Regulatory Highlights - Organic Process Research & Development

Regulatory Highlights pubs.acs.org/OPRD

Regulatory Highlights

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INTRODUCTION Compared to last year, 2015 may seem in comparison quiet in terms of new regulations; however, across a series of guidance areas, there has been a concerted reflection focused on practical implementation of the guidelines concerned. In the case for example of ICH Q3D1 elemental impurities, there have been a considerable number of symposia and publications centered on practical implementation, culminating in the continued development of training material by the ICH Q3D implementation group. In June of this year, the finalized ICH Q7 Q&A2 document was published; the content of which and the implications are explored in more depth later in the review. Similarly, there have been continued efforts to address the implementation challenges posed by ICH Q11,3 although there have been no further public disclosures upon which to comment. 2015 has also seen the evolution of a working framework for the eagerly anticipated ICH Q12 Product Life Cycle Management. What therefore may seem a quiet period ultimately turns out to have been an intriguing period; the actual as well as eventual output from ongoing developments will ultimately form the basis of practical implementation for many guidelines integral to drug substance development.

Figure 1. Derek predictions versus Leadscope predictions for 801 compounds tested in the Ames assay.

A chemist seeking to validate the drug substance process and the associated control strategy will desire assurance that the limits proposed are likely to be accepted by regulatory authorities. Establishing such limits is though difficult as data quality is often variable. To address this and other issues, a working group was established to develop an addendum table to ICH M7. In June this year the addendum table was issued as a step 2 document.9 This contains within it a table reproduced below (Table 1) containing proposed limits for some 16 reagents, in each case outlining the permitted limit as well as the method of calculation. In addition to the compounds described a series of other assessments were established by the working group for reagents for which there were extrapolated concerns over their mutagenicity. In many cases, for example mesityl oxide and acetamide, these concerns were shown to be unwarranted. Finally, concurrent to this regulatory review a special edition of OPRD has been constructed focused on ICH M7. This seeks to examine a number of different aspects linked to the guideline, including: • The topic of avoidance; • The practicality of seeking to eliminate the use of mutagenic reagents; • The challenge of assessing the potential formation of mutagenic degradants.

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DNA REACTIVE (MUTAGENIC) IMPURITIES ICH M7 ICH M7,4 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, was approved (Step 4) in June 2014. Within this was a time scale for implementation, that being for new products 18 months from publication, and hence it is therefore expected that organisations will have implemented the guideline by the beginning of 2016. Previous reviews have sought to examine the key challenges faced by the industry from a chemist’s perspective.5,6 One area in particular that has remained the focus of significant attention is structural evaluation. ICH M7 specifically defines the need to assess mutagenicity using two different methodologies, one rule based, and the other statistical. The challenge relates to the management of predictions between the two models and the role of expert evaluation within this process. Recently two reviews have examined this, Greene et al.7 and Barber et al.8 Both examine in depth the potential scenarios; Figure 1 shows this in Venn diagram form. Greene et al.7 showed that, when combining systems, nearly one-third of predictions were contradictory, demonstrating that in such circumstances expert review significantly enhanced predictive performance. Barber et al.8 illustrated what such an expert review may look like when graphically represented (Figure 2). While such an expert review clearly needs an in-depth knowledge of the systems and the methodological basis for their predictions, it also requires a detailed knowledge of the underlying chemistry. Again to stress a point made previously in this review, this must therefore involve a chemist in the process. Critical to any control strategy is establishing the level that must be achieved; this is amplified when addressing mutagenic impurities where the permitted levels are often very low. © XXXX American Chemical Society

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ELEMENTAL IMPURITIES (EIs) At the end of 2014, immediately after finalization of ICH Q3D,2 ICH took the unprecedented step of immediately establishing an implementation working group (IWG) to support the roll out of the finalized guideline, recognizing the practical challenges faced in its implementation. The primary purpose of the IWG is to produce training material to support

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DOI: 10.1021/acs.oprd.5b00318 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development


Figure 2. Decision matrix when evaluating two in silico predictions. OOD refers to out of domainthis reflecting the inability of the systems concerned to recognize either the whole or significant fragments of the molecule.

