Failure mode and effect analysis in human islet isolation: from the theoretical to the practical risk

Figures & data

Table 1. Repartition of risks according to the process of isolation and conditioning

Major steps in the process	Number of risks
Order, reception and preparation of raw materials	32
Acceptance, reception of the pancreas and laboratory preparation	26
Pancreas dissection, collagenase injection	23
Pancreas digestion	19
Islet purification	10
Quality control in process Islet culture	23
Culture medium change	14
Islet conditioning for transplantation	18
Quality control of islet preparation batch record	12
Islet preparation transport	16
Global process	36
Total	230

Table 2. Rating scale of occurrence, severity and detectability

Score	Occurrence	Severity		Detectability
		Impact on patient safety	Impact on process
1	Non-existent	No impairment, would not be noticeable by the patient, would not affect the provision of care	No/little impact on the isolation procedure	Very easy to detect Quality assurance in place
2	Occurred 1 time
3	Occurred several times in the past 5 years	Mild impairment, increase in the level of required care the event may be noticeable by the patient	Light boredom The process is lengthened without causing additional delay in patient care Loss of islets (100–9000 IEQ)	Easily detectable May not be detected in the absence of verification
4	1 time per year
5	Several times per year	Moderate involvement, may cause injury or increase the level of required care; clearly visible by the patient	Disorganized process Significant loss of islets (10.000–100.000 IEQ)	Detectable with verification
6	20% of isolation			Moderate difficulty in detecting
7	40% of isolation
8	60% of isolation	Serious injury	Very disorganized process Very significant loss of islets (> 50%)	Significant difficulty in detecting
9	80% of isolation
10	100% of isolation	Death	Destruction of islets Isolation failure	Impossible to detect No quality assurance in place

Table 3. Matrix of level of criticality according to the risk mapping

		Severity
		1	2	3	4	5	6	7	8	9	10
Occurence	1	1	2	3	4	5	6	7	8	9	10
	2	2	4	6	8	10	12	14	16	18	20
	3	3	6	9	12	15	18	21	24	27	30
	4	4	8	12	16	20	24	28	32	36	40
	5	5	10	15	20	25	30	35	40	45	50
	6	6	12	18	24	30	36	42	48	54	60
	7	7	14	21	28	35	42	49	56	63	70
	8	8	16	24	32	40	48	56	64	72	80
	9	9	18	27	36	45	54	63	72	81	90
	10	10	20	30	40	50	60	70	80	90	100

The RPN is the product of severity, occurrence, and detectability scoring of the risk.

In this table where only 2 attributes appear, the level of criticality is presented as follows:

Low risk: Moderate risk: Severe risk: Critical risk.

The score assessed for detectability does not change the risk classification.

Figure 1. Process mapping of human islet isolation and conditioning

Table 4. Highest scoring failure mode of different steps in islet isolation process

			Raw evaluation					Post FMEA Evaluation
Isolation Steps	Risk description	Risk consequences	O	D	S	RPN	Risk reduction measure	O	D	S	RPN
Preparation of raw materials	Reversal of 2 products during the preparation of aliquot	Adding an unwanted product in a medium	4	5	9	180	• Operator training • Aliquots of similar products or with similar packaging are not made at the same time • Control of aliquot manufacturing forms	2	5	9	90
Laboratory preparation	During the preparation of solution, wrong concentration of digestion enzymes	Poor digestion of the pancreas	4	7	8	224	• Operator training • Each batch of collagenase is tested before use • Use of the entire bottle of collagenase or neutral protease • Number of vials used to be manually noted on the batch file	2	5	8	80
Collagenase injection	Poor perfusion of the pancreas with digestion enzymes	Poor digestion Impact on the success of isolation	5	2	6	60	• Perfusion by double cannulation by peristaltic pump • Controlled and constant infusion pressure • Manual syringe infusion as a last resort	3	1	6	18
Pancreas digestion	Under digestion of the pancreas	Poor digestion Inadequate number of isolated islets and/or embedded islets	7	7	7	343	• Control of the digestion by regular sampling in the digestion chamber • Operator training	3	3	7	63
Islet purification	Poor mixing of the vials to make the concentration gradient	Ineffective purification Redo the step Time waste	7	8	7	392	• Both bottles to be mixed (Biocoll and Belzer) are labeled with the same wording • All the vials necessary for a purification are gathered in a the same box (purification kit)	2	5	7	70
Quality control in process	Insufficient number of IEQs for transplantation	Isolation without transplant Destruction of the preparation	9	1	10	90	• Change in donor selection parameters • Improvement of pancreas digestion • Improvement of purification technique • External factors	7	1	10	70

Figure 2. Distribution of risk level of criticality. Distribution of risk level for the 230 identified risks during the raw evaluation analysis (a) and after new evaluation post FMEA (b) during which the means of control and quality assurance procedures implemented were taken into account

Table 5. Highest scoring failure mode of different steps in islet isolation process

			Raw evaluation					Post FMEA Evaluation
Isolation Steps	Risk description	Risk consequences	O	D	S	RPN	Risk reduction measure	O	D	S	RPN
Culture medium change	Cross-contamination in case of simultaneous storage of 2 different islet preparations	Mixture of 2 preparations for 2 different patients	4	8	8	256	• The 2 preparations are identified with different colors and a different pancreas number • Placed on different shelves in incubators • The number of culture flasks used is recounted • Two isolation are never done simultaneously, but successively	1	4	8	32
Conditioning of islets for transplantation	Forgetting to add heparin to the tube containing the islet preparation before bagging	Possible Thrombosis Risk in the Patient Recipient	4	8	8	256	• Double-checking at the time of heparin addition	1	3	8	24
Quality control of islet preparation	Positive microbiological control by gram staining of the islet preparation	No transplantation of islet Destruction of the preparation	5	1	10	50	• Training of operators at work in sterile condition • Antibiotics present in all culture media before transplantation	3	1	10	30
Islet preparation transport	Missing infusion lines without filter or sending a line with filter	No transplantation	4	5	7	140	• Check list of the composition of the transport container • Double the infusion line in the transport container	1	3	7	21
Global process	Wrong pressure differential (<10 Pa) in the production room	Risk of contamination of the working environment and of islet preparation	10	5	5	250	• Check pressure differential before to start isolation • Adding of environmental controls during the process in case of bad pressure differential • Work under laminar flow hood/ceiling or in close system during isolation	10	5	5	250

O: Occurrence, D: non detectability, S: severity, RPN: Risk priority numb.