New Generic Drugs
The US FDA requires submitters of an Abbreviated New Drug Application (ANDA - new generic) that they must include a polymorphism study in order to demonstrate equivalence.
In addition, the International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH harmonised Tripartite Guideline) ICHQ6A states that the following is required: Evidence that polymorphism is or is not exhibited by a new drug substance. If polymorphism is exhibited, whether the different polymorphic forms can affect performance of the drug product, and what the potential for change is and how it might be controlled.
"Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product." [FDA guidelines]. In simple visual terms, the following scheme shows how to envisage polymorphism. The Drug Substance is shown as a rectangle which can pack together in a crystal in different arrangements. Each separate arrangement is a different polymorphic form. It is believed that 50-80% of all Drug Substances exist in at least 2 polymorphic forms
Each stage in drug development gets increasingly more complex. After finding a potential hit in a screen, the early drug development phase of 'hit to lead' follows. This 'lead' drug is then optimised and prepared for pre-clinical evaluation. Drug development during the pre-clinical phase is designed to determine a drug's safety profile and prepare the drug for use in clinical trials. During drug development, an initial scouting polymorph screen is designed to find a stable non-solvated form with good properties. Phase 1 clinical trials are the first time during pharmaceutical development that the drug is used in humans to test safety and tolerability. Larger Clinical Phase 2 studies assess how well the drug works. This is followed by Clinical Phase 3 trials, the most expensive of all, to assess drug effectiveness. Phase 3 drug development work includes a comprehensive polymorph screen find as many forms as possible in order to exhaustively cover the Intellectual Property space. Continuous monitoring of the polymorphic form is needed throughout the whole drug development process in order to ensure consistent manufacture of the specified polymorph
Analytical techniques are powerful tools employed during drug development: X-ray powder diffraction is used to provide unequivocal proof of polymorphism. Other methods, including Thermal Analysis; Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Hot-Stage Microscopy (HSM) and Raman spectroscopy are useful to further characterise polymorphic forms.
So what is polymorphism? It is simply a different arrangement a molecule might adopt in a crystal. Most drug molecules are crystalline. That is, the molecules pack together in a particular regular way. Some molecules, perhaps most, are able to pack together in more than one way and thus give rise to different polymorphs. A pair of polymorphs might have very different physical properties. Over 50% of all Active Pharmaceutical Ingredients (APIs) exist in at least 2 polymorphic forms.
During drug development, an initial scouting polymorphism screen is designed to find a stable non-solvated form with good properties. A later comprehensive polymorphism screen is to find as many forms as possible in order to exhaustively cover the Intellectual Property space. Continuous monitoring is needed throughout development in order to ensure continued control of polymorphism.
What can cause polymorphism changes? Crystallisation from different solvents may give rise to different crystal forms or solvates. Extremes of humidity or heat are among the more obvious factors affecting polymorphism. Changes in polymorphism can also be induced as a consequence of several common stages of API processing such as granulation, melting, spray drying, compression and milling that are required to produce the final dosage form.
X-Ray Powder diffraction and Raman spectroscopy are the two workhorse methods used to evaluate the presence and amount of different polymorphic forms found during screening. Differential Scanning Calorimetry (DSC), Differential Thermal Analysis (DTA), Dynamic Vapour Sorption (DVS) and hot stage microscopy are additional specialised techniques used to characterise different polymorphic forms.
All is not doom and gloom as the polymorphism properties of a chemical substance are patentable. A new polymorphic form therefore may be used to extend the patent life of a drug. A counter to this is that a new polymorphic form with advantageous properties may be able to supersede an existing drug and effectively 'bust' the original patent.
It's not surprising to learn that manufacturers & developers of generic drugs actively pursue new polymorphic forms of patented drug substances. This can be a highly litigious area.
National regulatory authorities require that all companies register the precise polymorph of any new drug. Moreover, manufacturers need to demonstrate that each polymorph is stable and can be reliably reproduced
Many small pharmaceutical companies do not intend taking their drug candidates all the way to commercialisation themselves but to seek to license at an earlier stage. This arises because of the considerable increase in costs as a drug moves through the clinic. If a polymorph screen is also included then the package is certainly stronger and the licensor can expect a further premium.
During pre-clinical development the quantity of an API that is available for studies is usually very low. Screening a wide variety of solvents and conditions needs to be conducted for that reason on a very small scale. Systems that can handle multiple experiments at the milligram scale are best. At some labs automated systems can handle up to 96 well plate formats and conduct experiments at 0.5-2mg scale. Thus the total amount of API used for an initial screen can be a modest 50-200mg.
