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Elemental impurities: a virtual company perspective: a look at risk assessments for elemental impurity determinations in oral tablet and parenteral drug products.

The assessment of the levels of elemental impurities--heavy metals--in drug products has gained considerable attention over the last several years with the introduction of USP General Chapters Elemental Impurities--Limits <232> and Elemental Impurities--Procedures <233>, (1) the ICH Q3D Guideline for Elemental Impurities (2) and the FDA Draft Elemental Impurities Guideline for Industry. (3) The USP general chapters and the ICH Q3D guideline are anticipated to be implemented in the U.S. on January 1, 2018 for existing NDA and ANDA products, and have been implemented by the Food and Drug Administration (FDA) for new NDA and ANDA products since June 1, 2016. (3) Similarly, the European Pharmacopoeia implemented the ICH Q3D guideline for new drug product authorizations containing new active substances and new marketing authorizations containing existing active substances in June, 2016 (4) and will implement the ICH Q3D guideline in December, 2017 for existing products. Note that the ICH Q3D document addresses BLA submissions while the FDA draft guidance focuses on NDA and ANDA submissions and references ICH Q3D for biologics submissions. For the purposes of this discussion, we will focus on NDA and ANDA submissions.

Providing assurance that the levels of elemental impurities (EI) of concern are below the Permissible Daily Exposure (PDE) is the responsibility of the holder of the NDA or ANDA associated with the drug product. The ICH Q3D document describes a number of scenarios by which the NDA/ANDA holder can demonstrate that the drug product contains levels of El below the PDE and ensure that it will remain compliant throughout its life cycle. This is accomplished in most instances through a formal Risk Assessment (RA) process. In our case, the risk assessment process takes the form of an initial screening of the drug product to assess if the concentrations of a broad range of elements could be of immediate or long-term concern, followed by a comprehensive evaluation of risks associated with drug product components, manufacturing contact surfaces and product-package interaction. This leads into development and validation of a drug product method capable of quantifying the key El at levels below the threshold of concern--level above which long-term monitoring may be necessary--of 30% of the PDE for each of the elements of interest, and the development of specifications for the drug product components that ensure long-term conformance to the ICH/USP PDE specifications. The steps in this process are described in more detail below. For virtual companies, a close collaboration between the drug product manufacturer and each of the suppliers of the drug substance and excipients is critical to the success of the process, in addition to the potential use of contract lab facilities if contract manufacturing organizations (CMOs) delegate this work externally.

ELEMENTS OF POTENTIAL CONCERN

The 24 elements of potential concern identified by the ICH Q3D document and their PDEs by route of administration are shown in Table 1. The impurities are classified according to their risk (i.e., their potential to cause toxicity coupled with their likelihood of occurrence). Thus, the Class 1 elements are toxic, of no health benefit, and ubiquitous environmental contaminants. The Class 2A elements are environmental contaminants likely to occur but of somewhat lower toxicity, the Class 2B elements are not likely to occur unless intentionally added, and the Class 3 elements are of low toxicity by the oral route but may be of concern in the parenteral or inhalational routes even if not intentionally added. Table 2 lists the El from the ICH Q3D guidance along with whether they need to be considered in a risk assessment based on the route of administration.

Note that all elements need to be considered if they are intentionally added, independent of route of administration, while the Class 1 and 2A elements need to be considered for oral administration, Class 1, 2A and Sb, Li and Cu for parenteral administration, and Class 1,2A and 3 for administration by the inhalation route.

INITIAL ELEMENTAL IMPURITY SCREENING OF THE DRUG PRODUCT

In addition to the 24 elements identified by the ICH Q3D document, there may be others of potential concern as well. Thus, the first step in our approach to controlling elemental impurities in the drug product is to screen the drug product for a broad range of potential El to assess if there are specific impurities of concern that would require immediate attention. This is typically done in conjunction with a contract analytical facility with inductively coupled plasma-mass spectrometry (ICP-MS) capabilities and a strong track record in the determination of El in oral and parenteral drug products. Typically, the drug product undergoes a closed-vessel digestion through the use of one or more strong acids, producing a clear solution, which is analyzed by ICP/MS for up to 65 elements of potential concern.

