Challenges to conclude elemental impurities risk assessment for pharmaceutical dosage form and submission in regulatory dossier

Abstract

ICH Q3D defines a science and risk-based assessment process to identify, evaluate, and define controls to limit elemental impurities in drug products. The present article comprise challenges and simplified approach to draw elemental impurities risk assessment and control in final drug product to satisfy current regulatory requirements using different calculation options. Detail risk assessment depends on information/knowledge of most significant potential sources of elemental impurities, i.e. drug product components, manufacturing process of drug substance or drug product, container closer system, etc. If there is lack of information available, the applicant may carry out end product testing as the initial strategy for risk assessment using option 3 calculation.

Keywords

Elemental impurities ICH Q3D risk assessment control strategy calculation option option 1 option 2 option 3

Introduction

Control of metal impurities was primarily based on pharmacopoeial requirements for heavy metals, which was widely used for routine screening of pharmaceutical ingredients since the early 20th century. The commonly used methodology was mainly intended to control metals which form a sulphide precipitate, such as lead, copper and other metals.¹ ICH Q3D guidance comprises safety-based permitted daily exposures for 24 elementals and recommendations for a risk-based and science-based approach to control of those elements in pharmaceutical products.² New NDA and ANDA applications submitted after 1 June 2016 should follow the recommendations of Q3D. For existing marketed products, manufactures should follow the recommendations of Q3D and/or comply with USP <232> by 1 January 2018.³

Challenges for the drug product manufacturer (applicant) regarding the health authority expectations on elemental impurities risk assessment submission⁴

– Where to start assessing the elemental impurities risk?

– Up to what level is the presentation of the risk assessment?

– How much data are required to support risk assessment conclusions?

– What are the most significant potential sources of elemental impurities?

– Where the information should be presented in the dossier.

– Category of supplement filing for products which are currently approved.

– Periodic testing of elemental impurities in drug products and components of drug products.

Q3D Guideline clarifies the risk assessment to be considered for elemental impurities based on their toxicity and potential source (Fig. 1) in new drug applications (Table 1) and abbreviated new drug applications.

Figure 1.

Potential source of elemental impurities.

Guidance has provided PDE and the calculation options (option 1, option 2a & 2b, option3) to describe some acceptable approaches to establishing concentrations of elemental impurities in drug products or components that would assure that the drug product does not exceed the PDEs.

The choice of calculation option is at the discretion of the drug product manufacturer as long as the resulting permitted concentrations assure that the drug product does not exceed the PDEs.⁵

Table 1.

Different classes of elements based on toxicity and requirement to consider under risk assessment in finish drug product.

Class	Elements	How toxic?	Risk assessment?
I	Arsenic (As), Cadmium (Cd), Mercury (Hg), and Lead (Pb)	Highly toxic	Yes; Test under all circumstances irrespective of any dosage form
IIa	Cobalt (Co), Nickel (Ni) and Vanadium (V)	Less toxic than Class I	Yes; Test under all circumstances irrespective of any dosage form
IIb	Gold (Au), Thallium (Tl), Palladium (Pd), Platinum (Pt), Iridium (Ir), Rhodium (Rh), Ruthenium (Ru), Osmium (Os), Selenium (Se) and Silver (Ag)	Law toxic	Yes if intentionally added
III	Antimony (Sb), Barium (Ba), Lithium (Li), Chromium (Cr), Copper (Cu), Tin (Sn), and Molybdenum (Mo)	Law toxic	Yes if intentionally added (for oral route), Considered in risk assessment (for inhalation route and parental route)
IV (Others)	Boron (B), Iron (Fe), Zinc (Zn), Potassium (K), Calcium (Ca), Sodium (Na), Manganese (Mn), Magnesium (Mg), Tungsten (W), and Aluminum (Al)	Low inherent toxicity (PDE not established)	Not required to be considered in risk assessment. If present in drug product, can be addressed as per particular regional regulations/ practices

Practical approach to present risk assessment of Solid oral dosage form in regulatory submission

It is better to capture detailed elemental risk assessment of drug product in pharmaceutical development section (3.2.P.2) and summary of the risk assessment in justification of drug product specification (3.2.P.5.6) of regulatory dossier.

