7th Conference in 2004

10 November 2004

FDA and EMEA Presentation on Hot GMP and Regulatory Topics

On 20-22 October among others, speakers from FDA and EMEA gave presentations on hot GMP and Regulatory Affairs Topics. More than 200 participants and 20 speakers joined the 7th European Conference on APIs presented by APIC/CEFIC and organised by CONCEPT HEIDELBERG in Lisbon.

Dr Moheb Nasr, FDA Director of the Office of New Drug Chemistry gave the first presentation. His talk was about the initiative "Pharmaceutical Quality of the 21st Century". At the beginning he stressed that the initiative is not intended to reduce the regulatory requirements but to have a strong public health protection. In order to achieve this FDA has defined specific objectives:

  • To encourage the early adoption of new technological advances by the pharmaceutical industry
  • To facilitate industry application of modern quality management techniques
  • To encourage implementation of risk-based approaches that focus both industry and Agency attention on critical areas
  • To ensure that regulatory review and inspection policies are based on state-of-the-art pharmaceutical science
  • To enhance the consistency and coordination of FDA's drug quality regulatory programs especially review and inspection activities

As part of the Risk-based Management Plan, Dr Nasr explained the risk-based model for inspectional oversight that has been published recently (September 29) in a White Paper.

The FDA Inspection will be planned on the basis of 3 key elements.

  1. The GMP History
    If the company has a "clear record" they will face less inspections.
  2. The Drug Product
    Not only how complex the dosage is, but also the capacity of a manufacturing site will have an influence on the frequency of inspections (e.g. if a great output of large volume parenterals is produced, the site will be inspected more often than a site with only a small output). Of course, also the dosage form itself will have an influence (e.g. parenterals have a higher risk than solid dosage forms).
  3. The Manufacturing Process
    "It doesn't really matter how complex the process is." The new approach is more based on the amount of information you have about your process and how you are able to control the process (e.g. by using state-of-the-art technology like PAT).

In the following, Dr Nasr stressed the importance of international collaborations. FDA will actively involve in ICH Q8 and Q9 and help to build up a group that will set up Q10.

The FDA has also decided to become a member of PIC/S. This will help FDA to deal with the limited resources.

Under the leadership of the Council on Pharmaceutical Quality the following activities are planned:

  • Develop additional guidance on quality systems for pharmaceutical manufacturing so that the Agency’s goals to enhance and modernize the regulation of pharmaceutical manufacturing and product quality is met
  • Continue development of the risk-based pharmaceutical quality assessment system that will replace the current CMC review system to remove hurdles to continuous improvement following drug approval
  • Revise the 1987 industry guideline on Process Validation to include 21st century concepts, including risk management and a life-cycle approach

Dr Nasr stressed that the famous 3 batches for process validation are no longer a proof that the company understands the process.

In addition, he mentioned the following activities under the leadership of the Council on Pharmaceutical Quality.

  • Continue to explore and formalize risk-based tools to enhance FDA's regulatory oversight
  • Refine the CGMPs and meet our harmonization (internal and international) goals
  • Continue timely communication of our current thinking on various quality issues to the public to facilitate compliance with FDA requirements
  • Further enhance FDA's own quality systems (including more mechanisms to facilitate communication within the Agency)
  • Continue and expand on opportunities to integrate science-based policy and standards into our product quality regulatory approach

Dr Nasr emphasised that FDA undergoes a "cultural change". The review practice and also the organisation of this activity will be very much influenced by this change. With regard to the CMC specification, Dr Nasr mentioned that they should be based on

  • Risk-based assessment
  • Clinical relevance (performance and safety considerations)
  • Process knowledge and understanding - not necessarily process capability and analytical method limitations!
  • Knowledge gained from Pharmaceutical Development Reports (PDR)
  • Better utilization of modern statistical methodologies

These issues will be addressed at PQRI Workshop in March 2005

Dr Katrin Nodop from the European Medicines Agency (formerly called European Medicines Evaluation Agency) gave a presentation about the new pharmaceutical legislation in Europe. As a result of this review, the following regulations and directives have been set up:

