Pharmaceutical Development with Focus on Paediatric formulations

1. Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

2. Pharmaceutical Development with Focus on Paediatric formulations Presented by: Name: Peter York Contact details: p.york@bradford.ac.uk

3. Pharmaceutical Development with Focus on Paediatric Formulations - Dosage form design and manufacture In this presentation: • Design of paediatric medicines – underlying principles • Critical factors related to API(s) properties • Formulation and manufacturing plan • Factors for formulation selection and design • Challenges for ‘forward thinking’ with paediatric medicines

4. Medicinal Products ACTIVE COMPOUND (API) MEDICINE (MOLECULES,  QUALITY MACROMOLECULE)  SAFETY  EFFICACY EXCIPIENTS MANUFACTURE

5. Medicinal Products PHYSICAL ADMINISTRATION REQUIRED PATIENT FORM ROUTE TIME OF AGE ONSET ACTION/ PERIOD OF DRUG DELIVERY SOLIDS ORAL SECONDS PRETERM INFANTS SEMI-SOLIDS PARENTERAL MINUTES TERM INFANTS (0 – 28 DAYS) LIQUIDS TOPICAL/RECTAL HOURS INFANTS, TODDLERS (>28 DAYS – 23 MONTHS) RESPIRATORY DAYS CHILDREN(2 – 11 YRS) EYE, EAR WEEKS/ ADOLESCENTS (12 – 16/18 YRS) MONTHS ADULTS

6. Design of Medicines PRIMARY FACTORS TO CONSIDER • API properties (e.g. solubility, absorption characteristics, BCS, stability, dose ……) • Route of administration (linked to API pharmacology/ therapeutics, pharmacokinetics, intended patient population (age etc)….) • Selection of type of dosage form (linked to selection of functional excipients) • Awareness of manufacturing process (GMP, efficiency, exposure to manufacturing ‘stresses’ ….) • Sourcing of quality APIs and excipients

7. Paediatric Medicines and Specific Dosage Forms SOLIDS • powders, granules, pellets • capsules, DPIs, implants • tablets, dispersible tablets, bilayer tablets SEMI-SOLIDS • suppositories • dermatologicals LIQUIDS • syrups, solutions, suspensions • pareterals • MDIs

8. Focus – Paediatric Medicines (HIV/AIDS, Malaria and TB) SOLIDS • powders, granules, pellets • capsules, DPIs, implants • tablets - dispersible, bilayer, chewable, buffered SEMI-SOLIDS • suppositories • dermatologicals LIQUIDS • syrups, solutions, suspensions • parenterals • MDIs

9. Paediatric medicines for HIV/AIDS, malaria and TB – additional issues • Continuous changes of medicine dispositional parameters • Dose, ADME, PK,….. • Dose ratios for fixed dose combinations (FDCs) • ‘Extemporaneous’ dispensing (eg dilutions, ‘fractioning’ of adult dosage form, packaging, stability….) • Compliance • Stability, transport challenges for liquid formulations

10. WHO Model List of Essential Medicines for Children (Oct 2007) • Antituberculosis medicines ethambutol: oral liquid (25mg/ml); tablet (100mg, 400mg) isoniazid: oral liquid (50mg/5ml); tablet (50mg (scored), 100mg, 300mg) pyrazinamide: oral liquid (30mg/ml); tablet (150mg (dispersible, scored), 400mg) rifampicin: oral liquid (20mg/ml); capsule and tablet (150mg, 300mg) rifampicin+isoniazid+pyrazinamide: tablet 60mg+30mg+150mg streptomycin: powder for injection (1g (as sulphate)in vial)

11. WHO Model List of Essential Medicines for Children (Oct 2007) • Intended for children up to 12 years of age • Core list – minimum medicine needs for a basic health care system • Specialized list – essential medicines for priority diseases for which specialized diagnostic/monitoring, specialist medical care, and/or specialist training are needed • http://www.who.int/medicines/publications/essentialmedicines/en/index.html