Case study 1

ANDA of X Tablets 5 mg and 10 mg; Maximum daily dose is 10 mg (see the tablet formula in Table 2).

Table 2.

Composition of X tablet

Composition	Level of inactive ingredient in Tablets (mg)
X drug substance	5.00	10.00
Lactose	79.00	74.00
Maize starch	20.00	20.00
Hydroxy propyl cellulose	5.75	5.75
Microcrystalline cellulose	31.80	31.80
Sodium starch glycolate	6.50	6.50
Colloidal anhydrous silica	0.75	0.75
Magnesium Stearate	1.20	1.20
Titanium dioxide	4.50	4.50
Purified water	qs	qs
Targeted weight of tablet	154.50	154.50

Container closer system: HDPE bottle with CR closer.

Supplier of each drug product component has provided limited information on elemental impurities present in each drug components, i.e.

– three of suppliers have provided statement that excipients provided are in compliance with ICH Q3(D) option 1.

– two of suppliers have stated that provided drug substance or excipients are having possible elemental impurities with limit of below control threshold as per ICH Q3(D).

– remained suppliers have provided observed level of possible elemental impurities with specification control limits.

– all of suppliers of drug product component have also stated that there are no any elements intentionally added or used during synthesis of excipient.

With above information/knowledge provided regarding elemental impurities present in each drug product components, initial risk assessment can be drawn as mentioned in Table 3.

Eleven elementals identified in Table 3 (Cd, Pb, As, Hg, Co, V, Ni, Li, Ba, Cu, Cr) were the only potential elemental impurities evaluated during the component assessments for the X tablets. Seven of these (Class 1 and 2A) are recommended for inclusion by Q3D irrespective of any dosage form and others (Li, Ba, Cu, Cr of Calss 3) are included because vendor certificates of analysis indicate potential levels of these class 3 elements. The rest of elements are not intentionally added to the any excipients or drug substance, so are not considered further in the risk assessment (see the Table 4)

Table 3.

Initial evaluation of the elements to be considered in the risk assessment⁶

Element	Class	Intentionally added?	Consider in risk assessment	Justification
Cd	1	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose
Pb	1	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose and Titanium dioxide
As	1	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose and Titanium dioxide
Hg	1	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose
Co	2A	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose and Titanium dioxide
V	2A	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Lactose and Titanium dioxide
Ni	2A	No	Yes	Considered in risk assessment for all components; Vendor provided information on observed levels in Magnesium Stearate, Lactose and Titanium dioxide
Tl	2B	No	No	Not intentionally added in any component
Au	2B	No	No	Not intentionally added in any component
Pd	2B	No	No	Not intentionally added in any component
Ir	2B	No	No	Not intentionally added in any component
Os	2B	No	No	Not intentionally added in any component
Rh	2B	No	No	Not intentionally added in any component
Ru	2B	No	No	Not intentionally added in any component
Se	2B	No	No	Not intentionally added in any component
Ag	2B	No	No	Not intentionally added in any component
Pt	2B	No	No	Not intentionally added in any component
Li	3	No	Yes	Vendor provided information on observed levels in Magnesium stearate
Sb	3	No	No	Not intentionally added in any component
Ba	3	No	Yes	Vendor provided information on observed levels in Magnesium stearate
Mo	3	No	No	Not intentionally added in any component
Cu	3	No	Yes	Vendor provided information on observed levels in Magnesium stearate
Sn	3	No	No	Not intentionally added in any component
Cr	3	No	Yes	Vendor provided information on observed levels in Magnesium stearate

Table 4.

