Dr Bettine Boltres, Product Manager, Pharmaceutical Tubing, SCHOTT, Germany in this white paper, touches on a risk-based approach of the evaluation and describes important facts to consider when assessing extractables and leachables from glass
Over the past years the increased development of biopharmaceuticals is making ever higher demands of the packaging components. The biologically developed drug formulations growing in the areas of therapeutic proteins, vaccines and monoclonal antibodies exhibit much higher sensitivities towards any foreign substances and changes in environment than the chemical drugs do. Additionally the liquid formulations containing surfactants, salts and chelating agents coupled with ever lower drug levels placed a global focus on the interactions between the formulation and the packaging material and thus the whole container closure system. Determination of potential extractables and/ or leachables became part of the process validation when filing new drug applications.
Both the EU and the US regulations state, “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”  . This regulation applies to all materials including metals, glass, and plastics. A good introductive overview can be gained from a BPSA publication. Other recently published guidelines reflect the increased focus: USP <232> and ICH Q3 for “elemental impurities” and USP <1663> and <1664> for extractables and leachables    .
Polymers are considered to have a high potential interaction with the product. However, other materials, often considered to be inert, such as glass or stainless steel, were shown to release substances into the drug formulation.
The FDA’s Final Report on Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach provides clear guidance on utilising scientifically sound, risk-based approaches to pharmaceutical cGMP requirements. Basically a risk-based approach means that drug container closure systems should not be evaluated according to the same procedure but on an individual basis. Furthermore, it is recommended to initiate this as early as possible in the development process when changes can be addressed more easily. Effective science- and risk-based assessments are best done from a foundation of comprehensive process knowledge, which is key to quality by design principles  . Starting with a risk-based approach at a very general level throughout the whole medical drug product range there is already a difference in the degree of concern and the likelihood of interactions of the drug with the container.
Oral tablets having a small manner of interaction with the packaging material pose just little concern whereas injectables having a high exposure to the primary packaging material surface pose the highest concern.
Focusing on injectables there are also several factors influencing the risk of creation of extractables and leachables. The highest risk is posed by a large volume medicine that is administered on a daily basis and is coming from a storage packaging material.
Table 2 shows a very structured risk-based approach.
In order to set up a compatibility study the definitions have to be clarified even more so as they have changed over the past years due to a gain in experimental knowledge.
Components of a certain packaging material that are released during a certain stress test procedure (e.g. aggressive solvents, exaggerated conditions of time and temperature).
Extractables are determined by exposing components or systems to conditions that are more severe than normally found in a biopharmaceutical process, typically using a variety of solvents at high temperatures. The goal of an extractable study is to identify as many compounds as possible that have the potential to become leachables .
Components of the container closure system that are migrating into the drug formulation during usual production process and storage. Up to now it was believed that leachables are a subset of extractables. Nowadays, it has become more clearly that there is a possibility of the occurrence of leachables that are not detected by the usual extractables screenings e.g. because they form under special and different conditions between the drug formulation and some material components. It is thus not recommended to rely solely on extractables data.
It is important to keep in mind that the concentration of a leachable in the final drug product is not as important as the dosage that is accumulated by the patient. The acceptable concentration of a leachable is higher for a 1 mL injection than for a 1000 mL transfusion. In other words, the concentration of the leachable in the 1 mL injection could be 1000 times higher and achieve the same dosage of the leachable (Table 2). Therefore, when addressing leachables from processing materials, the concentration measured during a leachables test must be translated to a final dosage level in the drug product .
Whether or not extractables and leachables are present at a level that might cause safety concerns should be reviewed by qualified toxicologists. As for the quality of the product it is important to know the potential leachables because some compounds can also affect product efficacy and stability.
However, to address these points it is most important to possess an in depth knowledge about the whole process and its interacting parameters.
Borosilicate glass has a distinct and known composition with a defined set of potential extractables and leachables.
In general borosilicate glasses consist of the following elements:
- Sodium, potassium
- Calcium, magnesium, barium
Depending on the type and manufacturer this can vary. For light protection iron and titanium or manganese are added.
As the nature of potential extractables and leachables from glass is known the amount being released from the glass is rather the question. However, this question can be neither be answered easily nor generally. As often the case for glass interactions it depends on a lot of different simultaneously occurring factors.
