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Beyond-Use Dates, Part 1
Introduction
Stability of pharmaceuticals involves chemical kinetics. As we are mostly involved in compounding solutions and suspensions, first order and zero order kinetics form the basis for what we do. In other words, chemical kinetic relationships form the foundation of the beyond-use dates that are assigned for compounded preparations (CPs) according to USP Chapters <795> and <797>.
Let's look at the BUD definitions because they are actually defined a little differently in the two USP chapters.
A Beyond Use Date (BUD) is defined in <795> as "the date after which a compounded preparation shall not be used and is determined from the date when the preparation is compounded."
A Beyond Use Date (BUD) is defined in <797> as "the date or time after which a compounded sterile preparation (CSP) should not be stored or transported, and this date is determined from the date or time the preparation is compounded."
What is the difference? In <795>, a preparation cannot be "used" after its BUD has been exceeded. In <797>, the preparation can continue to be administered if the BUD is exceeded during the administration time period and administration has already begun.
BUDs for compounded preparations are usually assigned on the basis of professional experience, which would include careful interpretation of appropriate information sources for the same or similar formulations. Ideally, BUDs for CPs are derived from preparation-specific chemical assay results using the Arrhenius equation. Manufactured products are determined differently following established guidelines and Good Manufacturing Practices (GMPs).
It is noted that a majority of CPs are prepared as aqueous solutions so the chemical kinetics of aqueous solutions should be considered. In aqueous solutions, hydrolysis or solvolysis are expected to occur where the dissolved ingredients undergo chemical degradation reactions. The extent of hydrolysis or solvolysis and other heat-catalyzed degradation reactions at any particular time point in the life of a CP represents the thermodynamic sum of exposure to elevated temperatures and the duration of this exposure. In drug hydrolysis, the reaction rates increase exponentially with an arithmetic temperature increase; thus in the case of beta-lactams, the exposure of a beta-lactam antibiotic solution for one day at controlled room temperature (temperatures between 20ºC to 25ºC) will have an equivalent effect on the extent of hydrolysis of approximately three to five days in cold temperatures (temperatures between 2ºC to 8ºC). Therefore, correct temperature storage of these finished preparations is significantly necessary. Personnel who prepare, dispense, and administer CPs must store them strictly in accordance with the conditions stated on the label of ingredient products and finished CPs. When CPs are known to have been exposed to temperatures warmer than the warmest labeled limit or to temperatures exceeding 40ºC for more than four hours, such CPs are to be discarded unless they have been assayed to show that the preparations are still within acceptable stability limits.
Background
Some may have forgotten the introduction to the first and zero order drug degradation rate reactions, Arrhenius equation, and the "Q" method of calculating BUDs that are based on science and mathematical relationships. However, a quick review may help to get the proper frame of mind for looking at drug stability, degradation rates, rate constants, etc.
Zero order and first order chemical degradation rates are calculated from experimental data and can be used for stability projections.
Solutions generally follow a first-order reaction, where the loss of drug is directly proportional to the concentration remaining with respect to time. This relationship is one of the most widely used as most compounded drug preparations, including intravenous admixtures, etc. are solutions. The first order degradation equation is given by:
-dC/dt = kC
where
C is the concentration of intact drug remaining,
t is time,
(-dC/dt) is the rate at which the intact drug degrades, and
k is the specific reaction rate constant.
The integrated and more useful form of the equation is:
log C = -kt/2.303 + log C0
where C0 is the initial concentration of the drug. The units of k for a first-order reaction are per unit of time, such as per second, per hour, per day, etc.
For suspensions, the zero-order degradation reaction is given by:
-dC/dt = k0
where k0 is the zero-order rate constant [concentration(C)/time(t)].
The integrated and more useful form of the equation is:
C = -k0t + C0
where C0 is the initial concentration of the drug. The units for a zero rate constant k0 are concentration per unit time, such as moles per liter-second or milligrams per milliliter per minute.
Next, we see how the energy of activation (Ea) for these reactions can be calculated using the Arrhenius equation, which can be expressed as:
log = k2/k1 = Ea (t2 - T1)/2.3 RT1T2
relating the reaction rate constants (k) to temperatures (T) with the gas constant (R) and the energy of activation (Ea). The relationship of the reaction rate constants at two different temperatures provides the "energy of activation" for the drug degradation. By performing the reactions at elevated temperatures instead of allowing the process to proceed slowly at room temperature, the Ea can be calculated and a k value for room temperature determined with the Arrhenius equation.
Another useful equation involves the Q10 method, based on the energy of activation, Ea, which is independent of reaction order. The relationship is:
Q10 = e{(Ea/R)[(1/T + 10) - (1/T)]}
where
Ea is the energy of activation,
R is the gas constant, and
T is the absolute temperature.
In usable terms, Q10, the ratio of two different reaction rate constants, is defined as:
Q10 = K(T + 10)/KT
The commonly used Q values of 2, 3, and 4 relate to the energies of activation of the reactions for temperatures around room temperature (25ºC). For example, a Q value of 2 corresponds to an Ea (kcal/mol) of 12.2, a Q value of 3 corresponds to an Ea of 19.4, and a Q value of 4 corresponds to an Ea of 24.5. Reasonable estimates can often be made using the value of 3.
The equation for Q10 shelf life estimates is
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t90(T2) = |
t90(T1)
Q10(ΔT/10) |
where
t90(T2) is the estimated shelf life,
t90(T1) is the given shelf life at a given temperature, and
ΔT is the difference in the temperatures T1 and T2.
As is evident from this relationship, an increase in ΔT will decrease the shelf life and a decrease in ΔT will increase shelf life. This is the same as saying that storing at a warmer temperature will shorten the life of the drug and storing at a cooler temperature will increase the life of the drug. This is a very simple method of recalculating shelf lives for storage at different temperatures.
Summary
According to the USP, BUDs for CPs are assigned on the basis of criteria different from those applied to assigning expiration dates to manufactured drug products. BUDs should be assigned conservatively and drug-specific and general stability documentation and literature should be consulted and applied when available. Factors to consider include (1) the nature (chemical structure, physical properties) of the drug, (2) degradation mechanism, (3) dosage form and composition, (4) potential for microbial growth, (5) container, (6) storage conditions, and (7) intended duration of therapy.
Next Month: Beyond-Use Dates, Part 2
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