ICH Q3D. Questions & Answers Q1: Q2: U n d e r s ta n d i n g the Risk Assessment Requirements. Knowing the Options

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1 ICH Q3D Questions & Answers Understanding the Risk Assessment Requirements Knowing the Options Controlling for Elemental Impurities Responsibilities U n d e r s ta n d i n g the Risk Assessment Requirements Q1: If a substance complies with a European Pharmacopoeia (Ph. Eur.) monograph containing limits for specific elemental impurities (EIs), should it be considered in the risk assessment? YES, A RISK ASSESSMENT IS NEEDED FOR ALL COMPONENTS. Compliance with a Ph. Eur. monograph is not sufficient, because all impurities have to be considered and assessed according to the International Council for Harmonisation (ICH) Guideline for Elemental Impurities Q3D and not only those that may be covered by the Ph. Eur. monograph. Moreover, the elemental-impurities level in the drug product should be estimated based on compendial limits and compared with permitted daily exposure (PDE). If the calculated amount exceeds PDE, tighter limits than those set forth in the Ph. Eur. monograph are necessary. Q2: A product has several active pharmaceutical ingredients (APIs) and about 10 excipients. Do we have to assess all of them? THE FIRST OPTION WOULD BE TO ASSESS THE FINISHED PRODUCT, IN WHICH CASE IT WOULD NOT BE NECESSARY TO ASSESS THE INDIVIDUAL EXCIPIENTS AND APIS. However, if any other option is taken wherein one or more ingredients are reviewed by the manufacturer or marketing authorisation holder (MAH) then every excipient and API must be assessed because of the possibility that any of them might contain an EI that is higher than the control threshold. If option 3 finished-product analysis is chosen, it s important to also include the packaging if the product was in a container. Page 1 of 10

2 Q3: One of the excipients in the finished product contains high EI levels, whereas the other excipients do not contain EIs to measurable amounts. Is this permitted? IT IS PERMITTED (E.G., ACCORDING TO OPTION 2B) IF, OVERALL, THE PRODUCT VALUES ARE BELOW THE 30% EI LEVEL OR THE 100% PDE LEVEL. If the 30% threshold to set up further controls is not exceeded for the entire product but only for a single component or some of the components, the manufacturer or MAH may want to decide whether to put those specific excipients under stricter control. But to the best of our knowledge, no control or variation is mandatory. When the permitted daily exposure values are exceeded (the 100% PDE values) for a single excipient but not for the entire product and when for the finished product the 30% value is not hit, then the same would apply. Q4: If upon performing a risk assessment we observe compliance with ICH Q3D for the drug product without further need of further controls, is it necessary to notify the health agency? Or can this be kept as data on file with contract manufacturing organisations or MAHs for agency inspections. SUCH DATA CAN BE KEPT ON FILE. Even if PDE or threshold is exceeded, a company should submit to the competent agency only the summary and not the assessment data. Q5: If the risk assessment concludes that an EI (class 1) has not intentionally been added and that the EI is unlikely to be present from any kind of source, is it necessary to carry out screening to demonstrate that fact? Or can this EI be considered to be absent. YOU MUST PROVE YOUR CONCLUSIONS. EIs may derive from various sources, and a screening of components or the finished product to reinforce your assessment with facts is always advisable. K n o w i n g the Options Q6: If we select option 3 assessing the concentration of elemental impurities in the finished product in the summary of risk assessment provided within the dossier, do we have to provide an explanation for our choice of that option, as opposed to taking a component approach? IT IS ALWAYS ADVISABLE TO EXPLAIN WHY YOU THINK AN OPTION IS MOST APPROPRIATE FOR YOUR PRODUCT. It also helps you determine whether that option is indeed the best course of action to take. One significant disadvantage to deciding to conduct an analysis of a finished product is that if the product exceeds the threshold for at least one EI, you won t know which component is responsible. That would make it difficult to determine which step to examine in your manufacturing process or which excipient has to be changed so as to decrease elemental impurities in the finished product. Page 2 of 10

