"Meringue" is not an Ingredient in Lemon Meringue Pie: Defining "Identical Medicinal Ingredient"

What do cooking and chemistry have in common? Apparently, the former provides great analogies to explain the latter. Apotex has recently applied for judicial review of a decision of the Director General of the Therapeutic Products Derivative (TPD) concerning its generic drug, Apo-Telmisartan. While several issues were raised in the application, of particular interest was a debate over the definition of the term “identical medicinal ingredients” in the Food and Drug Regulations (FDR) (C.08.001.1).

Telmisartan is a pharmaceutical used in the management of hypertension. It is marketed under the trade name Micardis, but several generic versions are also available. In an effort to obtain a Notice of Compliance and market its generic version of Micardis, Apo-Telmisartan, Apotex submitted an Abbreviated New Drug Submission (ANDS) on December 16, 2010. The main requirement of an ANDS is that the manufacturer of the drug demonstrate that the new drug is the “pharmaceutical equivalent” of a Canadian Reference Product (CRP) which is usually a brand-name drug, in this case Micardis (FDR C.08.002.1.(1)(a)). “Pharmaceutical equivalent” is defined as a new drug that, in comparison with another drug, contains identical amounts of the “identical medicinal ingredients”, in comparable dosage forms, but does not necessarily contain the same non-medicinal ingredients (FDR C.08.001.1).

However, over a series of correspondences and meetings between Apotex and the TPD, a decision to reject the ANDS was finalized on April 12, 2012. The reasoning of the TPD was that Micardis and Apo-Telmisartan did not contain “identical medicinal ingredients” and were therefore not “pharmaceutically equivalent”.

The only medical input ingredient in Micardis is telmisartan, a carboxylic acid. However, Micardis also contains the non-medical ingredient sodium hydroxide. During the wet granulation process employed during manufacturing, an acid-base reaction occurs between telmisartan and sodium hydroxide. As a result, the form found in the final drug product is, in fact, the salt telmisartan-sodium.

Similar to Micardis, Apo-Telmisartan contains telmisartan as the sole medical input ingredient and makes use of a wet granulation process during manufacturing. However, Apo-Telmisartan employs potassium hydroxide as an excipient (non-medical ingredient). Apotex claimed that no acid-base reaction occurs between telmisartan and potassium hydroxide and the form found in the final drug product is telmisartan and not the salt telmisartan-potassium. The TPD concluded it was unclear from the data whether the final product contained the free acid form of telmisartan or a mixture of the potassium salt and the free carboxylic acid.

Although the Health Canada Policy on “Interpretation of Identical Medicinal Ingredient” clearly provides that different complexes, esters, or salts of the same active moiety are considered non-identical, it does not indicate at what time (input or final product) the issue of identicalness should be addressed.

The TPD took the position that “identical medicinal ingredient” refers to the active substances as they appear in the final product and not the input ingredients. Therefore, the finished product in Apo-Telmisartan is either telmisartan or telmisartan-potassium, neither of which is identical to the CRP Micardis (telmisartan-sodium).

Apotex asserted that “identical medicinal ingredient” should assess whether the input ingredients were the same. Under this interpretation, as the input ingredient is telmisartan in both cases, Micardis and Apo-Telmisartan would be “pharmaceutically equivalent”.

Ruling in favour of Apotex’s position, Justice Kane relied on several fundamental principles of statutory interpretation to resolve the issue. Looking at the ordinary interpretation of the word “ingredients”, the original ingredients remain ingredients and are not referred to as the possible mixtures they might become. The judge uses a baking analogy where egg whites and sugar are used to create a meringue for a pie. If someone was asked what the ingredients were in the pie, the answer would not be meringue, but would be sugar and egg whites. In addition, C.08.002.1(3)(b) and (c) of the FDR requires the manufacturer to provide samples of the ingredients of the new drug and samples of the new drug in dosage form. This suggests that “ingredients” refers to something other than the final dosage form as they are listed separately.

Although I agree that there is a lack of clarity in the definition of the term “identical medicinal ingredients”, I was at first concerned that interpreting “identical medicinal ingredient” as the input ingredient and not the final dosage form could lead to some safety issues. As the neutral form and salt form of a compound can often have different properties, finding an input ingredient “pharmaceutically equivalent” to a CRP only to have that ingredient converted to a different compound during manufacturing could lead to a compound for which the safety and efficacy has not yet been verified. However, in this case Apotex supplied evidence that there was no safety concern involving the use of potassium hydroxide as an excipient and furthermore, the Director General of the TPD could assess the safety and effectiveness of the final product during the next stages of approval. After Justice Kane’s judicial review of the matter, it appears as though “identical medicinal ingredient” refers to the input ingredient and not the final product. For now, that’s how this cookie has crumbled.

Corey McClary is an IPilogue Editor and a JD Candidate at Osgoode Hall Law School.