REGULATORY APPROACH

One goal of this guidance is to tailor the Agency's usual regulatory scrutiny to meet the needs of PAT-based innovations that (1) improve the scientific basis for establishing regulatory specifications, (2) promote continuous improvement, and (3) improve manufacturing while maintaining or improving the current level of product quality assurance. To be able to do this, manufacturers should communicate important scientific knowledge to the Agency and resolve related technical issues in a timely manner. Our goal is to facilitate a flexible regulatory assessment involving multiple Agency offices with varied responsibilities.

This guidance provides a broad perspective on our proposed PAT regulatory approach. Close communication between the manufacturer and the Agency’s PAT review and inspection staff will be a key component in this approach. We anticipate that communication between manufacturers and the Agency will continue over the life cycle of a product and that communication will be in the form of meetings, telephone conferences, and written correspondence. Any written correspondence should be identified clearly as Process Analytical Technology or PAT. All marketing applications, amendments, or supplements to an application should be submitted to the appropriate CDER or CVM division in the usual manner.

We recommend general correspondence related to PAT be directed to our new FDA PAT Team. Manufacturers can also contact the PAT Team regarding any PAT questions or issues related to nonapplication drug products or not pertaining to a specific submission or application at the address below.

FDA Process Analytical Technology Team
Office of Pharmaceutical Science, HFD-003
Center for Drug Evaluation and Research
5600 Fishers Lane
Rockville, MD 20857

For currently approved products, during their planning phase, manufacturers should consider the effects of PAT on the current process, in-process controls, and specifications. When consulting with the Agency, manufacturers may want to discuss not only specific PAT plans, but also thoughts on a possible regulatory path.

This guidance is also intended to encourage research to explore suitability and validation strategies for new technologies prior to planning and implementing PAT-based manufacturing. If research is conducted in a production facility, it should be under the facility's own quality system. Information generated from this research along with other information that provides process understanding can be used to formulate and communicate implementation plans to Agency staff. Plans for implementing and regulatory assessment of PAT can be agreed to with the Agency through a variety of communication channels.

Section 116 of the 1997 Food and Drug Administration Modernization Act amended the Food, Drug, and Cosmetic Act by adding section 506A (21 U.S.C. 356a), which provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes. We recommend that manufacturers continue to consider all relevant FDA guidance documents for recommendations on the information that should be submitted to support a given change.

In general, PAT implementation plans should be risk based. We are proposing the following possible implementation options:

• PAT can be implemented under the facility's quality system; CGMP inspections by the Agency follow.
• PAT can be implemented following CGMP inspection by the PAT Team.
The PAT Team can assist manufacturers with pre-operational review of the PAT manufacturing facility and process (ORA Field Management Directive NO. 135). The recommendations in the inspection report will serve as a summary basis of final approval of the process and be filed in the relevant application, where needed, and facility databases within the Agency.
• A supplement (CBE, CBE-30 or PAS) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT Team or PAT certified investigator before implementation.
• A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies and time lines. Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation.
It should be noted that when certain PAT implementation plans neither affect the current process nor require a change in specifications, several options can be considered. manufactures should evaluate and discuss with the Agency the most appropriate option for their situation.