Biological products features:
There are mainly two packaging forms (vials, prefilled syringes) and two types of forms (lyophilized powder, aqueous solution injection).
Difficulties in sealing test application:
Biological products contain a certain concentration of macromolecular particles. In aqueous solution products with micropores, the particles will aggregate in the micropores and block the leak holes in a short period of time (generally 1-5 days), resulting in false positive test results for some leak detection methods.
Case analysis of a domestic biopharmaceutical (solution product):
1. (25% protein concentration, 3 hours after filling; test 1 negative sample and 3 positive samples respectively)
Mass extraction method (ug/min): ME2
| Sample No. | Flow ug/min (Threshold: 5.4ug/min) | result | Remark | ||
| Negative sample 1 | 3.139 | 2.976 | 2.527 | PASS | |
| 2.16um | Big leak | Big leak | 55.87 | Fail | |
| 2.29um | Big leak | Big leak | Big leak | Fail | |
| 2.35um | 55.81 | 46.98 | 49.34 | Fail | |
| in conclusion | Tested 3 times respectively; all negative and positive samples were detected 100% accurately, and the liquid leakage flow was obvious | ||||
Vacuum decay method (pa): VDL-P
| Sample No. | Differential pressure pa (threshold: 45pa) | result | Remark | ||
| Negative sample 1 | twenty three | twenty four | twenty three | PASS | |
| 2.16um | 65 | 63 | 67 | Fail | |
| 2.29um | 75 | 78 | 70 | Fail | |
| 2.35um | 70 | 88 | 75 | Fail | |
| in conclusion | Tested 3 times respectively; all negative and positive samples were detected 100% accurately, and the liquid leakage flow was obvious | ||||
2. (25% protein concentration, 24 hours after filling)
Vacuum mass extraction method (ug/min):
| Sample No. | Flow rate ug/min | result | Remark | ||
| Negative sample 1 | 2.132 | 2.319 | 2.490 | PASS | |
| 1.75um | 2.392 | 2.827 | 2.689 | PASS | False Positive |
| 2.10um | 2.760 | 2.418 | 2.498 | PASS | False Positive |
| 2.23um | 3.018 | 2.386 | 2.351 | PASS | False Positive |
| in conclusion | Positive samples were obviously blocked after 24 hours of storage, and the vacuum mass extraction method could not accurately detect | ||||
Vacuum decay method (pa):
| Sample No. | Differential pressure pa | result | Remark | ||
| Negative sample 1 | 25 | 27 | 27 | PASS | |
| 1.75um | 26 | 28 | 25 | PASS | False Positive |
| 2.10um | 29 | 30 | 32 | PASS | False Positive |
| 2.23um | 28 | 28 | 27 | PASS | False Positive |
| in conclusion | Positive samples were obviously clogged after 24 hours of storage, and the vacuum decay method could not accurately detect | ||||
High voltage discharge method (CW): SPAX-HV (testing 1 negative sample and 8 positive samples respectively)
| MAX CW THRESHOLD: 11.00 | ||||
| Sample No. | MAX CW | result | Remark | |
| Negative sample 1 | 8.3 | Ok qualified | ||
| 2.16um | 30.7 | NG | ||
| 2.29um | 313.6 | NG | ||
| 1.75um | 500.4 | NG | ||
| 2.10um | 56.3 | NG | ||
| 2.23um | 370.8 | NG | ||
| 1.97um | 24.2 | NG | ||
| 1.70 | 19.1 | NG | ||
| in conclusion | The high-voltage discharge method can detect leaks with 100% accuracy when the leak is completely blocked. | |||
In conclusion:
The mass extraction/vacuum decay method is only applicable to the process validation (manufacturing process) stage of solution biological products;
The high-voltage discharge method is suitable for the process validation and stability validation stages of solution biological products, and is more suitable for the sealing detection application of solution biological products.
For lyophilized biologics, the mass extraction/vacuum decay rule is more applicable.