FreeThink is committed to supporting our licensed ASAPprime® users and answering all of your software questions. Below is a list of the most frequently-asked questions. If your question is not addressed here and you still require technical assistance regarding your software purchase, please contact FreeThink’s ASAPprime® Tech Support Desk at firstname.lastname@example.org.
What are the technical specifications required to use ASAPprime® software?
The software will run on Windows 7™, 8™ and 10™. The software is designed to run directly on personal computers. It will run somewhat slower on older, slower models.
How is the system validated?
The software system was validated by using independent software for each part of the multi-step calculations. This confirmed that the values generated were the same using an extensive data set. This validation package is available to customers. The GMP status of the software (including validation and change control) is open to inspection, and has been passed by at least one major pharmaceutical company. This, of course, only validates that the software calculations are doing what the algorithm is stated to do. To validate that the calculations provide accurate estimates of ambient behavior, FreeThink has examined numerous real drug products stored within a range of packaging and environmental conditions. Except in cases where there was a phase change (e.g., loss of water of hydration, melt, etc.), the overlap between the error bars of the measured values and the predicted estimations were remarkably reliable. Many companies choose to test ASAPprime® in their own hands using a comparison between their long-term data and an ASAPprime® study carried out in conjunction with FreeThink.
Does the software work with solid dispersions?
Solid dispersions will work with ASAPprime® software, provided the accelerated conditions remain below the glass transition temperature (Tg) of the dispersion. There is evidence that ASAPprime® software can successfully predict chemical stability, but also can be used to estimate crystallization rates at ambient conditions.
Does the software handle potency loss?
ASAPprime® software has options for working with potency loss. Users are cautioned to use an adequate number of repeats to take into account the relatively high variability of potency values.
Does the software take into account micro RH?
In our studies on RH equilibration, we have found that the timescale for such equilibration is generally quite fast compared to the scale of most shelf-lives. Even film-coated tablets with so-called moisture protective coatings equilibrate in less than one week. Because the rate of moisture transfer into (or out of) a package is generally slow, the influence of microenvironments for humidity is assumed to be minor.
Does the software work for oxidation?
Absolutely. We have found that in some cases, oxidations have very low activation energies. However, the software has no particular problem with this.
Does the software work with bulk storage?
Absolutely. The user can estimate the MVTR of the storage container and input the value into the software. FreeThink continues to add measured values for various storage containers to its database to help users make better estimations.
Has ASAPprime® been successfully used in both IND and NDA applications?
Yes. ASAPprime® software has been used in numerous IND and NDA submissions around the world. With IND applications, companies have used ASAPprime® software alone (no other stability data) to set 12-month expiration for clinical supplies based on prototypes. They then monitor the clinical supplies using standard (ICH) stability studies. The result is that ASAPprime® licensees are able to get new drug products into the clinic at least two months sooner. This approach has generally met with few queries in different regulatory agencies (e.g., US, Canada, Bulgaria, Hungary, India, Philippines, Romania, Slovakia, South Africa, Spain, Taiwan), although several countries have not accepted this approach (e.g., Czech Republic, Ukraine, South Korea, Germany). For NDA submissions, ASAPprime® has been used to support product understanding with respect to formulation, process and packaging. Typically, companies provide their ASAPprime® modeling and show consistency with the ICH data. We are not aware of any company that has submitted an NDA without the long-term (ICH) data as well.
Can ASAPprime® help manage disaster/failures in the stability study? (e.g., out of control temperature and humidity beyond stipulated time limits).
This question is really about how to handle excursions during the ICH stability studies. While ASAPprime® software can support the impact of the excursions scientifically through our excursion module, the acceptability of this with regulatory agencies will require careful consideration. We are not aware of any company using ASAPprime® software to justify acceptability of long-term (ICH) stability studies, where the chamber conditions go out of the appropriate range.
Can ASAPprime® help me choose the best prototype from several possible product formulations?
ASAPprime® has been used extensively to effectively select formulations for advancement. The fast results (2-4 weeks) and accurate shelf-life projections allow a formulator to select an appropriate formulation. Each formulation requires a separate ASAP study. Usually, these studies are done simultaneously, and often use a simplified design. In many cases, prior accelerated formulation screening would rank-order formulations based on only one condition. We have shown that this often leads to a less stable formulation for ambient storage (i.e., the rank ordering at high temperature does not match that at room temperature). With ASAPprime®, the ambient stability is projected from multiple conditions and is therefore, not only fast, but more accurate in determining the best formulation. Moreover, in many cases, there will be multiple formulations that are all acceptable from a stability perspective. With ASAPprime®, an acceptable formulation that satisfies an important criterion (e.g., manufacturability, cost, etc.) can be used confidently via this selection process without having to use the most stable formulation.
How do you handle multiple degradants?
Users can input all the packaging information and store a session. They can then input the degradation data for each degradant individually. The output (PDF) can include all the degradants in one file. Generally, only one degradant is dominant. However, it is wise to examine all the major degradants individually, in order to determine which degradant is the shelf life limiting factor.
