CMC Strategy Forum Japan 2015 Introductory …c.ymcdn.com/sites/ Strategy Forum Japan 2015 ....

CMC Strategy Forum Japan 2015 Introductory Comments - Dr Nagano (PMDA)

Opened the program by noting that Japan is one of the few countries that develops innovative drugs, and that the pharma industry continues to grow rapidly here based on a successful interactions among experts in industry, academia and government.

Reminded us how the 3 main goals of PMDA 2015 Strategic Plan relate to advances in biopharmaceutical products:

I. Support availability of a wide variety of biological products (inc regenerative medicines and biosimilar products) with swift, but scientifically sound, product reviews

II. Work closely with other national health authorities to promote convergence of policies to maximize the efficiency of regulatory processes for globally-produced products

III. In partnership with other regions, leverage its knowledge and experience in biopharmaceutics to help build regulatory capacity in emerging training collaborations among regulators, industry and academia

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Recent Trends in the Regulation of Biopharmaceutical Products Moderated by Dr. Honda (PMDA) and Dr. Ridgway (HC)

Japan: Dr. Sato (PMDA) Slide on median approval times for new pharma products from 2004 - 2013 in US, EU, Japan, Canada, Australia and Switzerland all show trends in reduction with more review time consistency among them now than 10 yrs ago (see slide) Compared Early Access programs of US, EU and Japan (see slide)

Japan has priority reviews for Oncology etc. and Orphan products New approval path for Regen Med; 2 CT products approved in Sept, 1 was via conditional/time limited path (5 yr) (Q = what affects this decision; A = positive exploratory clin data; case by case) Forerunner Review; Two weeks ago, Sakigake was assigned to 6 pharma products (out of 51 applications); One was a biological product

Updated current regulatory issues for Biosimilars 7 biosimilars approved in Japan; approx. 25 consultations last year; expects 30 product applications in next 5 yrs. New update guidance soon for using non-Japan reference product in similarity studies Japanese Accepted Name (JAN) rules established for identification/traceability of biosimilars No decision on interchangeability, but extrapolation of indications possible with data

Product lifecycle (ICHQ12) important to PMDA for post-market review efficiency/effectiveness “Approved Matters” defines Mod 2 and 3 elements that are regulatory commitments in Japan

International cooperation and collaboration strategy launched June 2015 Review summaries available in English for global transparency of decisions (thank you ) New regulatory training center with partner countries for capacity building Highly engaged in regional and global regulatory cooperative/harmonization organizations


US: Dr. Kirchner (FDA CDER)Biosimilars:• Provided list of biopharm products approved/in progress and list of applicable guidances (see slides)• Showed case study of Neupogen BS 3-way bridge to utilize non-US ref prod clin data

• BS to US, BS to EU, and EU to US• Cannot assume two ref products are similar to each other; must have analytical data

• Statistical tiered approaches to analytical similarity studies (much discussion later!)• Tier 1 = Equivalence testing on highest risk CQAs (2-4 common among all BS candidates)• Tier 2 = Statistical ranges around moderate risk CQA (means, SDs around ref prod and BS data)• Tier 3 = Raw data/qualitative comparisons for low risk attributes

• Extrapolation of indications possible with data; interchangeability guidance soon (can’t discuss yet)• “Lessons learned”: Advisory Committee clinicians to better understand how analytical data impact residual uncertainty on S and E of BS product (informs the design needed for preclin/clin studies )

CMC Lifecycle (more later in ICH12 session)• New guidance on Established Conditions for commercial products (legally binding vs supportive)• Must still use PAC notification levels given in 21CFR601.12; must control change internally via QS

Expedited Priority Review Programs• Fast track, Accelerated, Breakthrough – all CMC need front-load data; prioritize critical path/highest risk items (minimize pre-approval changes!); consider impact of clin scale process on comm supply• Communicate early, often, and with sufficient relevant data (but resource intensive for FDA)

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Indonesia – Dr. Sparringa (NADFC)NADFC in progress of reorganization for better efficiency to meet needs of this major ASEAN region (40% of pop and GDP; fastest growing middle class); demand for biopharms rapidly increasingRegulations:• Similar review process using ICH CTD Q, S and E sections and similar postmarket inspection• Desire to switch focus from watchdog (reaction to inspection observations) to risk management (proactive prevention of quality problems)

