinotecan; MITC – mitomycin C; MP – melphalan; MT – methotrexate; OxaliPt – oxaliplatin; PMX – pemetrexed; PP – polypropylene; PTX – paclitaxel; PVC – polyvinyl chloride; PVDC – polyvinylidene chloride; RTX – raltitrexed; TMX – tamoxifen; TPT – topotecan; VNB – vinblastine; VNC – vincristine; VND – vindesine; VNR – vinorelbine
Figure 2
Ishikawa diagram of failure modes
Table 2
Risk priority rating of environmental monitoring findings assessing antineoplastic drug contamination [based on alert glove values from Dugheri et al. (34)]
| RPN | Number of detected ADs | Surface contamination spread (pg/cm2) | Percentage of contaminated surfaces (%) | Glove contamination spread (pg/cm2) | Percentage of contaminated gloves (%) |
|---|---|---|---|---|---|
| 1 – very low | 1 | LOQ–10 | <3 | <LOQ | <2 |
| 2 – low | 2 | 11–30 | 4–6 | 1/10 of AGV 90th percentile | 3–5 |
| 3 – moderate | 3 | 31–50 | 7–9 | AGV 90th percentile | 6–8 |
| 4 – high | 4–5 | 50–99 | 10–12 | 1/10 of AGV 95th percentile | 8–10 |
| 5 – very high | >6 | >100 | >12 | AGV 95th percentile | >10 |
[i] ADs – antineoplastic drugs; AGV – alert glove value; RPN – risk priority number
Figure 3
Risk levels strip for MRL comparison with ARL
Table 3
Evaluation of five failure modes with risk priority numbers (RPNs) for each antineoplastic drug group in FMECA analysis
| Failure mode | Powder ADs | Liquid ADs | Corrosive ADs | One-concentration ADs | Unstable ADs | No holder casing | High average therapeutic concentration | Poorly soluble | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MITC, DC, DNR, IP, FTM, VNB, GEM, CP, MP, VND, PMX, TPT, RTX | VNC, EPI, DXR, IRT, 5-FU, PTX, BSF, CarboPt, CisPt, CTB, DTX, ETP, GEM, IDC, MT, OxaliPt, PMX, VNR | BSF, TX, 5-FU | RTX, FTM, DNR, VNB, BSF | DXR, FTM, MP, MITC, VNC, MT | VND, VNC, VNR, TPT, RTX, MITC, MP, IP, IDC, DXR, EPI, CP, CarboPt | CP, IP, DC, GEM, MP, PMX, IRT, PTX, 5-FU | 5-FU, CP | |||||||||
| RPN | RPN | RPN | RPN | RPN | RPN | RPN | RPN | |||||||||
| M | A | M | A | M | A | M | A | M | A | M | A | M | A | M | A | |
| Packaging handling | 4 | 4 | 2 | 2 | 4 | 4 | 3 | 3 | 3 | 3 | 5 | 5 | 3 | 3 | 3 | 3 |
| Reconstitution | 5 | 4 | 1 | 1 | 2 | 1 | 4 | 4 | 3 | 2 | 3 | 2 | 4 | 3 | 4 | 3 |
| Dilution process | 3 | 2 | 4 | 4 | 2 | 1 | 4 | 4 | 3 | 2 | 3 | 2 | 4 | 2 | 4 | 3 |
| Pharmaceutical form | 2 | 2 | 3 | 2 | 3 | 3 | 3 | 2 | 3 | 3 | 2 | 2 | 4 | 4 | 3 | 3 |
| Waste disposal | 3 | 3 | 3 | 3 | 5 | 3 | 3 | 2 | 4 | 4 | 5 | 5 | 2 | 2 | 2 | 2 |
| Acceptable risk level (ARL) | 17 | 15 | 13 | 12 | 16 | 12 | 17 | 15 | 16 | 14 | 18 | 16 | 17 | 14 | 16 | 14 |
