Characterization of the iDDPs
A question that may arise about the proposed EbD approach is whether there are in vitro markers or biomarkers available for characterization of iDDPs. Literature information indicates that the in vivo drug delivery pathways may not be well documented for most pharmaceutical products, presumably because of the paucity of
methodology for study in this area. Nonetheless, some of the research tools may have been applied for these purposes during
drug discovery and development.
One example is the application of in vitro dissolution or release testing for predicting drug release in vivo.
In vitro dissolution and release testing has been routinely used to guide drug development as well as predict bioequivalence between
products before and after changes in formulation or manufacturing. The key issue is whether these methods adequately emulate
critical in vivo release or dissolution processes. As dictated in US regulations, in vitro dissolution or release testing can be used as an indicator for bioequivalence if it is correlated with and predictive of
human in vivo bioavailability data (2, 10). Indeed, a major problem with many of the current in vitro dissolution and/or release methods lies in the lack of correlation between in vitro and in vivo data.
Other methods may be used to explore the course of drug delivery in the body. For instance, radio-labeled studies and imaging
techniques such as gamma scintigraphy have been applied to examine drug deposition, transit, retention, or release from several
types of dosage forms in drug discovery and development (11–15). Current methods may be modified or improved for iDDP characterization.
In addition, the markers of iDDPs may be identified through the integration of knowledge and methodologies from various disciplines
such as biophysics, biochemistry, biopharmaceutics, and other relevant fields. It is hoped that the continuous innovation
in pharmaceutical industry may facilitate the development of more biomarkers or in vitro markers to characterize the iDDPs.
Potential factors affecting iDDPs
Several pharmaceutical factors are known to influence the course of drug delivery and release in vivo, which may include formulation, excipient, dosage form, product design, and manufacturing process. In addition, biopharmaceutical
considerations ought to be given with respect to the potential effects of certain excipients on drug bioavailability and possible
drug/formulation interactions with intrinsic or extrinsic factors. Although most excipients on the market are devoid of pharmacologic
action, some common excipients (e.g., sorbitol and polysorbate 80) have been shown to exert unintended influence on iDDPs
and in turn, bioavailability and bioequivalence (16). Similarly, the impact of various intrinsic and extrinsic factors on
iDDPs and drug absorption may have been underestimated.
The ICH E5 document has provided several good examples of intrinsic and extrinsic factors that may influence pharmacokinetic
and pharmacodynamic responses of many drugs (17). As illustrated, important intrinsic factors may include genetic, physiological,
and pathological conditions of the patient. On the other hand, relevant extrinsic factors may be related to the environment
(e.g., climate, sunlight, and pollution), food intake (e.g., beverage and diet), lifestyle (e.g., smoking and exercise), and
The potential interplay between pharmaceutical characteristics such as formulation and intrinsic factors such as gender has
also been studied and reported in the literature (18). In this case, bioequivalence studies were conducted on two extended-release
products containing the same drug substance. Higher plasma concentrations were obtained in females (compared with males) from
Product A, yet no gender difference was found for Product B. Investigation with in vitro dissolution testing at various pH values also showed dissimilar dissolution profiles between the two formulations. In the
case of Product A, a lower fraction of the drug dissolved at pH 4.5 and a higher fraction dissolved at pH 6.8, possibly reflecting
more drugs in the ileum and perhaps in the colon. For Product B, however, most of the drug dissolved at pH 4.5, suggesting
a rapid release at the duodenum and jejunum. Literature information revealed that women tend to have longer gastric emptying
time and longer intestinal transit time. With all the data collected, therefore, the pharmacokinetic differences observed
in this study have been attributed to the potential interaction between formulation and gender, as evidenced by the different
drug release profiles from the two formulations and differing GI transit time in men and women.
Apart from intrinsic factors, the impact of extrinsic factors on iDDPs may be exemplified by the market withdrawal of Palladone
(hydromorphone HCl extended-release, Purdue Pharma, Cranbury, NJ) capsules in 2005. As a derivative of morphine, hydromorphone
is known to be a potent centrally acting analgesic drug. Palladone was withdrawn because this extended-release product consisted
of a matrix system that was found to be prone to dose dumping when taken with alcohol. A similar problem occurred with fentanyl
transdermal delivery systems. It was suspected that an increased rate and extent of drug permeation through the skin might
have occurred after some of the fentanyl patches were exposed to heat.
Overall, the potential interplay between pharmaceutical attributes and intrinsic/extrinsic factors may be investigated during
the course of drug development. These interactions may be proactively explored through in vitro,
in silico, or in vivo methods that allow for the study of iDDPs before drug absorption.
Theoretical considerations prescribe that bioequivalence may be assessed by focusing comparisons on the in vivo drug delivery profiles (iDDPs) between formulations. The rationale for this approach rests on the premises that absorption
process is the key determinant for bioequivalence, given constant clearance within each individual across formulations. Because
drug absorption is chiefly controlled by when, where, and how the drug is released from the formulation, it follows that bioequivalence
assessment may be made by means of the comparison of iDDPs between products. Similarly, to achieve bioequivalence of advanced
pharmaceutical dosage forms or delivery systems, one can first determine the critical characteristics of the reference iDDP
and then use this information as the target profile for design and manufacturing of the test product. It is surmised that
in vitro markers or biomarkers are available or can be developed to characterize the pivotal stage(s) of an IDDP. In analogy to the
QbD paradigm for pharmaceutical development, this equivalence-by-design (EbD) approach can be applied to devise the test product
by mapping the target iDDP through the use of in vitro markers or biomarkers. Ultimately, successful design of an equivalent product can be accomplished with a better understanding
of all the relevant factors that may have potential impact on the iDDPs of the products in comparison.
Mei-Ling Chen, PhD, is associate director at the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug
Administration, 10903 New Hampshire Ave., Building 51, Rm. 4108, Silver Spring, MD 20993-0002, tel. 301.796.1658, fax 301.796.9997,