What we provide

We provide comprehensive analytical support during the development of drug formulations.

Our research and development (R&D) services combine innovative approaches, modern instrumentation and advanced knowledge in the field of analytical science in order to achieve high performance of analytical methodologies and quality data.

Every method is thoroughly tested to ensure its compliance with regulatory requirements and its ultimate performance, robustness and transferability.

Besides development, method optimization is essential in order to obtain reliable data in a shorter time and at lower cost.

The Services

Development of Analytical methods

The analytical methods are directly linked to the quality of pharmaceutical products, since they ensure the identity, purity, physical characteristics and potency of the drugs. The goal of development is to obtain an analytical procedure fit for its intended purpose.

According to the International Conference on Harmonization (ICH), the chemical methods may belong (but not only) to the following: (i) identification tests, (ii) quantitative tests of the active moiety in samples of API or drug product or other selected component(s) in the drug product, (iii) quantitative tests for impurities’ content, (iv) limits tests for the control of impurities.

Methods are developed to support drug testing against specifications during manufacturing and quality release operations, as well as during long-term stability studies. Methods may also support the product development, safety and characterization studies or evaluations of drug performance. Also, submitting knowledge and information related to development of analytical procedures to regulatory agencies provide additional evidence to demonstrate that the analytical procedure is appropriate for its intended use.

Effective method development ensures that laboratory resources are optimized, while methods meet the objectives according to the intended use. The selectivity of the method is of paramount importance, while increased robustness characteristics reassure the stable performance of the method over time, and the efficient transfer worldwide. Apart from the scientific goals, the simplification of the samples’ treatment and reduction of time and consumables (e.g. simultaneous determinations for combination drugs) are also an important part of the method development.

Minimal Approach

Analytical procedure development should include the following elements as appropriate:

·         Identifying which attributes of the drug substance or drug product need to be tested by the analytical procedure.

·         Selecting an appropriate analytical procedure technology and related instruments or suitable apparatus.

·         Conducting appropriate development studies to evaluate analytical procedure performance characteristics such as specificity, accuracy and precision over the reportable range (including the calibration model, limits at lower and/or higher range ends) and robustness.

·         Defining an appropriate analytical procedure description including the analytical procedure control strategy (e.g., parameter settings and system suitability).

Enhanced Approach

The enhanced approach offers a systematic way of developing and refining knowledge of an analytical procedure. An enhanced approach should include one or more of the following elements in addition to those already described for the minimal approach.

·         An evaluation of the sample properties and the expected variability of the sample based on manufacturing process understanding.

·         Defining the analytical target profile (ATP).

·         Conducting risk assessment and evaluating prior knowledge to identify the analytical procedure parameters that can impact performance of the procedure.

·         Conducting uni- or multi-variate experiments to explore ranges and interactions between identified analytical procedure parameters.

·         Defining an analytical procedure control strategy based on enhanced procedure understanding including appropriate set-points and/or ranges for relevant analytical procedure parameters ensuring adherence to performance criteria.

·         Defining a lifecycle change management plan with clear definitions and reporting categories of established conditions (ECs), proven acceptable ranges (PARs) or method operational 82 design regions (MODRs) as appropriate.

On top of the scientific drivers and appropriate software, the development team owns deep knowledge and indispensable experience in the field through hundreds of products and several publications in the research scientific literature and international conferences.

Dissolution development

The development of a product specific dissolution method is a significant element of the pharmaceutical products documentation. Dissolution testing serves not only as a routine quality control test of production batches but also as a guide during the early stages of a successful formulation development.

A dissolution procedure intended to be used as a routine control test for immediate release drug products should be robust, reproducible and discriminatory in order to assure a consistent product quality and to detect product quality attributes, which, if altered, may affect the in vivo performance.

The dissolution method development study includes the following:

  • Equilibrium solubility: Solubility of the drug substance is evaluated by determination of the saturation concentration of the drug in different media using the shake-flask solubility method at 37 ± 1 °C (using a temperature control orbital agitation platform).
  • Selection and validation of the analytical method for the determination of the examined substance.
  • Filter evaluation/ Filter compatibility: Compatibility with filter is performed in order to avoid absorption of drug substance; filter clogging and/ or not efficient removal of insoluble excipients.
  • Selection of dissolution medium/ Sink conditions: The dissolution testing should be performed close to physiological conditions, with the typical media for dissolution to be the diluted hydrochloric acid and buffers (phosphate or acetate) in the physiologic pH range of 1.2-7.5. The use of simulated fluids (with or without enzymes) is also an option for certain type of products. The use of aqueous solutions (acidic or buffer solutions) with a percentage of a surfactant in the lowest concentration to achieve sink conditions is also permitted however, with proper justification.
  • Stability of the drug substance in various media: Investigation of the drug substance stability in the dissolution media at 37 °C is evaluated.
  • Selection of the Apparatus type and rotation speed: Apparatus 1, 2 and 4 according to the European Pharmacopeia (Eur.Ph.) are available in our laboratory. The selection is based on the provisions of the Eur.Ph. and the formulation characteristics to be tested.
  • Discriminatory power evaluation: The discriminatory power is evaluated with the testing of batches manufactured with meaningful variations of the product formula, manufacturing process or material attributes.
  • Selection of Dissolution Specifications: The acceptance criteria for a dissolution test is a function of Q, which is expressed as a percentage of label claim of drug dissolved at a specified time. The specifications establishment should take into account the characteristics of the API (e.g., BSC classification), the formulation behavior and also the potential extrapolation to the bioavailability elements (e.g., for generic formulations the specifications should be set with the use of the bioequivalence batches).



Forced degradation studies

The purpose of the forced degradation studies is to stress the finished product under defined conditions in order to show that the methods used for the assay and the determination of impurities are specific and stability indicative when unknown degradation products are present.

The defined conditions depend primarily on the drug substance (light sensitive, easily oxidisable e.t.c.) and the form of the finished product (solution, tablet, gel e.t.c.). A general rule is to stress the product till a significant thermal, light, oxidative, acidic and alkaline degradation is observed.

According to the ICH Q2(R1) guideline, peak purity test (based on diode array detection) is used in order to show that the analyte peak is not attributable to more than one component. On top of that, an acceptable mass balance should be revealed by comparing the decrease of the API assay to the increase of total impurities.

Extractables and Leachables

Qualimetrix is a customer-driven Testing Laboratory that employs a structured and well-defined approach in order to design and implement optimized processes with the aim of transforming customer inputs and requirements into “customer value”. As such, the first and probably the most critical factor for a successful project is its proper definition in terms of both customer and technical requirements. To this end, a comprehensive study request form is provided to the customer with the following objectives:

  • The definition of the type and scope of the study
  • The provision of critical product information
  • The determination of the most suitable, expedient and cost-effective approach

The following figure presents a project setup; meaning the logical process by which a series of studies may be proposed to a sponsor.


Polymeric and elastomeric materials are commonly encountered during the manufacturing process of pharmaceutical products as well as components of the packaging / container closure system. During the product’s expected shelf-life and use, the constant contact, as well as the stressing, may bring about a change in the composition of the product stored, through interactions with its packaging.

Product packaging interaction studies focus on establishing this change in product composition brought about by the interplay of packaging and stored content through means of molecular exchange. This exchange involves the solubilization of compounds within the polymeric or metal matrix and their subsequent migration into the bulk of the stored product.

The main phases of interest in the product's life cycle that are relevant to drug-packaging interaction studies and hence to the safety assessment are schematically presented in the figure below and explained in more detail in the following paragraphs:



  1. Development: The first operational step related to product-packaging interaction studies is the material screening process. During this process, all candidate materials are evaluated in terms of their available information. The means by which this initial evaluation is performed are risk assessment and gap analysis, compendial testing, which is usually conducted by the supplier and extraction studies in order to establish the material composition and mitigate any information / data gaps.  

“Extractables” study

Controlled Extraction studies are of paramount importance in order to:

  • Characterize candidate materials and assess their suitability for use
  • Cover the safety gaps resulting from the lack of compendial testing or other material information that, in many cases, the suppliers are not eager to provide.
  • Identify “tentative” leachables that could be employed as target analytes for the development and validation of a “product-specific” methodology for the determination of leachables

The applied semi-quantitative generic methodology has been designed to cover representative leachables, designated by extraction studies of packaging materials available and which are commonly used in plastic manufacturing. The purpose of the initial screening of extractables is mainly to establish a “worst-case” potential leachables profile for the product-specific packaging materials and facilitate the establishment of qualitative and quantitative leachable-extractables correlations.

Extraction techniques commonly employed for this initial step include but are not limited to the following:

  • Maceration (solvent soaking)
  • Reflux
  • Soxhlet
  • Sonication
  • Sealed vessel

The profile of the extractable components is acquired by the use of leading edge, hyphenated, orthogonal analytical techniques, required to cover their significant chemical diversity (e.g. LC-HRMS, GC/MS, GC/FID, ICP/MS etc.). Extractions that are not solvent-mediated can also be performed through the use of Headspace Gas Chromatography (HS-GC/MS).