Will the software work properly if the sample never reaches isoconversion?
When isoconversion is not reached, the ASAPprime® software is designed to penalize the user by decreasing the confidence (increased error bars) in those values. Even when there is zero degradant found under an accelerated condition, ASAPprime® software can make predictions using the Limit of Detection (LOD) for the degradant. The LOD is used as a basis for determining the maximum rate that would have resulted in no observed degradant.
Can the software work with product color?
Yes, as long as the color is quantified. FreeThink can help with establishing the appropriate methods for such products.
Will it work with every degradant?
Yes, and even for total degradants.
How do you take into account the variability of the degradant?
The ASAPprime® software uses a default 10% relative standard deviation for the variability in degradant when there are no repeats entered. The software propagates this variability into the precision of the final predicted values. If repeats are indeed part of the data set then the precision of the ensuing ASAP model will be enhanced.
Are any special modifications needed to analyze prodrugs?
Prodrugs can be examined much the same as any other drugs. Usually, the specification limit is more generous, since the major “degradant” is most often the drug itself.
How does the program establish “best fit”?
Currently, the default fit for the isoconversion determination is to first use a line if the R2 is greater than 0.9. If not, two lines are used. Users can override this default to select from a number of different model fitting methodologies. Once the isoconversion data are calculated, the program uses a Monte-Carlo multi-linear fitting for the modified Arrhenius parameters and error bars.
If lot-to-lot variability is high, will the software work?
The ASAPprime® software provides a stability model for what is tested. When lot-to-lot variability is high, each lot will show different ASAP behavior (as it does in real time). At times, the variability in the ASAP parameters can provide clues as to the origin of the variability.
What if the MVTR is close to zero?
When the MVTR is low (such as with glass containers), the program will still model behavior effectively. In the experimental design, it may be worthwhile to narrow the relative humidity range of the testing, to be more representative of the narrower range the dosage form will see.
Will the software work with self-catalysis?
Self-catalysis (autocatalysis) results in a lag, then rapid rise in degradation. When this occurs, the ASAPprime® software provides the option of fitting the Avromi-Erofeyev model for lag behavior. With such models, it is important to use multiple time points at each condition.
Will the software work with suspensions?
In most cases, suspensions can be effectively modeled with ASAPprime® software. We generally advise that the API solubility be screened as a function of temperature, to determine the effect on results. This can be an issue, when there is a sharp rise in solubility with temperature.
How accurate are the isotherms in the software?
The isotherms used in the software have proven to be very close to what is found for most formulations. In late stage projects, measuring the actual moisture sorption isotherm is recommended. ASAPprime® software allows the user to input an isotherm.
How are dissolutions handled by the software? What about disintegrant failures?
Currently, the software does not directly handle dissolution. We have found that most systems show a critical RH, below which the dissolution does not change significantly with time. The software will determine what storage and packaging will maintain the RH below this critical value. FreeThink is available to help with the experimental designs for this issue.
Will the software work with crystalline API?
Yes, ASAPprime®, has been used with crystalline APIs.
Can the method of “fit” be changed for each sample?
No. ASAPprime® software assumes that if there is a scientific reason for one fit, it will apply under all conditions.
What type of simulation is used?
For the isoconversion calculation, an extrema method is used. For the modified Arrhenius calculation, a Monte-Carlo method is employed.
How is the R2 calculated?
The R2 reported in the program, is the least squares differential for the mean isoconversion values, versus the fit of the modified Arrhenius equation.
How are low degradant substances handled?
ASAPprime® software handles low (zero) levels of degradant by assuming that the limit of detection (LOD) represents the upper limit of what could have occurred without being observed. The program then determines a minimum isoconversion time from this. The mean isoconversion is defined as twice the minimum isoconversion. This provides a way to handle (conservatively) very stable drugs and drug products.
What are the graphing options?
ASAPprime® software allows users to generate the following graphs either in Excel™ or as PDF™ files: degradant vs. time, RH vs. time, RH vs. water content.
How is the permeability of the packaging handled?
ASAPprime® software has a database of bottle and blister permeability values as a function of temperature. The program corrects for dosage form size (for blisters) and the storage temperature. For bottles, the program uses a size function based on the volume, which we have calibrated from a number of bottles. Users also have the option to enter their own MVTR (permeability).
Is this a “first principals” approach?
No, the ASAPprime® software uses experimental data at a range of highly accelerated conditions, to model the behavior of a drug or drug product at long-term storage conditions.
How does the software handle finished product excursions?
The ASAPprime® software excursion module provides for direct entry of data-logger information for excursions,
Can ASAPprime® software be used to help establish re-test periods for APIs?
Yes, this has been one of the very successful uses of the program.
What is the default type of seal assumed by the HDPE bottle used by the software?
ASAPprime® software assumes the HDPE bottles have heat induction seals (HIS).
What types of desiccants are used by the software?
The ASAPprime® software includes a wide range of desiccant options in its database including silica gel, molecular sieves and clay minerals.
What output options are available?
