Regulatory due diligence.pdf
4 likes285 views
The document discusses common conflicts and pains that can lead to delays in the drug registration process from a commercial point of view. It identifies several key challenges, including lacking a project plan, regulatory intelligence, and issues with CMC data for both drug substances and drug products. Specific problems are outlined, such as invalid certificates, missing documentation, and inconsistencies between dossier sections. Recommendations are provided on how to address these challenges to minimize timelines and cut costs in the registration process.
Regulatory due diligence.pdf
- 1. The Commercial Point Of View Asmaa Khalil El-Kersh 5 September 2021 1
- 2. Agenda Commercial Point of view / Business Perspective (Business Consulting) 1. Common Conflicts and Pains 2. How to cut time & resources in time-consuming processes? 3. Planning & Tracking 4. SOPs, Processes & Guidelines 5. Professional assistance & review 6. Implementing eCTD software - do it yourself? 7. Outsourcing of publishing 5 September 2021 2
- 3. Business Development Production & Engineering Pharmacovigilance Methodology &Validation, QC Analysis, Microbiology, Stability study, Packaging materials, Raw materials Regulatory Affairs In process control, Process Validation, Documentation Whatis the Life cycle of Drug Product? Research & Development Quality Assurance Warehouse Quality Control Supply chain Medical Affairs Artwork/ Labelling Marketing 3
- 4. Introduction There are several obstacles that lead to delays/ extension of registration process. Each delay means: a delay in approval; and delay in time to launch and market your product. Time is money. So, clearly the aim has to be minimization of your time to submission, especially if your company is aiming to market its first product. We will identify some of the most common challenges & guide you by some insights on how best to overcome them☺ 5 September 2021 4 Preparing a submission dossier is similar to a football game, there are essential elements for minimizing your time to submission : Planning, Training, Collaboration spirit & Implementation of the plan during the game.
- 5. Common Conflicts and Pains – Project Plan Lacking a project plan Without having a prepared project plan, you will face obstacles in: • Documents uncomplying to the authorities’ requirements • Ineffective Collaboration • CTD contents won’t be harmonized “missing dependencies of documents on each other” • The deadline of your submission will be threatened 5 September 2021 5
- 6. Common Conflicts and Pains – Project Plan Where are you? • Perform regulatory due diligence & gab-analysis of your current submission status. Where do you need to be? • Define the members and their responsibilities • Who/what is the appropriate person/department to author documents for missed CTD Modules/sections? • Share the results of the performed studies with relevant departments (CMC regulatory compliance across the product lifecycle ) • Example: enclosing the appropriate container closure system docs depend on the results of your performed drug product “DP” stability study proofing the compatibility of your selected packaging materials with the DP. Regulatory compliance ensures the quality of all your products throughout their lifecycle, from R&D, manufacturing, distribution, and discontinuation 5 September 2021 6
- 7. Common Conflicts and Pains – Project Plan Where do you need to be? Identify the gaps, requested actions with their relevant timelines: • Does your submission need an updated valid CEP/COS instead of the expired CEP? • Is your API DMF/ASMF complying to the concerned authority regulations “US DMF or EU ASMF or In house”? • Do you need to translate the product information “PIL, SmPC & labelling” to the concerned submission region language? • What are the requested legalized/apostilled documents? e.g. CPP, Price cert., GMP cert. & ML 5 September 2021 7
- 8. Common Conflicts and Pains – Project Plan Lacking Regulatory intelligence “RI” RI is the act of processing targeted information and data from multiple sources, analyzing the data in its relevant context and generating a meaningful output, e.g. “outlining risks and opportunities to the regulatory strategy”. The process is driven by business needs and linked to decisions and actions. Your company needs to be compliant with new guidelines, through the synthesis of the information into actionable items to help ensure the success of your company (Often it is a matter of internal dialog within your company’s departments). 5 September 2021 8
