A Risk-Based Approach to Monitoring Elemental Impurities in Leachable Studies

The determination of elemental impurities is one of the standard tests performed as part of leachable and extractable studies for a final container-closure system (CCS). The Code of Federal Regulations(21 CFR 211.94) (1) states “drug product containers and closures shall not be reactive, additive, or absorptive as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.” To ensure that the CCS does not alter the performance of the product, nor that anything is being introduced into the final drug product, extractable and leachable testing is performed. FDA’s Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics (2) recommends that extraction studies be conducted for the critical components of the packaging system.

Extractable and leachable studies
An extractable study is initiated with all the components of the CCS that will be in direct contact (i.e., the primary component) with the drug product. For example, in a vial/stopper system, the vial and stopper are examined, but not the metal seal that secures the stopper to the vial. For a ready-to-use syringe, the syringe barrel, needle, needle shield, and stoppers are tested, but not the plunger. Oral products have blister packs, plastic bottles, or heat seals as contact surfaces. These primary components are examined individually and are subjected to a variety of conditions, such as extremes of temperature, pH, organic solvents, and placebo. The exact conditions are based upon the drug-product formulation and storage conditions. The extractable study is designed to provide a worst-case scenario to determine what impurities, if any, can be extracted from the components of the CCS. Studies are designed to minimize any degradation of the extracted compounds that might occur to provide an accurate profile of the extraction products.

The leachable study is designed to provide an estimation of the extent that any of the extractable impurities actually leach into the drug product during normal shelf life and storage conditions. To design the leachable study, a toxicological assessment of the compounds identified in the extraction study is performed to determine the safe level of exposure based upon the route of administration. Based on this toxicological assessment, target limits are established for the extractable compounds, methods are developed and validated for quantitation, and the leachable study is initiated. The leachable study is performed with the actual drug product (or placebo) in the CCS that is to be the final commercial presentation using materials obtained from the targeted commercial suppliers. The leachable studies are generally performed using the long-term stability study supplies.

Requirements for elemental impurity analysis
The extractable studies will include any elemental impurities that may be extracted from the CCS components. The results of these studies identify which elements will be monitored in subsequent leachable studies. Recently, the United States Pharmacopeial Convention (USP) issued in the United States Pharmacopeia (USP) a new General Chapter <232> Elemental Impurities-Limits (3), which provides a listing of the elemental impurities of potential toxicological concern as well as acceptable limits for those elements. USP General Chapter <232> applies to drug products.

The European Medicines Agency (EMA) also issued its Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents (4), which addressed elements of interest and maximum daily exposure limits for patients. In establishing its listing of elements and their corresponding limits, EMA evaluated existing toxicological information and based the final listing of elements and limits on patient safety. In 2012, the European Directorate for the Quality of Medicines & HealthCare (EDQM) in the European Pharmacopoeia (Ph. Eur. ) adopted the EMA guideline as a new chapter, 5.2.0 Metal Catalysts or Metal Residues (5), publishing it verbatim and thereby adopting both the EMA’s listing of analytes of interest and their corresponding limits.  

While the EMA guideline and the new USP General Chapter <232> are not completely harmonized, there is nonetheless, a considerable amount of harmonization between the two documents. For both EMA and USP, patient safety was the foremost reason for an element’s inclusion on the list of analytes of interest. These assessments are based on an assumed maximum daily dose of 10 g/day (of drug product) and have factors built into them to assure that the limits are well within the safety limits for each elemental impurity.  

Historically, any elemental impurities that are seen in extractable studies are further evaluated and followed during subsequent leachable studies. This testing is often done, regardless of whether there is any toxicological data that would indicate a potential for impact on patient safety or the contrary. As a result, costly and often unnecessary testing has been performed. Because the EMA and USP toxicological assessments have conservatively established limits based on patient safety, it is appropriate to use those limits to make any decisions regarding the need (or lack thereof) to monitor elemental impurities during leachable studies.