Evaluation of potential contributors of elemental impurities to the drug product

Potential source of elemental impurities	Information evaluated	Further consideration in the risk assessment?
Drug substance	As per the supplier confirmation, Class 1, 2 or 3 elements are not intentionally added and are not found as impurities in the drug substance	No further consideration in the risk assessment
Excipients	Information supplied from vendors confirms no elements (Class 1, 2 or 3) are intentionally added Vendor certificates of analysis indicate potential levels of the following Class 1 and 2A elements: Cd, Pb, As, Hg, Co, V and Ni Vendor certificates of analysis indicate negligible levels of the following Class 3 elements: Li, Ba, Mo, Cu and Cr.	Consider the potential impact of identified elements level in the excipients (Magnesium Stearate, Lactose and Titanium dioxide) of the drug product. The found levels in provided certificate of analysis by suppliers mentioned in Table 5
Water	Compendial grade water used throughout the process	Use of compendial water ensures minimization of potential elemental impurities from water used during processing. No further consideration in the risk assessment
Container closure system	HDPE bottles are the primary contact surface. Solid oral tablets have limited mechanism for transfer of elemental impurity from bottle surface to tablets.⁷	No further consideration in the risk assessment – negligible contribution of any potential elemental impurities to the drug product
Manufacturing equipment (drug substance and drug product equipment)	As per the drug substances supplier confirmation, Internal quality program for monitoring of equipment used in drug substance synthesis shows absence of elemental impurities in drug substance batches The drug product X tablet process is less likely to degrade the equipment contact surfaces ensuring negligible contribution from the drug product processing equipment	No further consideration in the risk assessment

Analytical measurements were performed on three components by vendor to support the risk assessment. Elemental impurity data are generated using a validated method (see the Table 5).

The product risk assessment identified Magnesium Stearate, Lactose and Titanium dioxide as excipients that have measurable level of elements present that can be carried into the drug product. The observed level of impurity (Table 5) indicates that, without additional controls it cannot be ensured that the elemental impurity level in X tablets will not exceed the PDE. To address this concern, an incoming material specification limit for observed elements for each of the excipient has been established. The specification limit for elemental impurities in identified excipients established by the supplier is mentioned in Table 5.

Table 5.

Summary of elemental impurity data for potential components of X tablets

Component	No. of lots	Element	Mean (µg/g)	Specification limit (µg/g)
Magnesium stearate	3	Ni	1	1.9
		Li	2.5	3.0
		Ba	1	1.5
		Cu	0.5	0.9
		Cr	0.2	0.3
Lactose	3	Cd	0.005	0.5
		Pb	0.02	0.5
		As	0.01	1.5
		Hg	0.003	3
		Co	0.005	5
		V	0.002	10
		Ni	0.051	20
Titanium dioxide	3	Pb	2.0	2.5
		As	0.15	0.25
		Co	0.17	0.59
		V	1.9	2.3
		Ni	1.5	2.0

Calculation of total elemental impurities in X tablets at the proposed specification limits for Magnesium Stearate, Lactose and Titanium dioxide demonstrates that adequate controls have been established to ensure that the level of total elemental impurities in the drug product will not exceed the PDE (see the Table 6).

Table 6.

Calculated concentrations of elemental impurities in X tablets using established specification limits and Q3D Option 2B [for Case 1]

Sr. No.	Drug product components	Mass of Component in a 5 mg tablet (g)	Mass of Component in a daily dose (2 tablets) g^a	Cd	Pb	As	Hg	Co	V	Ni	Li	Ba	Cu	Cr
1.	X drug substance	0.0050	0.0100	–	–	–	–	–	–	–	–	–	–	–
2.	Lactose	0.0790	0.158	0.079	0.079	0.237	0.474	0.790	1.58	3.16	–	–	–	–
3.	Maize starch	0.0200	0.0400	–	–	–	–	–	–	–	–	–	–	–
4.	Hydroxy Propyl Cellulose	0.0058	0.0116	–	–	–	–	–	–	–	–	–	–	–
5.	Microcrystalline Cellulose	0.0318	0.0636	–	–	–	–	–	–	–	–	–	–	–
6.	Sodium Starch Glycolate	0.0065	0.0130	–	–	–	–	–	–	–	–	–	–	–
7.	Colloidal Anhydrous silica	0.0008	0.0016	–	–	–	–	–	–	–	–	–	–	–
8.	Magnesium Stearate	0.0012	0.0024	–	–	–	–	–	–	0.005	0.007	0.004	0.002	0.001
9.	Titanium dioxide	0.0045	0.0090	–	0.023	0.002	–	0.005	0.021	0.018	–	–	–	–
Targeted weight of tablet (g)		0.1545	0.309
Maximum elemental impurities per daily dose when elements are at the specification limits, µg/daily dose				0.079	0.102	0.239	0.474	0.795	1.601	3.183	0.007	0.004	0.002	0.001
PDE (µg/day)				5	5	15	30	50	100	200	550	1400	3000	11,000

Maximum daily dose: 0.010 g per day. The total drug product administered would be 0.309 g (considering two tablets of 5 mg).