12. WHO Model List of Essential Medicines for Children (October 2007) • Antiretrovirals • ‘Subcommittee recommends and endorses the use of fixed-dose combinations and the development of new fixed-dose combinations, including modified dosage forms, non-refrigerated products and paediatric dosage forms with assured pharmaceutical quality’ • Nucleoside/nucleotide reverse transcriptase inhibitors eg abacavir: oral liquid (100mg/5ml (as sulphate)), tablet (300mg (as sulphate)) eg didanosine: buffered powder for oral liquid (100mg, 167mg, 250mg packets), capsule (unbuffered enteric-coated 125mg, 200mg, 250mg, 400mg), tablet (buffered,chewable, dispersible 25mg, 50mg, 100mg, 150mg, 200mg) • Non nucleotiside reverse transcriptase inhibitors eg efavirenz: capsule (50mg,100mg, 200mg), oral liquid (150mg/5ml), tablet 600mg • Protease inhibitors eg ritonavir: oral liquid (400mg/5ml), oral solid dosage fom (100mg)

13. WHO Model List of Essential Medicines for Children (Oct 2007) • Antiretrovirals • Fixed dose combinations (FDC) stavudine+lamivudine+nevirapine: tablets (30mg+150mg+200mg) zidovudine+lamivudine: tablets (300mg+150mg) zidovudine+lamuvidine+nevirapine: tablets (300mg+150mg+200mg)

14. WHO Model List of Essential Medicines for Children (Oct 2007) • Antimalarial medicines • For curative treatment ‘Medicines for the treatment of P. falciparum malaria cases should be used in combination. The list currently recommends combinations according to treatment guidelines. The Subcommittee recognizes that not all of these FDCs exist and encourages their development and rigorous testing. The Subcommittee also encourages development and testing of rectal dosage forms.’ eg amodiaquine: tablet (153mg or 200mg (as HCl)); to be used in combination with artesunate 50mg doxycycline: capsule (100mg (as HCl)), tablet (dispersible 100mg as monohydrate); for use only in combination with quinine quinine: injection (300mg (as HCl)/ml as 2 ml ampoule, tablet (300mg (as sulphate or bisulphate); used in combination with doxycycline

15. Critical factors related to API(s) properties

16. Active Pharmaceutical Ingredient(s) • Sourcing – patented and generic compounds • Specifications and standards • pharmacopoeial monographs (BP, USP, IP, EP); reference standards • focus on chemical identification and purity • increasing awareness of need to monitor physical, crystallographic and ‘functional’ properties • Other sources of information – • scientific literature, www, innovator product information.

17. API Routine Testing – ‘Good Practice’ • Provide assurance of quality and safety • Verification of CoA and magnitude of testing programme • Sampling programme/isolated quarantine storage areas • Retention/storage of batch samples • Training programmes for staff, SOPs, GLP and validation of methods • ‘Confidence’ in consistent quality of supply from chosen suppliers

18. API Properties – Formulation Design and Processing (1) • 50% of new APIs, and many others, have very low aqueous solubility which can constrain drug dissolution (ie rate of solution) and thereby limit bioavailability • Many APIs exhibit polymorphism (also solvation – hydration) – alternative molecular packing of the same chemical in crystalline material leading to different properties such as dissolution rate) • Moisture content control – hygroscopic material often difficult to process (eg tabletting); change in hydration state (eg during wet granulation) • Respiratory drug delivery – DPIs and suspension MDIs require drug particle size (aerodynamic) of 1 – 5 microns • All above are also examples of QUALITY issues when formulating and processing APIs; may require additional testing and/or control procedures

19. API Properties – Formulation Design and Processing (2) • Additional validated testing methods may be required to guide and direct formulation design, e.g. pH solubility profile • Pharmacopoeia now introducing general guidance chapters, information, testing methods ….. • Properties being introduced include • particle sizing (laser light diffraction method) • crystallinity (by x-ray powder diffraction) • amorphous content (by x-ray powder diffraction) • wettability (by liquid penetrating methods)

20. API properties – particle size • Many substances poorly aqueous soluble (BCS Class II and IV) • Reduce particle size to maximise dissolution (also for BCS Class III) • Such compounds routinely micronised – potential for chemical and crystallographic damage which can compromise stability and intra- and inter-batch consistency • Potential issues for liquid suspension formulations (eg particle size changes on stability)

21. API Properties - Polymorphism • e.g carbamazepine, ritonavir Representation of two polymorphic forms of a crystal consisting of a molecule represented by a ‘hockey-stick’ shape

