Deformulation is the technical term for reverse engineering a product’s formulation. When performed by a skilled chemist familiar with this type of detailed analysis, it will lead to the identification, quantification, and characterization of the API and all excipients, in both the core and coatings of a pharmaceutical or supplement. This data can then be used to develop a reformulated product which will meet bioequivalence requirements.
Why Reverse Engineer a Pharmaceutical Product?
Application for generic approval under ANDA requires the demonstration of a bioequivalent product. This means that the blood levels of the active ingredient need to track those of the innovator’s product over the time frame from ingestion to absorption. The simplest way to ensure this is often to mirror the innovator’s formulation so that the dissolution profiles are identical. For the case of biosimilars, mere bioequivalence is not enough and the product must be highly similar in composition. Despite this registration requirement, the FDA will not divulge the innovator’s formula as it is proprietary, leaving the generic manufacturer to figure it out through their own means, or have the application denied.
How Difficult is Reverse Engineering a Pharmaceutical?
While this may not seem very complicated, performing this in a laboratory can be very time consuming and complex. In order to properly deformulate a product to reveal its true base components one first has to separate out the components of the formulation before traditional analytical techniques can be used. Because some products matrices do not cleanly separate, the quantitation of ingredients, once identified, can also require specialized knowledge and advanced instrumentation to perform.
Some products are easier to deformulate than others depending on how many ingredients are within the product, levels, and product form. For example, a controlled release formulation will require not only chemical analysis of the contents, but an elucidation of the CR mechanism.
What Levels of Pharmaceutical Reverse Engineering are Available:
1st Level Deformulation- Identifies and quantifies the major ingredients. Typically quantitation is not performed. This is often used to verify label claims and/or give guidance to the formulation chemist.
2nd Level Deformulation- Identifies and quantitates all components of the formulation down to coloring/taste masking agents, the CR, and the coating systems for tablets.
3rd Level Deformulation- Everything in the first and 2nd level, as well as identification and quantitation of all impurities and process markers in the system which is needed to ensure the ANDA will meet with approval with consideration to ICH Q3B (R2), impurities in New Drug Products.
(FTIR) Fourier Transform Infrared Spectroscopy- All ingredients within a formulation are represented in an FTIR spectrum, which is then analyzed against known libraries. While this gives a great starting point using a FTIR is primarily only useful for the major ingredients within a formulation, as ingredients that are at very low levels may not appear.
(TGA) Thermogravimetric Analyzer- 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 that are inside of a sample. Based on decomposition temperatures clues to the composition of information can be obtained which can help direct which other instrumentation will be used next.
(Pyro GC/MS) Pyrolysis Gas Chromatography/ Mass Spectroscopy- This technique also decomposes a sample. Once decomposed a gas chromatograph can separate out the components in order to allow them to be identified using mass spectroscopy.
(FID) Flame Ionization Detector- A FID is a universal detector that can help further quantify ingredients within a sample. Using this along with traditional methods of separating the solvents and then identifying / quantifying them using GC/MS can lead to further knowledge of a samples composition.
Karl Fisher- An Instrument that is used to identify the amount of water that is within a sample.
(SEM/EDXA) Scanning Electron Microscope/Energy Dispersive X-Ray- Ash residue can be analyzed utilizing this instrumentation in an effort to determine the types of elements that are present within a product sample. This provides information about inorganic excipients.
(XRD) X-Ray Diffraction- Useful for the determination of polymorphs in a drug product.
(LC/MS) Liquid Chromatography/Mass Spectrometry- Useful in identifying materials with a higher molecular weight, in pharmaceuticals it is often used to identify ingredients used within the coatings. An MS is used to analyze the spectra that is produced from the LC which performs the separations.
(HPLC) High Performance Liquid Chromatography- Useful to quantify identified ingredients against purchased standards.
Why perform a deformulation analysis on a pharma product? Depending on its complexity breaking down a pharmaceuticals formulation can be a very complex endeavor. However the knowledge gained from a complete pharmaceutical deformulation reveals the information that is necessary in order to reproduce or reformulate the exact product. During such an analysis even the steps involved within a product production process can be re-engineered by carefully expanding upon the information gained in the chemical reverse engineering process and utilizing the abilities of an experienced formulation chemist. In addition to discovering how to re-develop a product this type of laboratory testing generates a wealth of key information which can help save significant time and money when developing a new but similar product formulation.
Similar pharmaceutical analyses are also performed in order to:
The ability to find specialized CRO’s who can effectively perform these services are vital to many companies within the pharmaceutical, nutraceutical, and supplement industries. Avomeen’s teams of chemists are led by experienced Ph.D. chemists that are leaders in their fields. Our chemists have extensive experience in the pharmaceutical and supplement industry.