Once the landscape of potential issues is understood through this initial screen, the next step is to evaluate the control issues exposed by the initial screen, if any, and if none are apparent, to establish controls that provide assurance that no problems will arise during the drug product's life cycle. Initial screens for the products in our portfolio have not shown any issues of immediate concern, allowing us to turn our attention to ensuring long-term control.

FACTORS IMPACTING ELEMENTAL IMPURITIES IN DRUG PRODUCT

In our example, since there are no elemental impurities of immediate concern and no elements identified beyond those presented in the ICH Q3D document, we focus on the seven Class 1 and 2A elements for oral tablets and the 10 elements identified for parenteral products (Class 1, 2A and Sb, Li and Cu). Seeing very low levels of El in the drug product, an argument can be made to stop here and validate a drug product procedure for the appropriate set of elements, that is, utilizing the USP <232> Drug Product Analysis Option, equivalent to ICH Q3D Option 3--Finished Product Analysis. However, without assessing the risk associated with each of the drug-product components and the drug product manufacturing process, it is difficult if not impossible to make a data-based decision of the long-term risk of EI contamination or to assess if the entire supply chain, and each step in the manufacturing process, is under control. Thus, for our products, the next step in the RA process is to assess the level of risk associated with the drug substance, the excipients and the drug product manufacturing process--USP <232> Summation Option plus manufacturing considerations.

To accomplish this, we examine the individual drug product components and process steps for potential elemental impurity contributions and for any controls (e.g., specifications for specific impurities) in place for the materials that could contribute significantly to the elemental impurity burden.

Broad categories of potential sources of elemental impurities include:

* Residual impurities resulting from elements intentionally added (e.g., catalysts) in the formation of the drug substance, excipients or other drug product components;

* Elemental impurities that are not intentionally added but may be present in the drug substance, water or excipients used in the preparation of the drug product;

* Elemental impurities that may be introduced into the drug substance and/or drug product from manufacturing equipment contact; and

* Elemental impurities that have the potential to be leached into the drug substance and drug product from container closure systems.

Figure 1 illustrates drug product components and equipment that may impact the elemental impurities burden on the drug product. (2) The risk of inclusion of elemental impurities can be reduced through process understanding, equipment selection, equipment qualification and GMP processes.

The first step in assessing the risk associated with the drug substance and excipients is to examine the certificate of analysis for each of the components of the drug product. Are there specifications for any of the El of interest? If there are, do the specifications ensure that even at the highest level used in the drug product there will be no issues, remembering that for any particular level of an element, contributions from all the components need to be considered--the USP Summation Option? The USP <232> Individual Component option could be employed, where each component is treated as if the dose were 10 grams and it was the only component of the drug product. This option often leads to specification limits that are much lower than typically necessary. A more realistic approach for drug products with daily doses of less than 10 grams is ICH Q3D Option 2a, which treats each component as if it was the only component of the drug, but normalizes to the actual daily dose. That is, the maximum allowable concentration per component for any EI is:

Concentration ([micro]g/g) = PDE ([micro]g/day)/daily amount of drug product (g/day)

ICH Q3D Option 2b is a generalization of ICH Q3D Option 2a and is based on the distribution of elements in the various drug product components. This option allows that the maximum concentration of a component may be higher than that allowed under Options 1 or 2a, but then is adjusted appropriately for lower amounts in the other drug product components. This then is a component-specific approach.

