Generic Drug Design, Development and Analytical Aspects

1. Generic Drug Design, Development and Analytical Aspects Julian Williams Manager, EU Development Projects Actavis Group hf

2. To be discussed • Project Approval • Preformulation considerations • Timeline & Product Requirements • Project team/meetings • Literature search • Patent review/reports • Reference samples • API selection • Formulations development • Lab • Trial • Pilot BE-study • Pilot production • Analytical method development and validation • API • Pharmacopieal status • Assay • Paricle size analysis • Bulk analysis • Impurities • Residual solvents • Other impurities • Sulphated ash

3. To be discussed • Analytical method development • Finished form • Dissolution • Assay • Impurities • Content uniformity • Average weight • other tests • Breakability Validation of analytical methods • API • Finished form • Stabilitystudies • Bioavailability Studies

4. 1. Project Approval • A development projects is approved through the evaluation of a Feasibility Plan. • The Feasibility Plan needs to include; • Technical Feasibility (Ability to develop) • Formulation Issues • Patent & Exclusivities review which determine Launch Possibilities • Biopharmaceutics • API Sourcing • Regulatory Requirements (Ability to Register) • Market analysis (Ability to sell) • Financial analysis (Future economic benefits) • Risk analysis

5. 1. Project Approval • As part of the approval process a Marketing Strategy for each project is generated; • Dosage form and strengths to be developed • Launch plan (market/territory orientated) • Target Completion Date (First Dossier Submission Date)

6. 2. Pre-formulation considerationsProject Definition • After project approval a detailed technical and patent evaluation needs to be undertaken. Once these key evaluations have been concluded a Development Strategy is defined.

7. 2. Pre-formulation considerations • Development strategy/Marketing Strategy • It is important in the beginning of the development • To define a Development Strategy for each Project that complies, (if possible), with the Marketing Strategy. This task provides the crucial definition of the project and also includes a Risk Management Plan. The information is recorded in the Development Plan. Areas to be covered include; • API Strategy • Formulation Strategy • Bioavailability/Clinical Efficacy Strategy • Patent Strategy • Registration Strategy

8. 2. Pre-formulation considerations It is important in the beginning of the development (cont.) • To review the Development Strategy for all development projects on a regular (f.ex. monthly) basis. The regular (monthly) meeting of the group working on the projects focuses primarily upon the issues/risks and opportunities associated with each ongoing development. The critical output of each meeting is the action plan that is designed to address and resolve these threats and opportunities.

9. 2. Pre-formulation considerationsThe Development Plan • The Development Plan includes; • The evolving development strategy • An evolving risk management plan

10. 2. Pre-formulation considerations Project team • In our case the project manager is responsible for setting up regular meetings with the team to discuss the project. • The first meeting is a startup meeting where the whole project team is involved. • The startup meeting is held as soon as possible after the project has been approved. • The responsibility of each team member is explained at that time point. The Development Strategy is formulated from basis of the Project Team strategy. • The Project Team will focus on the specific details, plans and timelines that need to be executed in support of this strategy..

11. 2. Pre-formulation considerations Project team • The Project Team meets to discuss all critical issues, provide solutions and make the necessary plans and strategic decisions to drive individual developments to a successful conclusion. • Discussions are based largely upon the development strategy i.e. API (crystal form, salt, particle size), possible patent infringement, formulation, bioequivalence studies etc….

12. 2. Pre-formulation considerations Literature search inital phase • Information should be gathered from various sources at the beginning of each project and made available to the Project team. • It is very important to gather as much information as possible in the beginning before starting the project

13. Pre-formulation considerations Patent search and review • Patent report for each development project • The Purpose of the Patent-Report is to give guidance for: • The Development-team to circumvent patents • Business Development for marketing • Management to oppose/invalidate patents • Management to estimate the patent risk. • Patent strategy; • Patent applications, oppositions. • Patents are investigated in the countries where marketing is planned and in the countries where development is going to take place. Consideration should also be paid to development and production sites of API and where bio-studies are performed.

14. 2. Pre-formulation considerations Patent reports • Patent reports needs to be updated on regular basis. • Patent report for each development project can be divided into the following chapters • Summary • Strategy • Product Patent • SPC status • Patents in specific countries as Iceland/Malta/Turkey • Method of use patents • API patents • Formulation patents • Other patents • Trademarks • Pre-launch possibilities

15. 2. Pre-formulations considerations Patent reports • Summary • Give overview of history and main patents • Marketing-, development- and management “should get the picture” by reading this section • Strategy • Suggest possible routes for development and marketing • Identify constraining patents and a strategy for circumventing • Invalidation and oppositions

16. 2. Pre-formulation considerations Patent reports • Product patent • Totally blocks an entry into the market • For Early Market Entry: • Identify countries with no product patents • Identify countries which only have process-patents • SPC • Supplementary Protective Certificate • First Marketing Approval in EU • Totally blocking for market entry.... if an extension from product patent • Patents in Iceland, Malta, Turkey, Bulgaria…. • Can influence where development is going to take place, e.g. formulation, bio-studies, stock-piling etc. • Method-of-Use Patents • Emphasize the patent situation of the indication used for the marketing purposes • Other indications • Summary of Product Characteristics (SmPC) • Patient Insert leaflets