Biosimilars:• 3 biosimilars in progress via tech transfer; 1 biosimilar being internally developed• Aligns with WHO / global guidances for biosimilars; follows ICDRA 2014 recommendations (see slide)• Three options on selecting ref product, inc one where product is no longer being produced (see slide)• Q=What if ref prod is not approved in Indo; could bridging be done? A = According to INDONESIA’s General Guideline on Evaluation of Biosimilar Products, there are conditions where reference product is not approved in Indonesia:

•If the originator product is not yet approved in Indonesia, reference product for biosimilar is the originator product that has been approved in country/ies with established evaluation system & never rejected in Indonesia•If the originator product is no longer produced, the refence product for biosimilar is the most established biotherapeutic product which has been approved based on full Q, S, E evaluation & has been marketed without any Q, S, E issues.

(See Slide No.23)4


Indonesia – Dr. Sparringa (NADFC) - continuedCMC Lifecycle:• Uses risk-based approach to evaluate post approval change with focus on impact to Q, S and E of product• ICHQ5E for biotherapeutics and WHO guideline for post approval changes for vaccines are the standard used for cmc post market changes evaluation in Indonesia; two case studies shown (see slides)• There are 3 categories for post approval changes in Indonesia: Pre-authorized major and minor, and minor with notification only.

International:• Highly engaged in International and regional groups activities (eg: ASEAN, WHO, DCVRN, APEC); As the ASEAN member states Indonesia uses the ASEAN CTD as the format for registration submission.• Member of PIC/S now (Q=How will NADFC use PIC/S? A=As benchmarks to improve quality and consistency of inspections of the numerous cGMP facilities in the country and manufacturing facilities outside Indonesia)• Strongly supports ongoing collaborative interactions with regional and global regulatory authorities

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Development of Biosimilars: Technical Aspects Moderators: Dr. Arato, Hokkaido University and Dr. Uchida, Kyowa Hakko Kirin Co., Ltd.

Development of Infliximab Biosimilar in Japan: Dr. Yamada, Nippon Kayaku Co., Ltd., Japan•NOTE: SLIDES NOT DISTRIBUTED AT OR AFTER MEETING•Details of case study CT-P13 (co-dev with Celltrion); approved 2012 Korea, 2013 EU, 2014 Japan•Analytical study used CT-P13 vs EU Remicade in >30 test methods (structural/functional)•Saw some differences in: IEX HPLC, Oligo profiles, CE SDS (nonreduced) and FcγRIIIa binding affinity•PMDA as well as EMA accepted that physicochemical properties had no impact upon efficacy in vivo•Did analytical bridge of EU Remicade to Japan Remicade; comparability shown•Preclin/clin used Japan Remicade head to head with CT-P13 to allow regional switch of product

Critical Considerations for Analytical Similarity Assessment: Dr. Liu, Amgen USA• Gave challenges to current analytical studies for biosimilar to reference product

• Tier 1 CQA may vary for diff sponsors of same biosimilar (should be same for consistency of reviews)• Statistically-relevant # lots of biosimilar and ref product (>10 )• True variability in ref product hard to determine (unknown # or age DS to DP; PACs to DS process)• Assay variability must be included in statistical ranges (but bias is intra-assay if side by side testing?)

• Fingerprint like SIMILARIITY is not the same as Fingerprint like METHODOLOGY• Good overview and comparisons of fingerprint-like METHODS (see slides)

Moved this slide to #6


Thailand– Dr. Boonprasirt (Thai FDA)Regulatory• Gave good overview of Thai regulatory agency (see slides for org charts)• Gave over of review processes (with timelines; see slides)• Listed applicable local, regional and global regulatory guidances (see slides)• Utilizes the ASEAN Common Tech Dossier (ACTD) and Common Tech Requirement (ACTR)• New submission process (inc on-line appointment!)• Piloting use of eCTD (first ASEAN country!) designed to shorten review time• Full implementation by 2016/2017

Biosimilars• General guideline (5 parts; Admin/prod infor, Q, Non clin, Clin, and Pharm Vigillance/Risk Mgmt)• Specific guidances now on 4 biosimilar products (somatropin, interferon alpha, Mabs, GCSF)• Q= How does Thai FDA define ‘conventional biological product’? A = A product with which they already have regulatory experience, eg plasma derivatives or vaccines• Q=Are there specific requirements for selection of reference product for biosimilar studies? A=Varies depending on the type of biosimilar product• Q=Are there any efforts underway to generate an ASEAN-specific biosimilar guidance? A=Yes, that effort will start very soon in the committee