- 9. Company registration (MAH/DP manufacturer/QC testing site/Batch releaser) Submission of valid legalized docs (e.g. GMP cert., ML, establishment cert., CPP). Attaching valid contracts of manufacturing/testing/MAH /PV activities Enclosing the recent updated version of SMF, site layouts & annexes. Harmonization between SMF & its annexes. 9/5/2021 Common Conflicts and Pains 9
- 10. Innovator =Originator = Brand Generic Hybrid Pre-clinical & Clinical study Non-Clinical study BA study The above mentioned studies are requested for innovator product. A Reference Listed Drug (RLD) is an approved drug product to which new generic versions are compared to show that they are bioequivalent. Medication created to be the same as an existing approved brand-name drug in dosage form, safety, strength, route of administration, quality & performance characteristics. BE studies vs. approved Reference Listed Drug (RLD): Once BE is conducted, evaluation relies on the HA’s previous safety & efficacy findings reported for the RLD. This criteria only applies when the new product & the RLD are bioequivalent, & possess identical characteristics: AI Dosage form Strength Route of administration Uses Medicinal drugs based on a generic molecule & have a different route of administration, format, strength, or indication from the original reference product. They require re-approval for market authorization, partly based on data from the original reference product & partly on data from new clinical trials on the modified version. BA studies vs. approved RLD: If the new formulation is bioequivalent to the RLD & the indication is the same, the number of subsequent studies is greatly reduced. If they are not bioequivalent, safety & efficacy needs to be established & submission requirements may include preclinical & clinical efficacy studies. 9/5/2021 Common Conflicts and Pains -Studies to be submitted within application 10
- 11. CMC data – DS: If the product contains multiple DS, then documentation for each substance should be provided in its own 3.2.S section. If a DS is manufactured at multiple sites or by multiple different manufacturing companies, documentation will be provided in 3.2.S section. If there are two sources for the API, equivalency between the sources should be demonstrated in the application. Comparative stability & release data from one batch of the drug product manufactured using the API from alternate source(s) against the primary source are recommended. Certificate of Suitability (COS/CEP) Invalid CEP (https://extranet.edqm.eu/publications/recherches_CEP.shtml) 9/5/2021 Common Conflicts and Pains - DS common raised inquiries by HA 11
- 12. CMC data - DS: 3.2.S sections are poorly bound. Drug Master File (DMF) All sections of DMF shall be available, except the following restricted sections which will be sent to HA directly by DS manufacturer enclosed within the LOA: Detailed information on description of manufacturing process & process controls (3.2.S.2.2). Control of materials (3.2.S.2.3). Control of critical steps & intermediates (3.2.S.2.4). Manufacturing process development (3.2.S.2.6). Inadequate stability study data Method (validation/verification/transfer) reports are not provided. LOA isn’t addressed to HA reviewing the dossier. 9/5/2021 Common Conflicts and Pains - DS common raised inquiries by HA 12
- 13. CMC data - DP: Pharmaceutical development: Overage in raw materials without sufficient justification to support the safety of the ingredients at the proposed level. Compatibility study is missed “if required: e.g. reconstitution diluents, excipients are different from reference product” The sterility assurance validation studies for terminally sterilized DP & aseptically filed DP. Method (validation/verification/transfer) reports are not provided. Microbial limit is not included in FP specifications. Excipients related subsections are missed for non-compendial excipients. 9/5/2021 Common Conflicts and Pains - DP common raised inquiries by HA 13
- 14. CMC data - DP: Insufficient container closure system documents “COA for all primary packaging materials”. Inadequate stability study data (Not complying to ICH regulations) Commitment to conduct ongoing stability studies (at least one batch per year). Commitment to place the first three production batches on long-term stability studies through the proposed shelf life period. Commitment to conduct prospective process validation on three consecutive production batches (for nonsterile products). Discrepancies on production batch size range. 9/5/2021 Common Conflicts and Pains - DP common raised inquiries by HA 14