3 Q7: Which kind of variation can be submitted as a result of the risk assessment? IF A RISK IS IDENTIFIED AND IF AN ELEMENTAL-IMPURITY LEVEL IS HIGHER THAN THE CONTROL THRESHOLD (30% OF PDE), AN ACTION MAY BE REQUIRED. First, a variation for change in the specification parameter and/or limits or test procedure of an active substance, a starting material, an excipient, a finished product, or immediate packaging may be submitted. In parallel, a change control may be implemented to define the need for further actions. This could result in the following variations. Change in the manufacture of the active substance or finished product Change in the manufacture of a starting material, a reagent, an intermediate substance, or an active substance Change in composition of the finished product or supplier of packaging components or devices Classification depends on: The nature of the change Whether the change is minor or major What is mentioned in the dossier (packaging) Dosage form, such as inhaler, biological product, or a nonstandard or complex process Q8: Can you please give one practical example for options 2a and 2b for EI calculation? AN EXAMPLE OF WHEN TO USE OPTION 2A WOULD BE A PRODUCT WITH 1 G API TAKEN ORALLY DAILY, DIVIDED INTO TWO SINGLE DOSAGES OF 500 MG EACH, IN WHICH OUT OF THREE INGREDIENTS, ONE INGREDIENT HAS EXCEEDED THE 0.15-µg VALUE FOR CADMIUM AND THE DAILY MAXIMUM IS 3 G. In this case, the calculation is concentration cadmium (ppm) = daily permitted dosage/maximum daily intake of finished product = 0.5 µg/g (control threshold). For each ingredient of the finished product, the cadmium concentration of 0.5 µg/g is not permitted to be exceeded. In the option 2b example, the same product, consisting of three ingredients, has a maximum daily intake of 3 g, with one ingredient hitting the calculated 0.5 µg/g value. The total daily intake is calculated based on cadmium = (cadmium value [API] x mass [API]) + (cadmium value [excipient A] x mass [excipient A]) + (cadmium value [excipient B] x mass [excipient B]). What it amounts to is that total daily intake of cadmium = (0.04 µg/g x 1 g) + (0.045 µg/g x 1.85 g) + (2.5 µg/g x 0.15 g) = µg <1.5 µg daily permitted oral intake of cadmium. In the latter option, even though one component has a comparably high cadmium value, it does not represent a risk, because it contributes to only 5% of the finished product. Page 3 of 10

4 Q9: How do we determine which option to use to assess permitted daily exposure? DECIDING WHICH OPTION TO TAKE TO ASSESS PDE ISN T ALWAYS STRAIGHTFORWARD. To start with, you should create a decision tree to assess which option is most appropriate for your product. For example, if the product is taken at a dose of less than 10 g/day and if every EI in every component of your product is below the 30% threshold, then option 1 might be most appropriate. If, however, one of the conditions is not met, you would next consider choosing option 2a. C o n t r o l l i n g for Elementa l Impurities Q10: If no elemental impurities were introduced into the product during the manufacturing process thereby making the existence of EIs highly unlikely is it still mandatory to screen all of the elements that have to be assessed according to ICH guidelines regarding the route of administration? YES, AN ASSESSMENT IS REQUIRED EVEN IF THE MANUFACTURING PROCESS DID NOT ACTIVELY ADD ANY EIS, SUGGESTING THAT EIS AREN T PRESENT. It is still necessary to prove every conclusion with real data. Q11: My product is taken as substitution therapy daily. Is a toxicological assessment necessary if several EIs are higher than the PDE 30% threshold but below the PDE level? SEE CHAPTERS 3 AND 5 OF THE GUIDELINE: IN THE DEVELOPMENT OF CONTROLS FOR ELEMENTAL IMPURITIES IN DRUG PRODUCTS, THE PRINCIPLES OF QUALITY RISK MANAGEMENT AS DESCRIBED IN ICH Q9 SHOULD BE CONSIDERED. The risk assessment should be based on scientific knowledge and principles. It should link to safety considerations for patients with an understanding of the product and its manufacturing process (ICH Q8 and Q11). In the case of elemental impurities, the product risk assessment would therefore focus on assessment of the levels of elemental impurities in a drug product in relation to the PDEs presented in this guideline. Information for this risk assessment includes but is not limited to data generated by the applicant, information supplied by drug substance and/or excipient manufacturers, and/or data available in published literature. The applicant should document the risk assessment and control approaches in an appropriate manner. The levels of effort and formality of the risk assessment should be proportional to the level of risk. It is neither always appropriate nor always necessary to follow a formal risk management process that uses recognised tools and/or follows formal procedures (e.g., standard operating procedures). The use of informal risk management processes that apply empirical tools and/ or follow internal procedures may also be considered acceptable. Tools that assist in risk assessment are described in ICH Q8 and Q9 and will not be presented in this guideline. Formally, the toxicological assessment is needed when it s possible Page 4 of 10