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Korea – Dr. Joung (MFDS and APEC )Regulatory

• New regulatory approach based on pilot of risk management plan (RMP); 7 products now running• New guidance on RMP approach; Compared RMP of US, EU, Japan and Korea (see slide)• Patent and exclusivity incorporated into drug approval process; “green list” (similar to FDA Orange Book?); it has 146 biological products (129 recombinants)• Harmonization of comparability data per APEC workshop on process changes; stability data needed (note that stability data came up later in discussions):

• Prev. always real-time stability data on DP for any DS changes; not mandatory now for DP• Majungmool (= ‘priming water’ of wells or pumps) started in 2014

• Enhanced support to academic, small scale orgs not familiar with pharma regulatory systemBiosimilars

• BS Products submitted = 26 in IND phase (17 local, 9 foreign); 5 approved (4 local and 1 foreign)

APEC Update from 2015 AHC Biotherapeutics Workshop• At Step 2 (Training and Workshops) of 4-Step Roadmap process started in 2013• Outlined the concepts and logistics for Centers of Excellence for regulatory training on biotech products• Three topics for pilot program:

• Basic: General orientation to regulatory guidances and processes for biotech/biosimilar products• Comparability: Biotech/biosimilar product lifecycle process changes (per ICHQ5E)• Biosimilarity: Unique aspects for biological products; analytical and preclin/clin studies (WHO)

• Launching 2 pilots (F2F and online formats) with Seoul Natl Univ and Northeastern University (US)• Might also partner with CASSS (further discussions?)• Q= Committee in place yet? A= Finalzing it now. Q=source of general case studies; A=TBD by committee8

Theme 1) - Innovative regulatory strategies for enabling the rapid development and the potential for early marketing approval of highly promising new biotherapeuticproducts, the associated challenges, and progress being made.

All HA’s have accelerated review pathways for designated products, but the challenge is that they consume time and attention of most senior reviewers in communication and assessments.

Quality elements are still critical, and in accelerated programs the CMC is more front-loaded. CMC could become rate-limiting; Suggest making minimal changes pre-approval (scales, sites, formulations) to allow rapid assessment . Also, since biotechsneed real-time stability data, lock into an initial formulation and container/closure to allow approval of adequate shelf life to support commercial supplies. Might be able to discuss leveraging stability data from other, similar products/formulations/C-C for BT products (if risks low).

Must also determine if clinical scale production can also support supply needs once approved, or will immediately go on shortage. Trade off with time and materials needed for assessing of scale up changes with analytical comparability studies. Can discuss options with HA’s for immediate post approval change plans.

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Theme 1) - Innovative regulatory strategies for enabling the rapid development and the potential for early marketing approval of highly promising new biotherapeuticproducts, the associated challenges, and progress being made.

Regional HA’s indicated they share the goals of rapid product approvals but have to balance speed of assessment with data needed for their scientific review.

Urged sponsors to follow all regional guidance documents available (eg WHO, ASEAN, country-specific), and communicate with HA’s for what is needed when. Cannot make decisions with incomplete dossier information!

ASEAN HA’s making great progress on review processes for BT/BS products. While they must honor legal jurisdictional constraints, no regional HA has time or resources to re-invent the wheel for product review strategies. The emerging ASEAN CTD format may greatly facilitate future of regional mutual review processes.

Does a SAGINAKE product have to be originated in Japan? No, it can be international so long as it is marketed first in Japan.

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Theme 2) - Evolving approaches to ensuring product quality (e.g., validation, post-approval changes, and facility inspections) or to specific product types (e.g., biosimilars), and updates on relevant guidelines, new or planned.

Concepts being discussed now include division of roles between reviewers/assessors and inspectors. Requires consideration of impact on existing PIC/S cGMP inspection harmonization program; TBD pending outcome of ICHQ12 discussions on Established Conditions (discussed later). Very sticky discussion ensued!

