FDA Publishes New Question and Answer Section on cGMP Compliance

With regard to the interpretation of the cGMP Guide, from time to time the FDA publishes questions and answers on current good manufacturing practices. On 12 November 2008, new items were added to this Q-and-A guidance.

This form of publication continues the former tradition of the Human Drug cGMP Notes. Today these publications have the status of "level 2 guidances" within the Good Guidance Practices and are supported by all relevant FDA centres, i. e. the CDER (chemically-based medicinal products for human use and APIs), CBER (biological/biotechnological medicinal products and APIs), CVM (medicinal products for veterinary use and APIs) and the ORA (Office of Regulatory Affairs).

Now the FDA published 4 new questions and answers in the section "Production and Process Control". Two answers inform about how to contact the PAT Team. The other two questions deal with the acceptance of ISO 14644 in the field of aseptic processing and the implementation of PAT. In the following you will find the questions and answers:

6. Is it generally acceptable from a cGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying their facility?

No.  It is generally not acceptable from a current good manufacturing practice ("cGMP") perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 Part 1: Classification of Air Cleanliness ("14644-1") and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 ("14644-2") when qualifying their facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control. Consequently, appropriate measures augmenting ISO's recommendations (e.g., with microbi-ological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.

Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones ("Federal Standard 209E").  In November 2001, the U.S. General Services Administration canceled Federal Standard 209E.

While not FDA regulations or FDA guidance, the Agency believes 14644-1 and 14644-2 are useful in facilitating the international harmonization of industrial air classification for non-viable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical).  As such, FDA adopted these particle cleanliness ratings in the 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice.  However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues) an aseptic processing manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying their facility.

Stephen Mahoney (HFD-326)

7. In 2004, FDA issued a guidance entitled "PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" that encouraged industry to modernize manufacturing through enhancements in process control.   How can I implement PAT (Process Analytical Technology)?

The objective of FDA's PAT program is to facilitate adoption of PAT.  In our 2004 guidance, we discuss FDA's collaborative approach to promote industry uptake of new and beneficial technologies that modernize manufacturing operations and enhance process control.  FDA recognizes that firms should be encouraged to promptly implement new systems that improve assurance of quality and process efficiency.  Accordingly, our approach to PAT implementation is risk based, and includes multiple options:

1. PAT can be implemented under the facility's own quality system. CGMP inspections by the PAT Team or PAT certified Investigator can precede or follow PAT implementation.

2. As another quality system implementation option, FDA invites manufacturers to request a preoperational review of their PAT manufacturing facility and process by the PAT Team (see ORA Field Management Directive No.135).

3. 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.  This option should be used, for example, when an endproduct testing specification established in the application will be changed. 

4. A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies, and time lines. Following collaborative review of the general strategy outlined in the comparability protocol, the regulatory pathway can include implementation under the facility's own quality system, a pre-operational review, CGMP inspections (either before or after PAT implementation), a combination of these, or another flexible approach.

Manufacturers should evaluate and discuss with the Agency the most appropriate option for PAT implementation.  For products regulated by the CDER, contact the Process Analytical Technology Team with any questions.

8. How do I contact CDER's Process Analytical Technology Team? 

Manufacturers are encouraged to contact the team via email regarding any PAT questions at: PAT@cder.fda.gov
To contact our PAT Team via mail, please see the PAT Web page (under the section "Contact Us") for our new mailing address at White Oak.

All correspondence should be identified clearly as "Process Analytical Technology" or "PAT."

Please also refer to the Web page to keep abreast of the latest information on PAT.

9 . How do I contact CBER's Process Analytical Technology Team? 
Manufacturers should contact the appropriate review division in CBER to discuss applicability of PAT to CBER-regulated products.

Contact Information:
• PAT Questions (CDER): PAT@cder.fda.gov
• PAT Team Members

The texts as well as the references can be found at:

Compiled by:
Oliver Schmidt
On behalf of the European Compliance Academy (ECA)


Conference Recommendations

Go back

GMP Conferences by Topics