5 that it might exceed the PDE value. To the best of our understanding, exceeding the 30% threshold would result in a regulatory action for controlling the API or excipient(s), but the toxicological assessment should be carried out only if needed. Levels of elemental impurities higher than established PDEs may be acceptable in certain cases that could include but are not limited to the following situations. Intermittent dosing Short-term dosing (i.e., 30 days or less) Specific indications (e.g., life threatening, unmet medical needs, rare diseases) Examples of justification of an increased level of an EI by taking a subfactor approach to a modifying factor are provided in the guideline. Other approaches may also be used for justifying an increased level. Any proposed level higher than an established PDE should be justified on a case-by-case basis. Q12: Do we have to perform routine testing of an EI in a drug product if the EI level is near the control threshold? WE RECOMMEND INTEGRATING ICH Q3D DATA INTO THE BATCH RELEASE PROCESS AND ALSO INTO CONTRACTS WITH SUPPLIERS. Thus, when suppliers provide data, routine testing might not be necessary. We recommend a risk-based approach. Q13: Have PDE values for all elemental impurities been developed with respect to the ophthalmic route? Are there publications or references on that? NO. No official PDE values have been established for the ophthalmic route. They have to be derived on a pharmacokinetic basis. However, if they have been established once, with clear reasoning, there is no need to repeat the process following assessment unless the composition has changed. Page 5 of 10

6 Q14: When a supplier does not provide values but only a statement that no element has been intentionally added, should we use zero for the calculations for risk class 1 (arsenic, cadmium, mercury, and lead) and 2a (cobalt, nickel, and vanadium) that are required to be assessed? NO, A STATEMENT THAT HEAVY METALS WEREN T INTENTIONALLY ADDED DURING THE MANUFACTURING PROCESS DOES NOT PERMIT YOU TO USE ZERO FOR CALCULATIONS. Section 3.2.P.5.6 sometimes gives a total amount of heavy metals that are contained in the finished product (e.g. >10 ppm), in which case you may calculate with those values. However, you must consider the worst case by assuming that each EI may be present at a level of 10 or more ppm in the finished product. It may therefore be advisable to ask for the real data or to actually measure EIs in the finished product. For example, inhaled products have a permitted daily limit (PDE) for mercury of 1 µg/day. Therefore, to stay within the 30% control threshold of 0.33 µg/day, your product dose should not exceed g/day. Referencing the same foregoing example, using the product of 100 mg/day would make it necessary to calculate the worst case of 10 or more ppm of heavy metal in the finished product and to then implement a control strategy. Q15: When a supplier has stated that no element has been intentionally added and that it also has analysed some batches whose results are below the limit of detection (LoD) or limit of quantification (LoQ), should we use the LoD/LoQ or use zero because no element has been intentionally added? YOU SHOULD USE THE LOD BECAUSE YOU HAVE TO ASSUME THE WORST CASE. Q16: With regard to APIs, if residual levels of EIs are higher than 30% of risk class 1, is it necessary to set a specification for this EI if it has not been intentionally added? IF THE ELEMENTS OF RISK CLASS 1 EXCEED THE 30% CONTROL THRESHOLD, THERE ARE A FEW POSSIBLE WAYS TO ADDRESS THE ISSUE. One would be to change the specification for individual components of the finished product if you observed that only one component had exceeded the EI threshold, in which case conducting a single additional purification step would be sufficient to decrease the EI level. Page 6 of 10

7 Q17: Is it mandatory to perform a screening if the result of risk assessment for class 1 or class 2a EIs is low risk? YOU ARE NOT PERMITTED TO ASSESS YOUR PRODUCT AS BEING LOW RISK TO STOP IT FROM BEING SCREENED. You must perform Q3D analysis for the product based on real values (specification of suppliers for each component either by measurement of the components or by measurement of the finished product) for each case. Q18: If an EI has a low risk of being present in an API and if any screening is performed, can we conclude that this EI is absent in an API? NO, YOU MUST ALSO CONSIDER THE LIMITS OF DETECTION. If your detection limit is comparatively high, it s possible that your product contains high amounts of EIs perhaps above the PDEs even if your screening still shows no EIs are present. Therefore, in a Q3D assessment, you must always include the LoD values to be sure they re low enough to meet the required levels. Q19: If an old legacy product fails the EI risk assessment, would a recall still be required, or is it possible to negotiate with the agency about its efficacy? OLD PRODUCTS THAT WERE AUTHORISED BEFORE Q3D WAS A COMPETENT-AUTHORITIES PRIORITY ARE NOT EXEMPT, AND AS OF 16 DECEMBER 2017, ALL PRODUCTS IRRESPECTIVE OF HOW LONG THEY HAVE BEEN ON THE MARKET MUST ADHERE TO THE REQUIREMENTS. However, if your product fails the Q3D assessment, it won t necessarily be recalled. First, you must perform a toxicological assessment, which should include (1) the patient group your product targets, (2) the treatment duration, and (3) the indication (e.g., life-threatening condition, orphan disease). After performing the toxicological assessment, you must provide the competent authority with reasons the authority should approve your assessment. And if the authority is satisfied, you might avoid a product recall. Page 7 of 10

