In the last few years, elastomer, thermoplastic or thermostable plastic polymeric materials have become established as basic components in many pharmaceutical and biotechnological manufacturing processes.
The range of polymeric materials available in the industry is very broad and materials have been developed with very different structural properties depending on the desired application. Some are designed to be used once only (single-use systems) such as bioreactors, freezing and thawing bags, sterilising filter equipment, outlining equipment or transfer systems. On the other hand, other polymeric materials can be used for multiple cycles, such as tubes and conduits, valves or joints. In any case, all of these polymeric materials are commonly used in manufacturing processes, in dosing systems and in primary, secondary and tertiary medicinal retrofitting systems.
2. Extractables in polymeric materials
Depending on their chemical nature and migratory properties from the container to the medium, the organic or inorganic impurities originating from the polymeric materials may be classified as extractables or leachables. As such, extractables can be defined as compounds released by the material in extreme temperature conditions, exposed at length, or released in the presence of organic solvents of different polarity or at different pH values. On the other hand, leachables are compounds that migrate from the material to the pharmaceutical product in normal use and storage conditions.
The presence of extractable or leachable impurities in the product originating from these polymeric materials may entail a change in its composition, therapeutic action, efficiency or stability. The presence of impurities in liquid forms for parenteral, ophthalmic and inhaled administration, among others, is particularly critical given the greater bioavailability that exists through these administration methods.
The potential impact of impurities on the quality of the product thus requires to carry out an exhaustive study on the materials, by means of a joint approach involving both the supplier and the end user:
– The supplier must set up a profile of significant potential extractable impurities and provide useful and full data to the user. Furthermore, they must control reproducibility of the extractable levels through the qualified selection of raw materials and controlling of the production processes.
– The user must check the data provided by the provider and carry out a risk analysis to assess the criticality of the material and its impact on the patient, as well as carry out extraction and leaching studies on the product whenever necessary.
3. Regulatory scope
The decrease in quality of the medication due to the presence of leachable impurities added to the risk they may entail to the patient have led to the development of an extensive regulation by healthcare agencies such as the FDA (Food and Drug Administration)1 and EMA (European Medicines Agency)2, recommendations of expert groups such as the PQRI (Product Quality Research Institute), the PDA (Parenteral Drug Association), the BPSA (Bio-Process Systems Alliance), the BPOG (BioPhorum Operations Group) or the chapter corresponding to single-use systems in the draft of annex 1 of the GMP.
Thus, the new draft of Annex 1 of the GMP3 introduces a new chapter on single-use polymeric systems, indicating the need to assess polymeric materials in which the risk of transfer of impurities into the product is higher. In these cases, the extraction profile data of the material will allow us to assess if additional leaching studies are necessary or not, in which we can rule out the presence of impurities in the product in real working conditions.
Likewise, the GMP for biological products (Annex 2, 2016)4 specifically indicate the need to assess single-use sterile systems in relation to suitability and compatibility with the product, using the results of extraction and even leaching studies, if they are deemed necessary. There are also specific regulations for certain materials such as International Standard ISO 13408-25, which introduces a new chapter regarding risk management in filtration systems, in order to check the compatibility between the filter and the product.
4. Risk analysis of materials
According to the different standards and expert recommendations, extraction studies of polymeric materials involved in manufacturing processes can be carried out on a scale depending on the criticality of its use. In this sense, it is particularly effective to analyse the risks of the materials which would allow for greater knowledge to be gained on extractables which may reach the finished product.
There are different guides and recommendations to assess the need to carry out extraction studies on retrofitting materials, such as the retrofitting systems guide of the FDA1, that of primary retrofitting plastic materials of the EMA2 or annex 9 of the GMP on packaging guidelines for pharmaceutical products6. Furthermore, there are multiple risk analyses available to assess the need to carry out extraction studies on polymeric materials and single-use systems such as those proposed by the PDA, the BPOG or in the United States Pharmacopeia (USP).
4.1 Risk analysis according to the USP
According to the recently developed proposals for chapters <665> and <1665> of the USP (Pharmacopeial Forum 43, 2017)7 the characterization and selection of plastic and polymeric
materials used in the manufacturing of pharmaceutical and biotechnological products could be developed based on four parameters which define the risk of transfer of components:
– Contact time
– Contact temperature
– Chemical composition of the fluid
– Polymeric material composition
Using these four parameters which define both the material and the process, a risk matrix could be developed which assigns three risk levels to each variable (high, medium and low), as shown in the following figure:
Table 1. Risk analysis of extractable transfer (based on USP Pharmacopeial Forum 43, 20177
In order to assess the total risk based on this risk matrix, reference values may be used, in such a way that when there is a high risk level in at least 3 parameters, a high value of total risk will be assigned, which establishes the need to carry out extraction studies on the material. On the other hand, if the risk value assigned is medium up to a maximum of three parameters, it will not be considered essential to carry out a full range of extraction studies for the analysis of the material.
