Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Change Control and Variations in Chemistry – Consequences on the regulatory workload for Active Substance Manufacturers ***

Sylvaine Hartmann (Abschlußjahr: 2006)

Language: English

This paper describes change control and the variations in chemistry as well as the consequences on the regulatory workload for active substance manufacturers.

The accepted international guideline issued by ICH for the production of APIs, ICH Q7, requires that “a formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or API”.

A change control system is a system where any change is logged, defined, documented, evaluated and confirmed before it can be implemented. The change must be evaluated from a technical, Quality and Regulatory perspective including Safety and Efficacy prior to implementation.

The evaluation of a proposed change should include consideration of the significance of the proposed change and the effect on quality of the final API. The impact on the dosage forms subsequently manufactured from API should be evaluated as well as the need to inform the concerned customers and, if necessary, to involve regulatory authorities.

Regarding documentation, it should be ensured that documents affected by the changes are actually revised (e.g. DMF, other regulatory documents, in-house instructions, and procedures, information given to customers, etc).

Communication between the active substance manufacturer and the finished product manufacturer is a key element in the management of changes affecting the active substance. The MAH is responsible in terms of public health. So the MAH is the one who has to notify the competent authorities of a modification of the terms of the marketing authorisation.

After the possibility of a change is approved by both regulatory partners of the active substance manufacturer and the marketing authorisation holder, it must be evaluated in the perspective of the international regulatory context - whether the change triggers a variation and whether it requires an assessment from the competent authorities.

The classification of variations and the corresponding submission procedures follow different schemes whether in the European Union or in the USA.

In the European Union, variations to the terms of a marketing authorisation are defined is a similar way in both CR1084/2003, for product approved through he Mutual Recognition Procedure, and CR1085/2003, for products centrally approved, as any amendment to the contents of the documents submitted to the competent authority as referred to in respectively Dir 2001/83/EC and in Regulation 726/2004.

Modifications can be categorised as follows:

  • a minor variation of Type IA or Type IB means a variation listed in Annex I of CR1084/2003 or CR1085/2003, which fulfils the conditions set out therein,
  • other modifications would not be variations because
    • the modification triggers a new marketing authorisation
    • the change is a line extension (as described in annex II of CR1084/2003 or CR1085/2003)
    • or the modification must follow a national law
  • any other modification would be a major variation of Type II.

For active substances, for which a CEP has been submitted, the procedure for revision of a CEP follows a pattern very similar to variations of a marketing authorisation. Then the revision of the CEP triggers a variation to be submitted by the MAHs of the related dosage forms.

In the USA, changes to the an approved New Drug Application are described in section 506A of the Federal Food, Drug, and Cosmetic Act and § 314.70 of the Code of Federal Regulations where four reporting categories of change are defined.

Reporting categories are based on the potential for the change to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety and effectiveness of the drug product.

When the potential is substantial, it is considered a major change and requires a Prior Approval Supplement.
When the potential is moderate, it is considered a moderate changeand requires either a

Supplement - Changes Being Effected in 30 Days (the drug product made using a moderate change cannot be distributed if FDA informs the applicant within 30 days of receipt of the supplement that a prior approval supplement is required) or a Supplement - Changes Being Effected.

And when the potential is minimal, it is considered a minor change. The applicant must describe minor changes in its next Annual Reportto FDA.

In the master thesis, examples are given of variations relating to the active substance in both the European Union and the US framework.

The approach of change control management and variations in the current regulations in the European Union and in the USA still shows regional specificities and differences.

There is a common conscience that this divergence of approaches to quality systems across the ICH regions leads to a less optimal use of ressources by both industry and regulators and causes inconsistent approaches between the three regions to compliance inspections.

A new regulatory environment is foreseen with the upcoming adoption of the ICH Q8 Pharmaceutical Development - and ICH Q9 Quality Risk Management - guidelines and the elaboration of ICH Q10 Pharmaceutical Quality System. The notion of design space as defined in ICH Q8 should help reduce the number of post-approval submissions since process improvements could be implemented on site without further regulatory review. ICH Q9 provides the tool of risk management and ICH Q10 should help implement ICH Q8 and ICHQ9. The combination of ICH Q8, Q9 and Q10 should lower risk operations, promote continual improvement and optimise change management.

ICH Q8, Q9 and Q10 together will enable the pharmaceutical community to move towards the desired state for the 21st century quality management.

Pages: 35

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