8 R e s p o n s i b i l i t i e s Q20: Can you confirm who s responsible for the risk assessment because the guideline actually specifies MAH/manufacturer? SEE THE ICH Q3D IMPLEMENTATION GUIDE FROM 26 FEBRUARY 2015 (EMA/CHMP/QWP/109127/2015), PAGE 2, WHICH SAYS, IMPLEMENTATION FOR EXISTING MARKETED PRODUCTS. To have a common approach among national competent authorities and to avoid unnecessary workloads from multiple variations, the following proposals have been made. A. Each national authority should notify MAHs in its own country about this new guideline according to its national information procedure. B. During the transition period, MAHs should perform risk assessments of the manufacture of their medicinal products by covering all potential sources such as active-substance starting materials, reagents, catalysts, process water, excipients, equipment, and container closure materials. It is envisaged that parts of this risk analysis may be common for several products, whereas others may be product specific. Q21: Does the ICH Q3D guideline apply to existing registered products as well? YES. The guideline specifies that it came into force for new applications and new marketing authorisations from July 2016 onward and for existing marketing authorisations from 17 December Q22: In which part of the Common Technical Document should we put all of this information, including the summary of the risk assessment? INFORMATION ABOUT ELEMENTAL IMPURITIES BELONGS IN SECTION 3.2.P.5.6, JUSTIFICATION OF SPECIFICATION. Q23: Which section of Module 3 should the risk assessment submit? IF INFORMATION ON THE DRUG SUBSTANCE IS AVAILABLE, WE RECOMMEND PROVIDING THE DETAILS IN SECTION 3.2.S.3.2. Regardless, however, a risk assessment summary should be provided for the overall finished product, as stipulated in section 3.2.P.5.6. Page 8 of 10

9 Q24: Is the ICH Q3D guideline applicable for new registration applications? YES. The guideline has applied to new applications since July 2016 and will apply for all authorised products from 16 December 2017 onward. Q25: Do we have to conduct a reassessment if we change the excipient supplier and have to inform the competent authority for elemental-impurity profiling? IF YOU CHANGE STEPS IN THE MANUFACTURING PROCESS, IT S ALWAYS ADVISABLE TO ASSESS WHETHER THE CHANGES HAVE ANY INFLUENCE ON THE Q3D ASSESSMENT OF THE FINISHED PRODUCT. A change of excipient supplier or of supplier of the active pharmaceutical ingredient has the potential to affect the assessment because either (1) another supplier may have different specifications for each elemental impurity or (2) the raw material may derive from different sources. For example, when excipients are derived from plants, the level of elemental impurities can vary according to the soil or terrain in which they were grown. In the future, if you wish to change a supplier of excipients and/or APIs, you should always request details about the EIs that are relevant to the route of administration for your product. To be on the safe side, you also should include this section in future contracts with your suppliers so as to require them to inform you whenever a change occurs that could affect Q3D assessment of your product. Q26: Is Q3D applicable to veterinary pharmaceutical as well? A NEW GUIDELINE APPLICABLE TO VETERINARY PRODUCTS IS BEING DRAFTED AND IS CURRENTLY UNDERGOING PUBLIC CONSULTATION. It will be applicable shortly. Q27: What is the UK deadline for submission of any required variation applications? THE UNITED KINGDOM IS STILL PART OF THE EUROPEAN ECONOMIC AREA, AND A RISK-BASED APPROACH IS RECOMMENDED. We are not aware of any UK-specific deadline. Page 9 of 10

10 Q28: When should approved variations be implemented after agency approval? A RISK-BASED APPROACH IS RECOMMENDED. The implementation of variations depends (1) on the values that were measured and in which level the variations exceed the permitted exposure levels of the product and (2) on regulatory authority recommendations. Q29: Which department or function should sign off on the risk assessment? Should regulatory or quality take ownership? ALL FUNCTIONS CONCERNED HAVE TO SIGN OFF ON THE ASSESSMENT: QUALITY, REGULATORY AFFAIRS/CMC, THE QUALIFIED PERSON, AND THE QUALIFIED PERSON FOR PHARMACOVIGILANCE. Q30: If a manufacturer does not provide the necessary data, would its qualified person withhold release product after end December 2017 in the absence of the risk assessment? THE MAH SHOULD BE PREPARED TO PERFORM AN ASSESSMENT ON THE FINISHED PRODUCT. Such an assessment can be independent of any action by the manufacturer. ProductLife Group Head Office 40 boulevard Henri Sellier, Suresnes, France Tel info@productlife-group.com ProductLife Group s extensive affiliate model in support of global regulatory and safety processes continues to expand. Visit for the most-up-to-date information on our emerging-market coverage. Page 10 of 10