Deformulation, also known as reverse engineering, is a key part of generic pharmaceutical drug formulation and the abbreviated new drug application (ANDA) process. According to 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.”
Understanding Abbreviated New Drug Applications
Generic drug applications are “abbreviated” because they typically don’t need to include preclinical (animal) and clinical (human) data to establish the safety and effectiveness of the generic drug. However, each ANDA submitted to the FDA must scientifically demonstrate that the generic product is bioequivalent to the reference listed drug (RLD). The RLD is a single approved drug product that the generic product will be compared to, and bioequivalent generic drugs perform in the same the manner as the innovator product.
An ANDA can only be filed for:
- Off-Exclusivity drugs
- Non-patented drugs
The first applicant to file a substantially complete ANDA containing a paragraph IV certification will be eligible for a 180-day period of exclusivity that begins from the date the generic drug product is commercially marketed, or from the date a court has ruled that the innovator’s patent is invalid, unenforceable, or hasn’t been infringed upon – whichever comes first. During that period, FDA can’t approve subsequently submitted ANDAs for the same drug, even if the ANDAs that were submitted later are otherwise ready for approval and the applicants are ready to begin marketing their product immediately. More information about 180-day exclusivity can be found here.
FDA Generic Drug Requirements
FDA has strict requirements for generic drugs, and when compared to brand-name, or innovator drug products, generic medications must:
- Contain the same active pharmaceutical ingredient (API)
- Maintain the same dosage form (i.e. liquid, tablet, capsule)
- Have the same strength, purity, and stability
- Use the same administration route (i.e. oral, injectable, topical)
The Role of Q1/Q2 (Q3) Deformulation in ANDAs
Q1/Q2 is a term that refers to the assessment of inactive ingredients that is part of all ANDA filings. In the chemistry, manufacturing, and controls (CMC) portion of Sec. 314.94, “Content and format” of an ANDA, it states 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.” For some complex ANDAs, Q3 similarity data may also be required.
Q1/Q2 Sameness Evaluation
- Demonstrate qualitative sameness
- Identify an inactive ingredient
- Provide information about grade and the chemistry of each inactive ingredient
- Demonstrate quantitative sameness
- Determine the quantity/concentration of an inactive ingredient
- FDA has typically found differences of +/-5% acceptable
- Confirm physicochemical similarity to the RLD
- Parameters may include appearance, pH, globule size distribution, rheological behavior, drug polymorphic form, drug release, etc.
Pharmaceutical Equivalence, Bioequivalence & Therapeutic Equivalence Explained
Pharmaceutical equivalence and bioequivalence data is necessary to prove a generic product is truly equivalent to the RLD and is a safe and effective generic drug. Pharmaceutical equivalence is considered in-vitro equivalence, while bioequivalence can be classified as in-vivo equivalence.
Pharmaceutical Equivalence (PE)
FDA requires pharmaceutical equivalence to the RLD, meaning that the generic drug must contain the identical amount of the same API, the inactive ingredients in the dosage form must be the same (+/-5%) as the innovator product and the route of administration must be the same.
To gain FDA approval, a generic drug product application must include data demonstrating that it 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. FDA has issued guidance documents on bioequivalence waiver studies that include IVRT, IVPT for topical creams and ointments, oral solutions and suspensions. The USP <1090> provides assessment requirements of solid dose products by bioavailability, bioequivalence and dissolution.
Therapeutic Equivalence (TE)
Therapeutically equivalent generic drug products are pharmaceutically equivalent and bioequivalent to the innovator product. They must be proven to contain the same active ingredient(s), dosage form and route of administration, and strength (Pharmaceutical Equivalence), as well as perform in the same manner as the reference listed drug (Bioequivalence).
Choosing the Right CMC Expert to Support your ANDA
Avomeen handles complex deformulation projects including Q1/Q2 analyses, grade identification of excipients and Q3 testing for full comparability to the reference listed drug (RLD). Plan to succeed in obtaining approval for your ANDA by consulting with Avomeen. Avomeen’s CMC experts have proven success with Q1/Q2 (Q3) deformulation and in-vitro bioequivalence (BE) studies. Click here to connect with our CMC experts.
Our expert blogger is Neelam Varshney, Avomeen’s Sr. Technical Director, Pharmaceutical Sciences. Neelam’s diligence and intellect brings incredible value to Avomeen and to our clients. She has extensive experience in all CMC aspects of pharmaceutical products from preclinical testing and submission to 510(k)/IND/NDA modules to post-approval regulatory requirements. Neelam’s great wealth of regulatory knowledge of all CMC aspects include expertise in E&L for all product types, including drug-device combination products, and Avomeen’s clients benefit greatly from her insight and expertise in cleaning validation. To all of this, Neelam brings 22 years of pharmaceutical industry experience, primarily applying ICH and other regulatory guidance to build compliant systems.