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Deformulation, otherwise known as reverse engineering, is essential to generic pharmaceutical drug formulation and the abbreviated new drug application (ANDA) regulatory pathway.

According to the US Food and Drug Administration’s (FDA’s) Generic Drug Facts, “a generic drug is a medication created to be the same as an existing approved brand-name drug in dosage form, safety, strength, route of administration, quality, and performance characteristics.” This article will educate on the ANDA regulatory pathway, and in particular, focus on Q1/Q2 (Q3) deformulation, as well as the differences in equivalence designations in ANDA filings.

Understanding abbreviated new drug applications (ANDAs)

Generic drug applications typically do not require the inclusion of preclinical (animal) and clinical (human) data to establish the safety and effectiveness of the generic drug and are therefore “abbreviated”. Yet, each ANDA submitted to the FDA must scientifically demonstrate the generic product is bioequivalent to the reference listed drug (RLD). The RLD is a single approved drug product against which the generic product will be compared. Moreover, bioequivalent generic drugs function and perform in a manner similar to the reference listed drug, also referred to as the innovator product.

An ANDA can only be filed for off-exclusivity drugs or non-patented drugs. The first applicant to file a substantially complete ANDA containing a paragraph IV certification with the FDA will be eligible for a period of exclusivity for 180 days. That period of exclusivity starts from either the date the generic drug product is commercially marketed, or from the date on which a court of law has ruled that the patent held by the innovator is invalid, unenforceable, or has not been infringed upon, whichever comes first. During the 180-day period of exclusivity, the FDA is unable to approve subsequently submitted ANDAs for the same reference listed drug, even if the ANDAs which were submitted later are otherwise ready for approval and applicants are prepared to immediately begin marketing their product. The FDA has published guidance with additional information regarding 180-day exclusivity titled 180-Day Exclusivity: Questions and Answers.

FDA generic drug requirements

The FDA has set forth strict requirements for generic drugs. When compared to brand-name drugs, reference listed drugs, or innovator drug products, generic medications must:

• Contain the same active pharmaceutical ingredient (API)
• Maintain the same dosage form (e.g., liquid, tablet, capsule)
• Have the same strength, purity, and stability
• Use the same route of administration (e.g., oral, injectable, topical, etc.)

The role of Q1/Q2 (Q3) deformulation in ANDA filings

Q1/Q2 is a term that refers to the assessment of inactive ingredients, which is a required component of all ANDA filings. In the chemistry, manufacturing, and controls (CMC) portion of Sec. 314.94, “Content and format” of an ANDA, it is stated that “an applicant must identify and characterize the inactive ingredients in the proposed drug product and provide information demonstrating that such inactive ingredients do not affect the safety or efficacy of the proposed drug product.” Additionally, Q3 similarity data may be required for some ANDAs, depending upon complexity.

Q1/Q2 sameness evaluation

Q1 assessments:

• Demonstrate qualitative sameness
• Identify an inactive ingredient
• Provide information regarding the grade and chemistry of each inactive ingredient

Q2 assessments:

• Demonstrate quantitative sameness
• Determine the quantity/concentration of an inactive ingredient
• Differences of +/-5% have typically been found to be acceptable by the FDA

Q3 similarity

Q3 assessments:

• Confirm physicochemical similarity to the RLD, and
• Parameters may include appearance, pH, globule size distribution, rheological behavior, drug polymorphic form, drug release, etc.

Pharmaceutical equivalence, bioequivalence, and therapeutic equivalence explained

Pharmaceutical equivalence and bioequivalence data must be generated to prove that a generic drug product is truly equivalent to the reference listed drug, demonstrating the generic drug is as safe and efficacious as the innovator drug product. There are important distinctions between pharmaceutical equivalence and bioequivalence, as pharmaceutical equivalence is considered in-vitro equivalence, while bioequivalence is classified as in-vivo equivalence.

Pharmaceutical equivalence (PE)

The FDA requires pharmaceutical equivalence be established when comparing a generic drug to an RLD. In summary, the generic drug must contain the identical amount of the same API, and the inactive ingredients in the dosage form must be the same (+/-5%) as the innovator product. Additionally, the generic drug must follow the same route of administration as the RLD.

Bioequivalence (BE)

To obtain FDA approval for a generic drug product, an ANDA must include data demonstrating the generic drug delivers an equal amount of the same drug to the site(s) of therapeutic action at the same rate and extent as the innovator product under similar conditions. Guidance documents have been issued by the FDA regarding bioequivalence waiver studies which include in vitro release testing (IVRT), in vitro permeation testing (IVPT) for topical creams and ointments, oral solutions, and suspensions. Additionally, the United State Pharmacopeia (USP), specifically USP <1090>, details assessment requirements of solid dose products by bioavailability, bioequivalence, and dissolution.

Therapeutic equivalence (TE)

A therapeutically equivalent generic drug product is both pharmaceutically equivalent and bioequivalent to an innovator product. Therapeutically equivalent generic drugs must be proven to contain the same active ingredient(s), dosage form and route of administration, and strength (pharmaceutical equivalence). They must also perform in the same manner as the reference listed drug product (bioequivalence).

Choosing the right CMC expert to support your ANDA

51³Ô¹ÏÍøhas a proven track record of successfully delivering complex deformulation projects including Q1/Q2 analyses, grade identification of excipients, and Q3 testing for full comparability to a reference listed drug. Successfully navigate the ANDA regulatory pathway and successfully obtain approval for your generic drug product with the support of Element’s consultative teams of scientific and regulatory experts and our deep experience in in Q1/Q2 (Q3) deformulation and in-vitro bioequivalence studies.