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Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007

Pharmaceutical Development. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007. Pharmaceutical Development. Pharmaceutical Development of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters

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Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007

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  1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007

  2. Pharmaceutical Development Pharmaceutical Development of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters Email: susanw@netspeed.com.au

  3. The Australian view of the world This place isn’t too bad either! We are here!

  4. What Australia gave to the world (1)

  5. What Australia gave to the world (2)

  6. Pharmaceutical Developmentof FPPs Outline of presentation We will: • Look at the development process as a whole & consider its objectives • Review relevant guidelines • Review sources of information • Go through a worked example

  7. Objectives of Pharmaceutical Development : What is the purpose? From the perspective of a generic manufacturer, the objective is to develop a product that is: • of appropriate quality & • interchangeable with the innovator brand (so we can avoid expensive & time-consuming studies of safety & efficacy)

  8. Objectives of Pharmaceutical Development : What is the purpose? From the perspective of the manufacturer of a new dosage form &/or strength (eg a paediatric dosage form), the objective is to develop a product that is: • Of appropriate quality, & • Of appropriate dosage form & strength, & • Either has been shown to be safe & effective for the claimed indications & patient population or has been shown to pharmacokinetically interchangeable with a brand that has been shown to be safe & effective for the claimed indications & patient population However safety & efficacy is outside the scope of this presentation so I will deal only with generics that contain the same API in the same dosage form & strength as the innovator

  9. Product & process development(sorry don’t know the source of this diagram) CONTINUOUS IMPROVEMENT

  10. Terminology – from ICH Q1A(R2) 2003 (stability) • Production batch: • A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified • Pilot scale batch: • A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger. • Laboratory scale batch [not an ICH definition] • A batch smaller than pilot scale that is manufactured for development purposes Remember that scale-ups must be validated – batch characteristics may change during scale-up

  11. Relevant non-WHO guidelines • ICH Q8 Pharmaceutical Development (2005) • ICH Q9 Quality Risk Management(Nov 2005) • ICH Q10 DRAFTPharmaceuticalQuality System(May 2007) • Note for guidance on Process Validation CHMP/QWP/848/96 (EU 2001) • An elderly guideline but informative & helpful

  12. Relevant WHO guidelines • Pharmaceutical Development, Section 3.2 of Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis, WHO PQP (2005) • Extension of the WHO List of Stable (not easily degradable ARV) APIs,Supplement 2 (Rev 1) toGuideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis, WHO PQP (2005) • Supplementary guidelines on Good Manufacturing Practices: Validation, Annex 4 to WHO TRS 937 (2006)

  13. Some relevant journals • Pharmaceutical Technology • Pharmaceutical Technology Europe • Pharmaceutical Industry • Pharmaceutical Development and Technology • Drug Development & Industrial Pharmacy • Pharmaceutical Manufacturing • Dissolution Technologies - A free on-line journal at http://www.dissolutiontech.com/ • European Journal of Pharmaceutics and Biopharmaceutics • Pharmazie in Unserer Zeit (often in German) • S.T.P. Pharma Pratiques (often in French) • Pharmaceutisch Weekblad (often in German) It is often possible to obtain access to journals via university on-line databases

  14. Some relevant websites • http://www.who.int/medicines/en/. • WHO medicines program. • http://mednet3.who.int/prequal/ • WHO prequalification program. • http://www.ich.org • ICH website • http://www.emea.europa.eu/htms/human/humanguidelines/background.htm • European guidelines for human medicines • http://www.fip.org/www2/sciences/index.php • international Pharmaceutical Federation: Pharmaceutical Sciences section • http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm • Dissolution methods for drug products

  15. How can we optimise the possibility of developing an acceptable product? - 1 • Form a development team • Include staff with experience in formulation, manufacturing, quality control, stability testing • Prepare a development plan, set goals & timelines, & monitor progress with regular meetings (eg weekly in the first instance) • Make use of experienced staff within your company, especially in relation to manufacturing equipment & procedures • Review the literature for information on: • Chemical & physicochemical properties of the API(s) • Information on the innovator product • Conduct experiments to fill in the gaps in information, • Especially concerning API properties & compatibilities • If possible, use the same excipients as the innovator. • Less likely to encounter problems with compatibility, stability, bioequivalence • If possible, use standard manufacturing procedures with which your company has experience • More likely to achieve suitable dissolution properties & reproducible manufacturing

