Dose accuracy of the follitropin alfa pen injector 2.0, the follitropin alfa:lutropin alfa 2:1 combination pen injector 2.0 and the choriogonadotropin alfa pen injector 1.0 used for fertility treatment

Figures & data

Figure 1. The Merck family of fertility pen injectors: the multi-dose r-hFSH pen injector 2.0 900 IU presentation (a), the r-hCG pen injector 1.0 (b) and the r-hFSH:r-hLH 2:1 combination pen injector 2.0 900 IU + 450 IU presentation (c). This figure is reprinted with permission of Merck KGaA, Darmstadt, Germany, who own the copyright of the images.

Table 1. r-hFSH pen injector 2.0, r-hFSH:r-hLH 2:1 combination pen injector 2.0 and r-hCG pen injector 1.0 target dose volume, and lower and upper specified limits, for each dial setting assessed (Studies 1–5).

Dose dial setting (IU)	Target dose (mL)	Lower specified limit (mL)	Upper specified limit (mL)
r-hFSH pen injector 2.0 and r-hFSH:r-hLH 2:1 combination pen injector 2.0
12.5 (1 increment/click)^a,b,c,d	0.0200	0.0000	0.0400
87.5 (7 increments/clicks) ^a	0.1400	0.1200	0.1600
150.0 (12 increments/clicks)^a	0.2400	0.2200	0.2600
162.5 (13 increments/clicks)^b,e	0.2600	0.2400	0.2800
237.5 (19 increments/clicks)^c,f	0.3800	0.3600	0.4000
300.0 (24 increments/clicks)^b,g	0.4800	0.4560	0.5040
450.0 (36 increments/clicks)^c,h	0.7200	0.6840	0.7560
r-hCG pen injector 1.0
260 (1 increment/click) ^i	0.0200	0.0000	0.0400
3,380 (13 increments/clicks) ^i	0.2600	0.2400	0.2800
6,500 (25 increments/clicks) ^i, j	0.5000	0.475	0.525

In order to reduce repetition, data for target doses and lower/upper limits for the r-hFSH pen injector 2.0, r-hFSH:r-hLH 2:1 combination pen injector 2.0 and r-hCG pen injector 1.0 have been combined in one table. ^aDose dial setting for r-hFSH pen injector 2.0 (150 IU presentation); ^bdose dial setting for r-hFSH pen injector 2.0 (300 IU presentation); ^cdose dial setting for r-hFSH pen injector 2.0 (450 IU and 900 IU presentations). ^ddose dial setting for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (300:150 IU, 450:225 IU, and 900:450 IU presentations; respective doses per increment/click 12.5:6.25 IU); ^edose dial settings for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (300:150 IU presentation; respective doses per increment/click 162.5:81.25 IU); ^fdose dial settings for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (900:450 IU and 450:225 IU presentations; respective doses per increment/click 237.5:118.75 IU); ^gdose dial settings for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (300:150 IU presentation; respective doses per increment/click 300:150 IU); ^hdose dial settings for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (900:450 IU and 450:225 IU presentations; respective doses 450:225 IU); ⁱAssessed in the single use/variable dose device classification (D2). ^jAssessed in the single use/single dose device classification (D1).

hCG, human chorionic gonadotropin. r-hFSH, recombinant human follicle stimulating hormone. r-hLH, recombinant human luteinizing hormone.

Figure 2. Summary diagram of V_min, V_mid, V_max for r-hFSH pen injector 2.0 (a) 150 IU*, (b) 300 IU^†, (c) 450 IU^†, (d) 900 IU^† (Study 1A, aubonne, Switzerland and Study 1B, Bari, Italy). The orange lines/dots represent the upper specification limits, and the gray lines/dots represent the lower specification limits. Error bars are calculated as k_tar*SD. *Final assembly at the Merck Biopharma production plant at Bari, Italy. ^†Final assembly at the Merck Biopharma production plant at aubonne, Switzerland.