Packaging and Production-related materials risk assessment

A preliminary assessment of the extent of component testing is necessary in order to establish the suitability of plastic components involved in both packaging and the manufacturing process stream (e.g. tubings, filters, connectors, etc.). The assessment is based on risk factors related to the nature and conditions of the contact between the product stream, the extraction propensity of the solvents used and the nature of the plastic materials.

Recently, a framework for the risk assessment conducted for leachables in pharmaceuticals has been introduced. The Extractables and Leachables Safety Information Exchange (ELSIE) group has proposed such a framework, based on the concepts of the ICH Q9 Quality Risk Management guideline, while the general chapter of USP–NF 2022, Issue 1, <1665> proposes a framework for the risk evaluation of production related materials prior to the design of studies that address this risk or gaps in data that hinder the risk evaluation process.

An evaluation strategy and a risk rubric proposed in relevant scientific literature has been reviewed, evaluated and properly amended by our scientific team, in order to form the “backbone” of risk assessment for a pharmaceutical product’s leachable species profile.

The actions that need to be taken for risk mitigation / reduction and acceptance are presented within the concluding section of the risk assessment report.

The Risk Assessment exercise for Leachable Species in Pharmaceutical Products” is a very demanding process considering that it is not restricted to data presentation but also inference based on existing data.  Depending on the reliability of the existing data and/ or constraints regarding the conditions/ processes/ materials that allow safeguarding quality, the risk assessment process may limit or even waive the required testing. For example, a low maximum dose pharmaceutical product, with a composition that does not exhibit a high propensity for leachable species solubilization, is likely to arrive to a “leachable species profiling” waiver through the risk assessment process – making the risk assessment procedure very cost-efficient. A high dose liquid injectable product on the other hand may even require testing through its shelf-life for determining the kinetics of migration and modifying the shelf-life appropriately so as to mitigate the risk of critical exposure.


  1. Submission and Approval: This phase reflects a product that is fully defined and completely characterized with respect to leachables. This practically means that a leachables study has already been performed on the final product by employing a validated method in order to establish the product's leachables profile.

Development and validation of product-specific analytical methodology

Based on the results obtained from the extraction study (or simulation study) previously performed, the generic methodology, comprised of the sample pre-treatment and analysis stages, is properly adjusted in order to become a "tailor-made" product-specific methodology targeting the analytes / potential leachable species, identified during the extraction study that exceed or have the potential to exceed the product's Analytical Evaluation Threshold (AET) during the actual leachables study. The next step is to make this "tailor-made" method also "fit for purpose" by means of method validation according to the principles set by ICH Q2 (R1) guideline.

The validated product-specific methodology is subsequently applied in order to perform the actual "leachables" testing and provide reliable quantitative results for the leachables of interest.

Simulation study (Assessment of final product packaging system, identification of target leachables)

However, since the leachables assessment should cover the product's shelf-life, it is rather hard to have relevant data available at the time of submission. To this end, simulation studies can be performed as a "surrogate" by submitting the final product to elevated temperature conditions in order to simulate the anticipated stressing effect at the end of shelf-life.

Moreover, simulation studies where the actual drug product is replaced by a solvent of equal or similar propensity can be performed in the following cases:

  •  Drug products with an extremely complex and challenging matrix (e.g. lipid emulsions) where a more “analytically expedient” sample needs to be produced for the evaluation of “leachables”
  • Identification of “probable” leachables that could be employed as target analytes for the development and validation of a “product-specific” methodology for the determination of leachables. The advantage versus the extraction study is that the long list of “extractables” is significantly reduced and the target analytes are much more relevant since the simulation study mimics the conditions experienced by the final drug product


  1. Final Product Assessment and Maintenance: This phase mainly comprises of the final and definitive assessment of the product at the actual end of shelf-life as well as issues that may arise from vendor-related raw material or compositional changes that may have an impact on the leachable species profile (change control)

"Leachables" study

Application of the validated “product-specific” analytical methods for the quantification of leachables in the final drug product, stored under normal and accelerated storage conditions (e.g. ICH conditions) at the end of the product’s shelf-life. Both target analytes, previously identified from extraction / simulation studies, and secondary leachables are monitored and determined.

On occasion, the authorities may express a request that is actually targeted on a specific substance or a group of substances. Based on the request, this may fall either under screening studies or targeted studies.

