The Role Of Originator Drug Characterization In Generic Drug Development

A generic drug is a drug that is consistent with the original drug (reference drug, RLD) in terms of dosage form, strength, route of administration, quality, curative effect, and use. Generics play a key role in the health care system, accounting for more than 50% of all prescriptions. Generic drugs are approved on the basis of therapeutic equivalence to RLD. Therapeutic equivalence consists of two parts: pharmaceutical equivalence and bioequivalence. Speed to market is the key to success in the generic drug market. Characterization of the reference drug product, also known as reverse engineering studies, can speed up the development of generic drugs. These studies, including the quantification of key excipients and the solid-state characterization of API, can provide key information for the formulation development of generic drugs. This chapter emphasizes the role of originator drug characterization in accelerating generic drug formulation development and simplifying the regulatory approval process.

Part 1 Introduction: Generic Drug Development Process

The Abbreviated New Drug Application (ANDA) proposed in the Hatch-Waxman Act (Drug Price Competition and Patent Term Compensation Act) issued in 1984 promoted the development of generic drugs in the United States. The bill allows generic drug companies to cite data submitted by brand-name drug companies in new drug applications (NDAs), thereby avoiding duplication of clinical trial studies. According to the requirements of the US FDA, generic drugs can replace original drugs on the basis of therapeutic equivalence. Therapeutic equivalence consists of pharmaceutical equivalence and bioequivalence, which are explained in the box below.

Once the compound patent expires, some generic drug companies can immediately put generic drugs on the market. In the highly competitive generic drug market, being first to market is critical. Increased generic competition is associated with lower drug prices. When a second generic hits the market, the price is often significantly lower. Therefore, generic pharmaceutical companies must ensure continuous new product launch in order to maintain revenue growth. Generic pharmaceutical companies must be highly skilled in product and process development to deliver cost-controllable, time-sensitive products.

Generic Term

Therapeutically equivalent drug: refers to a pharmaceutically equivalent drug that has the same efficacy and safety when administered under similar conditions.

Pharmaceutical equivalent drug: a pharmaceutical preparation containing the same pharmaceutical active ingredient, dosage form, route of administration, strength or concentration.

Pharmaceutical equivalence is not equivalent to therapeutic equivalence, as differences in excipients and/or manufacturing processes can lead to differences in drug properties. Drug properties may vary in in vivo or in vitro settings, such as dissolution rate and bioavailability.

Bioequivalent drug: A pharmaceutically equivalent drug or a pharmaceutical substitute drug that exhibits no significant difference in bioavailability under similar test conditions.

Bioequivalence: In a well-designed experimental study, when the active pharmaceutical ingredients (or active ingredients) of two pharmaceutically equivalent drugs (or pharmaceutical substitute drugs) are administered at the same molar dose, if the two ingredients Two drugs are defined as bioequivalent when there is no significant difference in the rate and extent of absorption at their sites of drug action.

In general, the development of generic drug products starts with the characterization of the original drug or reference preparation, followed by the design of pharmaceutically equivalent drugs, the development of effective production processes, and the conduct of key batch bioequivalence studies. Reference drug product characterization can range from testing only drug release behavior (solid oral dosage forms) or pH and viscosity (liquid oral dosage forms) to a comprehensive quantitative profiling of the formulation composition. This information can be derived from a systematic and scientific evaluation of the reference medicinal product. This process is also defined as reverse engineering research. Although generic pharmaceutical companies rely on the characterization of the originator drug many times, this topic is rarely addressed in the literature. This chapter focuses on summarizing the characterization of originator drugs during generic drug development from a prescription and regulatory perspective.

Part 2 Originator Drug Characterization As A Generic Drug Development Tool

In terms of pharmaceutical equivalence, improving the prescription similarity between generic drugs and reference preparations will increase the chances of developing drugs with better stability and bioequivalence to reference preparations. Most pharmaceutical products are multi-component dosage forms composed of various excipients and APIs, each of which has its own role. Although excipients are clinically inactive, in pharmaceuticals they are active and can affect the performance of the drug. For example, functional excipient stabilizers and dissolution modifiers are beneficial to drug stability and bioavailability. In some cases, even common excipients such as diluents such as lactose or microcrystalline cellulose can have a significant impact on process performance.

Quantitative information on excipients in oral formulations may not be disclosed in accordance with US law. In this context, characterization of originator drugs is a scientifically sound and cost-effective strategy to accelerate generic drug development. Using information from general literature sources, combined with reverse engineering studies, offers the possibility to develop formulations that are qualitatively and quantitatively similar to the reference preparation. This provides greater confidence in the assurance of generic drug performance.

