One of the more interesting and challenging aspects of stress testing involves interpreting the results of stress testing such that the data becomes meaningful to the development process. For example, what levels of instability are indicative of problems for analytical handling, manufac- turing/processing, formulation, patient “in use,” and storage and distribution? Can stress- testing results be easily interpreted to conclude whether or not a compound will have high-, medium-, or low-stability concerns for the development process? These questions are diffi cult as there are no (as yet) scientifi cally derived criteria for predicting the “developability” of a new drug entity. Such interpretive criteria would be very useful for the pharmaceutical development process.
Attempts have been made to use stress-testing results to classify compounds as extremely labile, very labile, labile, and stable ( 143 ). The basis for this classifi cation system was the per- sonal experience of the authors. In this section, we will attempt to outline and discuss some of
O N CH3 S OH O O H O N O OH O H
Duloxetine succinamide Duloxetine phthalamide
CH3
Figure 16 Structures of duloxetine succinamide and duloxetine phthalamide, the major impurities resulting from
interaction between duloxetine and the enteric coatings HPMCAS and HPMCP during stress testing or long-term stability studies.
Figure 15 Structures of enteric polymers HPMCAS and HPMCP.
O CH2OR OR OR O O O OR OR CH2OR R = HV CH3 COCH3 COCH2CH2COOH CH2CH(OH)CH3 CH2CH(OCOCH3)CH3 CH2CH(OCOCH2CH2COOH)CH3 n CH3 CH2CH(OH)CH3 COC6H4COOH HPMCP HPMCAS
the factors that need to be considered when attempting to interpret the results of stress testing, and to provide references to other resources. It is our opinion that insuffi cient information has been gathered to provide a defi nitive classifi cation system.
Interpretation of stress-testing results has several different facets. An obvious consider- ation is the degradation rate under a particular condition. The rates of degradation are critically important for determination of shelf life (although stress-testing results are, in general, not accurate enough to be used for shelf-life determination) and for handling considerations dur- ing manufacturing, formulation, and analysis. In addition to the kinetic interpretation, it is important to understand what the stress-testing results indicate about mechanism of degrada- tion (e.g., from the structures of degradation products and the degradation pathways involved). Such information is important in designing the appropriate degradation-control strategies ( 12 ) (e.g., developing a stable formulation, appropriate packaging and storage conditions, and relevant analytical methodologies).
Solid State
There are three main stress conditions evaluated during stress testing in the solid state: tem- perature, humidity, and photostability. The stress of elevated temperature is perhaps the stress condition that has historically been considered to lend itself most directly to predictive inter- pretation. This assumes, of course, that Arrhenius kinetics are observed within the range of long-term storage temperature to the stressed temperature(s). Assuming Arrhenius kinetics and reasonable energies of activation, predictions can be made to relate the amount of degrada- tion and increases of individual degradation products at the stress temperature to the long- term storage temperature. As discussed previously in the chapter (see section “Thermolytic Degradation”), the consideration of relative humidity is essential to enable the Arrhenius- derived predictions of degradation rates at different temperatures. Thus, it is possible to build accurate models of degradation rates using stress testing and a modifi ed Arrhenius equation that incorporates relative humidity ( 2 ).
The solid-state stress of exposure to light (i.e., ultraviolet and visible radiation) is guided by the ICH guideline on photostability ( 101 ). The ICH guideline is primarily directed toward confi rmatory photostability testing, which outlines photoexposure levels for the purpose of identifying potential photostability problems that may be encountered during storage and dis- tribution of the marketed product. Most of these types of problems can be addressed through modifi cations of packaging, labeling, and/or formulation (with some associated expense). Very little guidance is given to the interpretation of photostress studies (which the guideline refers to as “forced degradation testing”) in relation to the development process ( 101 ):
The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confi rmatory studies. These test methods should be capable of resolving and detecting photolytic degradants that appear during the confi rmatory studies. When evaluating the results of these studies, it is important to recognize that they form part of the stress testing and are therefore not designed to establish qualitative or quantitative limits for change.
Thus, photostressing studies are primarily useful for developing an understanding of the photochemistry of the drug and for developing appropriate analytical methodologies. See chapters 7 and 8 for further discussion of this topic.
One possible use of photostability/photostressing studies is the assessment of the poten- tial for problems in manufacturing and analytical handling. It has been recommended by EFPIA that 100,000 lux-hr is a reasonable amount of light exposure to determine whether or not special precautions should be considered during manufacturing ( 100 ). This level of light expo- sure should also provide a reasonable estimation of problems that might be encountered during analytical and formulation development. Of course, the potential for exposure to UV light may
also need to be assessed depending on the lighting conditions of the analytical laboratories and the manufacturing facility. The best way to assess the potential light exposure would be to make spectroradiometric measurements of both the UVA and visible regions in the actual laboratories and manufacturing facilities.
Solution: Acid/Base Stress-Testing Results
These results will indicate whether or not the drug molecule has a particular instability in aqueous conditions as a function of pH. An approximate pH-rate profi le can sometimes be constructed from the data, but caution should be exercised because it is not uncommon for a drug compound to be relatively insoluble in some pH ranges, and some samples may require co-solvents in order to achieve dissolution. If precise information on either kinetics or the pre- cise pH range of maximum stability is desired (e.g., for a compound that will have a liquid formulation), further studies in which the solvents, the ionic strength, the buffer type, and the concentration are carefully controlled, should be conducted.
