Material Qualification

The activity involves reviewing and evaluating the available qualification data in terms of extractables and leachables of in-process materials (devices and primary packaging) present in the process in order to issue a Risk Assessment on the approach to extractables and leachables of in-process materials in the light of the latest regulatory monographs with a focus on USPs.

The final document can be used as a starting point for further assessments of extractables and leachables.

The objective of the risk assessment is to evaluate the applicability of the extractables and leachates data provided by the suppliers of the process materials (plastic, glass, elastomer, polymer) for the production of the final product. On site, the possibility and/or necessity of a specific master plan for product and process extractables will be assessed.

The aim is to identify, analyse and assess the potential risks on the quality of the final product in terms of extractables and leachables from the process materials in contact with the specific product, according to the approach provided by ICH Q9 'Quality Risk Management', included in Part III of the EU GMP.       

It is important, before starting the risk assessment activity, to define a procedure that includes all risk variables and the risk classification system. This procedure should consider the specific aspects of the main product types in the specific production process. The final risk assessment document can be used as a reference standard for any control of in-process changes related to material qualification.

There are two control phases: 

The first: Collection of documents and data for any material in contact with the public (ICH Process Q9)

• Initiation of the quality risk management process: In order for this activity to be carried out, it is necessary to establish the material specifications:
  • Ph. Eur. and USP (e.g. Class VI for plastics)
  • Toxicity data according to USP <87> for in-vitro and/or in-vivo biological reactivity tests 〈88〉 and/or ISO 10993 Biological evaluation of medical devices
  • Extractable and/or leachable generic data available
  • The consequences of hazards will be identified taking these characteristics into account

The second: Risk assessment (ICH Process Q9)
It consists of three steps: 

• Risk Identification: in this step, all risks to the quality of the final product and patient safety (if applicable)As potential areas of risk, the risk variables related to the Material, the Pharmaceutical Product Composition and the Process, respectively, were considered according to the client's internal procedure.
• Risk analysis: is the estimation of the risk associated with the identified hazards.
• Risk assessment: compares the identified and analysed risk with the data provided.

The Extractables test is performed in the event of document gaps. It is performed when, in light of the results of the risk assessment, a risk reduction plan is necessary. The level of accuracy of the Extractables test depends on the risk value associated with the article under study. Low-risk articles could be supported by an exploration extractables test with NVR and FTIR analysis, while high-risk articles should be comprehensively evaluated with an analytical package characterising all compounds.

USP <1663> contains the scientific principles and best practices to be applied to any extractables assessment or extraction study of pharmaceutical packaging/delivery systems, packaging components or construction materials, in order to establish extractables profiles that can be used for various applications, such as leachate-extractables correlation and/or simulation of worst-case product leachate profiles. This approach should also be used for the functional components of equipment used for the production of pharmaceutical substances and products, such as filters, tubes, bags.

Since the packaging/delivery system of pharmaceuticals is considered the main source of potential leachables, the assessment of leachables should be preceded by an assessment of extractables on the packaging/delivery system or on critical primary and secondary packaging components or materials of construction of the system, in accordance with regulatory guidelines and best practice recommendations. Therefore, leachate assessment cannot be a stand-alone means of evaluation.

The design of an extraction study depends on the purpose of the extractables assessment: in general, extraction processes must be completed within a reasonable timeframe, but must not be so aggressive as to alter the qualitative and/or quantitative nature of the resulting extractables profile.

The main parameters to be considered for an extraction study are the following:

• Extraction medium: the ideal solvent should have a similar or higher propensity to extract substances than the drug formulation; in fact, the drug substance itself does not typically create the 'leaching power', but rather it is the ingredients of the formulation that determine the ability of the drug product to leach substances from a contacted material. Therefore, when the product itself cannot be used, the choice of solvent and/or the use of multiple solvents must be justified to be consistent with industry best practice recommendations.
• Extraction time and temperature: the combination of these factors determines the magnitude of the driving force and the degree to which equilibrium is reached; in an extraction simulation study, a high temperature could increase the extraction rate, so that a short experimental time could simulate a longer leaching time: accelerated conditions can be expressed and established by the Arrhenius equation. The profiles of extractables obtained with a given extraction medium and extraction technique can and should be monitored for equilibrium or asymptotic levels of extractables.
• Extraction stoichiometry: this parameter considers the physical mass of the test article relative to the volume of the extraction medium and the actual physical state of the test article during extraction.