  16. How can we optimise the possibility of developing an acceptable product? - 2 BOTTOM LINE: • Ensure our product meets WHO criteria for quality, stability & interchangeability • Ensure our product has similar dissolution characteristics as the innovator at various pH • May need to confirm bioequivalence with the innovator • See Annex 8 to WHO TRS 937 (2006) Proposal to waive in vivo bioequivalence requirements forWHO Model List of Essential Medicines immediate-release,solid oral dosage forms

  17. What are the chemical & physicochemical properties of API(s) that we need to know, or are at least useful? • Solubility at various pH • Acid or base? • pKa & partition coefficient • Stability under stress (eg oxygen, moisture, acid etc) • Compatibility with common excipients

  18. What literature should we look for? Look for…… • A WHOPAR, if one is available for your product • See http://mednet3.who.int/prequal/default.htm. Look for WHO Public Assessment Reports under Quick Links on the RH side of the page • Innovator documentation. • Can often be found on the innovator website. • The prescribing information is especially useful & often includes a list of excipients. • A drug approval package (DAP) via http://www.fda.gov/cder/foi/nda/ • An EPAR (European Public Assessment Report) • An official monograph in the PhInt • A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press (latest edition 2004). • A monographin The Merck Index, published by CambridgeSoft (latest edition 2001). • Regulatory information • See for example the WHO information line e-drug@healthnet.org.

  19. Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 1 Why do we need to know the chemical structure? • To determine whether the active is an acid, base or neutral • To assist in devising assay procedures • To determine likely compatibilities/incompatibilities • Based on a knowledge of organic chemistry • To inform other decisions & predictions that are based on chemistry

  20. Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 2 • We plan to develop a paediatric product that contains the same active in the same dose & dosage form as an existing paediatric product. • The innovator is Boehringer Ingelheim. The innovator brand name is Viramune® 50 mg/5mL oral suspension. • The product under development is a multisource (generic) product. • The quality, safety & efficacy of the existing product have been established. • The product will be an oral suspension containing 50mg of nevirapine in each 5mL. The drug is present as an equivalent quantity of the hemihydrate API. • Note that the API is often a salt or solvate of the active ingredient. In this case the API is the hemihydrate of nevirapine.

  21. What useful sources of information did we find? • An EPAR at http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf • A drug approval package (DAP) at http://www.fda.gov/cder/foi/nda/98/20-933_20-636S009_Viramune.htm • A letter of approval at http://www.fda.gov/cder/ogd/rld/20933s3.PDF • An official monograph in the PhInt. • A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press 2004. • A monograph in The Merck Index, published by CambridgeSoft 2001. • Regulatory information concerning a possible impurity in the API. See http://www.medicalnewstoday.com/articles/82050.php

  22. What useful information did we find? - 1 Nevirapine is lipophilic (partition coefficient 83) & is essentially nonionized at physiological pH As a weak base (pKa 2.8), nevirapine shows increased solubility at acidic pH The aqueous solubility (of the anhydrate) is 90μg/ml at 25°C Nevirapine is generally stable when stressed

  23. What useful information did we find? - 2 • There are two crystal forms of the API • No polymorphic changes were observed under stressedconditions • The API (hemihydrate) is non-hygroscopic • The synthesis of the two crystal forms is similar until the final drying step • The impurity profile iswell characterised • Impurities arising from the synthesis have beentoxicologically qualified • No degradation products were detected during stability testing of the API • The API is milled in order to obtain an acceptableparticle size distribution for the suspension • Nevirapine is official in the PhInt • Batch analysis data confirmed that nevirapine hemihydrate complies with thespecifications

