There has been increasing evidence in recent years that research in life sciences is lacking in reproducibility and data quality. This raises the need for effective systems to improve data integrity in the evolving non-GxP research environment. Reproducibility is a defining principle of scientific research, and broadly refers to the ability of researchers, other than the original researchers, to achieve the same findings using the same data and analysis data reproducibility is key to the reinforcement and credibility of scientific evidence. All results should be replicable by different investigators in varied geographical settings, using independent data, instruments, and analytical methods.
Some examples:
In 2022 there were 11 Federal Register notices with ORI findings of research misconduct that involved Public Health Service support or funding. These cases included falsified data submitted in National Institutes of Health grant applications and PHS-supported publications. These cases resulted debarment periods of up to four years and supervision periods of up to 12 years.
Without a doubt it is critical to build a quality culturewithin our research organizations. Through educating our scientific staff we can continue to innovate and discover new pathways, new drugs and new treatments. Efficient processes enhance research effectiveness and lead to scientific discoveries. Data integrity supports good science, drug safety, products and treatment development for patients and customers. While this looks similar in research as in later phases there are 4 primary pillars:
Train researchers on basic documentation processes and good scientific practices to ensure data integrity and quality. Targeted training should be added on new guidelines, processes and regulations applied to their specific activities.
Bespalov, A., Bernard, R., Gilis, A., Gerlach, B., Guillén, J., Castagné, V., Lefevre, I. A., Ducrey, F., Monk, L., Bongiovanni, S., Altevogt, B., Arroyo-Araujo, M., Bikovski, L., Bruin, N. de, Castaños-Vélez, E., Dityatev, A., Emmerich, C. H., Fares, R., Ferland-Beckham, C., … Steckler, T. (2021, May 24). Introduction to the EQIPD Quality System. eLife. https://elifesciences.org/articles/63294
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!).
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.
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
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:
Process performance and product quality monitoring system
Corrective action and preventive action (CAPA) system
Change management system
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.
ICH Stage appropriate quality system elements
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.
Consistency in execution
Document decision making
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.
Throughout the regulations and guidances you will find something like this: “As with other aspects of the development program, documentation may be ‘less vigorous’ in early phases, but ‘they would still need to be adequate in order to allow for traceability of the manufacturing process.'”
Agencies, like the FDA, have consistently stated that phase 1 is less vigorous but starting in phase 2 you are fully GMP. These regulations are meant to ensure basic safety and documentation standards are met in the manufacture and testing of phase 1 clinical trial material and to encourage the design of quality into the process. It is expected that enhanced process controls and GMP standards will be employed as the material transitions into later clinical stages.
With the speed of development, and the fact early phase material can support commercialization, this phased in approach is an important balancing act in advanced therapeutics like cell and gene therapy. It is crucial that manufacturers of phase 1 clinical trial material assess potential risks associated with their manufacturing process, facilities, equipment, methods, materials, etc. and the associated impact of these risks on the safety and quality of the material. All significant risks should then be mitigated, and appropriate controls implemented to reduce potential adverse impact for the patients and data generated.
Recognizing the difference between the elements of a strong quality system and what is needed for GMPs. Folks often confuse the two and have difficulties maturing quickly. The stuff in the orange? That’s system and is not GMP dependent.
Some GMP, such as clean room controls or starting materials controls should be robust from the beginning. Others, such as cleaning validation, are developed as you move through the phases.
Investigations of a Dog 