Regulatory Highlights pubs.acs.org/OPRD
Regulatory Highlights
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INTRODUCTION This article seeks to examine areas of regulatory guidance and practice that can be considered as being those of highest current interest and impact on the activities of chemists and engineers in process research and development of pharmaceuticals. This is because of either ongoing evolution of new guidance or, in the case of the specific areas examined in detail in this review, Question and Answer (Q&A) documents drafted with the intent at least to improve applicability and understanding of current guidelines. The end of 2016 saw the publication of two such Q&A documents: one pertaining to shared facilities;1 the other to ICH Q112 specifically to the topic of registered starting materials, a subject examined in a previous regulatory review.3 In addition we also look at a potentially important publication examining the topic of impurity qualification and duration of exposure, this relating closely to ICH Q3A and ICH Q3B. Before we look into each of these in more detail. A reminder. The deadline for compliance with ICH Q3d4 for established products is rapidly approaching. In both Europe and US you have until December 31st to comply. If you have yet to start your risk assessments then it is imperative you start now, for a single product a review period of up to 6 months is not unrealistic and this assumes no remedial action. A short note to also advise that the addendum to ICH M7− mutagenic impurities reached Step 45 at the beginning of June. This will bring to an end around 4 years of work, the benefit of which being that as an industry we will have one agreed limit for a range of chemically important mutagenic reagents. By having such an agreed limit it will mean that we can plan with assurance control strategies knowing the level at which control must be established. Given the complexity and at times variance of the associated safety data this is critical. Before this each applicant would need to define and defend such a limit.
on the modified Haber’s Law, absolute impurity levels of 5 mg/ day were demonstrated to be as safe for exposure durations of less than 6 months, as is the 1 mg/day level for lifelong exposure. Haber’s Law: c × t = c′ × t ′
Haber’s Law does not sufficiently factor for circumstances where the toxicity hazard might be an acute one; hence, the use of the conservative modified form. Modified Haber’s Law: c 3 × t = c′3 × t ′
where c = safe dose at time t = 1 mg, c′ = corresponding safe dose (concentration) at shorter duration t′, and t = lifetime − 75 years 24375 days. Therefore, for studies of 6 months duration or less c′ = 3√ 24375/182 = 5 mg. For potent drugs that have effective doses in the low μg to mg range, an absolute threshold of 5 mg/day for an impurity is not appropriate from either a quality or safety perspective. Therefore, the 5-fold higher threshold for the absolute value (1 mg to 5 mg/day) is combined with an additional restriction of a relative threshold of 0.7% (i.e., also a 5-fold higher relative level as compared to the ICH Q3A6 qualification level of 0.15%). The conclusion of the paper is that a value of 5 mg/day or a relative level of 0.7%, whichever is lower, may be considered to be safe and acceptable for qualification of nonmutagenic impurities during early development clinical trials with durations up to 6 months. This has the potential to significantly reduce the need for additional preclinical studies.
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EMA Q AND A DOCUMENT−SHARED FACILITIES GUIDELINE In December 2016 EMA issued a Questions and answers document focused on their earlier ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’.9 This was issued for consultation and comment, the deadline being end of April 2017. The original guideline was a topic of some contention when finalized in December 2013, in particular the challenges associated with its practical implementation. The guideline was issued to provide clarification around requirements for use of dedicated facilities thereby addressing previous issues relating to interpretation and practical implementation. The central tenant of the guideline was to provide clearer guidance around classification, addressing this though establishing a uniform practice in relation to calculation of limits. It proposed the use of toxicological data to generate a permissible daily exposure (PDE) limit, this then being used to define cleaning limits. The intent was to use such an approach to replace the previous
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ICH Q3A/ICH Q3B Established approximately 20 years ago, these two quality guidelines6,7 have provided the bedrock upon which impurity management and control has been defined. Both however only apply to marketed products which leads to the question what is an appropriate qualification limit for a nonmutagenic impurity within a short-term clinical study? Discussions within EFPIA among members over a period of years highlighted the absence initially of a systematic approach to this question. Recently Harvey et al.8 published proposals that link dose to duration in a manner analogous to that employed for mutagenic impurities (staged TTC). This first examined the basis for the 1 mg/day dose lifetime limit proposed within ICH Q3A,6 definitively demonstrating the appropriateness of this limit based on available safety data. Once established the paper then looked to address the question of durational limits. Using the 1 mg/day assumed safe dose for lifelong exposure to an unqualified impurity of unknown toxicity as representing a negligible risk of harm, a modification of Haber’s Law was used to extrapolate safe levels for short-term durations. Based © XXXX American Chemical Society
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DOI: 10.1021/acs.oprd.7b00243 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Regulatory Highlights