Systematically performed originator drug characterization facilitates decision-making at all stages of generic drug development (Figure 1). In the first stage, the information in the solid form of API facilitates the identification of valuable technical parameters and selection of suitable suppliers. Similarly, in order to develop a generic drug product that is qualitatively and quantitatively similar to the reference product, a highly refined pre-prescription research program is required.

The second phase of prescription research will obtain the most critical information from the characterization of the original drug. Quantitative information on key excipients will simplify the formulation optimization of formulations. Traditional formulation development work involves designing several formulations and examining the performance and stability of different formulations. Analyzing the quantitative information of the original drug can reduce the number of experiments to get the best prescription. Under the concept of quality by design (QbD), the quantitative information of the original drug can help to identify the critical quality attributes of the drug, so as to conduct more effective experimental design. At this time, the decision-making is less dependent on the experimental results such as dissolution, so the decision-making process will be more objective; although the experimental results such as dissolution are an effective tool, they cannot guarantee the development of bioequivalent products. Through the characterization of the original drug, the development of a drug that is quantitatively similar to the reference preparation and ensuring the similarity of its dissolution behavior to the reference preparation will make it easier to achieve bioequivalence between the generic drug and the reference preparation. Likewise, solid-state characterization of the API in the reference drug product can reduce risk during development, especially for drugs whose dissolution profile determines bioavailability.

Part 3 Originator Drug Characterization As A Tool To Support Registration Submissions

Information obtained through reverse-engineering studies on reference medicinal products can also be used to support certain registration claims, such as BE exemptions. Liquid preparations for injection, ophthalmic and otic use can be exempted from BE. Regarding the similarity of drugs, the US FDA has proposed the concepts of Q1 and Q2. Q1 means that the drugs are qualitatively similar, while Q2 means that the drugs are quantitatively similar. Quantitatively similar (Q2) means that the concentration or amount of inactive ingredients in the test preparation differs from the reference preparation by no more than 5%.

Differences in excipients are generally permissible, but regulators will require additional justification that these differences will not affect the safety or efficacy of the product. Some specific dosage forms have more stringent requirements in accordance with US Federal regulations. In generic liquid preparations for injection that are eligible for BE exemption, except for preservatives, buffers, and antioxidants, other ingredients must meet Q1 and Q2. Similarly, except for preservatives, buffers, thickeners or osmotic pressure regulators in ophthalmic and ear liquid preparations, other excipients must comply with Q1 and Q2. Topical medication (including aerosol and nasal liquid formulations) should comply with Q1. Details of these requirements and exceptions are contained in 21 CFR § 314.127(1)(8) and 21 CFR § 314.94(a)(9).

Oral immediate-release solid dosage forms of BCS Class I can also be exempted from BE when they fully meet the various conditions specified in 21 CFR § 320.22(b)(3). The US FDA also allows BE exemptions for products when the pharmacokinetic endpoints do not represent bioequivalence. Acarbose tablets and vancomycin hydrochloride capsules are two examples of BE waivers based solely on the Q1 and Q2 similarity of the generic product to the reference product. In such cases, a comprehensive characterization of the originator drug may be used to support a BE waiver.

Part 4 Contents Of Originator Drug Characterization

The characterization of the original drug can be divided into four parts: literature analysis, quantitative analysis of the composition of the prescription, solid state characterization of the API, and identification of the preparation process.

4.1 Literature Analysis

The qualitative formulation composition of the reference preparation can be obtained from public sources. The public portion of the “Summary of Approval Basis” submitted by the originator company is a good source of information for generic drug companies. This information can be found on the “Drug@FDA” section of the US FDA website. General sources, such as product information brochures and physician’s desk books, also contain useful information.

4.2 Quantitative Analysis Of Prescription Composition

The quantitative analysis of the composition of the reference drug formulation can be further subdivided into two steps:

1. Identification Of Key Excipients;

2. Quantitative Detection Of Identified Excipients.

4.2.1 Identification Of Key Excipients

The quantitative analysis of the formulation composition of the reference preparation should start with the identification of excipients that have a significant impact on the stability and performance of the drug product. These excipients are called key excipients. Key excipients include solubilizers and dissolution regulators for BCS class II or BCS class IV drugs, wetting agents for hydrophobic drugs, pH regulators/buffers for pH sensitive drugs, stability/antioxidant in drug formulations prone to oxidative degradation agent. It has been reported in the literature that some specific excipients such as sorbitol, mannitol, glycerol, and PEGs can affect the bioavailability of drugs by affecting solubility, dissolution rate, or permeability. This process informs the subsequent characterization of the originator drug and helps evaluate the advantages of reverse engineering studies, as sometimes traditional formulation optimization techniques may be more effective than reverse engineering studies. In general, pH adjusters, buffers, stabilizers (e.g. antioxidants and chelating agents), dissolution modifiers (e.g. surfactants, release rate controlling polymers) are most suitable for reverse engineering studies.

4.2.2 Quantitative Detection Of Identified Excipients

The next step is to quantitatively detect the key excipients in the solid preparation, because other excipients in the preparation may interfere with the detection process, so the process is more difficult. The quantitative detection of excipients involves two steps, the separation/extraction of excipients and the quantitative detection of excipients. The following techniques can be used to separate excipients from the tablet matrix: differential solubility, filtration (using filters of specific pore size or molecular weight cut-off), high-performance liquid chromatography (HPLC), high-performance thin-layer chromatography (HPTLC), size-exclusion chromatography. It is necessary to select the appropriate separation technique in combination with the quantity of interfering components in the system and their physical and chemical properties.

After the excipients are separated, they can be detected by gravimetric method or various detection tools, including ultraviolet-visible light, refractive index, evaporative light scattering detector (ELSD, HPLC), spectroscopic techniques (such as infrared (attenuation, transmittance, reflectance, etc.) coefficient) or near-infrared spectrum). The gravimetric method is most suitable for the quantitative detection of major excipients used in large amounts in preparations. Excipients such as stabilizers, surfactants, and pH adjusters used in small amounts are best suited for complex separation and quantification techniques such as HPLC and HPTLC. High molecular weight excipients such as polymers can be effectively detected by molecular exclusion chromatography.

Other useful techniques include gas chromatography, liquid chromatography-mass spectrometry, micellar electrokinetic capillary chromatography, colorimetry, potentiometry, variable-angle attenuated total reflection Fourier transform infrared spectroscopy, nuclear magnetic resonance, and capillary electrophoresis. The testing process requires care to eliminate false positive and false negative results. For the possible interference of other excipients in the preparation, the detection method must be verified. Recently, there have been some new developments in the field of detection instruments. For example, Malvern’s SyNIRgi near-infrared chemical imaging system claims to be able to detect the amount of each excipient in the preparation.

Part 5 Solid State Characterization Of API

From a pharmaceutical point of view, solid-state properties can be divided into properties at the molecular level, at the particle level, and at the overall powder level. Molecular-level properties include crystalline forms, hydrates, solvates, co-crystals, and amorphous states. Differences in intermolecular arrangement and free energy give these forms different solubility, manufacturability, bioavailability, and stability. These factors are critical parameters when characterizing the solid state form of the API in the reference drug product during generic drug development. In other literatures on ANDA, polymorphic forms have been described in detail. According to the current regulatory requirements, the regulatory provisions do not require generic drug companies to prove that “the API in the generic drug has the same physical properties as the reference drug, and the solid state of the drug has not changed.” Therefore, solid-state polymorphism of a drug is not a relevant item for demonstrating drug similarity in an ANDA.

Original drugs generally choose the most stable crystal form for formulation product development to avoid solid-state form transformation during the process and storage. To be on the safe side, generic drug companies also use the same crystalline form as the reference product to ensure stability and dissolution profiles are similar to the reference product. Sometimes, this strategy is not feasible because of the restrictions of crystal form patents, which have a longer term than compound patents. In this case, according to 505[j][2][A][vii], APIs with other crystal forms can be selected to develop generic drugs. Various techniques can be used to characterize solid-state forms of pharmaceuticals, such as XRD, FTIR, NIR, Raman spectroscopy, DSC, thermogravimetric analysis, and hot-stage microscopy. API particle size distribution (PSD) may affect dissolution rate and bioavailability, especially for drugs whose bioavailability is greatly affected by dissolution. It can detect the particle size distribution of API particles in original drug and generic drug preparation products. However, the initial particle size of the API may change under various process conditions, for example, (i) dissolution of the API during wet granulation followed by precipitation during drying; (ii) granulation during mixing/sieving particle size reduction; (iii) fragmentation during tableting. When the particle size distribution of API particles in pharmaceutical preparations changes, the control standard for the initial particle size distribution of API needs to be changed.

The challenge with particle size testing of APIs in formulated products is to measure the particle size of the API in the presence of other excipients. Conventional particle sizing techniques based on obscuration and laser light scattering are not suitable because these techniques cannot differentiate between API and excipients. The only available technique is microscopy.