These factors are among others:
- Glass composition
- Converting process: Flames and temperatures, burner gases, climatic conditions, materials that are in contact with the glass during formation, like steel or tungsten parts; washing, drying, annealing oven
- Container size/ volume ratio (concentration of extractables and leachables decreases with increasing container size due to a smaller surface area which is in contact with the solution)
- Pretreatments: Surface treatments can significantly change the appearance of extractables and leachables
- Rubber components: They can interact with a glass component
- Drug product: pH value, complexing agents, buffers, solvents, salts
- Storage and transportation conditions; time, temperature, humidity, impact of light
- Pharmaceutical process: washing process, drying, sterilisation process, stopper material
Borchert et al. describe an extractables study in their paper performed on borosilicate glass containers. They were monitoring different elements as well as the pH shifts and the total extractables. As a solvent they used unbuffered (pH 4.0, 6.5, 8.0. 9.5, 10.4) and buffered (pH 8.0, 10.0) aqueous solutions. The containers they used were from different global suppliers both tubing and molded. All glass components could be found in different concentrations. In addition rubber components could be identified as well (Na, Ca, Mg, Zn, Ti).
Bohrer performed the glass grains test using solutions of some inorganic salts like NaCl, KCl, CaCl2, MgCl2, NaHCO3, NaH2PO4, KH2PO4, sodium gluconate, citric acid and glucose. She also found the whole variety of glass components in the solution in a range of 8.8 to 33 ppm for silicate, 0.9 to 6.9 ppm for borate and 0.5 to 2.4 ppm for aluminum and confirmed that the basic solutions of NaHCO3 and gluconate extracted the highest amount of glass components .
As easily visible evaluating processing and packaging materials for extractables and leachables requires co-operation between vendors and end-users and a commitment to utilise the best science possible within a risk-based framework.
Additionally it becomes clear that a summation of the individual extraction values of each packaging material does not lead to a complete picture. Rather it is necessary to perform the studies on the final product container closure system in order to receive realistic values.
 European Comission of Glass, “Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use,” 2010.
 FDA, „Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics,“ 1999.
 US Government Printing Office, “Equipment construction,” CFR, Code of Federal Regulations, Food and Drugs, Title 21, p. Part 211.65, 2010.
 BPSA, “Recommendations for Extractables and Leachables Testing Part 2: Executing a Program,” BioProcess International, vol. 6, no. 1, pp. 44-53, 2008.
 USP 36, NF 31, Chapter <232>, Elemental Impurities – Limits, United States Pharmacopeia, 2013.
 ICH Q3D, Guidlines For Elemental Impurities, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2013.
 USP 36, NF 31, Chapter <1663>, Assessment of Extractables associated with Pharmaceutical Pacakging / Delivery Systems, United States Pharmacopeia, 2013.
 USP 36, NF 31, Chapter <1664>, Assessment of Drug Product Leachables associated with Pharmaceutical Packaging / Delivery Systems, United States Pharmacopeia, 2013.
 FDA, Pharmaceutical cGMPs for the 21st Century – A Risk-Based Approach, Final Report, 2004.
 D. Bestwick und R. Colton, „Extractables and Leachables from Single-Use Disposables,“ Bd. 7, Nr. S1, pp. 88-94, 2009.
 BPSA, „Recommendations for Extractables and Leachables Testing, Part 1: Introductin, regulatory Issues and Risk Assessment,“ BioProcess Int., Bd. 5, Nr. 11, pp. 36-44, 2007.
 S. J. Borchert, M. M. Ryan, R. L. Davison and W. Speed, “Accelerated Extractable Studies of Borosilicate Glass Containers,” Journal of Parenteral Science & Technology, vol. 43, no. 2, pp. 67-79, 1989.
 D. Bohrer, „Containers,“ in Sources of Contaminantion in Medicinal Products and Medical Devices, 1. Hrsg., John Wiley & Sons, Inc., 2013, pp. 185-227.
 D. Bohrer, P. C. do Nascimento, E. Becker, F. Bortoluzzi, F. Depoi and L. M. de Carvalho, “Critical Evaluation of the Standard Hydrolytic Resistance Test for Glasses Used for Containers for Blood and Parenteral Formulations,” PDA Journal of Pharmaceutical Science and Technology, vol. 58, no. 2, pp. 96-105, 2004.