Risk-based approach for elemental impurity analysis in leachable studies
With the publication of the EMA guideline, Ph. Eur. 5.20, and USP General Chapter <232>, the analytical community has been provided with a complete listing of the limits for all elements that have the possibility to negatively impact patient safety should they find their way into pharmaceutical products. Because the listing of elements and limits have been thoroughly vetted by a cadre of toxicologists from around the world, this information can be used to establish a risk-based approach for assessing elemental impurities in the context of leachables studies.

Risk-based approaches are permitted by the EMA guideline, the Ph. Eur., and the USP and take into account the entire process, requiring good control on all aspects of manufacture, including the supply chain of both raw materials and packaging components. Using this approach, it is possible to assess whether or not a specific test, or--in the case of elemental impurities--a specific element must be tested.  

Given the acceptability of a risk-based approach, and the acceptable safety limits provided by the EMA guideline, the Ph. Eur., and the USP, it is now possible to identify target limits for elements of interest in leachable studies based on the context of those documents. Table I provides a listing of the USP and EMA/Ph. Eur. elements of interest and limits. Although the permitted daily exposures (PDEs) provided in Table I assume a 10 g/day maximum daily dose, it is possible to calculate the appropriate daily concentration limit (µg/g) for a product with a different daily dose using the following equation:

Concentration limit (µg/g) =              PDE (µg/day)
                                           Maximum daily dose (g/day) (Eq.1)

Once the appropriate concentration limits are calculated, it is possible to use the listing of elemental concentration limits to determine whether or not to include a given elemental impurity in a leachable study. The example in Table II illustrates how this risk-based approach would be used for an oral dosage form. The same approach may be used for other routes of administration, such as parenteral. Use Equation 1 and Table I to calculate the appropriate concentration limits for the analytes observed in the extractable study--silicon (Si), sulfur (S), boron (B), pallidum (Pd), iron (Fe), lead (Pb), chromium (Cr), arsenic (As), sodium (Na), potassium (K), and mercury (Hg)--for an oral drug product with a maximum daily dose of 200 mg. Where the USP and EMA/Ph. Eur. limits differ, use the lower of the two limits. For example, for iron, the USP and EMA guidelines list the concentration limit as not applicable (N/A) and 13,000 µg/g, respectively, in Table I. Using Equation 1, the appropriate concentration limit would be (13,000 µg/day)/(0.2 g/day) = 65,000 µg/g. Table II provides those limits.

Element

Oral exposure daily PDE (µg/day)

Parenteral exposure daily PDE (µg/day)

Inhalation exposure daily PDE (µg/day)

Large-volume parenteral component limit (µg/g)

USP

EMA/ Eur.Ph.

USP

EMA/Eur.Ph.

USP

EMA/Eur.Ph.

USP

EMA/Eur. Ph.

Cadmium (Cd)

25

N/A

2.5

N/A

1.5

N/A

0.25

N/A

Lead (Pb)

5

N/A

5

N/A

5

N/A

0.5

N/A

Inorganic Arsenic (As)

1.5

N/A

1.5

N/A

1.5

N/A

0.15

N/A

Inorganic Mercury (Hg)

15

N/A

1.5

N/A

1.5

N/A

0.15

N/A

Iridium (Ir)

100

100**

10

10**

1.5

N/A

1.0

N/A

Osmium (Os)

100

100**

10

10**

1.5

N/A

1.0

N/A

Palladium (Pd)

100

100

10

10

1.5

N/A

1.0

N/A

Platinum (Pt)

100

100

10

10

1.5

0.07***

1.0

N/A

Rhodium (Rh)

100

100**

10

10**

1.5

N/A

1.0

N/A

Ruthenium (Ru)

100

100**

10

10**

1.5

N/A

1.0

N/A

Chromium (Cr)

*

250

*

25

25

0.01

*

N/A

Molybdenum (Mo)

100

250

10

25

250

N/A

1.0

N/A

Nickel (Ni)

500

250

50

25

1.5

0.10

5.0

N/A

Vanadium (V)

100

250

10

25

30

N/A

1.0

N/A

Copper (Cu)

1000

2500

100

250

70

N/A

25

N/A

Manganese (Mn)

N/A

2500

N/A

250

N/A

N/A

N/A

N/A

Iron (Fe)

N/A

13000

N/A

1300

N/A

N/A

N/A

N/A

Zinc (Zn)

N/A

13000

N/A

1300

N/A

N/A

N/A

N/A

* Not a safety concern.
** Subclass limit: total amount of listed metals should not exceed the indicated limit
*** Pt as hexachloroplatinic acid
N/A is not applicable (i.e., not included in the corresponding document).