Stress-testing information can be relevant for ADME concerns. Critical evaluation of the pH 1–2 degradation rate data can help assess the potential need for enteric coating of drugs to be administered orally. The pH of gastric fl uid (worst case) can be roughly simulated using 0.1 N HCl (pH 1). While transit times in the stomach are highly variable (dependent on variables such as % liquids/solids ingested, amount ingested, fasting level), most literature values fall within the time of 30 minutes to 4 hours ( 144 ). Assuming a worst case transit time (4-hour exposure to the acidic environment in the stomach), it seems reasonable to consider the potential need for an enteric-coated formulation if a loss of potency of ∼10–20% or greater is observed after 4 hours at 37–40°C in 0.1 N HCl; assuming fi rst-order kinetics of degrada- tion, this degradation rate would correspond to a half-life of ∼26 hours. Consideration of the potential need for enteric coating would involve many factors. For example, do the acidic degradation products raise questions of safety or effi cacy? How rapid is the absorption? What is the half-life of the compound in the body? What are the pharmacological needs for effi cacy of the parent? These questions need to be addressed on a case-by-case basis in an interdisciplinary manner (e.g., scientists from ADME, pharmacokinetics, analytical, formulations, and medical/clinical areas).
Evaluation of solution stability under neutral to moderately basic (e.g., pH 6–9) can help in assessing the potential for nonenzymatic breakdown of the compound under physiologi- cally relevant conditions (e.g., pH 7.5). Such information can be useful not only for metabolism studies, but also for pharmacokinetic concerns (i.e., understanding how long a compound might remain intact in vivo) and what degradation products might form under such condi- tions. Thus, for example, if a compound degrades at pH 7.5 at a rate signifi cantly faster than the in vivo half-life of the compound, the nonenzymatically formed degradation products will likely contribute to the metabolic profi le of the compound.
Evaluation of degradation rates under different pH conditions also provides needed information related to analytical concerns. For example, how much degradation might occur during the analytical work-up under specifi c pH conditions? Can samples be prepared and held at room temperature for a specifi ed length of time without appreciable degradation? Do samples need to be refrigerated in order to maintain stability during analysis? Answers to these questions are fairly straightforward if the analytical constraints are defi ned.
Solution: Oxidative Stress-Testing Results
It can be diffi cult to translate oxidative stress-testing results into accurate predictions of the susceptibility of a compound to oxidation. This is partially because oxidative mechanisms can be quite diverse and complex and oxidative degradation may not follow typical Arrhenius kinetic models, especially in solution. For a more in-depth discussion of this subject, see chapter 6 and the section “Hydrolytic Degradation.”
In chapter 6, Harmon suggests that the two most relevant tests for prediction of oxidative susceptibility of a drug compound involves the use of radical initiators (such as AIBN) for testing susceptibility to autoxidation and the use of dilute hydrogen peroxide for testing sus- ceptibility to oxidation by peroxides (e.g., from excipients). Boccardi has asserted that, assum- ing a test involving the use of AIBN in an equimolar basis with the drug, after 48 hours at 40°C, compounds that are sensitive to autoxidation will likely be degraded >10% whereas com- pounds that are relatively stable to autoxidation will likely be degraded no more than a few percent ( 91 ). A scientifi cally sound approach to a more accurate quantitative assessment of the oxidative susceptibility of pharmaceuticals would be a valuable contribution to the future of pharmaceutical development.
In the case of stress testing using hydrogen peroxide, it is diffi cult to associate a percent degradation with a classifi cation of oxidizability. If there are amines present in the molecule, especially tertiary amines, oxidation is usually rapid if the amine is uncharged (e.g., the free base). A protonated cationic amine is protected and the oxidation rate will be greatly reduced. In general, however, it is the experience of the authors that if a 0.3% solution of hydrogen per- oxide in the presence of the drug in an unbuffered water solution induces <5% degradation in 24 hours at room temperature, the compound is not particularly sensitive to peroxides and will likely not require special considerations for development. Alternatively, ∼20% or more degra- dation in 24 hours may indicate a particularly sensitive compound that could require special efforts in the formulation and/or storage conditions to ensure oxidative stability.
SUMMARY
Stress testing is an important tool for the prediction of stability-related problems. The results of stress testing can be useful to many areas of pharmaceutical research and development beyond the obvious areas of analytical, formulation, and packaging development. Well-designed stress- testing studies can lead to a thorough understanding of the intrinsic stability characteristics of the drug molecule, allowing a QbD-type approach where thorough knowledge and understanding are the foundation for building the stability control strategy. We advocate a chemistry-guided approach to stress testing, where structures of the major degradation products are determined and degradation pathways are proposed and tested. The quantitative interpretation of stress- testing results is an underdeveloped area that has made signifi cant progress in the last six years (since the publication of the fi rst edition of this book); continuing research is expected to contribute to new understanding and better tools for the future.
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