Typical examples include the following:

  • OVIs – Organic Volatile Impurities: This is usually triggered by the use of a rubber material in the product. It is addressed through a screening study but, as implied from the nomenclature, it is limited to volatile organic species.
  • Bis(2-ethylhexyl) phthalate (DEHP): A known endocrine disruptor for which a high exposure of the general population is suspected. The request is usually triggered by the use of PVC materials in either manufacture, storage or even dilution of a pharmaceutical product. This is a targeted request.
  • Benzophenone: A known potent photosensitizer species. The request is triggered by the submission of data on labeling to the authorities, that implies or states the use of a benzophenone or acetophenone photoinitiator. Depending on whether the data declare the exact compound used or not, the study may be treated as a targeted study or a screening study.

The techniques employed include:

  • LC-PDA- (ESI/ APCI) HRMS: A combination of liquid chromatography with mass spectrometry and UV/ vis-based detection. Contrary to conventional LC-UV chromatography, detection is not highly strained by co-elution due to HRMS’s capability for high resolution based on ion m/z. Species detectable correspond primarily to low volatility analytes with chemical moieties that are amenable to ionization or dipole induction; this practically includes almost all of the potentially bio-active chemical species: amines, amides, esters, alcohols, acids, ketones, sulfates/ sulfites, phosphates/ phosphites, etc.
  • (HS/L) GC-(EI/CI) MS: A combination of gas chromatography with mass spectrometry that allows sample introduction either in gas form (upon thermal desorption) or liquid form. The technique may employ electron impact or chemical ionization, with an emphasis on EI due to the extensive fragmentation libraries that exist under the convention of using a 70 eV field. Detectable species range from highly to semi-volatile species and while partial overlap with LC-HRMS is possible when targeting the “semi-volatile” range, GC-MS is necessary to allow the detection of non-polarizable species i.e. hydrocarbons, polymer oligomers, ethers, sulfides, halogenated hydrocarbons, etc.
  • ICP-MS: The successor to classic FAAS techniques that allows targeting of multiple elements in a single analytical run without the need for element-specific lamps. The detection of elemental impurities is based on the characteristic m/z values for their isotopes, while interference and instability due to sample composition is minimized due to the atomization process and the collision / reaction cell technology employed.

Evaluation of the methods based on the above, or other techniques if required (ion chromatography, size-exclusion chromatography, etc.), is mainly based on the principles of ICH Q2 (R1) guideline.


Nitrosamines testing

 In 2018, nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in a number of blood pressure medicines known as ‘sartans’. This led to some product recalls and to a regulatory review, which set strict new manufacturing requirements for these medicines. Subsequently, a nitrosamine impurity has been detected in batches of ranitidine, a medicine used to treat heartburn and stomach ulcers, and the Agency’s Committee for Medicinal Products for Human Use (CHMP) has started a review.

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. However, there is a very low risk that nitrosamine impurities at the levels found could cause cancer in humans. The European Medicines Agency (EMA) has asked marketing authorisation holders to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicines containing chemically synthesised active substances. Moreover, the EMA has provided guidance to marketing authorization holders (MAHs) on how to avoid the presence of nitrosamine impurities in human medicines, while the CHMP has requested MAHs for human medicines containing chemically synthesized active substances to review their medicines for the possible presence of nitrosamines and test all products at risk.

To this end, MAHs should follow the below steps:

  1. Conduct a risk evaluation to identify products at risk of N-nitrosamine formation or (cross) contamination. The evaluation should be in accordance with the risk management principles described in the ICH Q9 and in relation to toxicology assessment described in the ICH M7 guideline.
  2. Perform further confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross) contamination and report confirmed presence of nitrosamines as soon as possible, irrespective of the amount detected.
  3. Apply for a variation in a timely manner to introduce any required changes to the marketing authorisation, such as amendment of the manufacturing process or changes to product specifications.

Nitrosamines include but are not limited to:

  • NDMA
  • NDEA
  • NMBA
  • NDBA
  • NMOR
  • NMPA
  • MeNP
  • NDPA
  • N-Nitroso-APIs

Qualimetrix can assist MAHs as well as other parties involved in the supply chain of a pharmaceutical product in properly addressing the “nitrosamine issue” by fully undertaking the:

  • risk evaluation and
  • confirmatory testing

Qualimetrix has extensive knowledge and experience in the determination of nitrosamines in APIs, finished products of solid (tabs, caps) and liquid dosage forms (e.g. syrup, solutions) as well as water or excipients.