17. 2. Pre-formulation considerations Patent reports • Formulation patents • Guidance for formulator • Is the generic formulation infringing any patents • Other patents • Impurity profiles • Analytical methods • Trademarks • Color and shape of tablets • Own marketing – product names • Future Objectives • List all outstanding issues which need further attention, such as: • Potential opposition • Invalidations and • Vigilance over pending patent-applications

18. 2. Pre-formulation considerations API sourcing and qualification • The API sourcing is a important part of the development process it includes; • The first contact with the API supplier. • Sourcing and accepting samples and documentation from the suppliers – • Reviewing and testing samples and giving feedback to the suppliers and negotiate new specs with them to fit your purposes.- • Handle samples and documentations and have the same reviewed/analyzed (quality, specs, patents, regulatory compliance, inspection status, etc) • Handle communication to suppliers for technical issues for products in development • Receiving the route of synthesis from the supplier and having the same reviewed by the patent department. • Signing the confidentiality agreement with the supplier and follows up on the questionnaires that are sent to each supplier.

19. Pre-formulation considerationsAPI selection • Critical items; • Specifications • Purity (Impurity, Residual Solvent) • Crystal habit (X-ray, DSC, TGA) • Solubility, (PH & surfactant) • Physical attributes (effect on mfg) • Particle size • Stability & storage requirement • DMF, Tech Package., Specifications • Non-infringing material

20. 2. Pre-formulation considerationsSpecifications for the API • Specifications for the API • If working with two or more API suppliers the harmonization of the specifications is a critical factor. The specifications sheet is discussed within the project team and the member from the regulatory is giving huge input. It is important to set the preliminary specifications early in the product development and the ICH guidance is the Bible when setting those specifications. Crystal form, particle size, impurities, assay, LOD, sulfated ash …

21. 2. Pre-formulation considerationsCharacterisation of the Reference • Originator drug: • USA requirements: 3 different lots, smallest/biggest pack size for each strength? • EU requirements: samples from different marketing areas • Description - appearance • Tablet shape/size, coating, packaging material/sizes, desiccants • Compressional parameters • Weight, weight variation, thickness, hardness, disintegration, LOD, friability, punch sizes, score and markings • Additional parameters: • Qualitative and quantitative composition, dissolution profiles, pharmacokinetic parameters, impurities

22. 3. Formulation developmentPreformulation – direct testing of active • An investigation and data collection of physical and chemical properties of the drug substance alone or combined with excipients is a critical part • The objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass produced

23. 3. Formulation developmentPreformulation – direct testing of active • Physical and chemical tests: • Particle size distribution: Laser scattering • PSD affects flowability, dissolution/bioavailability, content uniformity and stability • Specific surface area: B.E.T testing, indirectly from PSD testing • SA affects dissolution/bioavailability and stability (contact area, H2O pockets) • Microscopic studies – electronic or optical • Crystal shapes, agglomerates • Xray Diffraction (XRD) or Solid State NMR – polymorphism - ISOR • Polymorphs solubility/stability differences – bioavailability – patent issues • Compressibility: Plastic/Fragmenting/Elastic • Important especially for a high dose drug • Chose excipients that match the compressional properties of the active • Chemical tests: Compendial tests, according to CoA or in-house tests • Quality and purity of the active drug

24. 3. Formulation development Compatibility studies • Compatibility testing • Sample of active + excipient (1:1 to 1:10) powder samples • Kept for one month at 40°C/75% RH in open/closed HDPE container • Impurity testing by HPLC (DSC, XRD, Isothermal microcalorimetry) • Manufacturing method: DC or Wet granulation • Direct compression: Dose: 2 – 100 mg (2 – 35% of tablet mass). Advantages: simple, economical (cost < 30%), better stability Disadvantage: segregation • Wet granulation: Advantages: good flowability and compactability Disadvantages: expensive, many steps, inferior stability Drying step: fluid bed drying, vacuum drying • On the basis of preformulation and compatibility testing few formulations are proposed made either by direct compression or wet granulation

25. 3. Formulation developmentLab/trial • The first formulations are developed and produced at Lab scale (1-3kgs). Few different formulations are tested and the first choice is always direct compression. • Dose proportionality is an important factor in the formulations development. The stability of few lab scale formulations are tested and the most stable and most robust formulation is produced in trial scale (5-10kgs) if needed. • In trial scale the robustness is checked further and if needed the stability is tested further. • Draft Specifications for the finished form are set at this time point

26. 3. Formulation development • Excipients • Excipient type and grade (PS, η, d0dt, MC etc) • Availability (cost, lead time, quality, quantity) • Drug-Excipient compatibility • Impurities (peroxide, iodine value etc) • Physical attributes (manufacturability) • Specific requirements (MeO-, HPO- content etc) • IIG Limits (USA requirments)

