10 December 2019
GMP News No. 690
16 March 2006
New FDA Compliance
Guidance for Inspection of API manufacturers
To provide guidance, the FDA supplies their investigators with so-called Compliance Program Guidance Manuals (CPGMs). On February 13 the FDA enacted the revised CPGM for API manufacturers which will give investigators directions for future inspections.
The fundamental requirement that medicinal products (drug products) have to be manufactured according to cGMP is stated in the Food, Drug and Cosmetic Act, Section 501(a)(2)(B). Specifically for the manufacture of medicinal products the FDA issued more detailed regulations in form of the 21 CFR 210 and 211. In the FDAs understanding Active Pharmaceutical Ingredients (APIs) produced for the use in medicinal products are still regulated in Section 501(a)(2)(B) of "the Act," as the FDA typically calls the "Food, Drug and Cosmetic Act." On the other hand the FDA already adopted the internationally harmonised guidance ICH Q 7A targeting API manufacturers in 2001 with the explanation that the document represents "the FDAs current thinking." Thus it was only consistent to use the guidance as foundation for the inspection of API manufacturers and to integrate them in a manual (CPGM) for investigators.
The requirements in ICH Q7A are very precise and much more detailed than in other guidances which also made an impact on the available CPGM for inspections of API manufacturers. If the directions are applied as rigorously and consequently as stated in the manual API manufacturers will have to prepare inspections as extensively as manufacturers of medicinal products. Most likely it will also have an impact on tolerating deficiencies and issuing warning letters.
The CPGM for API manufacturers inspections is similarly structured as the manual for inspections of medicinal products manufacturers. It also mandates the systems approach, and classifies 6 systems:
As in the ICH Q7A document, every system has to fulfil certain criteria to rate the system as "under control." These criteria are just as rigorous and detailed as for medicinal product manufacturers.
There is also a remarkable list of deficiencies which if found during an inspection causes a regulatory action, which commonly means a warning letter. The inspector will then conclude that the system is out of control, and the generally destructive judgment will be: "The firm is out of control if any one system is out of control."
Following a selection from the list with a total of 16 items:
This CPGM shows that the requirements FDA investigators will demand API manufacturers to fulfil in the future are no different from the requirements they demand from medicinal product manufacturers. API manufacturers should thus prepare early and thoroughly.
The following European Compliance Academy (ECA) seminars focus on of FDA/GMP compliance topics relative to API production:
Detecting, Identifying, Quantifying, Specifying and Reporting
Control of Raw Materials, APIs and Excipients
Source: FDA Webseite: http://www.fda.gov/cder/dmpq/7356-002f-CDER.pdf