Microscopic examination can differentiate API from excipients based on features such as particle shape and birefringence pattern. Under polarized light, crystalline drugs exhibit birefringence, while most excipients are amorphous and do not exhibit birefringence. Hot stage microscopy can identify APIs based on differences in melting points. Therefore, identification and characterization of APIs at the molecular and particle levels can speed up decision-making during formulation development. Although there is no relevant report, it is theoretically possible to detect particle size distribution using spectral imaging techniques.

Part 6 Identification Of Preparation Process

Most solid oral dosage forms are prepared by wet granulation, dry granulation, or direct compression, depending on the stability of the API, the weight ratio of the API in the tablet, and physical properties (eg, flowability and compressibility). In addition to processing properties, manufacturing techniques can also affect the stability and performance of pharmaceutical formulations.

Based on the physicochemical properties of the API, the preparation process of the reference product can be predicted, for example, the wet granulation process will not be used for water-sensitive APIs. Similarly, for low-dose APIs, it can be difficult to achieve proper blend uniformity using the direct compression process. Visual inspection of tablet breakage can provide some information about the granulation process. Wet or dry granulation processes result in rougher tablet fracture surfaces than direct compression. Alternatively, the tablets can be placed in water in a petri dish and the disintegration properties observed using a low-power light microscope. Tablets prepared by direct compression disintegrate into individual particles, while tablets prepared by wet or dry formulation disintegrate into granules. This information can be analyzed in conjunction with qualitative formulation composition information to determine the role of individual excipients in the dosage form. Some excipients may play multiple roles in a dosage form, such as hypromellose, starch, and lactose. Therefore, it is difficult to determine the function of each excipient only through the qualitative formulation composition.

Advanced imaging techniques, such as SEM, spectral imaging (Raman, NIR, MHz), XRF, can detect coating thickness and/or composition of tablets and pellets. This is valuable information for products with functional coatings.

Part 7 The Complexity Of Originator Drug Characterization

Various challenges can be encountered during the characterization of a reference product. The complexity of characterization of reference medicinal products can be reduced by understanding material properties, selecting appropriate sample preparation and analytical methods. However, due to the inherent complexity of pharmaceutical formulations, these challenges cannot be completely avoided, such as:

1) Low drug content (for example, API accounts for less than 5% of the total tablet weight)

2) The particle size of the drug particle is very small (for example, the particle size of the drug particle is close to submicron)

3) Complexity of crystal forms of excipients (e.g. formulation contains some crystalline/amorphous excipients)

4) Solid-state form transformation of API (for example, API is a metastable crystal form, process/solvent/temperature may cause its crystal form to change)

5) Birefringence, melting point, solubility and other physical and chemical properties of API and excipients and their similarities

6) Compound preparations

Part 8 Tablet Reverse Engineering Solution

Case 1: Reverse Engineering Research Of Ranitidine Hydrochloride Tablets

Ranitidine hydrochloride belongs to BCS class III drug. However, based on data on the drug’s therapeutic efficacy and therapeutic index, pharmacokinetic properties, and potential for excipient interactions, ranitidine hydrochloride immediate-release solid oral formulations may be exempt from BE. Therefore, ranitidine hydrochloride is a good example of a reverse engineering study to achieve similarity in the quantitative composition of the formulation. Characterization of the original research drug is carried out through four steps, namely: (i) literature research; (ii) quantitative detection of prescription composition; (iii) identification of preparation process; (iv) solid-state characterization of API.

Step 1: Literature Research

The information obtained from literature analysis shows that Zantac® 75 mg tablets are film-coated tablets, and the excipients contained include microcrystalline cellulose (MCC), hypromellose (HPMC), magnesium stearate, titanium dioxide, glyceryl acetate, Synthetic iron oxide, the main drug is 84 mg ranitidine hydrochloride (equivalent to 75 mg ranitidine). Select MCC, HPMC, magnesium stearate for reverse engineering research.

Step 2: Quantitative Detection Of Prescription Composition

Solubility difference, gravimetric method and FTIR were used to quantitatively detect the formulation composition. The reverse engineering research was helpful to obtain the quantitative composition information of the tablet core. The content of ranitidine hydrochloride was 84 mg, and the content of MCC was 61 mg. Magnesium stearate is a non-critical excipient and can be optimized during process studies. The core does not contain HPMC.

Step 3: Identification Of The Preparation Process

The identification of the preparation process was carried out by microscopically evaluating the disintegration mode. After disintegration, granules appeared, indicating that the tablet was prepared using a granulation process.