The determination of nitrosamines is based on published methods, proposed by the authorities (EDQM, FDA, Taiwan FDA) and on extensive literature research, which are finely tuned according to the needs of every matrix. The analysis is in line with the interim limits set, based upon the maximum daily intake, however the current methodologies are able to ensure absence (i.e. “not quantifiable” levels) of nitrosamine impurities (< 0.03 ppm). Qualimetrix is equipped with state-of-the-art instrumentation, dedicated for the analysis of nitrosamines, operating under GMP environment. Methodologies based on LC-(APCI)-MS/MS and (HS)-GC-MS are included in the portfolio of nitrosamine testing, with various extraction techniques, in order to ensure confident identification and accurate quantitation of the impurities. Nitrosamine testing is performed by our technically competent and experienced personnel. Method development and validation are designed in order to cover the needs, as per the demanding limits, challenging matrix and urgent requests.


NAP test

WHO NAP test or IQ consortium protocol:

During development of an analytical method, a reference standard of the relevant nitrosamine impurity is generally needed. If, despite extensive efforts, it becomes apparent that the relevant nitrosamine impurity cannot be synthesised, then this could be an indication that the nitrosamine either does not exist or that there is no risk of it being formed. In such cases, it may not be necessary to conduct confirmatory testing. This should be justified thoroughly on a case-by-case basis according to appropriate scientific principles. The justification could include relevant literature, information on structural/stereo-electronic features and reactivity of the parent amine, stability of the nitrosamine and experimental data to illustrate the efforts made to synthesise and to analyse the impurity.

In Vitro Release and In Vitro Permeation studies

Percutaneous absorption actually infers permeation of the drug through the epidermis and into the deep layers of skin and general circulation in vivo, a total process that includes transport through the skin and local clearance. Skin permeation relates to the first part of the process, diffusion across the skin. In percutaneous absorption either diffusion or clearance factors can, in principle, be rate controlling; however, with few exceptions skin permeation is the kinetically determining event. Thus, skin permeation observed in vitro is believed to reflect accurately the rate determining aspects of drug delivery in most instances and is, therefore, projected as a means of determining relative availability from dosage forms (Skelly et al 1987). Based on these principles, in the “Critical Opportunities Pathway,” the FDA identifies the in vitro diffusion study combined with rheological testing to demonstrate bioequivalence of qualitatively and quantitatively (Q1Q2) equivalent drug products.

The primary permeability barrier of the skin, the stratum corneum, is a rugged, non-living membrane like hair or nails, and it retains its barrier properties following excision from the body. The in vitro permeation test involves the use of a diffusion cell that maintains excised human skin at a physiological hydration and temperature. The excised skin is routinely dermatomed to a thickness that includes the epidermis (with its stratum corneum) and part of the dermis. The in vitro diffusion study set up for topical products consists of excised human skin between donor and receptor chambers. Test formulations are applied to the skin membrane surface facing the donor chamber. A physiologically based receptor solution bathes the underside of the skin and accepts drug diffusing through the skin with adequate solubility to maintain sink conditions. It is important to maintain the sink conditions by including solubilising agents in the receptor fluid, if needed. Minimal effect on the skin barrier properties from these receptor solutions is desired and should be demonstrated. The receptor solution beneath is sampled through a side-arm sampling port at various time points frequent enough to maintain sink conditions that would adequately mimic the clearance created by the dermal microcirculation. Sampling to measure dermal drug flux in the in vitro permeation test model is performed in a manner analogous to pharmacokinetic sampling by blood draws (Narkar 2010, Raney et al 2015).

Permeation studies are a useful tool for Systemically as well as Locally Acting – Locally Aplied products, not only dermal, but also ocular (ophthalmic), rectal, vaginal, nasal and mouth (through oromucosal) products.

Structural elucidation of unknown impurities

Structural Elucidation of an unknown compound is a challenging task, evolving rapidly in the field of pharmaceutical and forensic analysis. This critical analytical activity often emerges when unknown impurities are found to be present above the prescribed stringent identification threshold set by ICH Q3A/B, during routine control of an API or a final product (e.g. batch testing, stability study). The focus on impurities in pharmaceutical products closely relates to patient safety considerations associated with the induction of toxic or even carcinogenic effects. Furthermore, the identification / structural characterization of impurities serves the following purposes:

  • Provides a better insight on the nature and origin of the impurities which in turn highlights the critical synthetic / manufacturing process steps and enables the implementation of an effective control strategy.
  • Enables the synthesis of reference standards in order to achieve a “confirmed” impurity identification.
  • Enables the toxicological evaluation and the assessment of the genotoxic potential.
  • Facilitates the establishment of drug degradation pathways and mechanisms.

