Considerations in Pfizer-BioNTech COVID-19 vaccine preparation in clinic: Quality vs quantity

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The dilution process is considered simple, but inconsistency in certain steps of the process can cause variation in dosing. While preparing the vaccine vials for dilution, some of the steps can be easily overlooked because they are not clearly stated in the manufacturer's guideline 1 on vaccine dilution. Therefore, it is necessary to share these considerations with other pharmacists, clinicians, and/or vaccinators to achieve consistency in preparation.
A c c e p t e d M a n u s c r i p t NS withdrawal. In the cleanroom environment, adding to the vial a volume of air equal to the volume of the drug intended to be withdrawn is a typical step of the aseptic technique. The manufacturer's guideline does not include this step. If Pfizer-BioNTech COVID-19 vaccine dilution is performed in an International Organization for Standardization (ISO) class 5 environment, this step can be adopted. Compared to ISO class 5 room air, the human body carries the highest bioburden. Therefore, the aseptic technique is still an important factor in not contaminating any critical part of the syringe preparation operation.
When utilizing the aseptic technique, the introduction of bioburden into the sterile saline vial or vaccine vial will be significantly limited. The highest chance of bioburden intrusion might occur when the needle punctures the vial and the undiluted vaccine is removed. If the dilution is performed in room air that is unclassified and uncontrolled, adding uncontrolled air of equal volume into the vial may increase the likelihood of introducing contamination at the beginning of the preparation process.
Additionally, without adding air to the PF NS vial, direct removal of 1.8 mL of NS from a vial containing 2 mL of NS will generate negative pressure inside the vial. Of note, the 2-mL PF NS product from Fresenius Kabi comes in a 3-mL single-dose vial. Therefore, removing 1.8 mL of NS means removing 60% of the 3-mL container volume, which results in pressure  A c c e p t e d M a n u s c r i p t When 0.15 mL is added into the target transfer volume of 1.8 mL, that results in a less than 10% increase in volume and the concentration of the vaccine will not be lower than 90%.

Therefore, this margin of deviation is allowed, especially when the Centers for Disease
Control and Prevention is allowing the COVID-19 vaccines to be given even when a dose of 50% of the recommended vaccine volume can be considered as a full dose. However, avoidance of the additional NS diluent can be a good pharmaceutical practice to prepare consistent doses even though the lower final vaccine concentration may fall into the clinically acceptable dosing level, marginally.

Preparation of a 0.3-mL vaccine dose.
With proper calculation and considering the dead space of the needle hub, the final volume of Pfizer-BioNTech vaccine after dilution is not enough for 7 doses. Since the dead space volume inside of the needle hub can be easily overlooked, it is possible to miscalculate that there can be 7 doses in a vaccine vial. Before dilution, the vaccine vial contains 0.45 mL of vaccine. Adding 1.8 mL of NS diluent will provide a total volume of diluted vaccine of 2.25 mL. If this volume is divided by 0.3 mL, it will give 7 doses by calculation. However, this calculation does not account for the volume loss due to the dead space in the needle hub. This volume will remain in the needle hub after delivering 0.3 mL of vaccine. The volume loss from the dead space has been well summarized in the literature across organizations. 2 For example, even when a low dead volume (LDV) syringe is used, the volume from the needle hub is 0.035 mL or less, 2 which will be added into 0.3 mL of injecting volume. Therefore, each dose will need to be about 0.335 mL in order to provide 0.3 mL into the patient's arm. The theoretical total volume of a diluted vaccine vial is shown in Box 1, and the possible numbers of syringes per vaccine vial are calculated in Table 1. As shown in Table 1, there is not enough volume for the seventh A c c e p t e d M a n u s c r i p t dose even with use of an LDV syringe and needle, theoretically. Additionally, big air bubbles were often found in some syringes during inspections of 7-dose batches in a clinic setting.
To achieve herd immunity against COVID-19 effectively in a timely manner, it is important not only to maximize the numbers of doses from the vaccine vials but also to prepare quality doses consistently. Considering the unique preparation steps for the Pfizer-BioNTech COVID-19 vaccine, the following critical points can help to prepare proper 0.3-mL vaccine doses consistently:  During NS withdrawal, consider the effects of negative pressure.