By Judy Carmody, Ph.D., Carmody Quality Solutions, LLC
A drug stability program that is above reproach is critical to successfully navigating the complexities of drug development. A well-managed stability program with thoughtfully constructed protocols demonstrates your lab and quality systems are in control.
It shows how stable your material is during development and can provide insight into which degradants are formed and when and which potential orientations, formulation, packaging materials, or conditions may cause undesirable results. The data generated from these studies affects how the therapy is ultimately formulated, manufactured, packaged, stored, and administered.
Such stability programs have common attributes that should be maintained to deliver critical data needed to successfully navigate the drug development process:
- Stability is a full-time job. You need one leader to ensure success. This person oversees the program and the systems you put, or already have, in place. Smaller companies assume they will take an analyst out of the lab and make them the stability coordinator. But many things happen when no one is focused on managing the entire program. These include missed time pulls and ambiguous stability protocols, which result in not capturing information such as container closure composition or orientation.
- Stability-indicating methods are developed early. Understanding the stability profile and characteristics of the drug substance is fundamental in laying the foundation for subsequent stability testing. Confirm that your drug substance, drug product, and analytical methods are appropriate by staying current with the latest regulatory updates and warning letters.
- Make API substance stability part of molecular characterization.
Conduct forced degradation studies that stress-test these molecules to understand potential impurity or degradation peaks. Make certain stability is part of feasibility so it leads to the go or no-go decision.
- Stability work is continued through all phases of development. Work closely with formulation and process development groups to put material on stability after major process or formulation changes. This helps to demonstrate consistency in degradation profiles after major changes. Don’t forget to assess analytical methods after these types of changes to verify they are still fit-for-use, as they may also require modification and revalidation.
At each phase of development (preclinical, early/mid-clinical, and late clinical) are elements that can increase the probability of obtaining useful data to make critical decisions and gain FDA approval.
Preclinical Development: Make Stability Part of a Go/No Go Development Decision
The purpose of this phase is to understand and characterize your drug substance by conducting appropriate testing for identity, strength, purity, and stability. Stability is key before you even get into the clinic. The only reasons for a chemistry, manufacturing, and controls (CMC)-based clinical hold at investigational new drug (IND) Phase 1 are a safety concern or insufficient information to assess safety. The way to mitigate stability as a safety concern is to:
- Have plenty of technical data. Implement the proper systems and manufacturing process to gain a scientific understanding of the structure and breakdown pathways of the molecule. Assess the stability of samples used in model systems and, as required by regulations, pivotal toxicology studies. Data acquired later is always compared back to the data generated from your toxicology studies.
- Perform short-term, real-temperature, and accelerated stability of the active pharmaceutical ingredient (API)/drug substance (DS) and experimental drug product (DP), if available.
- Assess the stability of the test article and test article in carrier during pivotal preclinical trials, as required by the regulations.
Properly structuring your stability program at this stage allows for a detailed understanding of the profile and characteristics of the drug substance. It is on this foundation that subsequent stability testing will be built for eventual product approval.
Early to Mid-Clinical Development: “Do Your Homework” — Acquire Deep Stability Knowledge
The FDA notes “it is helpful if the stability protocol is submitted in an information amendment before or during Phase 3 studies and is discussed at the end-of-Phase-2 meeting.”1
At this stage, the stability program should be in full swing. To best position yourself for successful late-phase clinical development, it is important to:
- know degradation pathways, kinetics, and products of API/DS and DP to optimize stability-indicating methods for DS and DP and get them ready to validate or re-validate
- show stability of materials used in clinical trials
- develop primary and working reference materials
- fully characterize any degradants seen in real-time/temperature studies and primary accelerated studies (any studies used to establish/justify expiration date/shelf life)
- evaluate container/closure systems
- develop stability specifications and finalize them before manufacture of Phase 3 material.