Theme 3) - Regulatory updates on cell and gene therapy products …

FDA: CBER indicated CGT could also be BT products; have 1 currently in progress. Very case by case; some CMC elements cannot be postponed to PA due to risks to product.EU: Currently 6 approved ATPs inc 2 GTs; over 300 ATPs have been studied in trials during years 2011-2014. 3 guidelines in progress, 1 rev to current guidance, plus guidance on Q for ATP IND submissions and GMP for ATPsJapan: Several RM products approved, more expected.ASEAN: CGT discussions just starting; Indo govt has approved a few hospitals to manage CGT trials

Theme 3) - Regulatory updates on … biosimilars

**See speaker summaries and slides for details on global and regional guidances and processes; discussions in this session focused mostly on clarification of selected points**

Q – What if a biosimilar product yields better quality profile than the ref product?

A – All HA’s agreed that you cannot have a biosimilar AND biobetter at the same time. OK to have fewer process impurities (like HCPs or DNA), or more stable formulation (you will generate your own shelf life claims anyway). But cannot claim ‘better quality’ or “more pure” especially if used for marketing against original product.

Q re costs factored into HA decisions? A: No – all areas separate scientific decisions from marketing decisions on product pricing; subject for regional medical reimbursement schemes (if any)

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ASEAN: The working groups are very active; removing trade barriers first, then can establish MRA/MOUs like for GMP inspections. ASEAN guidelines very valuable to regional HA’s.

APEC is not mandatory collaborative group, but very important to be engaged in it for shared understanding of issues, challenges and possible solutions.

Capacity building is a big effort; regulatory training programs are high priority items in this region. Expect greater collaboration among industry, academics/ and regulators for science and compliance aspects of biotech / biosimilarproducts.

Japan: International collaboration is part of the 5yr plan; have confidentiality agreements with EU, US and Canada for internal information sharing; not yet in place with ASEAN countries but under discussion.

EU: Also highly engaged with other agencies, inc WHO. Strongly supports dialog including like CMC Forums to build trust and understanding with industry

Theme 4) - Efforts being made at international or regional harmonization, regulatory convergence and work sharing between health authorities

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Development of Biosimilars: Technical Aspects Moderators: Dr. Arato, Hokkaido University and Dr. Uchida, Kyowa Hakko Kirin Co., Ltd.

Biosimilars in the EU: Regulatory Update with a Focus on CMC Dr. Ekman, Finnish Medicines Agency, Finland

• Recently updated versions of several guidances; eg insulin BS w/o safety study (see slides)• No degrees of similarity defined in legislation of guidelines; •Clinical data cannot justify substantial differences in analytical characteristics between BS and RP• No specified statistical requirements, but sponsor can propose and justify relevant models if desired• Same basic principles apply: Expect to make a similar version of a known API that is S and E•Establish QTPP based on characterization of RMP; design mfr process to achieve the established QTPP ; examine risks of observed differences • Presented example of Remsima/Inflectra with diffs in glycosylation and FcγRIIIa binding (see slides)• CHMP concluded differences were not clinically meaningful and approved the BS• Speculated that in certain (more simple) products it might be possible to waive clin studies with convincing analytical and biological/ functional data. Comparative PK studies are, however, expected to be required also in the future.

Development of Biosimilars: Technical Aspects Panel Questions

In the biosimilar draft guidance that FDA has issued, what are the specific criteria of ”Highly similar with fingerprint-like similarity” that classified in the result of the comparative analytical characterization? When the biosimilar that categorized into ”Highly similar with fingerprint-like similarity”, is it interchangeable?

EU: All the same; it is similar or its not. FDA: Statutory definition is ‘highly similar’The pending issue is interchangeability, where the outcome of that legal decision could impact the degree of

similarity required to qualify for that classification. Interchangeability and substitutability have different definitions in different regions; a single global approach

may not be possible.HC is not ready to allow either inter or substitute due to manufacturing and indication changes in RLD and

BSP, which are allowed to occur separately after approval. Inter/subst would presuppose a lifetime link between RLD and BSP for these elements. Once a BSP is approved does the sponsor have to refer back to the RLD for all future comparability protocols for process changes.

EU: EMA is responsible only for approval of biosimilars; however, member states have their own policies after products are approved. FIMEA did a retrospective review (see paper on this) and have found no adverse events resulting from the switch between products..

Q: But was the detection of AE sensitive enough? The body is very sensitive and has immune memory; could trigger problems later? Amgen did see neutralizing Abs in some patients that can be highly severe; traceability was crucial in finding root cause (one batch of product).

