VALIDATION: Advances in the Validation of Chromatographic Processes - Improvements in process validation approaches have resulted in better process understanding. - BioPharm International


VALIDATION: Advances in the Validation of Chromatographic Processes
Improvements in process validation approaches have resulted in better process understanding.

BioPharm International

Resin Lifespan Studies

Resin lifespan studies may be more appropriately carried out concurrently, provided the analytical methods are demonstrated to be sufficiently sensitive and appropriate.10 Virus clearance by aged resins has been a topic of discussion for several years. Surrogate measurements that replace the need to evaluate virus clearance after repeated use have been proposed for some types of chromatographic steps (i.e., affinity and flow-through mode anion exchange chromatography used in MAb production).11,12

Conformance Batches and Beyond

Figure 3
Once the process is characterized and scale up verified, 3–5 consecutive batches are run at center point to demonstrate manufacturing consistency. The validation effort does not stop here, however. The level of process understanding increases with manufacturing experience (Figure 3).

Better process understanding may lead to changes to improve process control, increase productivity or reduce costs. Often, implementing such changes is delayed due to concerns about validating changes and submitting regulatory filings. The concept of design space, defined by process development, DoE, empirical studies, and experience, and approval of that space may now enable changes to be made within that space without incurring regulatory delays (see ICH Q8).

Validation Strategy and Activities for A Cation Exchange Step

Figure 4
Although there is no one protocol for process validation for a chromatography step, a strategy and activity plan for validating a cation exchange step in a purification process for a MAb summarizes the key elements (Figure 4 and Table 2).

To validate this step, it is necessary to know why it was designed into the process. Most monoclonal antibodies bind to cation exchangers. This step is used to capture the MAb and remove process impurities such as host cell proteins (HCP), DNA, leached Protein A, other process impurities from cell culture and clarification steps, and product-related impurities. This cation exchange step is also used to enhance overall virus clearance.

Process-related Impurities

Table 2. Validation of a cation exchange step in the production of a monoclonal antibody
Based on the intended use of this cation exchange step, assays are developed and validated. A decision will be made whether to use clearance studies, routine in-process assays, or API testing for removal of HCP, DNA, and Protein A. The choice is dictated by assay sensitivity, the practicality of performing the assay, and relevance of the assay for in-process control.

Product-related Assays

Antibody titer and purity by high performance liquid chromatography (HPLC) are commonly used methods for assessing product quality. Impurities, such as aggregates and other product modifications, may also be detected by the HPLC assay. Other modes of HPLC may be used to detect glycoforms, and isoelectric focusing (IEF) might also be a useful assay.

Viral clearance

Viral clearance studies will be performed in a scaled down model, validated to represent manufacturing scale. Adherence to the ICH guideline for virus validation will be confirmed, which means prospective cation exchanger lifespan studies must be performed.13 In the future, it is possible that the surrogate determinations (i.e., removal of a specific impurity, height equivalent to a theoretical plate (HETP), and backpressure) might be acceptable for assessing column performance for a cation exchanger.

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