Step 4: Solid State Characterization Of API In Tablets

The particle size of the API was detected using a hot stage microscope, and the results showed that the particle size distribution ranged from 2-33 μm, with a large amount (43%) of the API particle size distribution in the range of 10-15 μm. Using microscopy, FTIR, and PXRD techniques to detect the crystal form of the bulk drug, the results show that the crystal form of the bulk drug is type II.

Case 2: Detection Of Particle Size Of Raw Material Drugs In Tablets

This case is to detect the particle size of the raw material drug in Levitra® tablets (vardenafil hydrochloride). Vardenafil hydrochloride is a crystalline powder with a solubility in water of 0.11 mg/ml and a melting point of 192-194°C. The core excipient ingredients learned from the label information are: API, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. The melting point of the API is different from all other ingredients. Therefore, a hot stage microscope can be used to detect the particle size of the API in the tablet.

Detection was performed using an optical microscope (Leica DMLP, Leica, Germany) equipped with an imaging system (DC-300, Leica, Germany), in visible and polarized light modes, using Image Manager software, with a pre-calibrated stage micrometer The particle size of the API. A heat stage (Leica LMW 50) is connected to the optical microscope, which is used to observe the thermal changes of the sample and confirm the drug particles. First, use a sharp scalpel to peel off the coating layer of the tablet, take part of the tablet core and place it between two glass slides, press lightly, and place the powder on the microscope. The sample is heated to about 10°C above the melting point of the API. Once the drug substance particles have been identified, they can be sized.

Part 9 Reverse Engineering Solution For Liquid Formulations

A liquid formulation is a homogeneous dispersion of one or more chemical substances dissolved or dispersed in a suitable solvent system. According to the route of administration, liquid preparations can be divided into the following categories: oral, injection (intravenous, intramuscular, subcutaneous), ear, ophthalmic, topical. Liquid preparations for oral administration include solutions, syrups, emulsions, and suspensions. To avoid overcomplicating matters, we briefly describe oral solutions here. Liquid formulations often contain multiple excipients with widely varying structures and concentrations, making the system even more complex. Therefore, parsing a formulation can be as challenging as designing a new product.

As mentioned above, the interpretation of the reference product begins with the identification of excipients that improve the solubility and stability of the API. The total amount of solute dissolved in a solvent is generally much lower than its saturation solubility. Because the API exists in the system in a dissolved state, the solid form of the API does not affect the stability and performance of the liquid formulation. In liquid formulations, material properties such as the solid state form of the API, particle characteristics, etc. can affect process parameters such as dissolution rate.

The second step is the quantitative determination of the excipients used in the reference preparation. Unlike traditional methods (testing the compatibility of drug and excipients at different ratios), reverse engineering studies significantly reduce the number of trials and help optimize the final product. By adjusting the pH to achieve in-situ salt formation, using co-solvents, and complexation, it can be used to solubilize API. In addition, liquid formulations may contain buffering agents to adjust pH, stabilizers to maintain chemical and physical stability, preservatives to inhibit microbial growth, and flavoring and coloring agents to improve patient compliance. If the drug has a bitter taste, a taste-masking agent is usually added to the liquid formulation. Unlike tablets, solutions are less complicated to prepare. On an industrial scale, solutions are prepared by simply mixing the drug and inactive ingredients in large mixing vessels with mechanical agitation.

In vivo administration of oral solutions (elixirs, syrups, tinctures), injections (IV-intravenous, IM-intramuscular, SC-subcutaneous) and other topical solutions per 21 CFP § 320.22(b)(3)(i) The bioavailability is qualified and BE can be exempted. The premise is that the solution does not contain excipients that significantly affect the absorption of the drug, and the release of the drug in the pharmaceutical preparation is no problem. Differences in buffers, preservatives and antioxidants are allowed as long as bioavailability is not altered. However, the pH of the solution needs to be consistent with that of the reference preparation. Therefore, for solutions, the quantitative detection of their formulation composition is indeed a cost-effective and time-saving method.

Part 10 Conclusion

Cost and speed to market are key to success for generic drug companies. Achieving bioequivalence with reference preparations is a key link in the development of generic drugs, and the probability of bioinequivalence must be reduced. Comprehensive and systematic characterization of original drug is an effective tool for generic drug development, which can increase the probability of bioequivalence. Reasonable and reliable original drug characterization strategy (reverse engineering research on original drug), including quantitative detection of prescription composition, solid-state characterization of API and identification of preparation process, can shorten the product development cycle and reduce costs.