The next step is to go back to the component manufacturer and ask more direct questions around the control of elemental impurities. This might take the form of a questionnaire for the drug substance or excipient manufacturer where the specifics of the manufacturing process or sources of variability are probed more deeply. For the drug substance, for example, are catalysts used in the synthesis process? If there are catalysts utilized, they need to be considered in the RA and controlled at the level of the drug substance to ensure that they will not be an issue in the drug product. For excipients, are they tested and controlled for elemental impurities by the supplier? If there are mined excipients (e.g., NaCl, talc, TiO2), are the potential elemental impurities monitored and controlled? Is there potential for material with El at the high end of the specification to cause issues? Even if the current lots of material are low in El, some mined excipients may vary considerably in their level of El, depending on their sources (e.g., different mine, different location in a mine, different processing by different vendors), thus the specification, rather than the values for current lots, should be prioritized in assessing the level of risk involved. As with any process where the supply chain may vary, it is important to develop specifications that will enable a switch to a new supplier with minimal risk to the final drug product. Thinking of the elemental impurity burden on the drug product as a Critical Quality Attribute, and driving that thinking down into the individual components may help establish a framework for how to evaluate and control the risk of unacceptable levels of elemental impurities.

The treatment of water in the manufacturing process is a potential issue, especially in the case of parenteral products whose total mass is primarily water. The risk of water being an important contributor to the El burden can be minimized by the use of high-quality pharmaceutical-grade water such as Purified Water (PW) USP, or Water for Injection (WFI), USP. A Stimuli to the Revision Process article in USP Pharmacopeial Forum 39(1)--Elemental Impurities in Pharmaceutical Waters, makes the case that if the water used reliably meets the requirements of PW or WFI, and no El contamination occurs during or after purification, the risk of El contamination from the water is minimal.

The next consideration is the impact on the El burden created by the manufacturing processes and equipment. For the drug substance, this can be evaluated both by an examination of the steps in the synthetic process and by an assessment of the potential for El contamination and by testing the drug product itself. Testing and controlling the El levels at the drug substance stage provides a strategy to minimize any impact from drug substance El levels in the final drug product. As noted in the ICH Q3D document, the drug product manufacturing process is typically considerably less likely to contribute to the El burden than the harsher steps that may occur during the drug substance synthetic process. However, as part of the risk assessment process, it is valuable for the NDA/ANDA holder to work with the drug product manufacturer to understand each step in the process, including the solvents and equipment surfaces involved, to assess if there is any reasonable potential for issues to arise. This evaluation can typically only be done by the drug product manufacturer, so a close collaboration between the drug product manufacturer and the NDA/ANDA holder, and a clear set of expectations, are critical to making this effort proceed efficiently.

The final consideration is the impact of the container-closure/packaging system. It is acknowledged that for solid oral dosage forms--tablets and capsules--the impact of the container-closure system on EI contribution is negligible. (2) This may not be the case for dosage forms that are solutions and semi-solids--parenteral dosage forms and many topical applications. In these cases extraction or leaching of elemental impurities from the container, the closure system--rubber stopper--or the external labeling or packaging could result in an increased level of elemental impurities in the drug product over time. This is the opposite of the case of residual solvent levels, which tend to decrease with time over the shelf life of the product.

To assess the potential impact of the container-closure system on the El burden of the drug product, the first step is to work with the suppliers of each component of the system and assess whether any elements of concern were used in the manufacturing of the component, whether these elements remain in the component at levels that could be of concern were they to leach out during the shelf life of the product, and if they can leach out, to assess their impact and the need for a control strategy. Often, this can be a paper exercise based on knowledge of the manufacturing process, but if there is a potential for an issue for one or more elemental impurities, the appropriate accelerated and long-term stability testing should be done to assess the need for establishing a control strategy (e.g., different material, a specification on the elements) of concern, or change in expiration date).

PARENTERAL DRUG EXAMPLE--DRUG IN WATER FOR INJECTION

An approach that evaluates reduced risk from the use of high-quality pharmaceutical-grade water (HQPGW--typically water for injection (WE), Purified Water, or the European Pharmacopoeia or Japanese Pharmacopoeia equivalents), can be illustrated as in Table 3 for a parenteral drug product with a single drug product component (API) at a maximum daily dose (MDD) of 80 mg API corresponding to 2.00 g drug product mass including the Water for Injection (WFI) vehicle.