4.2 Risk analysis according to the PDA
According to the technical report of the PDA on the application of single-use systems in the manufacturing of pharmaceutical products (2014)8, depending on the type of process and the characteristics and structural complexity of the single-use material involved, the risk of transfer of components from the material to the product may be classified as high, medium and low, as summarised on the following table:
Table 2. Risk analysis of extractable transfer (based on PDA, TR 66., 2014)8
4.3 Risk analysis according to the BPOG
According to the recommendations of the BioPhorum Operations Group included in the “Best practices guide for evaluating leachables risk from polymeric single-use systems used in biopharmaceutical manufacturing”9, s, 5 decisive aspects must be considered during the risk analysis of materials for every material involved in the production process, such as:
– Distance from the material under study until the finished product,
– Operating temperatures,
– Exposure time,
– Interaction with fluids
– Dilution ratios
According to this group of experts, the values proposed to weigh each factor will range from 0 to 9, applying an additional weighting value for the distance parameter in the production chain, as shown in the following figure.
Table 3. Risk analysis of extractable transfer according to BPOG (adapted from BPOG Best Practices Guide for Evaluating Leachables Risk in Biopharmaceutical Single-Use Systems)9.
4.4. Risk analysis of materials according to Azierta
Azierta’s proposal is based on a comprehensive risk analysis in order to evaluate the criticality of carrying out extraction studies on polymeric materials used in pharmaceutical and biotechnological production processes.
This risk analysis has a transversal nature and considers the physicochemical parameters of the polymeric material and the manufacturing process used typically in risk analyses of the USP, the PDA or the BPOG. Furthermore, it also takes into account the toxicological profile of the material and the characteristics of the product itself which modulate the toxicological risk, such as the administration method or the dosage of administered product.
Thus, Azierta’s risk analysis allows us to safely and effectively narrow down the need for the assessment of polymeric materials, in such a way that only those materials which show a real risk of transfer of impurities and which also entail a risk for the patient from the toxicological point-of-view will be submitted to extraction studies.
Finally, where necessary, qualitative and quantitative extraction studies shall be carried out using complementary and high-resolution analytical techniques in order to create a profile of extractable impurities from the material. As was revised in a previous article on “toxicological assessment and risk analysis for extractable and leachable impurities” (Pharmatech, July 2018), the toxicological assessment (based on pre-clinical information, clinical information and information obtained using computational techniques) from the compounds obtained in the extraction studies ,along with the risk analysis which relates the toxicity of each extractable and its exposure through the product, will allow us to identify the components which, in effect, show a greater risk and which therefore must be controlled in the finished product.
The study on the impurities derived from polymeric materials shall be carried out using a holistic approach and coordinated based on extensive knowledge on the properties of the materials, the manufacturing processes and the characteristics of the product which may modulate the toxicological risk.
Therefore, the comprehensive risk analysis which safely and effectively narrows down the need to carry out tests on polymeric materials, along with the extraction studies on materials and the toxicological assessment of the results obtained, will allow us to define the risk derived from the polymeric materials used in manufacturing processes and lastly, maintain the quality of the pharmaceutical product and the safety of the patient.
At Azierta, science and health consulting, we have a specialized line in toxicological assessment being also corporate members of EUROTOX.
OUR SERVICES: We have accredited toxicologists and experts in the evaluation and qualification of organic impurities and residual solvents, always in accordance with the existing regulation.
1. Food and Drug Administration (FDA) Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics. 1999
2. European Medicines Agency (EMA) Guideline on Plastic Immediate Packaging Materials. 2005
3. Annex 1 GMP. Manufacture of Sterile Medicinal Products (Revision). 2017.
4. Annex 2 WHO good manufacturing practices for biological products Replacement of Annex 1 of WHO Technical Report Series, No. 822
5. UNE-EN ISO 13408-2:2018. Procesado aséptico de productos para la salud. Parte 2: Filtración esterilizante. (ISO 13408-2:2018).
6. Annex 9 GMP. Guidelines on packaging for pharmaceutical products. 2002.
7. USP Pharmacopeial Forum 43, 2017 In-Process Revision of chapter 〈1665〉 Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products.
8. Parenteral Drug Association (PDA) Technical Report No. 66 Application of Single-Use Systems
9. Biophorum Operations Group (BPOG) Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing.