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

ICH Q10 Diagram of the ICH Q10 Pharmaceutical Quality System Model (Annex 2)

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:

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.

Risk Assessments Do Not Replace Technical Knowledge

The US Food and Drug Administration (FDA) last month warned Indian generic drugmaker Lupin Limited over three good manufacturing practice (GMP) violations at its facility in Maharashtra, India that identified issues with the company’s written procedures for equipment cleaning, its written procedures for monitoring and controlling the performance of processing steps and the “failure to investigate all critical deviations.”

The FDA said the company “performed multiple risk assessments with the purpose to verify whether existing cleaning procedures and practices eliminate or reduce genotoxic impurities … generated through the manufacture of [redacted] drugs after you detected [redacted] impurities in your [active pharmaceutical ingredient] API.” The company also performed risk assessments to determine whether its cleaning procedures reduced the risk of cross-contamination of intermediates and API. However, FDA said the risk assessments “lacked data to support that existing equipment cleaning procedures are effective in removing [redacted] along with residual API from each respective piece of equipment to acceptable levels. “The identification of genotoxic impurities in quantities near their established limits suggests excursions are possible. All intermediates and API manufactured on non-dedicated equipment used to manufacture [redacted] drugs should be subject to validated sampling and analytical testing to ensure they are not contaminated with unacceptable levels of genotoxic impurities,” FDA said.

At heart this warning letter shows a major weakness in many company’s risk management approach, they use the risk assessment to replace technical inquiry, instead of as a tool to determine the appropriateness of technical understanding and as a way to manage the uncertainty around technical knowledge.

A significant point in the current Q9 draft is to deal with this issue, which we see happen again and again. Risk management cannot tell you whether your cleaning procedures are effective or not. Only a validated testing scheme can. Risk management looks at the aggregate and evaluates possibilities.

Computer Software Assurance Draft

The FDA published on 13-Sep-2022 the long-awaited draft of the guidance “Computer Software Assurance for Production and Quality System Software,” and you may, based on all the emails and posting be wondering just how radical a change this is.

It’s not. This guidance is just one big “calm down people” letter from the agency. They publish these sorts of guidance every now and then because we as an industry can sometimes learn the wrong lessons.

This guidance states:

Determine intended use
Perform a risk assessment
Perform activities to the required level

I wrote about this approach in “Risk Based Data Integrity Assessment,” and it has existed in GAMP5 and other approaches for years.

So read the guidance, but don’t panic. You are either following it already or you just need to spend some time getting better at risk assessments and creating some matrix approaches.

Data Integrity Warning Letter

In July 2022, the U.S. FDA issued a Warning Letter to the U.S. American company “Jost Chemical Co.” after having inspected its site in January 2022. The warning letter listedfour significant areas:

“Failure of your quality unit to ensure that quality-related complaints are investigated and resolved, and failure to extend investigations to other batches that may have been associated with a specific failure or deviation.”
“Failure to establish adequate written procedures for cleaning equipment and its release for use in manufacture of API.”
“Failure to ensure that all test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity, and failure to ensure laboratory data is complete and attributable.”
“Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to establish and follow written procedures for the operation and maintenance of your computerized systems.”

I offer them the above clip as a good mini-training. I recently watched the show, and my wife thought I was going to have several heart attacks.

In a serious nature, please do not short your efforts in data integrity.

Whistleblower protection

The FDA recently completed its “Internal Review of Agency Actions Related to the U.S. Infant Formula Supply.”

In general, this report has few real planned actions and does not fill me with the hope of internal changes driving improvement.

One of the recommendations really stood out to me. Finding 2 states “Inadequate processes and lack of clarity related to whistleblower complaints may have delayed the FDA’s response to those complaints. A complaint sent via mail and other delivery systems by a confidential informant to agency leaders at FDA’s White Oak campus was not delivered to the addressees.”

Recommendation: The FDA should identify clear definitions for the terms “whistleblower,” “confidential informant,” and “informant,” and develop policies and provide training to staff regarding how to identify, escalate, and appropriately manage confidentiality of such complaints. The agency should also consider connecting complaints from such individuals to information received from product safety complaints, and product manufacturing concerns systems to support more complete access to all safety information. The FDA is evaluating how best to integrate this data to gain a holistic view of all FDA-regulated products and/or manufacturing facilities. The FDA should also review and update its mail and package delivery procedures to ensure that all mail and packages are delivered and received by addressees in a timely manner.
FDA Evaluation of Infant Formula Response

There is a real lack of whistleblower protection in this industry. Often when you hear about a crisis, from baby formula to Theranos to the opioid epidemic you have you have to ask “where were the good people at that company.” It can be rather disheartening. It has long been worrisome that the FDA does not have strong whistleblower protection in place, and to see how definitely that contributed to this debacle is just plain scary.