The first numerical row is the ICH Q3D PDE limit for each of the 10 relevant parenteral elements of concern, assuming no additional elements were found as a result of the comprehensive risk assessment. The second row contains PDE values ([micro]g/g or ppm) calculated using the allowable drug product mass of 10 grams per day per ICH Option 1. The third row contains PDE values ([micro]g/g) that are calculated using the (actual) drug product mass of 2.0 grams per day per ICH Option 2a. The fourth row displays pg/g values determined if contribution from the water vehicle is not considered at all, (API only). While not recommended, this pathway is illustrative of the variation in PDE that can occur when the water risk is reduced to zero. The fifth row is a compromise calculation format where a 10% factor is introduced versus that calculated from the WFI-free scenario (API only).The point to the exercise is that if HQPGW is utilized in the drug product formulation and it is under a state of control with regard to elemental impurity content, then a compromise can be considered that would appropriately mediate this risk downward. The contribution from HQPGW is not eliminated from consideration in this example, but rather the risk is mediated via an evaluation of the water system qualification and its long-term potential to contribute EIs to the drug product. This process assumes that control of the EI levels in the HQPGW has been demonstrated and is well documented. In the example above, the mediated risk of 10% (API-only) versus the Option 2a calculation results in a level of 2.5x higher allowable PDEs.

It is up to the drug product manufacturer in collaboration with the holder of the NDA/ANDA to evaluate these choices and to choose which will meet their long-term goals while providing adequate analytical substantiation. Note that potential future dosage rate changes may be appropriate for consideration when choosing a course of action, and a conservative approach is highly recommended to eliminate revalidation if dosage is increased during a line-extension or similar dosage-altering activity. This evaluation should be integrated into the overall life-cycle management strategy for the drug product.

VALIDATED METHODS FOR EVALUATION AND LONG-TERM CONTROL

The final step in the RA is the development and validation of an analytical procedure for the evaluation of the drug product for quantitation of each of the seven elements (oral route) or 10 elements (parenteral route) of potential long-term concern. The lower limit of quantification of the procedure for each of the element should be 10--25% of the PDE to allow for observation of an issue prior to the point where the concentration of the elements reaches the 30% level of concern that would trigger the potential need for further specifications or other controls. Once the procedure is validated, several lots of drug product can be examined to ensure that there are no issues with currently-produced material and could be used to examine future lots depending on the results of the current testing and the long-term monitoring program (if any is needed) agreed-to by the NDA/ANDA holder and FDA. Note that given the results of the risk evaluation (e.g., no El approaching the 30% level of concern in the drug product and no scientific reason to assume there could be), there may be no need for specific regulatory specifications for any elemental impurities in the drug substance beyond providing the data that indicate the drug product meets, and will continue to meet the requirements of USP <232>.

Long-term control of elemental impurities is best accomplished by control of each of the materials in the supply chain such that even at the upper end of the specifications for each element for each drug product component, the drug product will meet its El PDE requirements.This may not always be possible, and there may be cases where control is accomplished based solely on the drug product analysis approach. When using a drug product analysis approach (ICH Option 3), or other option that cannot exclude the possibility of an unanticipated high El result, if a result either in excess of the prescribed PDE limits or above the 30% threshold of control is obtained, it will become critical to investigate the source of the elevated result. The investigation should initially focus on the individual drug product components (API and any excipients), prior to evaluation of product-package interaction with the container-closure system, manufacturing equipment or pharmaceutical-grade water, especially if these latter sources have been successfully mediated in the Risk Assessment.