- 15. Missing any section from m1 to m5 without a proper justification. Dossier isn’t : Submitted in the appropriate format specified by HA and isn’t compiled as per recent regulations structure. Written in one of the official languages. Prepared as per m1 & 3.2.R contents of the relevant HA. Enclose data about the usage of animal or human origin materials. MAH and manufacturing sites shall be unified in all data of dossier. ADR, confirm the reporting process as per each region/territory regulations. PV system & RMP documents to be enclosed as per HAs regulations. 9/5/2021 Common Conflicts and Pains - DP common raised inquiries by HA 15
- 16. Check each territory regulations for serialization/Data matrix/track & trace. SmPC/PIL/Mock-ups: Specified DP packaging materials data in m1 sections, shall be inline with all eight sections of DP. DP Shelf life & storage conditions consistency with DP sections. Composition formula (API & excipients) data aren’t similar to DP sections information. Indications aren’t complying to m4 & m5. In case of generic product, take care of innovator product patency & exclusivity data. 9/5/2021 Common Conflicts and Pains - DP common raised inquiries by HA 16
- 17. Common Conflicts and Pains 5 September 2021 17 Drowning in documents Manual compilation of docs from multiple departments using different systems (ERP, PLM) is a painstaking & confusing process which causes delays in submissions. Electronic systems simplifies the process of compiling, reviewing & approving docs from different teams. Forget monitoring of deadlines Project leader should send notifications of approaching deadlines for all concerned teams. Unavailability of staff Specify the substitute(s) plan, during absence of people. Define the authorized substitute for documents signing.
- 18. Common Conflicts and Pains Lack of experience / training • Trainings are needed for the different levels of your staff! • Select the key expert personnel • Authors / Reviewers • QAers & Approvers • Publishers • The “eCTD builder & publisher” criteria: • Should efficiently use publishing eCTD software • Good skills in using doc editing software as Adobe Acrobat & MS Word • Needs to have a specific technical qualification 5 September 2021 18
- 19. Common Conflicts and Pains Colleagues are not very familiar with the company's SOPs SOPs should be in place & reflect each operation in your organization! • Document creation & lifecycle process • Who writes the documentation? • Are there a review & approval cycles? • How is the document lifecycle managed? • Are module 1 documents included in this process? 5 September 2021 19
- 20. Common Conflicts and Pains Colleagues are not very familiar with the company's SOPs SOPs should be in place & reflect each operation! • Document creation tools • Do you have a ready template? • Are the granularity & the doc characteristics complying with the eCTD specifications? • Publishing & submission process • Who does dossier compilation? • Who perform submission/publishing of your dossiers to authorities? • What is your archiving system in place? 5 September 2021 20
- 21. Common Conflicts and Pains Uncontrolled changes/variations • Recognize interdependency of various documents: • If you are making a change in a specific doc, make sure same change is reflected in all other relevant docs and summaries. • Assure that all departments are aware of the change. • Example: Extension of DP shelf life shall be reflected in: • Stability study documentation • Pharmaceutical development docs • Process validation documentation “if requested by HA” • SmPC • COA of DP • CPP “if requested by HA” 5 September 2021 21
- 22. Increase your efficiency Create a Flowchart of your processes in RA: • Collect and visualize all information during the following steps: • Creation of documents • Data flow • Data revision • QA & approvals • All your involved departments are required to provide collated comments/feedback, so that the information within the functional line is consistent. • Work out any differences in interpretation before trying to approve the final doc. RA is the gatekeeper for communication between MAH/DP Manufacturer & global HAs. 5 September 2021 22 How to cut time & resources in time-consuming processes?