justification is provided for the thresholds defined in the document relating to the highly hazardous concept. Moreover these limits are a mixture of criteria relating to hazard (toxicity) and potency. Many are likely to argue that introduction of a new term and categorization process such as the highly hazardous category should be incorporated into the guideline itself. As highlighted above in relation to the original guideline there was a clear intent to move away from supposed empirical approaches based on 10 ppm or 1/1000th of clinical dose. However, within the Q&A document for those compounds deemed not to be highly hazardous, the response to Question 4 makes clear that the use of such approaches is acceptable. However, this is defined in the context of a product for which clinical safety profiles are well-established and that do not belong to the highly hazardous category. One has to wonder why in such a scenario there would be value in such an approach given that it is very likely data exist to generate a PDE. This does not address the far more likely scenario where use of such an approach would be valuable, and this is in the context of early clinical development where there is insufficient data to generate a PDE. This points to a general issue with this Q and A document that relates to scope. Does it apply simply to drug product or the drug substance? The use of 10 ppm or 1/1000th clinical dose in cleaning limits is addressed in Question 6, where the answer again suggests that such approaches may be acceptable. In respect to approaches during clinical development some further clarification is provided through the response to Question 10. This suggests that limits should be established based on all available data and as such assessments associated with Investigational medicinal products (IMPs) should be regularly reviewed. One challenge will be how often should this be reviewed? And also what happens if on reviewing the need to revise limits downward is identified? Another point of note relates to Question 13 that seeks to address segregation. It makes a valuable point that this is not a simple case of segregating highly hazardous products in a dedicated area from other lower risk products; i.e., there is a need to also address the risk of cross contamination between highly hazardous products. This is a valid point especially if the pharmacology and toxicology associated with the substances concerned is significantly different. The overall conclusion regarding this could be mixed, particularly in terms of concerns over the introduction of the concept of highly hazardous. Finally there remains the stand out issue regarding scopedoes it simply apply to drug product or is it applicable more widely to the manufacture of the active drug substance?
common practice of use of 10 ppm or 1/1000th clinical dose, seen, by some at least, as being empirical. In practice this presented further challenges. Where data are available it works well, although many organizations had to undertake extensive programs to generate and collate the safety data to define the necessary PDEs. However, the guideline was unclear around how to address this in the absence of data. For example • During the clinical development of the product, key critical data; e.g., reproductive toxicity is unlikely to be available until later phases. • Does the guideline apply to the API as well as the product? From a cleaning perspective, the two are quite different. In the case of API manufacture the proceeding process will be a solution-based process, often involving a chemical transformation, both providing further opportunities for removal of any residual active remaining. • What about synthetic intermediates where rarely, if ever, are the safety data generated to calculate a definitive PDE. It is against this backdrop that the Q&A document was issued. Within the document there are some 14 specific questions, topics include the following: a. Do companies have to establish Health Based Exposure Limits (HBELs) for all products? b. What products/active substances are considered to be highly hazardous? c. Could Occupational Exposure Limits (OELs) or Occupational Exposure Bands (OEBs) be used to support assessment of products to determine whether they may be highly hazardous? d. Can calculation of HBELs be based on clinical data only (e.g., to establish the HBEL on 1/1000th of the minimum therapeutic dose)? e. How can limits for cleaning purposes be established? f. How can inspectors determine the competency of the Toxicology expert developing the health-based exposure limit? g. How can the HBEL model be applied to early phase Investigational Medicinal Products (IMPs) where limited data are available? h. Where products for pediatric populations are manufactured in shared facilities with products intended for administration to adults or to animals, do the HBELs need adjustment? i. What role do HBELs play in meeting the requirements of GMP Chapter 5 section 2013? j. Is it acceptable to simply segregate highly hazardous products in a dedicated area as a means of controlling risk of cross contamination? k. Is the application of the Threshold of Toxicological Concern (TTC) as applied in the guideline of mutagenic products of 1.5 μg/person/day concept an acceptable default approach to establish an HBEL? It is interesting in reviewing this to immediately reflect on the answer to the first of these questions, especially based on the fact that an apparently new term is introduced, that being an HBEL. Although in the original guideline it talked about establishing health based exposure limits, these were described almost entirely in the context of PDEs; the term and acronym HBEL was not used. Further, the term highly hazardous was also not used. Of real concern is that no explanation or
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ICH Q11 Q AND A DOCUMENT The topic of starting materials has been a vexed topic for some period. Indeed concerns relating to lack of clarity and issues pertaining to practical implementation led the EMA in Sept 2014 to publish a reflection paperReflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.10 The paper sought to outline key issues as well as authority expectations; specific areas of interest identified included the following: 1. Variance in interpretation between applicant and reviewer. B
DOI: 10.1021/acs.oprd.7b00243 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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9. 10. 11. 12. 13. 14.
