New FDA Compliance Programme  Guidance for Inspection of API manufacturers

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 FDA’s 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 FDA’s 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:

• Quality System
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labelling System
• Laboratory Control System

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:

• No evidence that the water or any other solvents used for the manufacturing process is suitable for the intended use; no validation of the water purification system
• No adequate validation of the critical manufacturing steps and specifically the final cleaning
• No impurity profiles for the manufactured APIs; the FDA expects impurity profiles for each API, consisting of data on organic, inorganic and solvents derived impurities
• Reprocessed batches do not comply with specifications
• No existing change control system
• Incomplete stability studies, no identification of potential degredants
• No or inadequate validation of analytical test methods; use of an inadequately or untraceable reference standard
• Risk of mislabelling in packaging

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:

Impurities – Detecting, Identifying, Quantifying, Specifying and Reporting 
from 30-31 March in Berlin, Germany

Quality Control of Raw Materials, APIs and Excipients 
from 19-20 June 2006 in Barcelona, Spain

Author:
Dr. Gerhard Becker
On behalf of the European Compliance Academy (ECA)

Source: FDA Webseite: http://www.fda.gov/cder/dmpq/7356-002f-CDER.pdf