The Code of Federal Regulations at 211.110 is titled “Sampling and testing of in-process materials and drug products.”  This new draft guidance, issued by the FDA, is designed to assist drug product manufacturers in complying with this section of the regulations “to ensure batch uniformity and drug product integrity.  In addition, this guidance discusses related quality considerations for drug products that are manufactured using advanced manufacturing.  It also discusses how manufacturers can incorporate process models into commercial manufacturing control strategies.”  The FDA indicates that this draft guidance does not apply to the manufacture of active pharmaceutical ingredients.

While the guidance outlines the need to ensure batch uniformity and drug product integrity, such as by defining drug product and process and critical quality attributes, it also discusses how “[k]nowledge and understanding that manufacturers gain from robust product and process development are an important basis for establishing and maintaining control strategies throughout the lifecycle of a drug product.  This helps ensure that drug products have the required quality attributes.”

The draft guidance is broken down into two major sections:

  • General Considerations for In-Process Sampling and Testing; and
  • Additional Considerations for Advanced Manufacturing and Process Models
    (includes 3D printing and continuous manufacturing)

The Agency acknowledges certain problems with full-process models for control in that “to date, FDA has not been made aware of process models that demonstrate that: (1) the underlying assumptions of the process model will remain valid during routine manufacturing; and (2) the manufacturer can detect if an underlying assumption is no longer valid (e.g., a continuous mixing model that assumes uniform mixing would be unable to detect that uniform mixing is no longer occurring due to material agglomeration on the walls of the mixer).  In other words, current process models cannot ensure the continued validity of all of the model’s underlying assumptions at all times, particularly during certain unplanned disturbances.  In the event of an unplanned disturbance that is not accounted for by the model’s underlying assumptions, such control strategies would be unable to prevent nonconforming in-process materials (e.g., nonhomogeneous powder blend) from continuing through production and being used ‘in manufacturing or processing operations for which they are unsuitable.’  Therefore, control strategies that rely solely on current process models would be insufficient to satisfy the requirements of § 211.110.”  However, the guidance discusses how additional in-process testing, either on-line or sampling, can overcome this issue for advanced manufacturing and process models.

The guidance also advises that the “FDA encourages industry representatives and manufacturers to contact FDA if they are interested in using alternative control strategies” and suggests discussions as early as possible in the process of developing new control strategies.  The FDA says, “[t]hese discussions will also help inform future policy development to support the adoption of robust alternative control strategies.”

The new draft guidance can be viewed here.