Application of Q11 to linear and convergent syntheses Starting material specifications: key attributes Noncommercial starting materials Differences: Commercially available vs Custom Synthesis Requirements for justification of commercial availability Scope: postapproval change−preregistered starting materials 15. Life cycle management 16. Starting material Q11 vs Q7 definition: clarification that this is effectively the same It is beyond the scope of this review to examine the specific text associated with all 16 questions. In general though the position articulated throughout is pragmatic and also, in general, answers are clear and relatively concise. Key points of note include • “Significant structural fragment”: the document highlights the frequent misconception that this means that a proposed starting material should be structurally similar to the drug substance. It makes clear that in fact the intent is simply to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. • Questions 5.2, 5.4, and 5.5 relate to mutagenic impurities. The answers provided should be useful in assisting an applicant in applying the risk based approach defined within ICH M7.5 Prior to this there was a general misconception that a step that involved a mutagenic impurity needed to be part of the registered process. Such an assertion took no account of the highly reactive nature of such impurities and their propensity to be effectively purged.12 The answer to question 5.2 makes clear the framework for defining the impact of an MI on the quality of the final drug substance, aligning this directly to M7 and the adoption of the widely applied 30% of the limit principle, i.e. prove levels in the final active drug substance are below 30% of the acceptable limit. The answer to question 5.4. provides a commentary of the actual practical steps involved in assessing the impact of an MI. Importantly within this it contextualizes the actual risk posed by low level MIs with the following important statement • “Such mutagenic impurities and by-products are usually present at much lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents, or intermediates from the same steps.” In essence, provided any MI associated with a starting material is demonstrably controlled it is not necessary to register stages that simply employ the use of mutagenic reagents. • Another important point addressed within the document is ‘persistency.’ It seeks to make clear that even where an impurity associated with a starting material does impact on the quality of the drug substance that control can be defined at the stage of the starting material. A classic example would be a stereoisomer. General downstream processing would have little impact on levels. In many cases this has led to a view that the step where such an
2. The registration of short syntheses that employ complex custom-made starting materials. 3. Lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy. While the consensus was that overall this provided a useful perspective of at least the EMA’s interpretation of ICH Q112 and requirements for starting material selection, further discussion was required to address this subject to the satisfaction of both industry and regulators. In November 2016 ICH released a Q&A document pertaining to ICH Q11, the purpose of which is to clarify the expectations regarding the selection and justification of starting materials for drug substance manufacture. This has reached Step 2,11 a consensus document released for public comment, the deadline being March 2017. The document comprises a series of sections, beginning with an introduction. This makes clear that the focus of the Q&A document is on chemical entity drug substances, excluding Biologics at least in the sense of definition of starting materials. Another important proposal made within the introduction is that API starting materials that have already been accepted by regulatory authorities (e.g., for use in authorized medicinal products) would not need to be rejustified against the ICH Q11 general principles or the recommendations included in this Q&A document, unless significant changes are made to the manufacturing processes and controls. This is important as a concern may have been that criteria defined in the document would be retrospectively applied. It is though caviated, stating that a starting material accepted for one manufacturer’s process may not be considered acceptable for a different manufacturer’s process. It also states that designation of starting materials should be based on process knowledge for the intended commercial process. It emphasizes that all of the general principles in ICH Q11 Section 5 should always be considered holistically, together with the clarifications in this Q&A document, rather than applying a single general principle or Q&A clarification in isolation. This was a thread central to the argumentation within the earlier EMA guideline. The questions and answers are aligned to specific sections within the guideline, although all questions are focused specifically on Section 5Selection of starting material and source material. There are 16 questions in total covering the following aspects: 1. Significant Structural Fragment: how should this be interpreted 2. Impact on Impurity profile of final product: this relates to the guidance within Q11 to include all stages that impact on impurity profile of the drug substance. This seeks to clarify what level would be defined as impactful. 3. Clarification of persistence 4. How an applicant should determine which steps impact the profile of mutagenic impurities in the drug substance. 5. Do all steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included in the process description? 6. Clarification of the stated need to describe “enough” of the drug substance manufacturing 7. Should all the ICH Q11 general principles be considered and met in selecting starting materials? 8. Application of Q11 principles to telescoped processes C