Table 2. The r-hFSH pen injector 2.0 mean actual doses and deviations from target dose (Study 1A, Aubonne, Switzerland and Study 1B, Bari, Italy).

Pen injector presentation (IU)	Dose dial setting (IU)	Target dose (mL)	Actual dose (mL)					Mean deviation (mL)	Mean relative deviation (%)	kact	ktar
			Min	Max	Mean dose	SD	CV
150*	12.5	0.0200	0.0163	0.0241	0.0199	0.0019	9.5	0.0001	0.5	10.47	2.67
	87.5	0.1400	0.1302	0.1455	0.1403	0.0030	2.1	0.0003	0.2	6.57	2.67
	150	0.2400	0.2344	0.2526	0.2441	0.0031	1.3	0.0041	1.7	5.13	2.67
300^†	12.5	0.0200	0.0176	0.0287	0.0228	0.0023	10	0.0028	14	7.48	2.67
	162.5	0.2600	0.2597	0.2716	0.2672	0.0022	0.8	0.0072	2.8	5.82	2.67
	300	0.4800	0.4804	0.4950	0.4893	0.0031	0.6	0.0093	1.9	4.74	2.67
450^†	12.5	0.0200	0.0185	0.0243	0.0211	0.0014	6.6	0.0011	5.5	13.50	2.67
	237.5	0.3800	0.3817	0.3931	0.3858	0.0025	0.6	0.0058	1.5	5.68	2.67
	450	0.7200	0.7061	0.7359	0.7286	0.0052	0.7	0.0086	1.2	5.27	2.67
900^†	12.5	0.0200	0.0176	0.0256	0.0217	0.0019	8.7	0.0017	8.5	9.63	2.67
	237.5	0.3800	0.3779	0.3933	0.3846	0.0035	0.9	0.0046	1.2	4.40	2.67
	450	0.7200	0.7105	0.7353	0.7273	0.0048	0.7	0.0073	1.0	5.98	2.67

*Final assembly at the Merck Biopharma production plant at Bari, Italy. †Final assembly at the Merck Biopharma production plant at Aubonne, Switzerland. CV, co-efficient of variance; k_act, actual k value; k_tar, target k value; r-hFSH, recombinant human follicle stimulating hormone; SD, standard deviation.

Table 3. Mean actual doses and deviations from target dose for r-hCG pen 1.0 injector (Study 2, Bari, Italy [D1 device classification] and Study 3, aubonne, Switzerland [D2 device classification]).

Dose dial setting (IU)	Target dose (mL)	Actual dose (mL)					Mean deviation (mL)	Mean relative deviation (%)	kact	ktar
		Min	Max	Mean dose	SD	CV (%)
D1 device classification*
6,500	0.5000	0.5012	0.5146	0.5075	0.0031	0.6	0.0075	1.5	5.645	2.670
D2 device classification†
260	0.0200	0.0150	0.0269	0.0218	0.0024	11	0.0018	9.0	7.4903	2.6700
3,380	0.2600	0.2526	0.2635	0.2582	0.0025	0.9	−0.0018	0.7	7.2664	2.6700
6,500	0.5000	0.4885	0.5106	0.5013	0.0043	0.9	0.0013	0.3	5.5245	2.6700

*Final assembly at the Merck Biopharma production plant at Bari, Italy. †Final assembly at the Merck Biopharma production plant at Aubonne, Switzerland. CV, co-efficient of variance; k_act, actual k value; k_tar, target k value; r-hCG, recombinant human chorionic gonadotropin; SD, standard deviation.

Figure 3. Summary diagram of V_min, V_mid, V_max for the r-hCG pen injector 1.0 (D2 device classification: single use/variable dose device) (Study 3, Aubonne, Switzerland). The orange lines/dots represent the upper specification limits, and the gray lines/dots represent the lower specification limits. Error bars are calculated as k_tar*SD. Device tested at the Merck Biopharma production plant at Bari, Italy.

