Issue link: https://www.e-digitaleditions.com/i/1520859
38 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2024 PharmTech.com sidered to be low-risk if the plastic additives are ≤0.1% by weight, intermediate risk if the plastic additives are between >0.1% and ≤1% by weight, and high risk if the plastic additives are >1% by weight. By physi- cal properties, the risk dimension is considered to be high risk if the component is sterilized by irradiation or at high temperature. The component that is being assessed for risk is rated for risk dimensions as per Table I. The rating levels are assigned as 1, 2, or 3 in each of the risk di- mensions. A numerical risk sequence is obtained as a result of the four assignments. If the level of risk is high for all four dimensions, then the numerical risk sequence will be 3333. The numerical order of the risk sequence values is largely inconsequential, and proper use of the numerical risk sequence requires that the sequence be given in order of decreasing digit values. Considering all the possible outcomes of the above application of the risk evaluation ma- trix, links between the numerical risk sequence and the characterization level have been proposed by USP <1665> (see Table III). Once the characterization level is determined, the risk evaluation process should then consider the miti- gation factors that can be used to adjust the characteri- zation levels. After the component has been evaluated, the downstream process operations (such as the clear- ance step—for its ability to either eliminate, remove, or clear PERLs from the process stream or dilute them to an extent that the safety of the manufactured drug product is not affected since the extractables will not be present in the drug product as leachables post-this step) can be used to mitigate the risk by 1 level, and the level of characterization required. If the component is subject to f lush or rinse as a part of the manufactur- ing process and the flush/rinse waste does not go into the main process stream, then this flushing or rinsing has an ability to reduce the number and amount of ex- tractable in the final drug product. If the reduction or elimination of extractables has been established with the flushing or rinsing step, then the material reactiv- ity risk level can be reduced by one level, for example a "high risk" component can become an "intermediate risk" component. Process dilution to a certain extent TABLE III. Linking the numerical risk sequence with a level of characterization. If… And… Then characterization level is Four of the dimension scores are level 3 There is no additional qualifier (3333) Level C (High risk) Three of the dimensions scores are level 3 The other dimension score is level 2 (3332) Level C The other dimension score is level 1 (3331) Level C Two of the dimensions scores are level 3 The other two dimension scores are both level 2 (3322) Level C One dimension score is level 2 (3321) Level B (moderate risk) or Ca,b The other two dimension scores are level 1 (3311) Level A (low risk) or Bb,c All of the other dimension scores are level 2 (3222) Level B One of the dimension scores is level 3 One of the other dimension scores is level 1 (3221) Level B Two of the other dimension scores are level 1 (3211) Level A or Bb,c All of the other dimension scores are level 1 (3111) Level A None of the dimension scores is level 3 All of the dimension scores are level 2 (2222) Level B Not all of the dimension scores are level 2 Level A a If the Level 2 score is in temperature, solvent, or duration dimensions, then level C otherwise level B b In these cases the temperature, solvent, or duration dimension have a higher influence on the risk than do component composition c If one of the level 1 scores is in the component composition dimension, then level A otherwise level B. TABLE II. Chemical composition of the process stream (2). Process streams containing Definition of process stream Aqueous Somewhat organic Highly organic Organic solvents <5% by volume >5% and ≤40% by volume >40% by volume Surfactants (eg., polysorbate 80) ≤0.1% by weight >0.1% and ≤0.5% by weight >0.5% by weight Blood or blood-derivedsubstances (e.g., albumin) <1% by weight ≥1% and <25% by weight ≥25% by weight Lipids and proteins <1% by weight ≥1% and <5% by weight ≥5% by weight Risk Evaluation