The European Medicines Agency (EMA) has finalized guidance intended to help sponsors meet the data requirements for process validation for biotechnology-derived active substances.

The guidance, which goes into effect in November 2016, covers process validation for a host of biological active ingredients, such as recombinant proteins and recombinant polypeptides, and may be applicable to other biological products such as vaccines or plasma-derived products.

Process Validation

Process validation is defined in International Conference for Harmonization's (ICH) Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients as, "The documented evidence that the process, operated within establish parameters, can perform effectively and reproducibly to produce an intermediate or API [active pharmaceutical ingredient] meeting its predetermined specifications and quality attributes."

EMA breaks process validation up into two main components: process characterization and process verification.

Process characterization is further divided into process development and process evaluation, and involves a sponsor defining its manufacturing process for an active ingredient and evaluating the process to ensure it is adequately designed.

Process verification involves studies done at manufacturing scale to confirm the performance of the processes the manufacturer has specified.

According to EMA, "Process validation should not be viewed as a one-time event. Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production."

Guidance: Process Development and Evaluation

During process development, EMA says that sponsors should conduct studies to inform the design of their manufacturing process. Then, based on those processes, sponsors should identify any key inputs and outputs that need to be evaluated and verified through additional studies.

This can either be done through a traditional approach, relying on studies of processes, through an "enhanced approach," whereby a sponsor use risk management principles and existing scientific knowledge to select and characterize its manufacturing process.

For more details on process development for biotechnology-derived products, EMA refers sponsors to ICH Q11, Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities).

When evaluating a manufacturing process, EMA recommends that sponsors focus the "potential criticality" of the inputs and outputs identified during process development.

EMA also says that sponsors may want to evaluate certain steps in their manufacturing process under less than ideal circumstances in order to "demonstrate the robustness and the capability of the process do deliver product of the intended quality."

When submitting a marketing authorization application, it is not always feasible for sponsors to evaluate a manufacturing process at full commercial-scale. As such, EMA says sponsors may rely on "justified" small scale models.

"During process evaluation, small scale models enable evaluation of input material and parameter variability to an extent that may not be feasible at manufacturing scale," EMA writes.

When using small scale models, EMA says sponsors must be able to demonstrate that the inputs and outputs are relevant to full scale commercial manufacturing.

Process Verification

Once a sponsor has developed and evaluated its manufacturing processes, EMA expects them to verify that their processes will perform as expected on a commercial scale by producing batches of an active substance.

According to EMA, the number of batches required to verify a sponsor's manufacturing process is based on four criteria:

1. "The complexity of the process being validated;
2. The level of process variability;
3. The amount of experimental data and/or process knowledge available on the process; and
4. The frequency and cause(s) of deviations and batch failure."

Additionally, sponsors may be able to reduce the amount of data required for process verification if they can demonstrate that data from small scale studies is an "appropriate representation of the proposed commercial scale."

If sponsors are using an enhanced approach to process development, they may also be able to reduce the number of batches necessary by also employing continuous process verification.

To implement a continuous approach, EMA says that "companies should perform, as relevant, extensive in-line, on-line or at-line controls and monitor process performance and product quality on each batch."

For continuous process verification, EMA says that sponsors must also weigh:

• "Prior development and manufacturing knowledge from similar products and/or processes;
• The extent of process understanding gained from development studies and commercial manufacturing experience;
• The complexity of the product and/or manufacturing process;
• The level of process automation and analytical technologies used."

Exceptions

The guideline also details instances when different approaches to process validation may be required.

For instance, EMA says that under "exceptional circumstances," such as urgent medical need, sponsors may rely on concurrent validation by demonstrating that the studies done under process evaluation "are appropriate representations of the commercial process [and the] control strategy will properly verify that the process has performed as intended and that the active substance and intermediates comply with pre-defined acceptance criteria."

Additionally, for some niche products, EMA says it might not be possible to include full validation data in a marketing application.

"In these cases, the applicant may choose to present in the regulatory submission how the data generated through such verification activities will be managed to facilitate the acceptance of the claimed process step. This can be in the form of a protocol that indicates how process knowledge, control strategy and characterization methods will be deployed to assess product quality throughout the lifecycle of the product," EMA writes.

EMA