Conclusion (Case 1)

The risk assessment identified elemental impurities (i.e. Cd, Pb, As, Hg, Co, V, Ni, Li, Ba, Cu, Cr) that could be observed in three of the components of X tablets. The three components and the potential elemental impurity in each are: Magnesium Stearate (Ni, Li, Ba, Cu, Cr), Lactose (Cd, Pb, As, Hg, Co, V, Ni), and Titanium dioxide (Pb, As, Co, V, Ni).

An elemental impurity specification and associated limit are not proposed for X tablets; however, to ensure that identified elemental impurities levels are maintained at or below the respective PDE, a specification and limit for identified elemental impurities in three of the components were established. These incoming material controls ensure that the elemental impurities level will be maintained at or below the PDE in X tablets.

The risk assessment will be updated (as necessary) if the process is modified or suppliers of the drug product components are changed and that any subsequent changes to the control strategy will be reported to the Health Authorities within the current regulatory framework.

Case study 2

In the above-mentioned case study 1, specification limit of all target elements identified in the risk assessment is below the permitted concentration limit (PDE) except one, i.e. limit of Pb (2.5 µg/g) in Titanium dioxide.

In this case, if limit of Pb in Titanium dioxide is the same or below the PDE limit, i.e. 0.5 µg/g, it is better to go with ICH Q3(D) Option 1 calculation. The option 1 assumes the daily intake of the product is 10 g or less, and that element impurities identified in the risk assessment are present in all components of the drug product (see the Table 7).

Table 7.

Calculated concentrations of elemental impurities in X tablets using the permitted concentration limits and Q3D Option 1 [for Case 2]

Sr. No.	Drug product components	Maximum permitted concentration (µg/g)
Sr. No.	Drug product components	Cd	Pb	As	Hg	Co	V	Ni	Li	Ba	Cu	Cr
1.	X drug substance	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
2.	Lactose	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
3.	Maize starch	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
4.	Hydroxy Propyl Cellulose	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
5.	Microcrystalline Cellulose	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
6.	Sodium Starch Glycolate	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
7.	Colloidal Anhydrous silica	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
8.	Magnesium Stearate	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
9.	Titanium dioxide	0.5	0.5	1.5	3	5	10	20	55	140	300	1100
Maximum daily intake (µg/day) (0.309 g × Permitted con.)		0.1545	0.1545	0.4635	0.9270	1.5450	3.0900	6.1800	16.995	43.260	92.700	339.90
PDE (µg/day)		5	5	15	30	50	100	200	550	1400	3000	11000

Conclusion (Case 2)

An elemental impurity specification and associated limit are not proposed for X tablets, because the identified elemental impurities levels do not exceed the option 1 concentration in all drug components and all these components can be used in any proportion in the X tablets.

In the above two cases, risk assessment has been drawn using information provided from drug component suppliers, knowledge of drug product manufacturing process and container closer system. Most of the drug product applicants may try to conclude elemental risk assessment using option 1 or 2 calculations in which final drug product analysis may not be required and it is a cost-effective approach.

Case study 3

On other side, if there is lack of information available from suppliers of drug product components, lack of knowledge regarding manufacturing process of drug substance or drug product, and lack of knowledge regarding container closer systems, the applicant may choose to carry out end product testing as the initial strategy for risk assessment (see the Table 8).

Table 8.