27. 3.Formulations development Scale-Up Consideration • Batch Size (Short & Long Term Demand) • Manufacturing Issues • Compliance Issues • Cost Analysis • Process evaluation protocols • Process parameter & range • Equipment capacity • Reproducibility

28. 3. Formulation development Scale-Up Consideration • Compliance Issues: • Specification • IQ, OQ, PQ etc. • Training, SOP • Cleaning validation • Environmental requirements • Cost, Technology & Environment • Optimum Output & Reproducibility • Technology to be Versatile • Cost Effective • Environmental Friendly • Safety • Process Analytical Technology (PAT) • Packaging

29. 3. Formulation development Pilot scale production • Tablet/capsules design, punches • The product is produced in pilot scale and as a minimum if the product is of 3 strengths and the formulations is dose proportional is to produce 2X100.000 units of each strengths from material from the first API supplier for EU submission. • If the product is of one or two strengths (dose proportional) a 3 batches of each strengths needs to be produced (one batch of each strengths can be smaller than 100.000). • Those batches are used to evaluate the robustness of the formulation and the manufacturing process. The blending time of the granulate is set according to the C.U results of the mixture after a set mixing time points. The hardness limits, speed of the tablet machine and other parameters are set at this time of the development. • Coating • The breakability is tested and other tests are performed

30. 3. Formulation development Packaging • Packaging for the stability study. Decision of which packaging material to be used is based upon market requirements. Which packaging material is the innovvator using. Can we use the same or similar packaging material. Stability issues.

31. 4. Analytical Method Development • Test Methods & specifications • The main methods developed and validated for are: • API • Pharmacopieal status • Assay • Paricle size analysis • Bulk analysis • Impurities • Residual solvents GC methods for determination of residual solvents • Other impurities • Sulphated assh • LOD

32. 4. Analytical Method Development • Test Methods & specifications • The main methods developed and validated for are: • Finished form • Dissolution • Discriminatory • Quality Control • Assay • Impurities • Content uniformity • Average weight • Breakability • other tests • Assay methods for cleaning validation studies. • Upgrading old methods • Automation of Testing • Method Transfer (R&D to QC),

33. 4. Analytical Method validation Validation of analytical methods are performed according to relevant ICH guidance's. • API • Finished form

34. 4. Analytical Method validation • Documents produced during method development and validation work are: • analytical development report, • validation protocols • validation reports. • Responsible person is approving the protocols and the analytical validation reports. • The validation report is the base for method description in release masters used in the QC release laboratory  and are also included into registration documents.

35. 5. Stability study • Stability studies on both products in development and fully developed products are important. • This includes • Compiling the stability protocols • Starting stability studies, • Preparing analytical masters, • Analysis • Compiling stability reports and approving the results

36. 5. Stability study • Before packaging the stability protocol needs to be compiled, reviewed and signed. • The stability program is set up according to the ICH guidance's and if a special conditions are requests they are included in the protocol. • Accelerated 40°C/75% RH • Intermediate 30°/65% RH • Long term stability 25°/60% RH • Matrixing and bracketing • Requirements for different markets referring to temperature, RH and packaging material. Document; Stability report.

37. 5. Stability study • Documents produced during stability work are • P8 Stability • 8.1 Stability Summary and Conclusion • 8.2 Post-approval Stability Protocol and Stability Commitment • 8.3 Stability Data

38. 6. Bioequivalence studyIn vitro/in vivo correlation • Comparison of dissolution profiles for the test and the reference aimed for the bioequivalence study at different pH. Minimum 3 pH and 12 tablets of the reference and the test is tested at each conditions. Different methods tested based on the physical-chemical properties of the drug. • 1. Highly water soluble drug, • 2. Slightly soluble drug • 3. Insoluble drug • 4. SR drug

39. 6. Bioequivalence studyIn vitro/in vivo correlation • Which country in EU the reference in the Bio study is taken from is important, this decisions needs to be taken early in the development phase. The reference country is chosen carefully based on which market is the most critical one, which strength is marketed in most of the countries. • Based on the results from in vitro correlation the decision is taken which pilot batch is used for the bioequivalence study. The batch that has the most similar profile in all dissolution media is chosen as the bioequivalence batch. This is critical to minimize the risk of failing.

40. 7. Compilation of the registration dossier • Each part of the development will end with a report. Those reports will come as a part of the registrations dossiers • Product Development Report (Formulations people) • Preformulation Characterization • Formulation development info • Process selection & Critical steps • Analytical Method development and validation report (analytical department) • Process Evaluation report (QA/FD) • Scale-up and submission batch info • Cleaning validation & process Evaluation • Stability report • Bioequivalence study report

41. Key to Success • Key to Success • Development Efficiency • Product selection • Speed & accuracy in development work • Communication (supportive groups) • Quality integration in the system • Communication with authorities/ FDA • Address legal issues in timely manner • Invest in technology and scinece • Partnership (development and marketing) • Long-term progress objective