Structural elucidation of unknowns requires high throughput techniques and sophisticated chemometric tools. Mass spectrometry (MS) is the technique of choice, combined with a separation technique, mainly Liquid and Gas Chromatography.

The structural elucidation is based on information over the physicochemical properties of the molecule, as well as its chemical formula, derived from information of its molecular weight and fragmentation pattern. Sophisticated software combines the available information and based on advanced algorithms, a probable structure is proposed, with a certain degree of confidence. Moreover, the chromatographic retention time plausibility of the proposed structure is evaluated through chemometric models.

Accurate mass measurements, through high resolving power mass analyzers (HRMS) can contribute to the confidence degree of the proposed structure. Complementary techniques, regarding separation or detection, such as HILIC chromatography or NMR can boost the identification, by providing additional evidence for the characterization. Statistical evaluation and high scientific know-how, are necessary, as a final step for the identification.

MS techniques, mainly HRMS, together with statistical models and chemometric methods can maximize the retrieved information and combined with scientific expertise can frame the scheme of the identification of unknown impurities.

Qualimetrix combines the range of the required hyphenated techniques, mentioned above, with “cutting edge” software and scientific expertise in order to facilitate and successfully complete the challenging task of structural elucidation. A tailor-made approach and methodology is applied according to the purpose of the study and the customer’s requirements that may include, but is not limited to, the following:

  • Transfer” of the chromatographic method employed for QC testing / Development of a MS-compatible analytical method.
  • Isolation of the unknown compound by means of semi-preparative chromatography.
  • Analysis of the isolated compound by means of hyphenated techniques and computer-assisted software and libraries.
  • Extractables / Leachables identification.
  • Elemental analysis.
  • Literature-based and in-silico toxicological assessment of the identified impurity.

All of the above aim at both the identification of the unknown impurity and the determination of its source so that the most effective control strategy can be defined and implemented.


Regarding the confidence provided during the identification of an unknown compound, there are different identification confidence levels, as described by the diagram above.

Level 4 is the first step of information regarding the unknown compound, as it is derived from the chromatographic data.

At Level 3, a molecular formula is proposed to the mass, by evaluating the MS spectrum profile and taking into consideration the accurate mass, isotopic fitting and if present, adduct ions.

Level 2 is evaluating the MS/MS information of the compound, along with additional experimental data, in order to propose a tentative candidate structure.

Level 1 represents the ideal situation, where the proposed tentative structure is confirmed via comparison with the respective reference standard, purchased if available.

Reverse engineering / Investigation of the Reference Product composition

According to Article 10 (1) of Directive 2001/83/EC the applicant is not required to provide the results of pre-clinical tests and clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product. A generic medicinal product is defined as a medicinal product that has:

  • the same qualitative and quantitative composition in active substance(s) as the reference product,
  • the same pharmaceutical form as the reference medicinal product,
  • the bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.

Based on the above regulatory provisions the knowledge of the reference products quantitative composition is not mandatory in order to develop a generic product however, it could be a key issue in several cases, such as:

  • Depending on the nature and quantity, the excipients may have a significant impact on the drug bioavailability. Qualitative (Q1) and quantitative (Q2) formulation similarity is a way of lower risk in order to achieve similar bioavailability.
  • There are several cases where a pharmaceutical product can waive bioavailability studies pending on the drug solubility, the formulation form etc. Scientific justification can be significantly enhanced by demonstrating Q1 and Q2 formulation similarity.
  • The stability behavior of the product could be influenced by the drug – excipients interaction.
  • For topical applied products (hybrid applications), the excipients may have a significant impact on the release from the dosage form, on the skin barrier properties and drug penetration, directly affecting the rate and the extent of exposure at the site of action.
“Essential similarity” establishment for generic and hybrid applications
Compatibility studies
Toxicological evaluation

According to ICH M7(R1) Toxicological evaluation and PDE calculation is required in order to categorize impurities

Part 1: In-Silico Model Derived Data

Software: Lhasa DEREK and Lhasa SARAH

Presentation of Data on Toxicological endpoints:

  • Carcinogenicity
  • Mutagenicity
  • Genotoxicity
  • Skin Sensitization
  • Teratogenicity
  • Irritation
  • Respiratory Sensitization
  • Reproductive Toxicity

Part 2: Commendation from Toxicological Expert on NOAEL and PDE calculation

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