22. Ritonavir – Issue of Polymorphism • Ritonavir (originator Abbott) – HIV protease inhibitor • Norvir product introduced in 1996 as ‘semi-solid’ capsule preparation containing a ‘solid-solution’ of drug in PEG • Summer 1998 – capsule supplies threatened as a new much less soluble crystal form of ritonavir precipitated in the capsule • Drug dissolution was slowed down, compromising bioavailability • Product was withdrawn and reformulated in soft elastic capsule form with new form of ritonavir (Baur et al, Pharm Res 18 (6) 859-866 (2001))

23. API Properties – Formulation Design and Processing (3) • Alternative pre-treatment and processing of APIs (eg alternative final solvent used during final crystallisation step during synthesis of API; use of crystallisation rather than milling process for particle size reduction ) can lead to different surface properties of particles, such as interparticle cohesion and surface ‘charge’ • These phenomena can lead to different secondary processing behaviour and potentially variation in product performance

24. API Properties – Characteristicsto be considered when formulating medicines

25. API Property Classification – inter-dependencies between ‘groupings’

26. Formulation and manufacturing plan (Development pharmaceutics)

27. Design of a Paediatric Dosage Form (1) Development pharmaceutics; formulation and manufacturing plan Define API(s) and dosage regime Consider – route of administration - suitable dosage form What are pharmacokinetic Determine relevant properties of characteristics of API(s)?) API(s) - t50, Cmax, AUC - physicochemical, crystallographic • BCS (for oral products - stability under ‘stress’ conditions • BA/BD issue - compatibility with second API and/or common excipient • Select dosage form and strength

28. Design of a Paediatric Dosage Form (2) Selection dosage form and strength Consider suitable formulations and manufacturing processes Prototype formulations and manufacturing route, and prototype packaging Optimisation techniques Validation (formulation and Manufacturing process) Selection final formulation Sources of information Innovator literature Company experience Other literature sources Testing Phys/chem stability (Dissolution) Relevant product tests (Pilot BE study) Define ‘design space’, process control DoE AI tools

29. Design of a Paediatric Dosage Form Select final formulation, manufacturing process and packaging Process scale-up studies/batches Confirmatory stability (dissolution) studies (BE study) Documentation for prequalification/ registration dossiers

30. Factors influencing formulation selection and design

31. Paediatric medicines- liquid formulations • Solutions, syrups -preferably avoid sugar and alcohol in formulations -drug solubility (dose/volume), stability, pH, -API(s) compatibility with vehicle/liquid diluents -taste (taste masking), colour, flavour - single dose vs multidose (preservatives etc) • Suspensions (and liquids products reconstituted from powders/granules) - as above - viscosity, API(s) particle sedimentation volume/redispersion - suspending/flocculating agents - particle size/crystallinity changes on storage/shelf life

32. Paediatric medicines – solid formulations • API(s) compatibility with excipients/other active(s) (need to separate APIs?) • Selection of ‘appropriate’ functional excipients • API dose and/or physicochemical properties may direct selection of manufacturing route (eg direct compression for low dose products, heat/light sensitive APIs…) • Key product performance test is dissolution of drug(s) • QC test (meet specification, batch reproducibility…) • Potential ‘surrogate’ test for in vivo performance, but ivivc (in vitro/in vivo correlations) remain challenging for most solid dosage forms • Critical test for BE waivers (BCS Class I and III)

33. Paediatric medicines - all dosage forms • Stability indicating assay for shelf-life testing • Establish sensitivity of API(s) to applied ‘stresses’ during selected manufacturing processes • Packing is an integral component of the medicinal product

34. Challenges • Quality, safe and efficacious medicines, appropriately designed medicines for children • Clinical pharmacology; dose versus age; clinical trial evidence aiding dose and design criteria • ADME/PK/pharmacogenetics knowledge/data base for APIs • Elimination of ‘dose-risk’ at point of delivery (administration) of medicine • ‘Innovative’ yet ‘pragmatic’ solutions to dose dilution, and dose ratio options for FDC products

35. Pharmaceutical Development with Focus on Paediatric formulations In this presentation: • Design of paediatric medicines – underlying principles • Critical factors related to API(s) properties • Formulation and manufacturing plan • Factors influencing formulation selection and design • Challenges for ‘forward thinking’ with paediatric medicines