Characterisation of extractables is typically achieved through the application of various different analytical techniques that allow the discovery, identification and quantification with a reasonable degree of scientific certainty of all individual extractable compounds present above a certain level or threshold.

The study of extractables can also be approached by considering a list of standard solvents that could be applicable, after verification of the actual formulation, to different product solutions. The list of solvents and the level of chemical characterisation of the extractables depend on the calculated risk of the different processes and the material risk variables in an appropriate risk assessment matrix. An extraction temperature of 40° provides an appropriate acceleration factor: this choice is dictated by the desire to accelerate, but not alter, the extraction process. The test conditions in terms of extraction duration also depend on the type of material and the process conditions.

The AET is defined as the threshold at or above which a particular extractable and/or potentially leachable substance must be identified, quantified and reported for potential toxicological evaluation. The AET can be derived from the SCT (Safety Concern Threshold) or other threshold concepts based on factors including the dosage parameters of the drug product.

Since safety thresholds are derived from exposure data, they are considered in terms of exposure units, such as MDI (Maximum Daily Intake).

As there are different threshold concepts applicable, a worst-case approach is generally applied based on the SCT established according to the route of administration and dose parameters for a given drug product and specific process parameters, such as batch size and number of devices/process materials.

According to the test approach, results will be provided as extractables per component: compounds found to be above the AET value must be correlated with the process parameters (batch size) and the MDI for the product in question to determine whether they exceed the SCT value. A toxicological evaluation of extractables and/or potential leachates exceeding the SCT value must be performed to specifically address the safety impact of the specific leachates at their specific accumulation levels under the specific conditions and dosages associated with product use. The final result of the toxicological assessment provides the PDE (Parenteral Daily Exposure) level; if compounds quantified above the SCT are also above the PDE, they must be monitored during a leachables study. Although a leachables study is mandatory for primary packaging, despite (e.g.) the absence of compounds posing a toxicological problem, for in-process material an adequate extractables test may be sufficient if no compounds above the PDE value have been quantified.

The management of leachables is an important issue for pharmaceutical manufacturers and regulatory authorities, because some leachables above specific concentrations may pose a safety problem for patients and/or a quality problem for pharmaceutical product formulations.

To assess these risks and manage the potential problems posed by leachables, it is necessary to know their identity and accumulation levels in the finished pharmaceutical product during its shelf life.

Simulation studies

To facilitate the discovery and identification of probable leachable substances, the extraction study should be similar in structure to a leachable substance study of a drug product, to produce a test sample that is easier to analyse and characterise than the drug product formulation itself.

The differences in the study design between the simulation study (extractables) and the leachables study are as follows:

• The pharmaceutical drug product formulation is replaced with a simulant solvent that mimics the formulation, which means that the solvent used must have almost the same leaching propensity as the drug product formulation.
• Contact conditions must be accelerated to increase both the concentration of the probable leachates and their rate of migration into the simulant solvent.
• The test sample may be the entire packaging system or separate components of the system itself.

In these cases, the results of the simulation study may be sufficient to establish the safety of the patient and the impact on the quality of the actual leachables. Insofar as the simulation study mimics the leachable drug product study, the potential safety or quality impact of a compound as an extractable is an estimate of the potential safety or quality impact of the compound as an actual leachable.

Extractables themselves, or substances derived from extractables, have the potential to leach into a drug product during normal storage and use. In many cases, evaluations of extractables in pharmaceutical products are based on, or facilitated by, knowledge derived from evaluations of extractables performed on pharmaceutical product packaging systems, packaging components and packaging construction materials.

If a leaching test is required, the entire transfer line (where possible) or individual components are brought into contact with the drug formulation under actual process conditions. A complete analytical package (organic and inorganic profile) must be performed on the samples to monitor, characterise and quantify the leaching compounds. A final comparison with the PDE values can assess whether there is a toxicological concern for the patient and, consequently, an impact of the in-process material on the chemical quality and safety of the final product.