“The ICH Q7 Guideline is implemented successfully in the regulatory framework by WHO and most authorities around the world. However, experience gained with the implementation of ICH Q7 since the approval in November 2000 shows that uncertainties related to the interpretation of some sections exist.” Technical issues with regard to GMP of APIsalso in context with new ICH Guidelinesneed to be addressed in order “to harmonize expectations during inspections”. Specific areas were identified for consideration arising from changes in requirements and expectations since Q7 was adopted in 2000, these included: 1. Technical issuesincluding supply chain management and the management of GMP within contract manufacturing facilities. Key within this is which activities can be delegated and which cannot, seeking to clarify the accountabilities within the quality assurance units within the customer organization. 2. The alignment of ICH Q7 to new guidelines (ICH Q8/ Q9/Q10/Q11), a specific concern being the variable interpretation of starting materials, i.e., the point of introduction of GMP controls. 3. Changes to Process Validation requirements; 4. Changes to Cleaning Validation requirements; 5. Review of existing Q&As from training sessions and conference documents, particularly information gathered by Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S). This review relied on input not just from the 6 ICH parties but also on input from other regions, e.g., Brazil, formal ICH observers including the WHO and key industry bodies including PIC/S. From the areas identified, some 19 different areas were examined through nearly 70 specific questions and answers. Of those areas, those highlighted in bold represent the bulk of the Q&As: 1. IntroductionScope 2. Quality Management

the process. The material is still under development with no formal date for finalisation, what is known is that it is likely to take the form of: • A general overview; • Safetydetermination of PDEs for non-ICH Q3D elements/limits for other routes of administration/ justification of higher limits/parenterals; • Qualityrisk assessment processes/control strategy; • Case studies. In addition to material being produced by the IWG, Teasdale et al. published an article specifically focused on the Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and Opportunities.10 Within this the assessment of the drug substance was examined. Potential sources of EIs are illustrated in Figure 3. Of the sources highlighted, the greatest risk comes from intentionally added metals (e.g., metal catalysts used in the process). Although manufacturing equipment is a potential source of EIs, in general control can be achieved through GMP, typically through conduct of an equipment compatibility assessment. Indeed the most commonly used materials of construction such as Hastelloy, stainless steel, and glass, are selected due to their specific chemical resistance. Solvents used in the manufacture of drug substances are also unlikely to represent a significant risk of EI contamination. Solvents are typically purified by distillation, and few involve the direct use of metal catalysts in their manufacture. Overall it can be concluded that, while drug substance manufacturing often involves a complex series of processes, the risk of EI contamination is low. Indeed simple scientific principles can be applied to clearly demonstrate that elemental impurity levels in the final drug substance are controlled to appropriate levels.

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ICH Q7 QUESTION AND ANSWERS In June 2015 the finalized Q&A document was published by the ICH Q7 Implementation Working Group (IWG).2 The IWG was established to address the following problem statement: B




Table 1. Acceptable Intakes (AIs) or Permissible Daily Exposures (PDEs)

13. 14. 15. 16. 17.

Change Control Rejection and Reuse of Materials Complaints and Recalls Contract Manufacturers (including Laboratories) Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 19. APIs for Use in Clinical Trials The questions and their related answers are all crossreferenced to specific sections of the guideline itself and are

3. 4. 5. 6. 7. 8. 9.

Personnel Buildings and FacilitiesContainment Process EquipmentCleaning Documentation and Records Materials Management Production and In-Process Controls Packaging and Identification Labeling of APIs and Intermediates 10. Storage and Distribution 11. Laboratory Controls 12. Validation C




