Properly planned, executed and managed stability studies arecritical for understanding data generated during clinical trials
The approval of a drug for the marketplace relies heavily on the success or failure of the clinical trials. Equally important is the understanding of its stability both as an active pharmaceutical ingredient (API) and as a finished drug product (FDP).
As with clinical trials, it is imperative to properly plan, document and manage stability study cycles or programs. There are several items to be considered and planned for which, if addressed, can result in reliable information-rich data or, if overlooked, may result in investigations or jeopardize approval of the drug.
A Clear Study Objective
Without a clear understanding of the objective of the stability study, the study is at high risk of failure and could not only result in enormous loss of valuable time and resources, but also failure of the drug. The objective should be defined by input from all pertinent parties (i.e., project management, R&D, manufacturing, etc.).
Definition of the objective should include considerations for retest or shelf life of the drug and the proper storage conditions. Also keep in mind packaging and marketing locales as these will help define the environmental storage conditions for the stability study and consideration of the packaging materials will assist in defining the number and orientation of samples.
Stability studies are run concurrently with toxicological studies to determine the safety of the drug, so consideration of all facets of the drug’s potential degradation during the definition of the objective will greatly improve the quality of the data and the success of the stability program.
In the overall program, defining the objective is usually overlooked, but should be considered one of the most critical steps.
Forced Degradation Study
To adequately detect, quantitate and trend a product’s degradations that are generated during a stability study, the methods used for testing must be stability indicating. To ascertain a method’s stability indicating capability, it is necessary to perform a forced degradation study.
Generally, a forced degradation study is performed prior to commencing stability testing by exposing the drug to a variety of extreme conditions, such as pH, photolysis, oxidation and temperature, over a very short time period.
Drugs are exposed to a range of pH levels to ascertain the drug’s susceptibility to hydrolysis. Photolysis of the drug demonstrates whether exposure to light results in unacceptable changes. Oxidation and elevated temperatures potentially generate a variety of impurities that may differ from that of the photolysis or pH conditions. The degraded drug products provide information into the potential impurities of the drug that may be generated during stability testing.
Forced degradation studies can also be used to quickly assess packaging material compatibility or sensitivities.
Stability Study
After clearly defining the objective of the stability study, ascertaining the capability of the methods and determining the potential impurities of the drug from the extreme conditions of the degradation study, the
drug is then evaluated on a much larger scale by performing a stability study.
Stability studies determine the drug substance or products degradation as a result of exposure to a variety of conditions, such as temperature, humidity, light, orientation and packaging materials over an extended time frame2. The length of the study and storage conditions are critical in developing an understanding of the drug substance or product stability.
Testing frequency of the drug substance or product is dependent on the proposed retest period of the drug. Generally, long-term stability studies involve an initial evaluation of the drug followed by analysis every three months for the first year and then every six months for the next year or two. Short term stability studies, such as in an accelerated stability study, should have a minimum of three time points, such as the time zero, three-month and six-month.
Accelerated stability testing is also performed on drugs by exceeding the storage condition parameters. The accelerated stability testing differs from the forced degradation study by only exposing drugs to elevated changes in the intended storage conditions with the goal of determining how the drug will react to short-term conditions outside of the intended storage conditions.2 For example, the optimal storage conditions for oligonucleotides is -20°C or 5°C. During a stability study, lyophilized oligonucleotides are exposed to the optimal storage condition as well as accelerated storage conditions, such as 30°C/60% relative humidity (RH) or 25°C/60% RH. The exposure of the lyophilized oligonucleotide to the accelerated storage conditions determines if short term exposure to elevated temperatures and/or humidity would be deleterious to the composition of the oligonucleotide.
The drug’s physical appearance and purity might change from it being chemically degraded faster at intensified storage conditions. The accelerated conditions may cause significant changes to the drugs, but valuable information on the long term chemical stability at the intended storage conditions can be obtained.
Intermediate stability testing, running concurrently, involves exposing drugs to storage conditions between the intended conditions and accelerated conditions. The intermediate storage conditions might also cause significant changes in the drug. However, if the purity and physical appearance of the drug remain unaltered, then the specifications for storage could be increased and valuable knowledge on the shelf life of the drug will be determined. Therefore, stability testing should encompass several storage conditions, whenever possible, to ensure greatest understanding of the drug’s shelf life.
Analytical Testing Specifications
During stability testing, drug substance are removed from the various storage conditions, analyzed and compared to specifications. ICH and the FDA define a specification as “a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described… Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.”3
The drug must conform to these specifications when tested by the proposed analytical tests to be considered for its intended use. New drug substances, at a minimum, are tested for description, assay, impurity and identity. New drug products may require additional analytical tests due to the fact that the drug may be in liquid, tablet or parenteral form.3
Additional analytical testing, such as pH and moisture content potentially determined from the forced degradation study, of the drug can be performed when the result of each test may have an impact on the quality of the drug. The description of the drug’s physical appearance after being exposed to the various environmental conditions provides the first observation on whether the environmental conditions have affected the drug.
Many different analytical instruments, such as HPLC and capillary gel electrophoresis (CGE), exist to evaluate the purity, assay, identity and impurities of the drug. In some cases, an impurity will co-migrate with either the parent peak or another impurity in one analytical method, but can be identified in a different method.
For example, the N-1ps impurity associated with synthesized phosphorothioate oligonucleotides coelutes in reverse phase HPLC analysis with another impurity, but is resolved under CGE.
However, in the CGE analysis, the oxidated form of the phosphorothioate oligonucleotide will co-migrate with the parent peak. Therefore, multiple analytical tests may need to be performed to elicit the entire impurity profile of a particular drug substance or product.
Conclusion
Properly planned, executed and managed stability studies are critical for understanding data generated during clinical trials. Organized stability studies yield meaningful, information-rich data which supports or enhances clinical data.
In some cases it may give insight on or help prevent potential problems. The key to successful stability studies is in the planning and defining stages. Understanding the objective and following the FDA guidelines will result in more useful data, understanding of the product and processes, shorter time to market and greater cost savings.
References:
1. ICH Harmonised Tripartite Guideline Q1B: Stability Testing: Photostability Testing of New Drug Substances and Products
2. ICH Harmonised Tripartite Guideline Q1A (R1&2): Guidance for Industry Stability Testing of New Drug Substances and Products
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