EU: Not expected – seems more theoretical risk than actual observations for current products.Q: What if the analytical data show BS not adequately similar to RP? EU will tell the sponsor if differences are

significant enough to jeopardize approval. Q: What is the process is different from originator? HA’s don’t expect the processes to be similar; they focus

on the product characteristics only. If the process was really the product then biosimilars would not be possible at all. HA’s process review is a standalone issue for each product, original or biosimilar.

Q: What was the FDA’s rationale for the ranges in statistical guidance, eg why is is 1.5 vs 1.48 vs. 1.52? A: Just a starting point guide for sponsors; they can justify other ranges if reasonable. However, if ranges are very

wide, it leaves open too great a degree of uncertainty on the comparison of the BS to the RP.Q: How does assay variability factor into equivalence testing approach, since very imprecise assay rewards

equivalence (easier to show equivalence than with a precise assay). Amgen: struggled with this; and concluded that the comparison data should be robust and reliable so long as each

assay is :– adequately qualified for intended use– has acceptable intermediate precision– has good system suitability to assure each run is valid– Uses statistically relevant number of sample replicates and assay runs– Uses meaningful number of product lots of BS and RP

FDA: A bad method will not be allowed even if the equivalence tests pass mathematical ranges!PMDA: Regardless of whether stats are use or not, analytical quality comparison design is critical.EU: Usually clinical trials are needed to confirm things that cannot be analytically measured (like immunogenicity)

Q: What if cannot make enough lots of BS or get enough lots of RP? A: Will definitely challenge the analytical study design and conclusions; fewer lots = higher uncertainty for true

variability (both products); impacts conclusions of comparison to RP plus ability to set specs on BS process control and product consistency.

Development of Biosimilars: Technical Aspects Panel Questions (contd)

In the biosimilar draft guidance that FDA has issued, what are the specific criteria of ”Highly similar with fingerprint-like similarity” that classified in the result of the comparative analytical characterization? When the biosimilar that categorized into ”Highly similar with fingerprint-like similarity”, is it interchangeable?

ICH Q12 Overview: Established Conditions / Approved MattersModerators: Dr. Kishioka, PMDA and Dr. Nashabeh, F. Hoffmann-La Roche Ltd.

Intro, Dr. Nashabeh: 3 major gaps ICH 12 to close: Only ICH guidance specifically for commercial products; different interpretations of regulatory-binding information; ICH Q8/11 have not yet achieved expected benefits of QbD.

ICH Q12 - Pharmaceutical Product Lifecycle Management: Current Status and Future Perspectives: Dr. Kishioka, PMDAConcept paper: ICH Quality Strategy workshop identified 5 priorities to promote innovation and continual improvement in globally licensed products: Lifecycle Management, API Starting Materials, Quality Overall Summaries, Analytical Procedures, Continuous Manufacturing of Pharm.

Current Discussion Topics: Reg Commitments/Approved Matters/Established Conditions ; how can the ICH CTD

format be used to support regional requirements? What role of PQS to manage post approval changes? Different views of industry /

agencies but agree that PQS must be robust.Post Approval Change Management Protocol (PACMP); if accepted, lowers reporting

category for described changes (faster review time); single protocol across multi-products; acceptability across ICH regions?

See slide on Product Lifecycle Process (draft) – links roles of industry/reg (assess-inspect)Goal is self contained, harmonized global guidance that is pragmatic and forward-looking


NDA of Biotech Products in Japan: Approval Contents / Legal Binding Related to CMC Part Dr. Kojima, JPMAJ-CTD Mod 2 is the primary review unit for PMDA; in Japanese; more detail than in US/EU QOSJ-M 1.2 Application form contents if approved become legally binding matters; mostly CMCPartial Change App (PCA) vs Minor Change Notification (MCN) (no Annual Report updates)Gave example of PCA vs MCN for biotech product, with changes of J-M1.2 docs (see slides)Biotech J-M1.2 changes likely all PCA; question is what should be internally controlled by cGMP vs what is in dossier details and controlled by reg agency? Eg manufacturing process, test methods and specifications?