To demonstrate well-constructed stability studies, moving toward full GMP compliance in preparation for pivotal efficacy trials, create protocols with the following elements:
- manufacturer of DS, DP, and excipients
- proposed retest or expiration date
- type, size, and number of batches
- type, size, and source of containers and closures
- test parameters
- validated stability-indicating test methodology for each parameter assessed
- storage conditions
- container orientations
- sampling plan
- test time points
- acceptance criteria
- information on how data will be reported or presented
- statistical approaches and methods for evaluation of results and determining retest or expiration dates
- outline of the stability commitment
- how the protocol can be modified and amended.
Late Clinical Development: Phase 3 — Full GMP Compliance
During this phase, not only is stability performed on the API/DS, drug product intermediate (DPI) (as applicable), and DP, but also stability of diluents, reconstituted drug product, and drug product in multi-use containers (e.g., vials) must also be performed.
Work performed at this stage enhances the chances of getting an approval letter (rather than a “complete response” letter). Phase 3 requires GMP-compliant protocols, validated methods, change control, and well-documented investigations of all deviations, discrepancies, and out-of-specifications (OOSs). There is a high risk of failure at this stage. The company’s commitment to quality will be evaluated here, specifically, in what you do when things go wrong (i.e., how effective you are at documenting and handling such events). Ensure success by having robust OOS, investigation, corrective and preventive actions (CAPAs), and deviation systems and rigorous training on their execution. To this end, stability reports should include:
- general information
- summary information
- specifications and test methodology
- study design and conditions
- data and data analysis
- degradation product information
It is also important to include references to any deviations and/or OOS documentation. Reports should be clear and concise; include the rationale for the design, statistical handling of data, and specific conclusions to help inspectors or auditors understand the connectivity of the data to the overall development of the drug. Do your due diligence instead of waiting for the FDA to do it. Find out where the gaps are, acknowledge those gaps, and put a plan in place to mitigate them.
This also is the time to prepare for an FDA inspection of your stability program. The easier you make it for an inspector to follow your drug development road map and the better you explain how stability data supports decisions made, the less likely you will have something appear in any 483s.
Post-Approval/Licensure: “Color Within The Lines.” Honor Stability Commitments
The role of stability at this phase is to demonstrate continued consistency in manufacturing. It is important to:
- Keep stability commitments to the FDA. If you say you will conduct long-term studies on the first three commercial lots, do it. Make sure to conduct an annual stability batch (or more) or special stability studies (e.g., lots requiring reprocessing) as applicable, track and trend everything, and keep it current.
- Make sure you have a rationale, and the data, to support everything you do. When there is a stability failure and you decide not to conduct a recall, have documented rationale, data, and justification.
- Seriously consider the impact of process, formulation, and delivery method changes on existing stability data and scrutinize any protocol modifications.
- Investigate any trends that extrapolate to being OOS before end of shelf life and any other similar events with and determine the root cause. Perform an impact assessment and execution of CAPAs, if necessary, and track the effectiveness of systemic CAPAs with all proper documentation.
- Submit field alert reports (FARs) and biological product deviation reports within required timelines.
GMP compliance is an intricate ballet. Not only do you have to execute many steps flawlessly, but you also must perform them in the correct order. There is much to building, managing, and maintaining control of a stability program. But being in control will prepare you for any number of unforeseen developments, surprise inspections, or audits.
Editor’s note: To help you optimize the stability program at your company, the author has created comprehensive checklists for each phase of the drug development process. You can download them for free at http://www.carmodyqs.com.
- Guidance for Industry: INDs for Phase 2 and Phase 3 Studies, FDA, May 2003.
About The Author
Judy Carmody, Ph.D., is the founder and principal consultant of Carmody Quality Solutions, LLC, based in the Boston area. With 20+ years of expertise in operations, quality assurance, control, systems, validation, and analytical development, she has a reputation as a quality turnaround specialist in the pharmaceutical and biotechnology industries. Find her on LinkedIn.