Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality

Stress Factors in Primary Packaging, Transportation and Handling of Protein Drug Products and Their Impact on Product Quality

“…Appropriate analytical methods for assessing the effect of the stresses of different manufacturing processes are discussed in USP chapters <1787>, <1788>, <1790>, and several excellent review articles. 2,[18][19][20][21][22] For subvisible particle analysis, it is highly advisable to apply analytical methods that are sensitive to protein particles, which are often translucent and not well detected by the compendial methods (i.e., light obscuration). The panel of analytical methods used in development should include those that can also differentiate proteinaceous particles from other types of particles which may originate from the device or the formulation components.…”

“…Container closure integrity, as well as a detailed discussion of analytical procedures including potency assays are out of scope, as is the manufacturing process and formulation considerations which were covered in the previous 2 manuscripts. 1,2 This paper captures the major risk factors to protein DP related to packaging, transportation, handling and administration. The discussions include potential negative impact of these risk factors on PQAs, and appropriate mitigations through process development and robustness studies.…”

“…The risk of VHP on drug product quality and corresponding mitigation strategies were covered extensively in part II of this series. 2 It has been shown that the method of sterilization of polymer components can influence the respective extractables/leachables (E/L) profile quite significantly. Thus, we can expect that the amount and the kind of leachables from the primary packaging to vary according to how it is sterilized.…”

“…A vast majority of protein-based biologics are produced using recombinant DNA technologies in cell culture processes, and encounter stresses throughout the drug substance and drug product production. 1,2 Developing a stable, safe, and efficacious product starts with target identification in early discovery and progresses through all phases of development and manufacturing, finally resulting in administration of the commercial product to the patient. This manuscript is the last in a series of 3 papers describing the stresses to which a biotherapeutic is exposed throughout production.…”

“…The first 2 focused on stresses encountered during the manufacturing of the drug substance, and those involved in the manipulation of drug substance (DS) into the drug product (DP) formulation and dosage form at the manufacturing facility. 1,2 In the final steps for getting drug to patients, the DP must be packaged (fill and finish) into a primary container or device as appropriate, stored, and distributed to the patient (either in the clinic or at their home), and then administered; this is the focus of the current manuscript. DP quality including potency may be impacted by external factors such as primary device material, container closure, product viscosity, and stress during transportation, and these should be taken into consideration during DP design.…”