Reverse Engineering
Reverse engineering - decoding of an innovator product’s formulation parameters (quantitative
composition, solid-state characterization, manufacturing process).
1. Decoding the quantitative formula
a. Identify excipient the mostly affect formulation’s performance; Best candidates
are ph-adjusting agents, buffers, stabilizers, and dissolution modifiers
b. Separate excipient from tablet matrix thru differential solubility, filtration, HPLC,
size exclusion chromatography
c. Quantify excipient using UV light, refractive index, spectroscopic techniques
2. Solid State Characterization of API - polymorphism, micronization, microscopy
3. Identify manufacturing process - based on API’s physicochemical profile
4. Protocol for reverse engineering
a. Stage 1 - information about the API's solid form can expedite the identification
of meaningful specifications and the selection of suitable vendors. Similarly, a
highly truncated preformulation study protocol is needed for generic products
that are qualitatively and quantitatively similar to the RLD.
b. Stage 2 - will have the most perceptible effect on reverse engineering.
Quantitative information about key ingredients will simplify prototype
formulation optimization. A traditional approach involves making several
prototypes of varying compositions and testing them for performance and
1. Near Infrared Spectrometry
- Can also be used to distinguish illegal counterfeits of drugs
- Has expansive library of spectra of raw materials
- Can determine API concentration after blending of raw materials
2. Consulting FDA’s Inactive Ingredient Database
“The manufacturer can consult the inactive ingredient database (IID) for information on excipients used in
FDA-approved drug products. The IID is publicly available and is maintained by FDA to provide information
regarding excipients to pharmaceutical industry stakeholders. For a specific excipient in FDA-approved
products, this database provides the highest amount (maximum potency) present per unit, route of
administration and dosage form.”
3. Expired Patent Details
4. Near Infrared Chemical Imaging (NIR-CI) is a technique which may be used to determine the
excipients of the drug as well as its properties, such as: homogeneity of powder sample, particle
size, product composition, concentration and distribution of components in solid tablets, content
uniformity, and other information in a drug product. -Hao
5. Acquire Certificate of Analysis from reference drug product manufacturer?? Hahaha ewan
According to the application form: 1.) A copy of product labelling (summary of product
characteristics), as authorized in country of purchase, and translation into English, if
appropriate. 2.) A copy of the comparator product carton outer box. The name of the product,
name and address of the manufacturer, batch number, and expiry date should be clearly visible
on the labelling. This information should be cross-referenced to the location of the Certificate of
Analysis (CoA) in this biowaiver submission.
Sabi dito if available lang daw. Eh what if hindi hehehehehee
6. Deformulation analysis
7. Use of analytical techniques such as titrimetric, chromatographic, spectroscopic,
electrophoretic, and electrochemical and their corresponding methods
1. Titrimetric
2. Chromatographic
a. TLC
d. Gas Chromatography
3. Spectroscopic
a. Spectrophotometry
b. Near Infrared Spectroscopy
c. NMR
d. Fluorimetry and phosphorimetry
4. Electrochemical methods
a. Voltametry
b. Polarography
c. Amperometry
d. Potentiometry
5. Electrophoretic methods
a. Capillary electrophoresis
6. Flow injection and sequential injection analysis
8. MAS
-Obtain bulk drug product
-Check BCS Class (if need ng biowaiver of not)
-Determine ingredients used through product insert
-Review Documents:
* Review of the product selection document
* Review of any pertinent patent information
* Obtain samples of reference product and packaging
* Evaluate physical characteristics of the reference product
* .Determine reference drug release characteristics through “in-vitro” dissolution profiling.
* Obtain and review all available public information about the innovator or “reference” product
i.e. PDR, CPS, Merck Index, product labels and inserts, published literature in pharmaceutical
and medical journals, etc.
* Characterize drug substance to determine drug form (i.e. crystalline, powder, amorphous),
drug solubility, polymorphism, particle size, bulk density, flow characteristics, chemistry (i.e.
pKa, functional groups), drug absorption characteristics (pharmacokinetics), incompatibilities,
sensitivities (light, heat, moisture), etc.
* Identify a discriminating dissolution procedure with relevant in-vitro/in-vivo correlations
-Determine Active Ingredient and determine possible excipients through the Book of excipients
and through researches
-List the different possible excipients and determine compatibilities
-Perform physico-chemical tests.
-Perform assay to determine amount of AI/ingredient
-Physical Testing: Appearance, average weight and weight variation, disintegration time
-Chemical Testing: Dissolution profiles vs. reference product, assay, content uniformity,
chemical identification, impurities and related substance, ICH Stability
Development trials continue until a formulation with a matching dissolution profile, relative to the
reference product, is obtained in one or more dissolution media.
This formulation should then be scaled-up to a slightly larger size and the resulting dosage form
packaged, and placed on accelerated stability stations for monitoring. In the meantime,
additional trials should be prepared to optimize various formulation and process parameters.
Source Placebos from Clinical Trials
Classifying placebos with chemical ingredients
Placebos don’t contain active substances and so they can’t be classified in Chapter 30 as
medicinal preparations. Instead they’re classified according to their contents.
If they’re made purely from chemical ingredients, then they’re covered in Chapter 38. Because
they commonly contain a mixture of ingredients they’re normally covered under heading code
3824. This heading code covers ‘products of the chemical or allied industries (including those
consisting of mixtures of natural products), not elsewhere specified or included’. For example
this heading code would cover tablets made up of mixtures of chemical products.
However, if any of the ingredients is a food substance, or a substance with nutritional value,
then the product can’t be classified in Chapter 38. Instead it’s covered in Chapter 21 under
heading code 2106.
Medicinal preparations of placebos and comparators used for clinical trials
Comparator drugs contain active substances and are defined as medicaments - or medicinal
preparations. These are preparations used (either internally or externally) to treat or prevent
human or animal diseases or ailments. They’re covered in Chapter 30 under heading codes
3003 and 3004, depending on how they’re supplied. They must have a therapeutic or
prophylactic effect to be classified under either heading code.
Medicaments that are neither made up into measured doses, nor packaged for retail sale are
covered under heading code 3003.
Heading code 3004 specifically covers medicaments that are:
made up into measured doses - such as tablets, ampoules, syringes and capsules
packaged for retail sale
It also covers placebos that are packaged together with medicinal preparations for retail sale even though placebos are mainly covered in other chapters. This is because the active
substances in the medicament part of the combined product (or set) satisfies the requirement
that it should have a therapeutic or prophylactic effect.
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