4. Post-Approval Change Management Plans and Protocols: (a) this will seek to articulate how a post-approval management plan may be used to proactively identify postapproval changes and the mechanisms for both submission and review; (b) establish criteria for postapproval change management protocols that can be adopted by the ICH regions. As well as highlighting areas the guideline will seek to address, the concept paper also highlights the anticipated benefits. One area likely to be of particular interest from a chemist’s perspective is the desire that Q12 will facilitate the early adoption of new technological advances, such as continuous processing and the use of PAT. This itself is not a new concept indeed the FDA 21st Century Initiative instigated in 200414 highlighted the need for more effective implementation of new technologies. During a recent presentation15 Christine M. V. Moore, Ph.D. FDA Acting Director, Office of Process and Facilities candidly reflected on the lack of progress, highlighting that focus has been on enhanced product and process understanding rather than advanced Manufacturing Controls. That often the enhanced knowledge gained was not used to justify “regulatory flexibility” (e.g., design space), that in reality there had been little advancement in achieving “true continual improvement.” The presentation highlighted the blockers to such innovation, these mirroring those also defined in the ICH Q12 concept paper. It also examined how the concepts described above, articulated in the Q12 concept paper, will help to address the current blockers. There are clear expectations that knowledge and risk management processes will facilitate the desired “operational flexibility” lowering the barriers to continual improvement and innovation including the successful implementation of new manufacturing processes and the use of PAT. It is important to recognize that currently both EMA and FDA have existing protocols, e.g., Post Approval Changes to Manufacturing Process (PACMPs) and comparability protocols addressing post approval change; indeed the EMA and FDA have an ongoing pilot for “Parallel Assessment” or “Consultative Advice” for QbD applications.16 This specifically focuses on protocols for flexibility of post-approval changes and new technologies and was recently extended to April 2016. Japan MHLW announced in June that they would incorporate PACMPs into law as part of implementation of Q12. Similarly from the positive perspective, the FDA Established conditions draft guidance issued in June this year in line with current thinking in EWG. The potential benefits of Q12 are far-reaching, and should it achieve its primary goals, it may well finally bring about the flexible, innovation-driven industry envisioned for the 21st century.

Figure 3. Potential sources of elemental impurities in the drug substance.

constructed based on the principle of outlining “what to do”. It is important to also reflect on what the Q&A was expressly aiming to avoid. It is not prescriptive, there being no attempt to provide “how to do” guidance, nor does it seek to enlarge the scope of ICH Q7 or establish new requirements.

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EXAMPLE QUESTION AND ANSWERS It is recommended that the document be read in its entirety; however, from a chemists’ perspective there are specific Q&As that are likely to be of the most interest. Those are reproduced in Table 2, including some personal reflections on their potential significance or impact.

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ICH Q12 In June 2015 the Expert Working Group (EWG) for Q12 issued a work plan for development of the guideline.12 This indicates that the step 2a document for public consultation will be issued mid 2016, in line with timings originally set out in the concept paper.13 Ahead of this it is however possible to gain an insight at least into the thinking associated with ICH Q12. The associated concept paper articulates the proposed harmonization, the relationship to other key guidelines, i.e., ICH Q8, Q9, Q10, and Q11, and the current barriers to the idealized state. Specific attention is paid within the concept paper to the issue of change management, this being highlighted as an integral part of any quality system and seminal to any affective post-approval change process. Within this specific areas are highlighted: 1. Regulatory Dossierthe need for Q12 to develop a harmonized approach to “regulatory commitments”; including the need for guidance pertaining to the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier. 2. Pharmaceutical Quality System aspects (ICH Q10)for Q12 to define criteria that would allow a risk based approach to be taken in the evaluation of the impact of any change on quality, safety, and efficacy. 3. Knowledge management systems and how such systems ensure product quality and the capture of process information throughout the product lifecycle.

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ICH Q3C In June 2015 a revision to ICH Q3C (R6)17 was published as a step 2 document for consultation; the deadline for comments is December 31, 2015. This focuses on two specific solvents, triethylamine (TEA) and methylisobutyl ketone (MIBK). In the case of TEA a specific Permitted Daily Exposure (PDE) has been proposed based on new toxicological data. In the case of MIBK, a revision of the PDE, based on new toxicological data, is proposed. In the case of MIBK, the change to the proposed limits results in it is reclassification as a class 2 solvent; however, in reality the newly calculated PDE of MIBK of 22.6 mg/day is D




Table 2 answer

reflection

Should GMP according to ICH Q7 be applied for manufacturing steps before the defined “API starting material” ?

question

ICH Q7 does not apply to steps prior to the introduction of the API starting material. However, there is an expectation that an appropriate level of controls suitable for the production of the API starting material should be applied [ICH Q7, Section 1.3]. Normally, the “API-starting material” is defined in the regulatory filing by the applicant and approved in the regulatory reviewing process. Additional guidance is provided to define and justify “API starting material” derived from various sources [ICH Q11, Section 5]; for master cell banks, see [ICH Q5B; ICH Q5D].

When are dedicated production areas expected?

