Confirming that a process or a system
meets its predefined quality attributes

Validation Activities

Qualimetrix provides validation services in a wide range of analytical activities as well as validation of the final product characteristics.

These include, but not limited to, the following

Methods are validated in accordance to the current regulation (e.g. ICH guidelines, Pharmacopoeia monographs), and sponsor’s specific protocol. The critical parameters that may affect the method performance are taken into consideration, and the study involves among others the following:

Specificity and selectivity
Linearity and range
Repeatability and intermediate precision
Accuracy
Robustness
Standard and sample solution’s stability

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.

Regulatory guidelines and various best-practice recommendations state that assessment of the potential impact of contact between a component or material and a final dosage form involves evaluating the final dosage form with respect to leachables. This assessment can include a migration or leachables study whose purpose is to discover, identify, and quantitate leachables that have migrated from the contacted system, components, or materials and accumulated in the dosage form. Alternatively, this assessment may involve performing a simulation extraction study, when use of such a study in lieu of a migration study can be justified.

During the course of manufacturing, packaging, storage, distribution, and administration; dosage forms and their constituents can contact components and materials of construction of manufacturing and packaging equipment, and primary and secondary packaging components and systems. Such contact may result in interactions between the dosage form and these components and materials. One such interaction is the migration or leaching of substances from any of these components and materials into the dosage form with subsequent delivery to the patient during drug administration.

Patients also can be directly exposed to substances via direct contact with the packaging/delivery system during drug administration. Leachables, which can include both organic and inorganic chemical entities with wide chemical diversity, are of concern due to their potential safety risk to patients and potential compatibility risks for the drug product. In order to assess these risks and manage the potential issues posed by leachables, it is necessary to know the identities and the levels to which leachables will accumulate in the finished drug product over its shelf-life. These two pieces of information can be used to establish the magnitude of patient exposure (dose) and therefore the safety risk posed by an individual leachable, as well as the likelihood of any compatibility issues involving the drug product.

Leachables” studies can be used within the context of an overall leachables assessment to:

Facilitate the timely development of safe and effective dosage form packaging/delivery systems, manufacturing systems, and processes by assisting in the selection of components and materials of construction
Facilitate the establishment of qualitative and quantitative leachables–extractables correlations in drug products, when coupled with an appropriate extractables assessment(s)
Establish the worst-case drug product leachables profile in a manner that facilitates the development of drug product leachables specifications and acceptance criteria (should these be required), and the safety evaluation/qualification of leachables
Identify trends in drug product leachables accumulation levels over the shelf-life of a particular drug product
Facilitate change-control processes for drug product packaging/delivery systems (as appropriate), packaging components, materials of construction, formulation constituents, etc.
Facilitate investigations into the origin(s) of identified leachables whose presence causes out-of-specification (OOS) results for a marketed drug product.

Comprehensive stability testing services that are conducted according to ICH guidelines, preapproved Stability Study Protocols and under strict quality procedures and GMP requirements.

All climatic zones: I, II, III, IVa and IVb.

Long term, intermediate and accelerated storage:

25 °C / 60% R.H.

25 °C / 40% R.H.

30 °C / 65% R.H.

30 °C / 75% R.H.

40 °C / 75% R.H.

5 °C

-20 °C

-80 °C

Sponsor’s specific storage requirements can be discussed on a case by case basis.

All chambers are fully controlled and monitored, while they are connected to a 24 hour alarm system.

Besides storage and analysis, our services also include guidance and advice on:

The design of the study: Full Design or Bracketing and Matrixing Reduced Design (ICH Q1D guideline)
The statistical evaluation of the stability data: extrapolation of data and declaration of the storage conditions (ICH Q1E guideline)

According to ICH Topic Q1B (CPMP/ICH/279/95) Note for Guidance on the Photostability testing of new Drug Substances and Products, the photostability testing is typically performed in a climate chamber where the temperature is maintained at 25 °C and the relative humidity at 60%.

The climate chamber is equipped with an appropriate light source which after a specific time exposure provides overall illumination of not less 1.2 million lux hours and an integrated ultraviolet energy of not less than 200 watt hours/square meter.

 The light source is the combination of two tubes which leads to a spectral distribution according to option 2 of the Guideline CPMP/ICH/279/95 (Q1B):

Fluorescence tubes cool white: T8 fluorescence tube in the form of a rod with a tube diameter of 26 mm. Emissive range in the spectral range of 400 to 800 nm. The relative spectral distribution meets the F6 standard (cool white) acc. to ISO 10977.
Fluorescent tube: T8 fluorescence tube in the form of a rod with a tube diameter of 26 mm. Emissive range in the visible spectral range of 400 to 800 nm and in the UVA range of 320 to 400 nm.

The samples are exposed side-by-side with a validated chemical actinometric system to ensure the specific light exposure is obtained. A solution of 2% w/v quinine monohydrochloride dihydrate is prepared and two aliquots, one wrapped in an aluminum foil and one uncovered are exposed side-by-side with the drug products for the same duration.

In accordance with the ICH Guideline Q1B, the light exposure and further testing are usually performed on: a) the unpacked drug product, b) the drug product in the primary packaging, c) the drug product in the full marketed packaging system (including secondary packaging), d) the drug product covered by aluminum foil for application of dark conditions.

The purpose of the in-use stability testing is to provide information for the labelling on the preparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution, e.g. an antibiotic injection supplied as a powder for reconstitution.

As far as possible the test should be designed to simulate the use of the final product in practice, taking into consideration the filling volume of the container and any dilution or reconstitution before use.

At intervals comparable to those which occur in practice appropriate quantities is removed by the withdrawal methods normally used and described in the product literature.

The physical, chemical and microbial properties of the final product susceptible to change during storage are determined over the period of the proposed in-use shelf-life.

Testing is performed at intermediate time points and at the end of the proposed in-use shelf-life on the final amount of the final product remaining in the container.

A minimum of two batches, at least pilot-scale batches, should be subjected to the test. At least one of these batches should be chosen towards the end of its shelf-life.

Sterilizing filtration is the process of removing microorganisms from a fluid stream without adversely affecting product quality. To this end, most filter manufacturers provide results of tests performed according to applicable compendial methods to qualify their filters as suitable for pharmaceutical applications. However, this qualification documentation supports but does not replace, performance qualification as part of process validation conducted by the filter user. Qualimetrix facilitates this task, by undertaking the following tests according to PDA technical report No 26/2008, for which a short description is given:

 

Filterability test: The scope of the filterability test is to evaluate the potential clogging of the membrane by measuring the rate of the filtration (filtered weight against time), under constant pressure. This test also serves as a means of predicting manufacturing-scale performance by using flux and pressure conditions representative of the actual process.
Filter extractables (and potential leachables): It is a crucial part of filter validation studies to ensure that the filter does not adversely affect the process stream. To this end, filter extractable and possibly filter leachable species should be assessed. Extractables are chemical compounds that can be extracted from product contacting surfaces when exposed to an appropriate solvent under exaggerated conditions (i.e. time and temperature). Leachables are chemical compounds that migrate from a contact surface into the drug product or process fluid during storage or normal use conditions. The first step of the approach followed is to perform an extraction study with a suitable model solvent simulating worst-case conditions. Non-specific methods, such as non-volatile residue (NVR) and Fourier-transform infrared spectroscopy (FTIR) are employed to provide general quantitation and qualification of potential leachables. This represents the essential and simplified approach. Alternatively, and upon client’s request, an extensive extractable species profile assessment can also be implemented, by using various extraction media, to cover and extract the total pool of potential leachables, and by employing specific orthogonal techniques (LC/UV/MS, GC/MS, ICP/MS) to address their chemical diversity and provide information with respect to both their identity and concentration levels. The second step is to evaluate the levels of extractables following a risk-based methodology in order to determine the need for conducting a leachable species study. Both extractables and leachables testing for filters and other production-related materials (e.g., tubes) are an integral part of our services portfolio.
Compatibility: It is well known that numerous chemical interaction possibilities exist in a filter system. The effects of these interactions should be adequately characterized prior to filter selection and in most cases a simple chemical compatibility chart will not often provide enough information for predicting filter system compatibility, thereby requiring additional testing. Integrity testing is a non-destructive test that relates to microbial retention and is a determinant of compatibility. This test can be performed by means of either a diffusive / forward flow or bubble-point test. It is worth noting that both extractables and integrity testing constitute a combination of tests that serve to establish compatibility and detect subtle incompatibilities that a single test is usually not able to reveal.
Viability study: In order to determine the appropriate challenge test methodology, the test organism’s viability should be verified by direct inoculation into the carrier fluid (product or surrogate). To this end, the test filter membranes are exposed to the product solution, under worst case processing conditions in order to determine the effect of the product on the viability of Brevundimonas diminuta (ATCC 19146) for a given filtration time and define the most suitable method of performing a liquid bacterial challenge test for product and process specific filter validation.
Bacterial challenge: The bacterial challenge test validates filter membrane classification and demonstrates complete microbial removal from the product. The challenge organism is inoculated into the product (or surrogate) to deliver a minimum challenge level of 107 cfu/cm2 of filter surface area. The bacterial retention validation study should demonstrate that the filtration process of the product with the use of the specified filter, achieves the consistent removal of the high levels of the standard bacterium Brevundimonas diminuta (ATCC 19146) during the simulated processing conditions.

Optionally and upon request, an adsorption test can also be performed, in order to assess potential product binding to the filter membrane that could affect product composition and concentration.

Cleaning Validation is very essential when it comes to prevent contamination and cross-contamination of pharmaceutical products. Cleaning validation is documented evidence that a cleaning procedure of manufacturing equipment provides clean equipment, suitable for its intended use. The objective of Cleaning Validation is to prove that the employed cleaning methods reduces potential carryover of products, cleaning agents and microbial residues to an acceptable level.

At Qualimetrix:

We provide our clients with integrated support regarding cleaning validation activities.
Taking into consideration the latest regulatory requirements we develop detailed cleaning validation master plan and protocols in order to establish the residues acceptance levels and design the sampling plan.
We develop and validate efficient analytical methods based on adequate detectability and appropriate validation characteristics.
We provide our clients with guidance and assistance for the protocol implementation and the results evaluation.