Quality by design: questions and answers

It is anticipated that the introduction of PAT-based systems will change the way knowledge is presented in the dossier demonstrating greater understanding of the variables that affect product quality attributes, as well as the methods to monitor and control them.

One of the expected outcomes is that a 'design space' within the boundaries of the knowledge described in the development part of the dossier will be established and that the process control strategy will fall within this space. The European Medicines Agency envisages that manufacturers will be able to introduce adjustments without the need for a variation submission provided that the manufacturer operates within the design space defined in the original submission or subsequent variation.

Currently, there is no universally accepted definition of the term 'process signature'. Therefore, applicants will have to carefully describe what they mean in any regulatory submissions.

However, the Agency has noted that the concept of process signature may be applicable in controlling manufacturing processes. From this, the Agency sees the process signature as a possible means of demonstrating that a process is operating within an approved design space. However, as far as expanding the design space in the post-approval phase is concerned, a number of factors need to be considered, including:

• how the process signature is being used;
• what has been accepted and agreed to in the submission;
• how it is proposed to expand the design space.

Extensions to the design space are subject to prior regulatory approval, but when more experience with process signatures is gained in the future, this might be reconsidered.

In current European Union legislation, a medicinal product must have two specifications: release and end of shelf-life that take into account relevant monographs of the European Pharmacopoeia.

How the manufacturer ensures compliance with the release specifications is open but has to be described in the submission.

In the case of PAT-based submissions, the Agency foresees a third specification based on process measurements and controls that the manufacturer will base release decisions upon. A key issue that has to be addressed in the submission is the relationship between these parameters and the release specifications. Nevertheless, when tested after release using conventional methods, the product must comply with the end-of-shelf-life specifications.

It is important to distinguish between process specifications and finished product specifications. In principle, as elaborated above, it should be possible to introduce adjustments provided that they fall within the design space already defined in the dossier without the need for further variation application. On the other hand, changes to the finished product specification will be subject to the variations regulations.

The Agency is prepared to accept that where a product is subject to enhanced process understanding and monitoring, a state of continuous validation could be achieved. The validation strategy should be adequately justified.

Any PAT method must be shown to be fit for purpose. This, together with a quality risk-management approach, will dictate the level of validation required. If the method is not for quality control, in order for the information that is being gathered to be meaningful and have value (dictated by what use is being made of the information) the applicant must have confidence that the results are relevant and repeatable, and consequently must carry out appropriate validation to confirm this.

The focus of such an inspection, if requested, is likely to concentrate on data supporting the critical process parameters and design-space ranges. Consequently, this information should be available for inspection.

It is acknowledged that some laboratory experiments will not have been carried out in accordance with full good-manufacturing-practice (GMP) requirements and that there would be no need to repeat every one of these under GMP conditions. However, it would be expected that raw data would be documented according to a predefined archiving strategy and traceable as a matter of good scientific discipline.

It is nevertheless recommended that development work is carried out within a quality system environment such as that described in ICH Q10. Where experiments are key to establishing critical process parameters and design space, it would be expected that these would be verified by repetition and under GMP conditions, but it would be anticipated that the majority of these would actually form part of the normal progression and verification of the proposal into the production environment.

The level of interaction during (and possibly after) the assessment process will depend upon what is actually proposed, which could be quite varied and of different levels of complexity. Where needed, a discussion between the assessor and inspector is important to achieve a common understanding of the applicant's proposal and its potential impact on the marketing-authorisation dossier and on-site situation.

The potential requirement for an inspection will depend upon the applicant's approach to and justification for RTRT and on existing experience of the manufacturer with this approach, i.e what the basis is for RTRT and what in-process controls will be applied, and how this will be done, e.g. the technology applied. If complex technology (such as near-infrared or Raman spectroscopy) is used for RTRT for the first time at a manufacturing site, a product-specific inspection is likely to be requested. If the RTRT approach merely involves an increased level of at-line testing in lieu of finished product testing, then this would not necessarily require a product-specific inspection prior to approval, but will be taken into consideration as part of a future routine GMP inspection.

The focus of such an inspection, if requested, is likely to concentrate on data supporting the critical process parameters and design-space ranges. Consequently, this information should be available for inspection.

It is acknowledged that some laboratory experiments will not have been carried out in accordance with full GMP requirements and that there would be no need to repeat every one of these under GMP conditions. However, it would be expected that raw data would be documented according to a predefined archiving strategy and traceable as a matter of good scientific discipline.

It is nevertheless recommended that development work is carried out within a quality system environment such as that described in ICH Q10. Where experiments are key to establishing critical process parameters and design space, it would be expected that these would be verified by repetition and under GMP conditions, but it would be anticipated that the majority of these would actually form part of the normal progression and verification of the proposal into the production environment.

For biological products or when models (design-space or calibration models for complex technology such as near infrared, etc.) are part of the RTRT scheme, results of parallel testing on commercial-scale batches should normally be included in the marketing-authorisation or variation submission.

In event that parallel testing of a sufficient number of batches is not complete at the time of submission or approval, this may be completed by inclusion in a post-approval change-management protocol and the marketing authorisation can be granted on the grounds of finished product testing.

Once parallel testing is complete, RTRT may be implemented by either notification to (type IA), or approval by, the competent authority (type IB) as appropriate. The route for implementation will be indicated to the applicant during the assessment of the initial application.