ICH Q7 expects dedicated production areas for highly sensitizing materials such as penicillins and cephalosporins because of the patient risk (e.g., anaphylactic shock in penicillin-allergic patients) from trace amounts of these compounds in other medicines [ICH Q7, Section 4.40]. For materials of an infectious nature or high pharmacological activity or toxicity, a risk-based approach should be used to determine appropriate containment measures, which may include validated inactivation, cleaning, and/or dedicated production areas [ICH Q7, Section 4.41]. While ICH Q7 does not define high pharmacological activity or toxicity, these are generally determined by evaluating relevant animal and human data collected during research and development. Important considerations in this evaluation of pharmacological activity or toxicity may include Occupational Exposure Limit (OEL), Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE), Threshold for Toxicological Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S Guidelines, ICH E2E, Section 2.1.1], and the consequences of crosscontamination [ICH Q9, Section 4.3]. Different phrases are used to describe the expectation for evaluation of suppliers of materials [ICH Q7, Sections 7.11, 7.12, 7.31], including traders, if any. [ICH Q7, Section 7.12] states that all materials are purchased against a specification and from suppliers approved by the quality unit [ICH Q7, Section 7.31]. Prior to approval of any supplier, an evaluation should be conducted using a risk-based approach [ICH Q9, Appendix II.5; ICH Q7, Section 7.31]. More extensive evaluation is needed for suppliers of those materials classified as “critical” [ICH Q7, Section 7.11]. Yes. Differing yield ranges [ICH Q7, Section 8.14] may be described and justified in the manufacturing procedure/master batch record explaining the ranges [ICH Q7, Section 6.41]. For example, the first batch in the series of production of batches of the same material (campaign) may leave residual material in the equipment, resulting in a low yield in the first batch and contributing to an increased yield in a subsequent batch of the campaign. No. However, information from the investigation into a process deviation (s) can be used to support expanding the range of a process parameter. Additional work and studies are normally needed to adequately demonstrate that the expanded range for the process parameter consistently produces API of the necessary quality [ICH Q7, Sections 2.16, 12.11, 13.13]. Any change in the API starting material should be assessed for impact on the API manufacturing process and the resulting API quality [ICH Q7, Section 7.14]. Additional validation studies of the API process may be warranted if the change in the API starting material is deemed significant. In most cases, validation would be expected for a different source of the starting material unless otherwise justified [ICH Q7, Sections 12.1, 13.13]. Prospective validation is normally expected for processes introduced since the publication of ICH Q7. The concept of retrospective validation remains acceptable as an exception for existing, well-established products prior to the implementation of ICH Q7 [ICH Q7, Section 12.44].

In many ways the answer is self-explanatory; ICH Q7 does not apply to steps prior to the API starting material. What though is interesting is the comment that an appropriate level of control is required to ensure the quality of the manufactured starting material. This cuts to the heart of much of the current discussions around the definition of starting materials and the need to ensure the quality of the starting material is maintained. It is likely therefore that primary within the controls expected prior to the starting material is effective change management. Also of importance is cleaning and the effective control of residues from other materials manufactured in the same facility. What is in some ways most interesting is the absence of any direct reference to the recently published EMA shared facilities guideline.1 One obvious reason is that the guideline in question is specific to one region, i.e., Europe. It does though nevertheless still beg the question, does the EMA guideline have any relevance to API manufacture?

What is expected in terms of evaluation of suppliers of materials?

Can yield ranges defined for the first batch differ from latter batches within a campaign?

Can the range of a process parameter be expanded based only on a process deviation (s)? Would additional process validation studies be needed to support a change in the source of an API starting material? Is a retrospective approach to validation still acceptable?

Is validation expected for the recovery of material from mother liquor?

This again is an important question and answer in the context of Q11 and the definition of starting materials. A central concern of regulators is the lack of visibility/control of stages preceding starting materials. In practice many starting materials are likely to be supplied to the ultimate API manufacturer, and hence the points outlined are clearly germane to the management of SM suppliers and their evaluation. It is certainly useful to see the Q&A document advocate a risk based approach linked to criticality. This would for example be a filter heel or drier heel. It should not be construed to mean that inadequate cleaning resulting in variable yield is in any way acceptable

There is a clear link here to the principles outlined in Q11. The overall theme is that changes need to be supported by “good science”.

Again there is a clear correlation with the concepts outlined in Q11 relating to API starting material. There should be sufficient understanding of the fate of impurities in the new SM. If more/ different impurities carry through to the API, then validation would be expected.