Figure 4. Summary diagram of V_min, V_mid, V_max for the r-hFSH:r-hLH 2:1 combination pen injector 2.0 (A) 900:450 IU, (B) 450:225 IU, (C) 300:150 IU (Study 4, Bari, Italy). The orange lines/dots represent the upper specification limits, and the gray lines/dots represent the lower specification limits. Error bars are calculated as k_tar*SD. Devices tested at the Merck Biopharma production plant at Bari, Italy.

Table 4. Mean actual doses and deviations from target dose for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (Study 4, Bari, Italy).

Pen injector presentation (IU)	Dose dial setting (IU)	Target dose (mL)	Actual dose (mL)					Mean deviation (mL)	Mean relative deviation (%)	kact	ktar
			Min	Max	Mean dose	SD	CV
300:150	12.5:6.25	0.0200	0.0179	0.0244	0.0204	0.0013	6.3	0.0004	2.0	15.08	2.67
	162.5:81.25	0.2600	0.2531	0.2619	0.2563	0.0016	0.6	−0.0037	1.4	10.19	2.67
	300:150	0.4800	0.4765	0.4853	0.4802	0.0021	0.4	0.0002	0.04	11.33	2.67
450:225	12.5:6.25	0.0200	0.0166	0.0242	0.0208	0.0021	10.1	0.0008	4.0	9.14	2.67
	237.5:118.75	0.3800	0.3717	0.3840	0.3776	0.0023	0.6	−0.0024	0.6	7.65	2.67
	450:225	0.7200	0.7139	0.7267	0.7211	0.0035	0.4	0.0011	0.2	9.97	2.67
900:450	12.5:6.25	0.0200	0.0211	0.0252	0.0229	0.0010	4.3	0.0029	14.5	17.10	2.67
	237.5:118.75	0.3800	0.3756	0.3852	0.3807	0.0023	0.6	0.0007	0.2	8.39	2.67
	450:225	0.7200	0.7194	0.7315	0.7246	0.0027	0.3	0.0046	0.6	11.63	2.67

CV, co-efficient of variance; k_act, actual k value; k_tar, target k value; r-hFSH, recombinant human follicle stimulating hormone; r-hLH, recombinant human luteinizing hormone; SD, standard deviation.

Table 5. Mean actual doses and deviations from target dose for r-hFSH:r-hLH 2:1 combination pen injector 2.0 (Study 5, Aubonne, Switzerland).

Pen injector presentation (IU)	Dose dial setting (IU)	Target dose (mL)	Actual dose (mL)					Mean deviation (mL)	Mean relative deviation (%)	kact	ktar
			Min	Max	Mean dose	SD	CV
300:150	12.5:6.25	0.0200	0.0153	0.0232	0.0188	0.0017	9.04	−0.0012	6.00	11.06	2.67
	162.5:81.25	0.2600	0.2499	0.2610	0.2562	0.0026	1.01	−0.0038	1.46	6.23	2.67
	300:150	0.4800	0.4732	0.4855	0.4792	0.0025	0.52	−0.0008	0.17	9.28	2.67
450:225	12.5:6.25	0.0200	0.0183	0.0252	0.0224	0.0017	7.59	0.0024	12.00	10.35	2.67
	237.5:118.75	0.3800	0.3742	0.3844	0.3806	0.0023	0.60	0.0006	0.16	8.44	2.67
	450:225	0.7200	0.7162	0.7306	0.7244	0.0033	0.46	0.0044	0.61	9.58	2.67
900:450	12.5:6.25	0.0200	0.0209	0.0278	0.0242	0.0012	4.96	0.0042	21.00	13.17	2.67
	237.5:118.75	0.3800	0.3702	0.3876	0.3811	0.0030	0.79	0.0011	0.29	6.30	2.67
	450:225	0.7200	0.7140	0.7282	0.7216	0.0033	0.46	0.0016	0.22	10.46	2.67

CV, co-efficient of variance; k_act, actual k value; k_tar, target k value; r-hFSH, recombinant human follicle stimulating hormone; r-hLH, recombinant human luteinizing hormone; SD, standard deviation.