J-Module 1 Preparation (CMC): Model Document for Manufacturing Process DescriptionMr. Nishimura, JPMAPreparing a draft J-M1.2 Mock Up for biotech Mab DS for discussion with PDMA Basis is 2006 study on impact of J-M1.2 for biotech products plus exper w/ approved MabsIncluded Q8, Q9 and Q10 concepts in considerations for mock up draftGrouped US/DS elements into proposed to be included/excluded in J-M 1.2 (see slides)Included – Changes controlled by PCA/MCN; Excluded = Changes controlled by cGMPExamples of brief descriptions of US or DS operations with general info only (see slides)


Japanese Application Form: PMDA’s Perspective on Manufacturing Process Description Dr. Yanagihara, PMDA

• 9 projects of ‘Projects Across Multi-Offices’ ongoing in PMDA (see slide)• Comments here are her own view; not final comments from PMDA on mock up• J-M1.2 a good regulatory tool; clear, transparent communications on legal commitments• Details are given in PFSB/ELD 2005 notification No. 0210001 inc. Appendix 3 for biotechs• Now available in English on PMDA website• Can denote PCA vs MCN parameters; justification based on product dev/prior know/data• CMC review focuses on elements that maintain process control and product quality • Gave examples of how the current form can be used for P flexibility (see slides)•Biopharms are not within the scope of Notice PFSD/ELD Jan 1 2010 but the table shown in the Notice (see slides) can be used for biopharms to explain rationale for parameter description (range, PCA/MCN/excluded) to reg agency•Elements of Mgf process essential for quality assurance should be described in J-M1.2 including non-CPPs Risk assessment result is not the only determinant for included/excluded in J-M1.2 •Agrees that having a mock up J-M 1.2 from JPMA could be useful for continued discussions

ICH Q12 Overview: Established Conditions / Approved Matters Panel Questions

What are the Established Conditions? How are established conditions chosen?How should the company separate “Established Conditions” from supporting information in the regulatory dossier? How can the Established Conditions facilitate the post-approval changes in each region/country? What level of details is required in the Established Conditions?What should we take into consideration to introduce Regulatory Commitments into regulatory procedure in each country?

Very challenging discussions – wide range of regional approaches and emerging ideas

Could add value to industry for submitting, and HA’s for reviewing, fewer notifications on changes in dossier, but could also result in inconsistent expectations across products and among reviewers – would impact concept of level playing field for all products and sponsors.

Main points:• Issue didn’t seem to be IF post-approval changes (PAC) for biotech products have to be done under ANY control system – all agreed they do require at least internal review and approval (PQS)• Debate is whether control system was at review level (dossier) or inspection level (GMP), and how much flexibility is associated with one vs the other (ie “ask then do” vs “do and document”)• Some regions have tiered PAC notification systems (inc Annual Reports) while others do not • WHO guidance on PAC for vaccine (soon therapeutics) seems to be for establishing consistency in regional notifications (tactical)•ICHQ12 designed as strategic guidance (assumes tiered notification systems already in place)• Questions on how the EC/AM would be presented (list form like J-M1.2? CTD like FDA guidance?)•HA concern was that filed dossier would soon lose accuracy for what was actually being done • Also that tiered risk-based changes would be replaced with simple inspectional control after the fact20

ICH Q12 Overview: Established Conditions / Approved Matters Panel Questions

What are the Established Conditions? How are established conditions chosen?How should the company separate “Established Conditions” from supporting information in the regulatory dossier? How can the Established Conditions facilitate the post-approval changes in each region/country? What level of details is required in the Established Conditions?What should we take into consideration to introduce Regulatory Commitments into regulatory procedure in each country?

Envision the EC to be stand alone section, eg in Mod 2 QOS (still TBD) with regional differences as needed (like J M1.2)FDA guidance is draft now; could either be updated to align with final ICHQ12 decisions, or rescinded at that time

Q: Who decides what elements must be Established for any process/product?A: Still based on total control strategy concepts for biotech products; same as current approaches for defining CPP, etc… Would enhance this justification/rationale for these control elements

Q: Would EC be different for existing legacy products vs new products with less history?A: Yes, very likely – would be data-driven strategy, and legacy products would have much more historical data on process/product control than new ones. Possible that EC could start out bigger for new products, then decrease as data and experience with the process/product increases.

JPMA was asked if a presentation could be prepared of their Mock Up Mab for discussion at Dec ICHQ12 meeting as an example for how it could work with J-M1.2 AM process.

