Phase Appropriate – An Unpacking

There is no term more misused and misunderstood than “Phase Appropriate.” It is one of those terms that just about everyone involved in FDA-regulated industries has an opinion on and one where we all get tripped up.

What do we mean by phase?

Drug development can be divided into discovery, preclinical studies, clinical development, and market approval. 

Each one of these phases is further broken down.

It is also important to remember that certain activities may start in earlier phases. For example, for manufacturing, tech transfer, and commercial manufacturing can start in Phase 3 (and more and more these days even 2!).

A similar approach can apply to medical devices.

The GxPs – a brief definition

Phase Appropriate GMPs

A Review of Regulations

21 CFR 210.2(c)	An investigational drug for use in a phase 1 study, as described in § 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter. However, this exemption does not apply to an investigational drug for use in a phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study, as described in § 312.21(b) and (c) of this chapter, or the drug has been lawfully marketed. If the investigational drug has been made available in a phase 2 or phase 3 study or the drug has been lawfully marketed, the drug for use in the phase 1 study must comply with part 211.
FDA Guidance	CGMP for Phase 1 Investigational Drugs
EMA/INS/GMP/258937/2022	Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice
Eudralex Volume 4 Annex 13	Investigational Medicinal Products

What Activities are Phase-specific for the GMPs

Phase 1:

• Critical quality attributes identified with safety Critical Quality Attributes (CQAs) clearly documented
• Process changes as information is accumulated
• Controls for analytical methods

Phase 2:

• Processes characterized and Production and Process Controls (PPC) identified
• Analytical methods are qualified
• Materials acceptance criteria
• Critical vendors qualified

Phase 3:

• Processes validated with Production and Process Controls (PPC) identified and controlled
• Validation of analytical methods
• Materials have been fully qualified and tested upon receipt as appropriate

What About the Quality System?

ICH Q10 clearly spells out the PQS requirements, breaking down into stages of Pharmaceutical Development (usually Phase 1 and earlier), Technology Transfer (usually phase 2), Commercial Manufacturing (which may start before approval) and Product Discontinuation. Q10 then lays out the expectations by these stages for the four key elements of:

1. Process performance and product quality monitoring system
2. Corrective action and preventive action (CAPA) system
3. Change management system
4. Management review of process performance and product quality.

	Pharmaceutical Development	Technology Transfer	Commercial Manufacturing	Product Discontinuation
Process Performance and Product Quality	Process and product knowledge generated and process and product monitoring conducted throughout development can be used to establish a control strategy for manufacturing.	Monitoring during scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Knowledge obtained during transfer and scale up activities can be useful in further developing the control strategy.	A well-defined system for process performance and product quality monitoring should be applied to assure performance within a state of control and to identify improvement areas.	Once manufacturing ceases, monitoring such as stability testing should continue to completion of the studies. Appropriate action on marketed product should continue to be executed according to regional regulations.
Corrective Action and Preventive Action	Product or process variability is explored. CAPA methodology is useful where corrective actions and preventive actions are incorporated into the iterative design and development process.	CAPA can be used as an effective system for feedback, feedforward and continual improvement.	CAPA should be used and the effectiveness of the actions should be evaluated.	CAPA should continue after the product is discontinued. The impact on product remaining on the market should be considered as well as other products which might be impacted.
Change Management	Change is an inherent part of the development process and should be documented; the formality of the change management process should be consistent with the stage of pharmaceutical development.	The change management system should provide management and documentation of adjustments made to the process during technology transfer activities.	A formal change management system should be in place for commercial manufacturing. Oversight by the quality unit should provide assurance of appropriate science and risk based assessments.	Any changes after product discontinuation should go through an appropriate change management system.
Management Review of Process Performance and Product Quality	Aspects of management review can be performed to ensure adequacy of the product and process design.	Aspects of management review should be performed to ensure the developed product and process can be manufactured at commercial scale.	Management review should be a structured system, as described above, and should support continual improvement.	Management review should include such items as product stability and product quality complaints.

Together with ICH Q9, this sets forth a framework of building knowledge and risk management into all aspects of the system together with a robust issue management mindset. There are really three things driving this.

1. Consistency in execution
2. Document decision making
3. Follow through

Some aspects remain pretty steady in all phases/stages, while others will grow as the organization develops.

The Difference Between Maturity and Phase Appropriate

People confuse phase appropriate with maturity all the time. Phase appropriate means doing the right activities in the right order. Maturity means the how is the most effective possible.

Quality Management Maturity (QMM) is the state attained when drug manufacturers have consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement. This is both composed of phase independent and phase dependent aspects.

Remember, a Quality Culture is the foundation that makes the rest of this happen.