New draft guidance issued by the US Food and Drug Administration (FDA) is intended to clarify which changes to a pharmaceutical company's manufacturing process must be reported to federal regulators, and how.
The draft guidance, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products, focuses on changes made to chemistry, manufacturing and controls (CMC)—the core components of the drug production process.
At the time a drug (chemical or biological) is approved, its approval is based upon not only the drug's safety and efficacy, but also the manner in which it is produced. Because changes to a drug's method of production can impact its quality, and therefore its safety and efficacy, FDA maintains a tiered system of oversight over these changes.
While FDA must, per 21 CFR 314.70, be notified of all changes to a drug's method of production, the manner and timing of those notifications depends upon the severity of the change.
A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. – 21 CFR 314.70(b)
These are more commonly known as pre-approval supplements (PAS), and require FDA's approval before they can be implemented.
Other types of changes include 30- or 0-day notifications, which are used to notify FDA of changes expected to have a "moderate" impact on drug quality. These notifications do not require FDA's explicit approval, but provide an opportunity for FDA to reject the application upon review. [21 CFR 314.70(c)]
Finally, for changes only expected to represent a "minor" impact on drug quality, a company may also notify FDA of changes in its annual report to the agency. [21 CFR 314.70(d)]
Need for Guidance
That regulatory framework is quite familiar to most regulatory professionals.
What isn't so clear, FDA explains in its guidance, is how certain changes need to be reported. For example, FDA's regulations require a company to report changes with respect to "each change in each condition established in an approved application beyond the variations already provided for in an application."
By "established conditions," FDA essentially means the condition of manufacture established by a company in its FDA-approved application. Or, if you prefer FDA's exact definition:
the description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in an application, that assure process performance and quality of an approved product.
The problem, FDA explains in its guidance, is that, “There has not been a common understanding of the meaning of the phrases 'each condition established in an approved application' and 'established in the approved license application(s).' "
And that's not a small matter, FDA continued.
Confusion over regulatory semantics "could have a negative impact on change management activities and could discourage continual improvement in product manufacturing processes, lead to unnecessary submission of post-approval supplements to FDA for changes that could be managed solely by a manufacturer’s Pharmaceutical Quality System, or, upon inspection, lead to Form 483 observations for changes that should have been reported to FDA."
Some changes are obvious. For example, replacing one excipient with another would always be considered a change under FDA's existing regulations.
Where things become trickier is on the edge of "established conditions," such as process controls meant to assure process performance or product quality. Some of those process controls fall under FDA's definition of "established conditions," while others do not, regulators said.
If a process control was submitted in an application, it may be considered an "established condition," FDA said. Examples included by FDA in its guidance are:
- Drug Substance (DS)/Drug Product (DP) (including in-process materials) manufacturing and testing facilities.
- Source of and specifications for starting materials for biological products.
- Process, including in-process tests and sequence of operations, equipment; and process parameters and their ranges.
- Specifications, including the tests, analytical procedures and acceptance criteria; including specifications for the DS, other components, in-process materials, and the DP.
- Container closure system, components, and specifications.
- Maintenance strategy for chemometric and/or multivariate models (e.g., for models that may have a high impact on product quality).
In some cases, the conditions will be facility-specific, FDA noted.
All changes should be noted in the appropriate section of the Common Technical Document (CTD), which is explained in depth in FDA's guidance.
On the other hand, certain data elements most likely won't be considered "established conditions" under FDA's regulations. For example, batch records, development data, characterization data, validation data and batch analysis data would likely be excluded.
Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products