When investigating the API and excipients, any release testing conducted for elemental impurities in these materials can of course be checked and components eliminated based on results obtained. However, for those materials that do not have elemental impurity release requirements, testing may be necessary to find the contributor(s) to the elevated results. It is expected that analysis of individual drug product components can be conducted with a validated drug product analysis method. However, it is prudent to consider including in the drug product method validation protocol the primary and secondary individual mass components of the drug product, putting priority on those components that do not require individual release for elemental impurities at the manufacturer or other analysis site. Once the source of the problem is identified, steps should be taken to either ensure that the problem cannot reoccur or to develop a routine monitoring program to ensure the levels of the EI(s) in question remain below the required PDE.

From a regulatory perspective, a summary of the state of control of El upon regulatory filing is provided to the FDA through the NDA or ANDA submission. Filing requirements will depend on whether the application is for a new drug product approved under an NDA or ANDA, for drugs already approved under an NDA or ANDA or for drugs not approved under an NDA or ANDA. For a new drug application, the P.2 (Pharmaceutical Development) section of the submission is an appropriate section for the risk assessment. For existing, approved drug products, this information may be provided to the FDA in an annual report. The regulatory submission provides a summary of the formal risk assessment and its conclusions, with the appropriate background and supporting information remaining with the sponsor and available upon request by the regulatory agency (e.g., either written request or site audit). Examples of what might go into a risk assessment for oral and parenteral drugs are provided on the ICH website in Module 8 of the training set. (5) This module contains examples of what information an NDA/ANDA holder might generate for an RA and which of that information might be submitted in an NDA or ANDA filing. Note that these are examples, not templates, and the actual RA will be different for each product. For drug products not subject to NDA/ANDA approval (e.g., over the counter drug products), it is advisable to perform the risk assessment and maintain the material suggested in Module 8 for retrieval in the event of a request for the material by the FDA--written or via an on-site inspection.

CONCLUSIONS

Relative to the requirements of USP General Chapter <231>, the introduction of General Chapter <232> and the ICH Q3D guideline has placed a considerable burden on virtual companies in terms of complying with requirements for the control of elemental impurities. While the need for long-term routine testing for the levels of El may be eliminated at some point, there is considerable up-front work to do to demonstrate that the drug product is in control and will remain in control for the lifetime of the product. A complete risk assessment and subsequent product control strategy requires a close collaboration between the NDA/ANDA holder, API manufacturer, excipient suppliers and the drug product manufacturer to understand the levels of El that can be present and to establish specifications such that changes in manufacturing will not result in an El risk to the product, given that the established El specifications carry over to the new material. Working as a team, a deep product understanding and a long-term strategy can be developed that demonstrates that the product is in compliance and will remain so throughout its life cycle.

References

(1.) USP Key Issues Website, http://zimrw.usp.org/usp-nf/key-issues/elemental impurities Accessed January 4, 2017.

(2.) Guideline for Elemental Impurities, Q3D. Current Step 4 Version Dated 16 December 2014. https://umrw.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Cuidelines/Quality/Q3D/Q3D_Step_4.pdf, Accessed January 4, 2017.

(3.) Draft Elemental Impurities in Drug Products Guidance for Industry http:// www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm509432.pdf Access January 4, 2017.

(4.) http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/03/ WC500184920.pdf Accessed January 4, 2017.

(5.) ICH training Module 8. Note: The authors wish to thank Kahkashan Zaidi, USP, for her review of this manuscript.

TONY DESTEFANO is a member of the Editorial Advisory Board of Contract Pharma. He was Vice President and Sr. Vice President of General Chapters at USP from 2008-2013. He currently is a pharmaceutical industry consultant in the areas of CMC, bioanalysis and compendial issues.

THOMAS KESTER is currently the Director of Analytical Services at Recordati Rare Diseases, Inc. in Lebanon, NJ. He has over three decades of experience in the analytical sciences within the pharmaceutical, biological and beverage industries,

Caption: FIGURE 1

Drug product components and equipment that may impact the elemental impurities burden on the drug product.
TABLE 1.