Typically, a salt selection project will precede a polymorphism study: once a salt is found that has the most promising properties, it will be further developed, characterised and might be the subject of a further polymorphism screen during the normal course of pre-clinical development.
These days, we all need to keep an eye on the bottom line. Perhaps if your company was to cast an eye over the other lines as well and make use of specialists inpolymorphism to do this research for you, you wouldn't have to worry so much about your future prospects!
New Polymorphic Form
The vast majority of countries do not present a specific mention in the Law for polymorphic form patent application, but still many patents are granted. The polymorphic forms are expressly regulated in India, as long as patentability requirements are met and efficiency is increased.
Both second medical use and new polymorphic forms are currently patentable according to Law, evaluating the novelty and inventive activity in Brazil; however, the guidelines were not clear. A guideline proposal for the evaluation of patent application for new polymorphic forms is being prepared.
Guideline Proposal for the Evaluation of new polymorphic forms
- Definitions were established for: polymorphism, crystalline and amorphous forms, medicine, pharmaceutical composition, pharmaceutical formulation, adjuvant, excipient and monocrystal.
- It is indispensable that the descriptive report has the necessary characteristics to the complete description of new polymorphic forms, according to technologies inherent to its perfect characterization, such as the following examples, or validated alternative techniques that best identify them:
a) Single-crystal X-ray diffraction (monocrystal XRD);
b) X-Ray Powder Diffraction Method; (XRD Powder Method);
c) Solid-state carbon-13 nuclear magnetic resonance spectroscopy (NMR-13C)
d) Infrared Spectroscopy;
e) Raman Spectroscopy;
f) Electronic Microscopy (hot stage);
g) Thermal Analysis: Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (ATG) and Differential Thermal Analysis (DTA).
- In case of a monocrystal of the chemical substance, the XRD technique of single crystal is sufficient for the prefect characterization of the crystalline structure.
In case of absence of monocrystal of the chemical substance, the X-Ray Powder Diffraction Method technique with indexing must be used, that is, the Miller index of the interplanar distances, the Bragg angles and the relative intensities of at least 20 reflections must be presented, in addition to the unitary cell parameters.
- If the indexing is not presented, the presentation of the other described parameters is necessary, and also the complementation of the X-Ray Powder Diffraction Method with other analysis methods (minimum of 2), in addition to the proof of sample purity.
The analysis technique used for the determination of the chemical substanceand its purity level pharmaceutically acceptable must be informed, since sample impurities may cause interferences in the quality of the characterization analysis results of the crystalline structure.
The inventive activity of a polymorphic form shall be checked by verification of an effect solving a problem of the prior art that is sufficiently differentiating, for instance: stability increase, apparent solubility and processability.
Pharmaceutical Composition of the Polymorphic Form
A composition is a grouping of ingredients for a certain purpose. The composition presents a novelty when one of the constituents is a crystalline form different from the one disclosed in the prior art.
The inventive activity to be presented by the composition containing the new polymorphic form, there must be an evaluation of the differentiated effect authentically solving a technical problem, based on its giving special attention to comparative specific parameters in relation to the prior art, the proof of its physical and chemical stability for its industrial use.
Process for Obtaining the Polymorphic Form
The process must be new, inventive and clearly described in order to allow the reproducibility by a person skilled in the art.
Parameters as exemplified below, or alternative parameters best describing such process, must disclose the following:
a) concentrations of the different solutions used, which are critical to the process;
c) cooling rate;
e) temperature of the different stages of the process;
f) torque or addition of seeds of the desired crystalline form. The seed preparation process must also be clearly and sufficiently described in the application when the crystallization process is developed with seeding.
The same criteria are applied to the pharmaceutical and medication formulation, repressing it.
Process for Obtaining the Pharmaceutical Composition
The process for obtaining a pharmaceutical composition containing a new polymorphic form is new. The inventive activity shall be evaluated whenever it is not evidently originating from the prior art (for the person skilled in the art).
As new polymorphic forms may disclose different physical and mechanic properties, including particle size, density, hardness, outflow and compactness, they may have sufficiently differentiated characteristics solving a problem of the prior art, which may bring an inventive activity requisite to the obtaining process of the pharmaceutical composition.
The same criteria apply to the process for obtaining the pharmaceutical and medication formulation.