7-冗余过滤

– If this is not done, then the filtration can no longer be considered redundant
F1 “Redundant”
F2 “Primary”
P3
Filling Line Waste Line Drug Product Flow
REQUIRED READING – PDA Tech Report 26, pages 35-36
每个企业需要自行进行风险评估
Often this means implementing redundant sterile filtration at the final step in their process (final filling).
If one filter fails the pre-use integrity test, what is the recommended course of action?
Thought leaders and controlling documents US FDA GMP FDA对于冗余过滤的建议
Use of Redundant sterilizing filters should be considered in many cases
Thought leaders and controlling documents EU GMP Annex 1 欧盟GMP则没有明确定义
New GMP Annex 1 from SFDA
SFDA has issued the following draft guidance regarding redundant filtration Due to the potential risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilized micro-organism retaining filter is recommended. 应当采取措施降低过滤除菌的风险。宜安装第二只已灭菌的除菌过滤器再次过滤药液 The final sterilizing filtration should be carried out as close as possible to the filling point. 最终的除菌过滤滤器应当尽可能接近灌装点 The integrity of the sterilizing grade filter should be verified by proper method after use. Results of these checks should be included in the batch record. An appropriate method includes bubble point, diffusive flow and pressure hold test. 除菌过滤器使用后，必须采用适当的方法立即对其完整性进行检查并记录。常用的方法 有起泡点试验、扩散流试验或压力保持试验。 Key impact on sterile filtration processes! How does a customer decide to use a redundant filtration system How to design the system? What are the challenges in redundant system implementation and operation? How to integrity test redundant filtration systems?
Gas
除了使用 Millibarrier 以外的方式
对于尺寸较大的过滤器，使用Millibarrier是比较经济的方案。 而对于尺寸较小的过滤器，可以使用储罐的方式。
储罐用于收集润湿及完整性测试后的液体。 储罐与整个管路一起灭菌。 储罐上需增加气体除菌滤器，便于完整性测试的气体排放。 to filling
Utilization sequences
T-line filter

Start product filtration? Final flushing? Post-use integrity test?
Utilization sequences
In-line filter horizontal
冗余过滤完整性测试方式
Aervent
P1 P2
Sight glass or Level switch
P3
MilliBarrier
T
MilliBarrier filter design MilliBarrier 亲/疏水除菌过滤器
One disk pair
Liquid Condensate
3 Hydrophilic membranes 1 Hydrophobic membrane
Sterilizing grade filter identification
Bioburden reduction Sterilizing filtration
P 1
P 1
NMT 10 cfu / 100 ml
P 1
P 1
P 1
P 2
Redundant
As required
P 1
P 1
P 2
In series
One filter could fail….
P1 P2
F1 串联过滤和冗余过滤有什么区别？
F2
Two filters should be integral
Is this a Redundant Filtration System?
Is this a Redundant Filtration System?
Regulatory requirements according to SFDA guidance:
– Post-use testing of product filters
P1 P2
Sterile Gas Filter
If EITHER F1 or F2 fails a pre-use integrity test (after repeated rewetting and re-testing), the filter should be discarded
..A second filtration via a sterilized microorganism retaining filter, immediately prior to filling, may be advisable.. 111. Due to the potential additional risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilised microorganism retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.
Note: • If two filters are needed to ensure that the effluent is sterile then it is SERIAL filtration but not REDUNDANT • If two filters are used in series to ensure that at least one filter passes integrity testing, then the filtration can be declared REDUNDANT • If two filters are needed to ensure that the final filter receives no more than 10 cfu/mL than it is SERIAL filtration but not REDUNDANT
Hold
up volume?
Utilization sequences
In-line filter Vertical
Is redundant sterile filtration required? 冗余过滤器的安放区域
Regulatory guidance suggests that redundant filtration should be considered in many cases, but it is not a regulatory requirement.
As required
Thought Leaders and Controlling Documents PDA TR 26
“Defines” the second filter as ‘primary sterilizing’ filter & first filter as ‘redundant’ filter
Thought leaders and controlling documents PDA TR 26
6.11 Filters in Series
Two or more filters in a series may be used to ensure the following: • effluent is sterile • at least one filter passes integrity testing • the final filter receives no more than 10 cfu/100 mL Serial filtration may also be used where bacterial penetration of sterilizing-grade filters is suspected. under these process conditions, both filters would need to meet pre- and post-filtration integrity testing acceptance criteria.