Binomial sampling plans for validation and quality control in blood product manufacturing

The collection, manufacturing, and storage of blood and blood components include process validation and activities performed to provide confidence that all elements that influence the quality of the blood products are functioning as expected. Statistical methods play an important role in designing sampling plans in blood product manufacturing, especially for validation and quality control (QC). An x/y criterion is often employed to demonstrate at a certain level of confidence (x%) that more than y% of the products meet a success standard. The values of x and y set the criterion, and they are the only two factors that need to be satisfied during the study size calculation by this approach. Theoretically, they can be any value between 0 and 100. In practice, frequently both x and y are set at 95, hence the well-known “95/95” criterion. This statistical algorithm is used in many regulatory applications to the Centers for Biologic Evaluation and Research of the United States Food and Drug Administration (FDA), especially with respect to blood components. For example, the 95/95 criterion is utilized for the evaluation of the in vitro pH of platelet products at the end of storage or at issue where the success standard is defined as pH ≥6.2 in one FDA guidance. In this paper, we consider a sample as a success if it meets the success standard (e.g., pH ≥6.2) and a failure otherwise. Although different statistical approaches are available to test against the 95/95 criterion, the Binomial Sampling Plan is one approach commonly used. For example, it allows either zero failures among at least 59 platelet samples (0/59), or at most one failure among at least 93 samples (1/93), or at most two failures among at least 124 samples (2/124). Note that a non-binary variable, such as a continuous outcome, will need to be dichotomized for applying this approach. Another FDA guidance recommends the binomial method as one approach for the qualification of leukocyte reduction performance: 95% of the products should have the residual white blood cell content of a leuko-reduced unit of Red Blood Cells <5.0 10 with 95% confidence. It is not uncommon to observe one more failure than permitted in initial testing. This may not be due to a bad production run, but could be due to an extreme outlier or the inherent variability encountered in biological products, including blood components. If no further testing is performed, such studies are considered to have failed. However, as described in the referenced guidance documents, FDA allows additional testing, designed so that an overall sampling plan still meets the 95/95 criterion. This is known as two-stage testing. An additional 90, 163, and 100 samples need to be tested with no failure in the second stage if 1/59, 2/93, or 3/124 occurs, respectively. However, if one or more additional failures in the initial testing is observed (e.g., 2/59), or if one or more failures in the second stage testing (e.g., 1/59 + 1/90), the study is considered to have failed and no additional testing is recommended. This approach can also be viewed as a kind of adaptive design in single arm studies. Lower success rates are recommended for some outcomes in these guidance documents to accommodate variability. For example, the 95/75 criterion (95 is the confidence level) for evaluating apheresis platelet yield at the end of storage requires the proportion of successes to be greater than 75%, instead of 95%, where success is defined as >3.0 10 platelets in the component. When a very high success rate is thought to be clinically relevant, Received: 6 January 2021 Revised: 22 March 2021 Accepted: 25 April 2021