Partnering with a specialized CRO that can effectively perform pharmaceutical deformulation is vital to many companies within the pharmaceutical, nutraceutical, and supplement industries. Avomeen’s team is guided by experienced chemists whom are considered to be leaders in the pharmaceutical industry.
Depending on the composition of the innovator’s product, reverse engineering a pharmaceutical formulation can be a complex endeavor. However, when performed by a skilled chemist familiar with detailed analyses, it will lead to the identification, quantification, and characterization of the API and excipients present in both the core and coating of a pharmaceutical or supplement. This data can then be used to reproduce or formulate a product which will meet bioequivalence requirements. In addition to discovering how to re-develop a product, laboratory testing generates a wealth of key information which can help save significant time and money when developing a generic version of an innovator’s product.
Reverse Engineering a Pharmaceutical Product for an ANDA
Applications for generic approval under an ANDA require the demonstration of a bioequivalent product. Despite this registration requirement, the FDA will not divulge the innovator’s proprietary formula, leaving generic manufacturers to determine the formula of the innovator’s product through their own means or have their applications denied.
The Process of Reverse Engineering a Pharmaceutical Formulation
In order to properly deformulate a product to identify and quantify its constituents, an analyst must separate the components of the formulation before traditional analytical techniques can be used. As some product matrices do not cleanly separate, the quantitation of identified ingredients can also require specialized knowledge and the use of advanced instrumentation.
Several factors impact the complexity of pharmaceutical deformulation, including the number of ingredients within the product, the amounts of those ingredients, and what form the product takes. For example, a controlled release formulation requires chemically testing the innovator’s product over the ingestion to absorption timeframe.
Available Pharmaceutical Formulation Reverse Engineering Tiers
Not every task calls for a complete, in-depth deformulation and analysis. Avomeen offers differing levels of deformulation that help you accomplish your objectives.
- Q1 Deformulation – Identifies the major ingredients, and quantifies select ingredients as necessary. This is often used to verify label claims and provide guidance to the formulation chemist.
- Q2 Deformulation – Identifies and quantitates all components of the formulation down to coloring and taste-masking agents, the time release technology, and the coating systems for tablets.
- Q3 Deformulation – Identification and quantitation of all impurities and process markers in the system, as well as everything in Q1 & Q2. All of this information is needed to meet ANDA-approved standards with consideration to ICH Q3B (R2), Impurities in New Drug Products.
Techniques and Instruments Used in Pharmaceutical Deformulation:
- Fourier Transform Infrared Spectroscopy (FTIR) – All components within a formulation are represented in an FTIR spectrum, which is then compared against libraries which contain thousands of known compounds. While this is an appropriate starting point, FTIR is primarily only useful for identifying the major components within a formulation, as compounds present at very low levels may not appear.
- Thermogravimetric Analyzer (TGA) – Samples are decomposed through a heating process. While additives and organic material will be burned away during this process, inorganic fillers will remain. This process is commonly used to quantify the amount of residue and resin within a sample. Based on decomposition temperatures, insight as to the composition of information can be obtained, which can assist in determining which other instrumentation will be used.
- Pyrolysis Gas Chromatography & Mass Spectroscopy (Pyro GC/MS) – This technique also decomposes a sample. Once decomposed, a gas chromatograph separates the components in order to allow them to be identified using mass spectroscopy.
- Flame Ionization Detector (FID) – An FID is a universal detector that can help further quantify components within a sample. Along with traditional methods of separating the solvents and then identifying and quantifying them using GC/MS, it can lead to further insight to sample composition.
- Karl Fischer – An instrument that is used to quantify the amount of water within a sample.
- Scanning Electron Microscope/Energy Dispersive X-Ray (SEM/EDXA) – Ash residue can be analyzed utilizing this instrumentation to determine the types of elements that are present in a sample, providing information about inorganic excipients.
- X-Ray Diffraction (XRD) – Useful for the determination of polymorphs in a drug product.
- Liquid Chromatography/Mass Spectrometry (LC/MS) – Often used to identify compounds used within coatings, and is useful in identifying materials with a higher molecular weight. An MS is used to analyze the spectra that are produced from the LC, which performs the separations.
- High-Performance Liquid Chromatography (HPLC) – Useful to quantify identified components against purchased or provided standards.
Similar pharmaceutical analyses are also performed in order to:
- Determine the identity of an unknown material, impurity, contaminant, or degradant
- Identify the purity of a raw material
- Compare competing products at a very detailed level
- Discover active and inactive compounds within a product
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