Output from ASAPprime® software includes both PDF™ and Excel™ options.
Can ASAP analysis be used to assess the stability and shelf-life of large molecule drug product?
For proteins, ASAP predictions work well in solution and solid-state for individual chemical degradation processes. In addition, ASAP works well when the stability is based on the primary structural changes. Unfortunately, ASAP does not work well for denaturation and aggregation.
How does ASAPprime® software manage high B terms?
The software fits the input data to determine the B value without limitations. We do warn users that B values in excess of 0.11 should be looked at carefully, to make sure that there is no phase transition with relative humidity.
What is the FDA’s opinion on ASAP and ASAPprime® software?
Many examiners are aware of ASAP. In general, ASAP (and ASAPprime® software) are consistent with the FDA’s drive for better rationale for formulation, process and packaging choices. ASAP also can be used as part of a QbD filing.
How can ASAPprime® be used to select the best prototype from several possible product formulations?
ASAPprime® can be used to select among different prototype formulations very effectively. The fast results (2-4 weeks) and accurate shelf-life projections allow a formulator to select an appropriate formulation quickly and with confidence. In the past, rapid degradation techniques provided only a rank-order assessment of stability. These rank orders could be erroneous, since they assumed that the temperature dependence of degradation was the same for a range of formulations. Moreover, ASAPprime® allows for selection of a formulation that is not necessarily the most stable, but rather one that is adequately stable, but satisfies other important criteria such as manufacturability. In a more general sense, traditional formulation development requires that many formulations be evaluated simultaneously, because the time-frame for testing is so long that there is a need to do work in parallel. With ASAPprime®, formulations can be developed in a tiered approach: One to three formulations are looked at see if at least one is acceptable. If so, that one is progressed. If not, a second tier of formulation options is examined. Even with three rounds of testing, the results are generally available in a time-frame faster than with the traditional stability approaches. For the majority of cases examined to date, the first or second tier provides a product with adequate stability.
What is LOP?
“Limit of Patience, or LOP” is a term coined by Ken Waterman, the lead scientist behind the development of ASAPprime®. LOP describes how long one is willing to wait to determine the stability of a sample. The greater the LOP, the lower the temperatures that are needed to hit isoconversion; and therefore, the lower the divergence in the predicted shelf-life range.
How do you establish the DOE/combination of temperatures and RH?
This can be complicated since it will vary with what is known about the drug/drug product and what information is desired. The ASAPprime® software now includes the ASAPdesign™ module that assists users in the design of experiments, sample analysis order and scheduler options to provide the user with a statistically optimized ASAP model.
What do you do when the R2 is below 0.85?
When the ASAPprime® software determines a fit to the mean isoconversion values with a low R2, there are several options and considerations. First, the user should study the residual graph to see if there is an obvious outlier. If so, this may indicate a phase transition, or some type of erroneous data. If all the isoconversion points’ error bars overlap with the zero-residual line, the predictions should still be acceptable (although they will probably have large estimation error bars). If the isoconversion error bars do not overlap, it may be advisable to increase the default standard deviation. This will increase accuracy at the price of increasing the estimation error bars. Another possibility for improving the R2 is to look at whether a different fitting model is appropriate for the entered data. This only applies if there is more than one time point entered.
Can the B term ever be negative?
While not common, there have been a few cases of small, negative B terms. All examples of larger negative B terms have ultimately been found to be related to phase changes.
What is the minimum number of data points needed for solids?
While both the software and theory allow a user to input just three points (varying both temperature and RH), this is akin to fitting a line to two points (i.e., zero degrees of freedom). It can be done, but the confidence in any predictions will be low. We generally suggest users employ at least five conditions (two degrees of freedom).
Is water vapor pressure important?
Relative humidity (RH or water activity) is the ratio of water vapor pressure at a temperature compared to the saturated vapor pressure. RH determines the impact of the water rather than the vapor pressure itself. The amount of water present is less important than the water’s activity coefficient (RH).
Are there any special issues to watch out for when evaluating experimental data?
Phase transitions such as melts and deliquescence points (where samples take water from the air) can make modeling difficult. Often, ASAPprime® provides the first clue that there is such a transition occurring with a drug.
Do you need to continuously monitor storage conditions?
Most stability chambers provide adequate control of temperature over the 2-3 weeks of an ASAPprime® study. As a result, continuous monitoring of the temperature inside the chamber is not necessary.
Can each sample be analyzed separately or should they be analyzed in a “batch”?
While the statistics are generally better with a batch approach, in many cases the added variability will not change the results. Most ASAPprime® software users have found that the total work load is reduced when analyzing samples as a batch.
How important is packaging headspace in the ASAP calculations?
In general, the headspace volume plays little role in determining the RH in a package. This is because the moisture sorption capacity of most materials greatly exceeds that of air. Most materials can buffer the RH of their environment such that the headspace makes little difference.
Contact FreeThink Technologies, Inc. to learn more about licensing options, request a demo version of the software, or to schedule a live demonstration via WebEx®.
FAQs updated 15-December 2016