- 23. Increase your efficiency Workflows Approval processes, status, dates, records, etc. • Use of templates for authoring eCTD ready documents (granularity & file formats) • Use of a file system or DMS to manage the files • Set your internal roles & responsibilities for the various steps of the process • Who is authoring docs, QA, approving, filing & interfaces? • How is version controlled in docs? And how are your submissions established? • Set your archiving sequences 5 September 2021 23
- 24. Increase your efficiency Time Management • Document creation tools: • Do you have a template? • Are the granularity & the doc characteristics complying with the eCTD specifications? • Ready-Made Templates • eCTD authoring tools • Special functions • Shortcuts for content re-use • Process Optimization (Gap analysis) • Planning & Tracking • Distribution of work / responsibilities • Due dates & tracking • Re-Use of Data in your global submissions • Identify your top priorities 5 September 2021 24
- 25. Document Revision The Workflow: Processes in RA 5 September 2021 25 Document Creation (Author) Document changes (Author) Document flow “sharing with all your involved depts“ Compilation of final eCTD eCTD sequence publishing Follow up with authority till granting the approval Final Signing & Approvals
- 26. Planning & Tracking • Define the timelines & interdependencies of: • Authors • Reviewers • Approvers • Publishers • Plan ahead: • Reserve / block resources • Plan for substitutes for busy and critical times • Handling your submissions in more than one territory 5 September 2021 26
- 27. Planning & Tracking • Consider IT maintenance: • Check IT infrastructures regularly • Protect your deadlines during hot phases • Align any updates or IT changes outside of hot phases • Make sure your system is up to date beforehand • Planning & tracking tools: • MS Excel • Professional tools (e.g. EXTEDO's Activity Planning & Tracking solution "Wrike for Life Sciences") Real-time reports and analytic dashboards, automated processes, workflows and project management functionality all combine to give your projects the best chance to succeed. 5 September 2021 27
- 28. SOPs, Processes & Guidelines Establish SOPs • Minimum information to be included. • Include the activities, main responsibilities, tasks. Defined Processes & Guidelines • Who does what and when? • Schedule the deadlines for your changes & submissions. • Classify your quality changes into 4 reporting categories: Major, Moderate, Minor, No Impact. 5 September 2021 28
- 29. Professional assistance and review Assign an expert leader to review your business & processes: • Leadership should: • Map out review schedules of docs • Assign your team work • Clarify Responsibilities: • Who writes the document? • Are there a review & approval cycles? • How do you manage the document lifecycle? • Are module 1 documents included in your process etc.? 5 September 2021 29
- 30. Professional assistance and review • Identify Key Persons in your process, especially during critical review of docs: • Assure key persons won’t become “bottlenecks” in busy times • Assure key persons can control multiple overlapping demands Key persons must have specific skills each, unique in the team. • Goal: avoid bottleneck effect! • How to prepare for this in advance? • How you deal with this when it happens? • How to set focus? • Important: Training in multi-tasking! 5 September 2021 30
- 31. Professional assistance and review • Publishing & validation system, available options are: • In-house software • Host rental system • Outsourcing service • Responsibilities: • Authoring eCTD ready documents • Reviewing • Submission of a dossier • Maintenance of a dossier • You have to discuss in your organization the appropriate decision for publishing (e.g. whether your company has to purchase software or use outsourcing service) 5 September 2021 31
- 32. Implementing eCTD software Do it yourself? What you need to consider: • Related IT infrastructure changes, new server / hardware • Inter-connectivity, DMS connection, training, planning ahead, budget • Maintenance, regular updates • IT outsourcing as an option? 5 September 2021 32
- 33. Outsourcing of Publishing – Preparation • How is the organization of the regulatory group in your company? (i.e. global, regional or local) • Publishing Volume: • How many submissions are you expecting per year? • In which countries? • Non-eCTD submissions (electronic or paper) • Are they still needed? • How can you create them out of the system? • Is it necessary to create custom non-CTD structures for dossiers? • How can such a structure be built up? • How to handle your submissions in more than one country? • Reduce redundant work • Plan re-use of content where possible 5 September 2021 33
- 34. Outsourcing of Publishing – Best Practice • You should have a backup plan to cover peak times (e.g. outsourcing some tasks on high peak work load) • Be aware of your team’s output capability • Stay with the same publisher! • Plan your publishing & submission process: • who compiles the dossiers? • who sends the dossiers to customers and authorities? • what archiving system is in place? • Using a friendly eCTD creation tool (e.g. eCTDmanager) 5 September 2021 34
- 35. Contact Details 📥e-mail : ( asmaa.khalil@gmail.com ) 📱 Mobile no.: 002 01005044453 🌍 LinkedIn account: www.linkedin.com/in/asmaa-khalil-el-kersh-5a98755b