Inactive Ingredients Database.
The information on the IIG website provides the highest level of an ingredient approved for a single unit (2). As the information
is for single unit, we highly recommend that the ANDA sponsor exercise caution in using this information in formulating their
drug product. The scope of the information provided in the IIG database is limited to the use of an excipient in the Center
for Drug Evaluation and Research (CDER) approved product and for this reason it is imperative the sponsor do the requisite
due diligence to justify the use of the excipient in their product line. Citing the IIG may be sufficient is most cases but
not in all drug products. Having this supportive information in the application will eliminate any question related to this
critical concern. In cases, where citing IIG is found to be insufficient, the ANDA sponsor should follow the recommendations
provided in the Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients in providing supportive data (9).
Per 21 CFR 314.94 [(iii)(a)(9)(v)], the applicant is required to both identify and characterize the excipients in the proposed product
demonstrating that they do not impact safety (7). This includes the composition or "make-up" of the ingredients. In many cases,
complex coatings, colors, and flavors are proposed for use in the drug product. A composition should be provided in the ANDA
or if the information is proprietary, a drug master file (DMF) reference or the composition of such components should be provided
by the supplier directly to the Agency. This allows for a through evaluation of the composition of the materials proposed
including iron oxides in coatings or other components from a quality and safety perspective. Certification from the manufacturer
of coatings should be provided that the components of the coating either are found in the CDER approved products or applicable
CFR citations should be provided for the use of these components in the coatings.
With respect to the use of iron oxides, there are times that a sponsor is asked to justify that the use meets the requirements
in the CFR. The ANDA sponsor should indicate that their product meets the 21 CFR 73.1200 requirements for exposure of NMT 5 milligrams elemental iron per day (10). It also is recommended that sponsors include
the detailed calculation of total daily intake of iron based on the intended formulation. Additionally, there are other requirements
in the CFR with respect to quality of iron oxides used including identity, additive mixtures, specifications and impurities (e.g,. arsenic,
lead, and mercury). As stated above, the ANDA sponsor should be able to justify use of excipients in their product line by
providing supportive data.
Compatibility of excipients with API.
With respect to design of the intended product, the lack of understanding of the chemistry and performance of excipients is
one of common causes for production failures and recalls. Thus, it is important to study the compatibility of the excipients
with the API and understand the critical material attributes prior to finalizing the drug product formulation. Performance
characteristics will be discussed in a later section in this article.
• What evidence supports compatibility between the excipients and the drug substance?
In response to this question in 2.3.P.2.1.2 regarding the compatibility of the API with the excipients, the sponsors frequently
provide justification for not conducting these studies based on the facts that the excipients are "common" for the given dosage
form and the stability data for the exhibit lots are acceptable. Some of the sponsors are found to monitor only the change
in the physical appearance of the mixture of API with the proposed excipients. It needs to be understood that the premise
of the excipient-API compatibility studies is to provide justification based on mechanistic understanding of chemical interaction
of drug substance and excipients and manufacturing process. Thus, justifying excipient compatibility based on end product
testing or monitoring changes in physical appearance are not acceptable.
An example of a so called "common" excipient significantly affecting the formulation, is lactose, when used in conjunction
with APIs which are primary or secondary amines. The formation of "Amadori" complexes has been found to be detrimental to
the stability of many drug products. Polacrillin potassium is another excipient which may form complexes with APIs containing
amines based on the manufacturing process (high heat) or pH of the formulation and result in low assay of the active ingredient
over shelf life (11). Another relevant interaction that is frequently observed is that of polyols with free carboxylic group
Justification for not performing excipient-API compatibility studies based on the fact that the formulation is similar to
that of the reference listed drug has its flaws, too. It is often found that based on the grade and supplier, the impurity
and residual solvents profile of the excipients may differ significantly. The sponsors are encouraged to identify the impurities
and residual solvents in excipients which have the potential of adversely affecting the quality of the drug product. A few
examples of impurities in excipients which may affect the product stability may be the following:
- Levels of methacrylic acid and divinyl benzene in polacrillin potassium
- Residual peroxides in povidone, crospovidone and/or polyethylene glycol
- Heavy metals or other metal reagents in talc.