Concentration found in extractable study (µg/g)

PDE (µg/day)

Calculated limit (µg/g)

Silicon (Si)

8

N/A

N/A

Sulfur (S)

22

N/A

N/A

Boron (B)

5

N/A

N/A

Iron (Fe)

225

13,000

65,000

Lead (Pb)

3

5

25

Chromium (Cr)

16

2500

12,500

Arsenic (As)

110

1.5

7.5

Sodium (Na)

318

N/A

N/A

Potassium (K)

2315

N/A

N/A

Mercury (Hg)

19

15

75

Pallidium (Pd)

15

100

500

Because Si, S, B, Na, and K are not listed as elements of interest by either the USP or the EMA, they are, therefore, not considered to be a safety concern, and, therefore, would not need to be monitored in a leachable study. The levels for Fe, Cr, Pd, Pb, and Hg observed in the extractable study are below the calculated concentration limits, and as a result, are therefore not considered to be a safety concern. As a result, using the risk-based approach, they would not need to be monitored in a leachable study. The results of the extractable study that was performed yielded only one concentration in excess of the calculated elemental concentration limit (As: 110 µg/g versus 7.5 µg/g). The As concentration in the extractable study would be considered a safety concern. A leachable study, therefore, would need to be performed; however, only As would need to be monitored.

There are instances where an element is not included found in the USP and/or EMA/Ph. Eur. listing of elemental impurities, or where, despite being present below a toxicological limit of concern, it is necessary to monitor it for product quality or stability reasons. Some biologic products, for example, can be significantly affected by the presence of metals. In these cases, it may be warranted to include these elements in either a leachable study or a separate laboratory-scale experiment to assess potential product quality impact even though they do not pose a patient-safety concern.

Conclusion
By using the list of elemental impurities and their accepted PDE limits provided by the USP and EMA/Ph. Eur., it is possible to develop a risk-based approach, based on patient safety and toxicology, to determine the need to include elemental impurities analyses in leachable studies. This approach has the potential for considerable savings in terms of time and money, thereby reducing the cost of developing drugs and  lowering costs to patients. This approach was applied to a leachable study that included five elements that had been observed in the extractable study. Based on the outsourcing costs associated with the method development, validation, and sample analysis for all five elements for the course of the 36-month study, a cost savings of $68,000 (26% overall) was achieved.

The emphasis of the recently issued USP Chapter <232> and EMA’s Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents/Ph. Eur 5.20 on the toxicological concerns for patient safety provides a scientific basis for the development of a risk-based analytical strategy for the selection of elemental impurities to be included in leachable studies of CSS. The use of this approach provides the industry the ability to more effectively use its resources, reduce cycle times, and maintain drug-development costs while ensuring the highest level of patient safety and drug-product quality.

Acknowledgments  
The authors gratefully acknowledge the contributions of Wendy Luo, manager, quality/toxicology with Bristol-Myers Squibb.

References

1. CFR, Title 21 Part 211.94 (Government Printing Office, Washington, DC), Revised April 2013, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.94, accessed Sept. 18, 2013.

1. FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics--Chemistry, Manufacturing, and Controls Documentation (Rockville, MD, May 1999).

1. USP 35-NF 30 General Chapter <232>“Elemental Impurities--Limits,”
   (US Pharmacopeial Convention, Rockville, MD, February 2013), p. 5633.

1. EMA, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents (London, 2008).

1. Ph. Eur. Supplement 7.7, General Text 5.2.0, Metal Catalysts or Metal Residues (EDQM, Strasbourg, France, 2012), p. 50085.