The most intriguing aspect of this is the point relating to redefinition of a step as critical. One specific area where this may be envisaged in is relation to the nonacceptance of a proposed SM. In such a scenario it is very likely that the applicant will have produced launch stocks of the API, and yet the step in question if it precedes the proposed SM will likely not have been validated. This might offer the potential to retrospectively validate the step in question while permitting the use of the existing launch stocks.

If regulatory discussions redefine a step as critical, which had previously been considered noncritical, a protocol describing retrospective analysis of data together with the commitment for concurrent or prospective validation may be an option. Regardless of the type of validation, the quality system should confirm the ongoing robustness of the process (e.g., product quality review). It depends. Recovery of material(s) from mother liquor is a process and the need for validation should be assessed as for any other process step [ICH Q7, Section 14.40]. Recovery of material from mother liquor in any process step that must be controlled within predetermined criteria to ensure the API meets its specification is, by definition, a critical process step and should be validated. For example, recovery of API from mother liquor would be considered a critical process step and should be validated [ICH Q7, Sections 12.11, 12.12, 14.41, 14.43, 20see Glossary for definitions of “critical”, “materials”, “mother liquor”, and “validation”]. E




QuestionsandAnswersonCurrentGoodManufacturingPracticescGMP forDrugs/UCM176374.pdf (accessed Oct 8, 2015). (15) An FDA Perspective on Post-Approval Change Management for PAT and RTRT, IFPAC 2015, January 26, 2015. http://www. infoscience.com/JPAC/ManScDB/JPACDBEntries/1425486934.pdf (accessed Oct 8, 2015). (16) http://www.fda.gov/downloads/InternationalPrograms/ FDABeyondOurBordersForeignOffices/EuropeanUnion/ UCM259808.pdf (accessed Oct 8, 2015). (17) Impurities: Guideline for Residual Solvents Pde for Triethylamine and PDE of Methylisobutylketone http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3C/Q3C_R6__Step_2.pdf (accessed Oct 8, 2015).

unlikely to have a significant impact on existing processes. Equally the proposed limit for TEA of >50 mg/day and definition as a class 3 solvent is also likely to have little impact either.

Andrew Teasdale*

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AstraZeneca, Macclesfield SK10 2NA, United Kingdom

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]

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REFERENCES

(1) ICH Q3D Step 4 16th December - Guideline For Elemental Impurities. http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf (accessed Oct 8, 2015). (2) Q7 Implementation Working Group - ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. Questions and Answers. http://www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Quality/Q7/ICH_Q7-IWG_QA_ v5_0_14Apr2015_FINAL_for_publication_17June2015.pdf (accessed Oct 8, 2015). (3) ICH M7 Step 4 June 2014- Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. http://www.ich.org/fileadmin/Public_Web_Site/ ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf (accessed Oct 8, 2015). (4) ICH Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). Http:// www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q11/Q11_Step_4.pdf (accessed Oct 8, 2015). (5) Teasdale, A. Regulatory Highlights. Org. Process Res. Dev. 2014, 18, 468−472. (6) Teasdale, A. Regulatory Highlights. Org. Process Res. Dev. 2014, 18, 1164−1168. (7) Greene, N.; Dobo, K.; Kenyon, M.; et al. Regul. Toxicol. Pharmacol. 2015, 72, 335−349. (8) Barber, C.; Amberg, A.; Custer, L.; et al. Regul. Toxicol. Pharmacol. 2015, 73, 367−377. (9) Addendum to ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk - Application of the Principles of the Ich M7 Guideline to Calculation of Compound-Specific Acceptable Intakes. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Multidisciplinary/M7/M7_Addendum_Step_2.pdf (accessed Oct 8, 2015). (10) Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and Opportunities. http://images2.advanstar.com/ PixelMags/pharma-tech-eu/digitaledition/03-2015.html#1 (accessed Oct 8, 2015). (11) Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. http://www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2014/11/WC500177735.pdf (accessed Oct 8, 2015). (12) ICH Q12 EWG Work Plan. http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_ EWG_Work_plan_11June2015.pdf (accessed Oct 8, 2015). (13) Final Concept Paper Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (accessed Oct 8, 2015). (14) Pharmaceutical cGMPS For the 21st CenturyA Risk-Based Approach. http://www.fda.gov/downloads/Drugs/ DevelopmentApprovalProcess/Manufacturing/ F


Regulatory Highlights - Organic Process Research & Development

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