[i] M=manual preparation; A= automated preparation. The Acceptable Risk Level (ARL) is the sum of RPNs. 5-FU – 5-fluorouracil; BSF – busulfan; CarboPt – carboplatin; CisPt – cisplatin; CP – cyclophosphamide; CTB – cytarabine; DC – dacarbazine; DNR – daunorubicin; DTX – docetaxel; DXR – doxorubicin; EPI – epirubicin; ETP – etoposide; FTM – fotemustine; GEM – gemcitabine; IDC – idarubicine; IP – iphosfamide; IRT – irinotecan; MITC – mitomycin C; MP – melphalan; MT – methotrexate; OxaliPt – oxaliplatin; PMX – pemetrexed; PTX – paclitaxel; RTX – raltitrexed; TMX – tamoxifen; TPT – topotecan; VNB – vinblastine; VNC – vincristine; VND – vindesine; VNR – vinorelbine
Table 4
Evaluation of five failure modes with risk priority numbers (RPNs) related to environmental monitoring data
| Failure | Powder ADs | Liquid ADs | Corrosive ADs | One-concentration ADs | Unstable ADs | No holder casing | High average therapeutic concentration | Poorly soluble | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MITC, DC, DNR, IP, FTM, VNB, GEM, CP, MP, VND, PMX, TPT, RTX | VNC, EPI, DXR, IRT, 5-FU, PTX, BSF, CarbPt, CisPt, CTB, DTX, ETP, GEM, IDC, MT, OxaliPt, PMX, VNR | BSF, PTX, 5-FU | RTX, FTM, DNR, VNB, BSF | DXR (Miocet), FTM, MP, MITC, | VND, VNC, VNR, TPT, RTX, MITC, MP, IP, IDC, DXR, EPI, CP, CarboPt | CP, IP, DC, GEM, MP, PMX, IRT, PTX, 5-FU | 5-FU, CP | |||||||||
| RPN | RPN | RPN | RPN | RPN | RPN | RPN | RPN | |||||||||
| M | A | M | A | M | A | M | A | M | A | M | A | M | A | M | A | |
| Number of detected ADs | 3 | 3 | 3 | 3 | 1 | 1 | 2 | 2 | 2 | 2 | 3 | 2 | 3 | 3 | 2 | 2 |
| Surface contamination spread | 5 | 5 | 3 | 3 | 5 | 5 | 4 | 3 | 4 | 3 | 5 | 4 | 5 | 5 | 5 | 5 |
| Percentage of contaminated surfaces | 3 | 2 | 3 | 3 | 1 | 2 | 4 | 4 | 3 | 3 | 4 | 4 | 4 | 3 | 3 | 3 |
| Glove contamination spread | 4 | 4 | 3 | 1 | 4 | 4 | 4 | 3 | 3 | 4 | 4 | 3 | 3 | 3 | 3 | 2 |
| Percentage of contaminated gloves | 5 | 5 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 2 | 5 | 5 | 3 | 2 | 5 | 4 |
| Measured risk level (MRL) | 20 | 19 | 14 | 11 | 15 | 13 | 18 | 14 | 14 | 14 | 21 | 18 | 18 | 16 | 18 | 16 |
| Acceptable risk level (ARL, Table 3) | 17 | 15 | 13 | 12 | 16 | 12 | 17 | 15 | 16 | 14 | 18 | 16 | 17 | 14 | 16 | 14 |
| Assessed risk | High | High | Moderate | Moderate | Moderate | Moderate | Moderate | Moderate | Moderate | Moderate | High | Severe | Moderate | Severe | Severe | Severe |
[i] The measured risk level (MRL) is the sum of RPNs. Acceptable risk level is taken from Table 3. M=manual preparation; A= automated preparation. 5-FU – 5-fluorouracil; BSF – busulfan; CarboPt – carboplatin; CisPt – cisplatin; CP – cyclophosphamide; CTB – cytarabine; DC – dacarbazine; DNR – daunorubicin; DTX – docetaxel; DXR – doxorubicin; EPI – epirubicin; ETP – etoposide; FTM – fotemustine; GEM – gemcitabine; IDC – idarubicine; IP – iphosfamide; IRT – irinotecan; MITC – mitomycin C; MP – melphalan; MT – methotrexate; OxaliPt – oxaliplatin; PMX – pemetrexed; PTX – paclitaxel; RTX – raltitrexed; TMX – tamoxifen; TPT – topotecan; VNB – vinblastine; VNC – vincristine; VND – vindesine; VNR – vinorelbine