DOI: 10.1021/acs.oprd.7b00243 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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impurity might arise must form part of the registered process, i.e. the stage of introduction of chirality. This now makes clear that, provided this is effectively controlled within the starting material, registration of earlier stages is not required. Again, the key concerns raised by the EMA reflection paper10 are reflected on, i.e. registration of short syntheses that employ complex custom-made starting materials and a lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy. Arguably in that context the answer provided to question 5.6 is the most critical in the Q&A document. Question 5.6 ICH Q11 states that “enough of the drug substance manufacturing process should be described in the application···” What considerations should an applicant apply in the selection of the proposed starting materials to ensure that enough of the drugs substance manufacturing process will be described in the process description in Section 3.2.S.2.2 of the application? The response highlights several key aspects. Of primary importance is that the applicant must first evaluate which chemical transformation steps in the manufacturing process impact the impurity profile of the drug substance. With the clarification now provided in respect to MIs and “persistency” this should be more straightforward than previously was the case. Another key point made is the need for an applicant to examine steps immediately upstream of those identified as critical and within those upstream to consider if: • They include a unit operation that has been added to the manufacturing process to control specific impurities that would otherwise impact the impurity profile of the drug substance. The key point made here is that you cannot simply add multiple purification steps prior to a proposed starting material. • Tight control (e.g., within narrow parameter ranges) is required to prevent generation of impurities that would otherwise impact the impurity profile of the drug substance. If either are the case then these should be included within the registered synthesis. Perhaps the most contentious aspect of the response though is the caveat that if having conducted the assessment described and if based on this the result is that only a small number of chemical transformation steps need to be registered, the Q&A document articulates a need to include one or more additional steps. The reasons stated for this needing to be considered are • Due to the risk of contamination arising from a late starting material and the impact this would have on drug substance quality and • The risk of changes made to the route/process for the starting material impacting again on drug substance quality. Many organizations will I’m sure challenge this, as it seems to suggest little or no control around quality of starting materials; in reality that is far from the case. Ultimately does the response to this question and the overall document adequately address regulatory concerns, in particular those outlined EMA? Only time will tell, but overall this is a welcome development.
Regulatory Highlights
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REFERENCES
(1) Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities EMA/CHMP/ CVMP/ SWP/169430/2012 http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2014/11/WC500177735.pdf. (2) ICH Q11 - Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)Q11 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q11/Q11_Step_4.pdf. (3) Teasdale, A. Regulatory Highlights. Org. Process Res. Dev. 2015, 19 (4), 494−498. (4) ICH Q3D Guideline for Elemental Impurities http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3D/Q3D_Step_4.pdf. (5) Assessment and Control of Dna Reactive (Mutagenic)Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1) March 2017 http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_ Step_4_31Mar2017.pdf. (6) ICH Q3A Impurities in New Drug Substances http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3A_R2/Step4/Q3A_R2__Guideline.pdf. (7) ICH Q3B Impurities in New Drug Products http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3B_R2/Step4/Q3B_R2__Guideline.pdf. (8) Harvey, J.; Teasdale, A.; Fleetwood, A.; et al. Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development. Regul. Toxicol. Pharmacol. 2017, 84, 116−123. (9) Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/ CHMP/CVMP/SWP/169430/2012). http://www.ema.europa.eu/ docs/en_GB/document_library/Other/2017/01/WC500219500.pdf. (10) Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2014/10/WC500175228.pdf. (11) ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) − questions and answers http://www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Quality/Q11/Q11_Q_A_Step_2. pdf. (12) Teasdale, A.; et al. Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate Control. Org. Process Res. Dev. 2013, 17, 221−230. (13) EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use https://ec.europa.eu/health/ sites/health/files/files/eudralex/vol-4/chapter_5.pdf.
Andrew Teasdale* AstraZeneca, Macclesfield SK10 2NA, United Kingdom D
DOI: 10.1021/acs.oprd.7b00243 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
