FDA Plans to Revise cGMP Guide Focussing on Outsourcing and Raw Materials

The FDA is going to revise 21 CFR 210/211 as part of their initiative to update cGMP requirements in a stepwise approach. On 20 July 2007 FDA's Fred Blumenschein gave a presentation at the 2nd European GMP Conference in Heidelberg, Germany (see our GMP News). He described the strategy of FDA to implement the changes.

As a first step FDA withdrew the proposed changes from 1996 and introduced minor changes to the cGMP Guide. A summary of these changes can be found in our GMP News.

At a conference of Xavier University FDA's Brian Hasselbalch explained the next step of this initiative. Due to the globalisation trend, FDA is facing a new challenge. Between 2001 and 2007 the number of Foreign Drug Sites doubled. Especially India and China export an increasing number of medicinal products and APIs to the US.


Taken from the presentation: Between 2001 and 2007 China and India Drug Products Increased 4- and 7-fold

Today most drug manufacturing facilities are no longer located in the US. In addition over 80% of the APIs are manufactured are imported. One major step to reply to this development is to modernise the cGMPs. Brian Hasselbalch listed the following possible component control improvements:

- Know supply chain
o Original manufacturer and subsequent handlers
o Audit original manufacturer
- Test each container in each shipment until...
- Require T-E packaging and security features
- Notify FDA of contaminated shipments/lots
- Use only components recognised as safe for their intended use or listed in an approved application

Phase 2 of the cGMP proposal could therefore contain the following new requirements:

- Establish "management responsibilities":
- Assure compliance to cGMPs; provide resources; perform periodic reviews
- Require self-inspection and response
- Enhance existing regulations defect/problem response:
- Defect investigations and follow-up
- Evaluation of data to detect a problem
- Require change control procedure
- Document training and effectiveness
- Establish Purified Water for component use; test potable
- Withdraw OTC expiration dating exemption

An additional focus will be given to the topic of outsourcing and contract manufacturing. Contract manufacturers are responsible for manufacturing products in conformance with cGMP. The firm that hires a contract manufacturer may also assume certain specified responsibilities under 211 or elsewhere. Sponsors and private-label distributors are also accountable under the statute. An important element to assure that pharmaceutical manufacturers have oversight of the processes which are no longer part of their own organisation are Quality Agreements. The following elements are important to consider:

- Identification of the contract site address, building, and equipment/line, and services/materials to be provided
- Description of the drug, its intended use: all specifications
- Provide for periodic audits to CGMP and contract specifics
- Commitment to share regulatory inspection findings
- Procedures for change control
- New equipment, facility modifications, change in key personnel, change in SOPs and test methods
- Full disclosure of all errors, deviations, changes, OOS results, investigations, as well as adverse events that did or might impact the drug 

The information provided in the presentation file shows that the FDA continues to react to the industry trend to outsource and purchase more and more components especially from Asia.  Outsourcing and purchasing from countries without appropriate GMP supervision need the special attention of the regulators, especially since all details of the Heparin case became public.

Source: Xavier University Website http://www.xavier.edu/xlc/med-xu/documents/XavierUnivpresentationHASSELBALCH.pdf

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