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ICH Q12 Overview: Post-approval Change Management Protocol (PACMP) Moderatos: Dr. Koga, Daiichi Sankyo Co., Ltd. and Dr. Madden, Biogen

Regulatory Perspective on Comparability Protocols in Biologics: A Tool to Effectively Manage Post-approval Changes Dr Markovic, CBER, FDA, USA

Gave very comprehensive overview of reg requirements and FDA, EMA and ICH guidances (see slides)

Provided breakdown of types of CPs received from 2004 – 2014 at FDA . Referenced CMC Forum paper on Comparability (see CASSS website for copy)

Found that success of CP implementation is directly proportional to the amount of product and process knowledge, risk assessment and effectiveness of the control strategy. Biggest challenge: setting meaningful prospective acceptance criteria for conclusion of comparability.

Feels that CP may enable greater predictability regarding expectations and timing of implementation including a more expedited product distribution

CPs may offer an opportunity for a reduction in regulatory oversight (e.g., when associated with a reduced reporting category and/or fewer requests for additional information, when applicable to future changes)

Experiences at FDA show that CPs might be an underutilized regulatory tool (e.g., ~12% of all CMC manufacturing supplements are submitted as CP)

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Post-approval Change Management Protocols - Current Status and Next Steps on the Way towards a Global Tool Dr. Ho (replaced Dr. Goese), F. Hoffmann-La Roche Ltd., Switzerland

Gave overview and contents of an EMA PACMP from 2010 guidance (and Q&A doc) Most biotech variations are major (Type II) (examples shown; see slides)

Also gave overview of FDA 2003 guidance with note on 2015 update FDA and EMA have very similar strategies for tiered notifications, but other regions have considerable differences

Talked about expanded CP (CMC Forum on QbD in 2009)*see CASSS website for eCP Forum summary paper*

Gave update on FDA QbD pilot program (see slides)

Final note:ICHQ12 is intended to incorprate PACMP as part of the overall product lifecycle strategies; details are still being discussed in the EWG


Industry Perspective: Current Status of Global Change Control Management Dr. Kawakami, Chugai Pharmaceutical Co., Ltd., Japan

Gave detailed overview of current elements of Change Control Management in Japan (see slides)Gave excellent case study on Chugai’s Global Change Control Management process

Provided specific examples of US and EU changes that would be subjected to Change Control Management ProcessConclusions:

•Successfully introduced Global Change Control Management System in Chugai; strong emphasis on frequent communication among all experts involved•For the regulatory compliance, it is necessary to have a change control management system that functions efficiently and effectively•Different regulatory actions based on different binding information for a change may burden the management system – many parallel changes to manage•Expectation to the globally unified established conditions and its simplified regulatory actions for better regulatory compliance

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ICH Q12 Overview: Post-approval Change Management Protocol (PACMP) Questions

Highly diverse HA systems, legal requirements, policies and practices. Very challenging at this point to find common strategies that would still fit within regional constraints. But that is what dialog is for… If industry and HA’s can think outside of the historical ‘box’ on post approval changes

ICHQ12 vs QbD approach – how does EC impact the QbD design space ? Should be independent of nature of development strategy. Could still use CP for changes that are outside of your QbD conditions

Is a PACMP applicable to accelerated products, Saginake, BT, etc…? The hope is that it will be equally applicable to large and small firms, new and legacy products. Basic premise is that sufficient amount of knowledge exists to prospectively specify the comparability acceptance criteria. Could file PACMP after the initial approval for post market changes that support the accelerated approval.

Different regions have different tiers of notification levels that are legally codified, while in other regions it is in policies. ICHQ12 could not supersede legislation, but could consider new policies that support implementation of some PACMP elements, especially for transparency and consistency of data requirements. But hope would be not to lose sight of the goals of downgrading and minimizing regulatory burdens for reviews and inspections prior to implementation of low-risk types of changes.

Discussion on possibility to leverage mutual reviews from other HA’s on approved PACMP; outrageous proposals inc benchmark HA approvals mutually recognized by others; or sponsors sharing HA decisions with other HA’s for their consideration in approvals.

Multi products/multifacility ? FDA has experiences with trans-BLA, ie SINGLE change across MULTIPLE products; could incorporate some elements of this in ICHQ12; multiple change/multiple products would be a very large PACMP with risk if one change fails one product does it fail all? 25

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