Regulation replacing current Regulation 2309/93/EEC
-> Reg. 726/2004
Directive amending Directive 2001/83/EC ("Human code")
-> Dir. 2004/27/EC
-> Dir. 2004/24/EC (Traditional Herbal Products)
Directive amending Directive 2001/82/EC ("Veterinary code")
-> Dir. 2004/28/EC

Two of the main changes with GMP consequences are:

  • Inspection and control
  • Databases - manufacturing authorisations, GMP certificates, adverse reactions

Dr Nodop emphasised that the review has not defined that API manufacturers have to be inspected by a European authority. But it has been defined in "Title IV: Manufacture and Importation, Human Art. 46(f) and veterinary Art.50(f), Chapter 1":

The holder of a manufacturing authorisation is obliged to comply with the principles and guidelines of GMP for medicinal products and to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on GMP for starting materials.

As the ICH Q7A Guide on GMP for APIs (in Europe Annex 18 of the EU GMP Guide) will be the relevant guide, there is a need for a review of Annex 18. The reasons are:

  • General agreement that principles of GMP for APIs are included in Annex 18
  • Priority has to be given to revise the scope of Annex 18
    - inclusion of veterinary medicinal products
    - possible exclusions (radiopharmaceuticals?, herbals?, ?)
    - identify gaps and overlaps

In "Title IV: Manufacture and Importation, Human Art. 46(f)" it is mentioned that

  • This point shall also be applicable to certain excipients, the list of which as well as the specific conditions of application shall be established by a Directive adopted by the Commission.

Currently the Commission is evaluating which excipients will be covered by this requirement. A questionnaire was published recently.

Although there is no legal obligation for the competent authority to carry out inspections, it is clearly stated in "Title XI: Supervision and Sanctions Human Art. 111(1) and veterinary Art. 80(1)" that

  • The competent authority may also carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials,…. whenever there are grounds for suspecting non-compliance with the principles and guidelines of GMP referred to in Article 47 (vet Art. 51).
  • These inspections may be carried out at the request of
    - a Member State
    - the European Commission
    - the EMEA
    - the EDQM (linked to certification of conformity with the monographs of the European Pharmacopoeia)
    - the starting material manufacturer himself

and in "Human Art. 111(5) and veterinary Art. 80(5)" that

  • Within 90 days of an inspection as referred to in paragraph 1, a certificate of GMP shall be issued to a manufacturer if the outcome of the inspection shows that the manufacturer complies with the principles and guidelines of GMP as provided by Community legislation.

In the future, a Community database for GMP will be set up. The proceeding for the GMP database will be:

  • Member States shall forward to the Agency a copy of the manufacturing authorisation. The Agency shall enter that information on the Community database.
  • Member States shall enter the certificate of GMP which they issue in a Community database managed by the Agency on behalf of the Community.
  • If the outcome of the inspection as referred to in paragraph 1 is that the manufacturer does not comply with the principles and guidelines of GMP…, the information shall be entered in the Community database as referred to in paragraph 6.

For the first time, also negative information (e.g. a site is not GMP-compliant) will be put into the new database.

As future activities for EMEA in the field of GMP for APIs and excipients, Dr Nodop mentioned:

  • Annex 18 to be extended to veterinary products and other exclusions
  • Forms on inspection reports
  • Form and content of GMP certificates
  • Form and content for manufacturing authorisations
  • Define list of excipients
  • Define triggers for inspections
  • Community database for GMP
    - definition of content
    - input possibilities
    - output capabilities
    - access to different stakeholders
    - Linkages to existing systems (MS / Community)
    - Language requirements

According to the time table the implementation of these new provisions have to be finalised until 30 October 2005. And, industry has to implement the new provisions as well.

In addition to these two presentations, many authority and industry presentations were given on current GMP and Regulatory Affairs topics.

APIC/CEFIC and CONCEPT HEIDELBERG would like to thank the exhibitors:

  • Hecht Anlagenbau
  • Nycomed Austria

They would like to express special thanks to Hovione for acting as sponsor of the Social Event. All participants and speakers appreciated the sight-seeing tour, the visit to the museum and the excellent dinner afterwards.

The 8th APIC/CEFIC Conference on Active Pharmaceutical Ingredients will be organised in 2005.

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