Established Permitted Daily Exposures (PDEs) for
Elemental Impurities (2)

Element    Class     Oral PDE     Parenteral PDE   Inhalation PDE
                   [micro]g/day    [micro]g/day     [micro]g/day

Cd           1          5               2                2
Pb           1          5               5                5
As           1          15              15               2
Hg           1          30              3                1
Co          2A          50              5                3
V           2A         100              10               1
Ni          2A         200              20               5
Tl          2B          8               8                8
Au          2B         100             100               1
Pd          2B         100              10               1
Ir          2B         100              10               1
Os          2B         100              10               1
Rh          2B         100              10               1
Ru          2B         100              10               1
Se          2B         150              80              130
Ag          2B         150              10               7
Pt          2B         100              10               1
Li           3         550             250               25
Sb           3         1200             90               20
Ba           3         1400            700              300
Mo           3         3000            1500              10
Cu           3         3000            300               30
Sn           3         6000            600               60
Cr           3        11000            1100              3

TABLE 2.

Elements to be Considered in the Risk Assessment (2)

                                      If not intentionally added

Element    Class   If intentionally   Oral   Parenteral   Inhalation
                      added (all
                       routes)

Cd           1           yes          yes    yes          yes
Pb           1           yes          yes    yes          yes
As           1           yes          yes    yes          yes
Hg           1           yes          yes    yes          yes
Co          2A           yes          yes    yes          yes
V           2A           yes          yes    yes          yes
Ni          2A           yes          yes    yes          yes
Tl          2B           yes           no    no           no
Au          2B           yes           no    no           no
Pd          2B           yes           no    no           no
Ir          2B           yes           no    no           no
Os          2B           yes           no    no           no
Rh          2B           yes           no    no           no
Ru          2B           yes           no    no           no
Se          2B           yes           no    no           no
Ag          2B           yes           no    no           no
Pt          2B           yes           no    no           no
Li           3           yes           no    yes          yes
Sb           3           yes           no    yes          yes
Ba           3           yes           no    no           yes
Mo           3           yes           no    no           yes
Cu           3           yes           no    yes          yes
Sn           3           yes           no    no           yes
Cr           3           yes           no    no           yes

TABLE 3

Max daily dose = 0.080 g API/day

Max daily dose = 2.00 g drug product
mass/day (including water)

Element                   Cd     Pb     As      Hg     Co

Parenteral Dose PDE--     2      5      15      3      5
[micro]g Elemental
Impurity/day

Parenteral Dose PDE--    0.2    0.5     1.5    0.3    0.5
[micro]g Elemental
Impurity/gram drug
product mass per ICH
Option 1 (</=10
grams MOD).

Parenteral Dose PDE--    1.0    2.5     7.5    1.5    2.5
[micro]g Elemental
Impurity/gram drug
product mass per ICH
Option 2a, (2.00 g
MDD).

PDE for API-only         25.0   62.5   187.5   37.5   62.5
calculation
([micro]g/g)

PDE compromise at        2.5    6.3    18.8    3.8    6.3
-10% of API-only
calculation (ppm)

Element                   V      Ni     Li      Sb      Cu

Parenteral Dose PDE--     10     20     250     90     300
[micro]g Elemental
Impurity/day

Parenteral Dose PDE--    1.0    2.0    25.0     9.0     30
[micro]g Elemental
Impurity/gram drug
product mass per ICH
Option 1 (</=10
grams MOD).

Parenteral Dose PDE--    5.0     10     125     45     150
[micro]g Elemental
Impurity/gram drug
product mass per ICH
Option 2a, (2.00 g
MDD).

PDE for API-only         125    250    3125    1125    3750
calculation
([micro]g/g)

PDE compromise at        12.5   25.0   312.5   112.5   375
-10% of API-only
calculation (ppm)
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Date:Apr 1, 2017
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