Calculated concentrations of elemental impurities in X tablets using the Q3D Option 3 [for Case 3]

	Cd	Pb	As	Hg	Co	V	Ni	Li	Ba	Cu	Cr
Mean test conc. found in X tablets, µg/g (N = 3)	3.5	7.6	5.1	4.3	6.9	8.8	5.5	10.1	8.9	8.8	9.4
Max. daily intake (µg/day) (0.309 g × observed con.)	1.08	2.35	1.57	1.33	2.13	2.72	1.70	3.12	2.75	2.72	2.90
PDE (µg/day)	5	5	15	30	50	100	200	550	1400	3000	11,000

Elements of class 1, class 2a and other elements if identified in initial risk assessment must be covered into analysis of final drug product.

The maximum permitted concentration of each elemental impurity in the drug product may be calculated (see the Table 9) using the daily intake of drug product and the PDE of the elemental impurity as per below equation.

Concentration (μ g / g) = \frac{PDE (μ g / g)}{dailyamountofdrugproduct (g / day)}

Table 9.

Maximum permitted concentrations of elemental impurities in X tablets using the daily intake of drug product and the PDE [for Case 3]

	Cd	Pb	As	Hg	Co	V	Ni	Li	Ba	Cu	Cr
Max. permitted conc. limit in X tablets (µg/g)	16.18	16.18	48.54	97.09	161.81	323.62	647.25	1779.94	4530.74	9708.74	35598.71
Maximum Daily intake (µg/day) (0.309 g × conc. limit)	5	5	15	30	50	100	200	550	1400	3000	11,000
PDE (µg/day)	5	5	15	30	50	100	200	550	1400	3000	11,000

Conclusion (Case 3)

The observed elemental impurities levels in three lots of drug products are far below the permitted concentration limit in X tablets based on daily intake of drug product and PDE. Hence, an elemental impurity specification and associated limit are not proposed for X tablets.

Periodic Testing⁸

Periodic testing may be applied to elemental impurities according to the principles described in ICH Q6A. Where the risk assessment indicates that routine testing is considered unnecessary but some additional assurance is needed post approval, and periodic testing of the drug product or one or more individual components may be proposed by the applicant and implemented upon acceptance by the regulatory authority.⁸

Life-cycle approach to control strategy⁸

Product and/or process changes across the product lifecycle have the potential to impact (positively or negatively) the elemental impurity content of the drug product. Changes can include, but are not limited to changes in synthetic routes, excipient suppliers, materials, processes, equipment, container closure systems or facilities. The impact of such changes on the original risk assessment should be evaluated, and implications for the control strategy should be considered. The regulatory implications of modifications to the risk assessment and control strategy should be considered, and appropriate variations should be submitted according to regional requirements. Consideration should be given for periodic review of the control strategy, as part of ongoing continual improvement.⁸

Footnotes

Declaration of conflicting interests

The information is built from work, literature search and experience, and reflects the point of view of the author. It is not the official position of organizations identified above.

Funding

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author biography

Dr. Jignesh Prajapati is a regulatory professional having 9 years of industry experience. He holds Ph.D (Pharmaceutical science), M. Pharm (Quality assurance) and master degree in business administration. At present, He is working with Intas Pharmaceuticals Limited, India.

References

Final Concept Paper on Q3D: Guideline for Elemental Impurities, prepared by International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Endorsed by steering committee on 29 October 2009.

Guideline for elemental impurities Q3D, ICH harmonised guideline, Step 4 version, dated 16 December 2014.

Guidance for industry: Elemental impurities in drug products, published by centre for drug evaluation and research, department of Pharmaceutical Quality/CMC, June 2016.

Mark G. Schweitzer, Presentation on Implementation of ICH Q3D, FDA/PQRI Conference on Evolving Product Quality, 17 September 2014.

Presentation: Calculation Options, Q3D training module 7, prepared by the Q3D implementation working group, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

Presentation: Product risk assessment general approach, Q3D training module 5, prepared by the Q3D implementation working group, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

Jenke D, et.al. A compilation of metals and trace elements extracted from materials relevant to pharmaceutical applications such as packaging systems and devices. PDA J Pharm Sci Technol 2013; 67: 354–375.

Presentation: Controls of Elemental Impurities, Q3D training module 6, prepared by the Q3D implementation working group, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.