Assessment of the Risk That Microbial Endotoxins Could Enter the Purification Process Stream Given the Preparation Equipment and Procedures Illustrated in Figure 1.
| Base Case Analysis | Analysis of Alternative Cases | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Failure Mode | Potential Effects of Failure Mode | Severity | Potential Causes | Current Controls | Occurrence | Detection | RPN | Permutation | Severity | Occurrence | Detection | RPN | Comment/Explanation |
| Microbial endotoxins enter purification equipment from buffer. | Endotoxins may enter the drug substance process stream and may not be removed. High endotoxin concentrations in the drug product will result in adverse patient reactions. | 10 | [A] Bioburden (that can form endotoxins *) is present in salts. [B] Bioburden present in CWFI. [C] Bioburden enters from the environment (CNC background) [D] Bioburden transferred to interior of tank by operators. [E] Bioburden present on exterior surfaces of raw material packaging and is transferred to interior of preparation vessel. [F] Preparation vessel and/or transfer line is inadequately cleaned and sanitized before use. There is bioburden present in the vessel or transfer line prior to the start of the batch. [G] Solution sits in vessel a long time at room temperature before filtration into storage bag and bioburden grows within the tank. [H] Initial level of bioburden within the solution is too high and filter is unable to retain the bioburden. [I] 0.2 micron filter is not integral. Bioburden can pass through during filtration. [J] Single-use tubing or storage bag is not integral. Bioburden can enter through integrity breach. [K] Single-use tubing or storage bag inadequately sanitized by the vendor and contains bioburden. [L] Bioburden accumulates within the bag during storage. Organisms die and release endotoxins into the formulation buffer. | [A] Bioburden specification limits for salts. [B] Many design and engineering controls in place to avoid bioburden in CWFI. [B] Periodic sanitization of CWFI distribution system. [B] Regular environmental monitoring of CWFI. [C, D, E] Solids added so that exposure of the interior to the vessel to the environment is minimized. [F] Tank and transfer line are designed for proper cleaning and draining. A validated cleaning and sanitization sequence is executed for the vessel and the transfer line prior to each lot. Periodic environmental monitoring (i.e., rinse sampling) to verify continued effectiveness of cleaning procedure. [G, H] Validated time established from beginning of batch preparation to end of filtration. Time stamps are checked in the batch record to ensure batch was prepared and filtered within the allowed time. [I] Filter vendor quality system. [I] Post-use integrity test performed on each filter. [J, L] Single-use vendor quality program. [J] Operator training for inspecting single-use elements prior to use and to avoid damaging single-use elements during handling. [J] Integrity breach may become evident during filtration and transfer. [K] Radiation indicators on gamma sterilized elements that are received. [L] Solution is 0.2 micron filtered prior to storage. Measures J and K are in place to prevent the buffer from being contaminated during the storage period after filtration. NOTE: Drug substance is tested for microbial endotoxins. The material is not released for final drug product manufacturing if the specified limit is exceeded. | 3 | 1 | 30 | [C'1] Solution preparation and storage is performed within a Grade A background environment rather than in a CNC environment. [D'1, E'1)] Solid components are added through an open manway rather than via a protected connection. [G'1, H'1] Preparation and filtration time is increased from 12 to 24 h. [G'2] Decrease preparation temperature from 20 °C to 5 °C. | 10 10 10 10 | 3 5 7 3 | 1 1 1 1 | 30 50 70 30 | [C'1] Probability of occurrence does not change if operation is performed in a Grade A background environment. The ingress of microbial load from the environment is already negligible in the base case in comparison to other potential sources (e.g., from raw materials). [D'1,E'1] The open manway provides a greater opportunity for bioburden from the environment or the operator to enter the vessel during preparation. [G'1,H'1] Increasing the allowable preparation and filtration time could increase the potential microorganisms present in the raw materials an opportunity to grow and produce endotoxins. [G'2] Decreasing the preparation temperature decreases the growth rate of potential microbial contaminants present in raw materials. |
↵* This is assumed whenever bioburden is mentioned within this example.