  24. What useful information did we find? - 3 • The innovator markets an oral suspension (Viramune ® 50 mg/5 ml) containing nevirapine (present as the hemihydrate at 10.35mg/ml). • That is….the active is nevirapine & the API is nevirapine hemihydrate • Excipients in the innovator formulation are: • Carbomer 934P (synthetic high molecular weight crosslinked polymers of acrylic acid), methyl & propyl hydroxybenzoates, sorbitol, sucrose, polysorbate80, NaOH, purified water. • The shelf life of the innovator is 3 years. • The product should be used within 2 months of opening (‘in-use’ stqbility). • The innovator has no special precautions for storage

  25. What useful information did we find? - 4 • The innovator’s containeris a white HDPE bottle with two piece child-resistant closure (outer shellwhite HDPE, inner shell natural polypropylene) with LDPE foam liner. Each bottle contains 240 ml of oral suspension. • Included with the innovator product is a clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber piston seal, & a clear low density polyethylene bottle-syringe adapter. See http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf http://www.fda.gov/cder/ogd/rld/20933s3.PDF • A monograph (PhInt) is being developed for the FPP, nevirapine oral suspension • NB check the WHO website for the latest information

  26. What useful information did we find? - 5 • The HDPE bottle is inert & has been shown to becompatible with the active substance & other ingredients of the innovator’s formulation. • % content of antimicrobial preservatives has been correlated with antimicrobial effectiveness when tested accordingto PhEurmethodology • Acceptable data are available to demonstrate theprecision & accuracy of the innovator’s dosing syringe • None of the synthesis impurities are degradants • The method of preparation of the oral suspension is standard for this dosage form & has been welldescribed. Validation data presented for three production batches manufactured using three differentlots of nevirapine demonstrated that the process is under control &ensures both batch-to-batch reproducibility & compliance with standard specifications. Tests atrelease are typical & ensure reproducible performance of the product.

  27. What useful information did we find? - 6 • Stability data are available for up to 18 months for the innovator. Long-term stability data have been promised on an ongoing basis. • An in-use stability study has beenperformed that mimics delivery of a 2mL dose, representing one of thelowest projected doses using the delivery device intended for marketing • An additional study has been conducted on the stability of the product exposed to freeze-thawconditions • On the basis of results from these studies, an in-use shelf life of 60 days with nospecial storage precautions is claimed

  28. What useful information did we find? – 7 In vivo data provided by the innovator included the following : • Nevirapine is readily absorbed (> 90 %) after oral administration in healthy volunteers & in adultswith HIV-1 infection. • A 3-way crossover study comparing the bioavailability of three production/commercialscale batches that had varying dissolution profiles showed that all three batches were bioequivalent with respect tosystemic exposure (AUC). The statistically significantly different values for Cmax and tmax were considered not tobe clinically relevant. • In studies in which the suspension was administered directly using a syringe,it was demonstrated that the suspension & tablet formulations were comparably bioavailable withrespect to extent of absorption. • In a study in which the suspension was administered in a dosing cupwithout rinsing, the suspension intended for marketing was bioequivalent to the suspension usedduring clinical trials but was not bioequivalent to the marketed tablets. This was attributed toincomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.

  29. What useful information did we find? – 8 • Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatricpopulation. A 4 mg/kg dose is proposed for all children regardless of age. Although no particularstudy has been performed to find the optimal lead-in dose, this dose was considered acceptableconsidering the enzyme induction to achieve initial antiretroviral activity. • The following doses were approved: • Patients from 2 months to 8 years, 4mg/kg once daily for 2 weeks followed by 7mg/kg twice daily • Patients from 8 years to 16 years, 4 mg/kg once daily followed by 4mg/kg twice daily

  30. Benchmarking the innovator – 1(these slides were taken from a presentation by János Pogány ) • Obtain a sample for confirmation of characteristics • Batch numbers • Shelf life: 3 years and within 2 months of opening. • Storage instructions: No special precautions for storage • Container and closure system: as per EPAR • QC analysis(hypothetical figures) • Assay: 99.9% of labelled amount (LA) • Methylhydroxy benzoate (HPLC): 0.18% w/v • Propylhydroxy benzoate (HPLC): 0.02% w/v • Total related substances: 0.03% • Specific gravity (at 25oC): 1.150 • Viscosity (at 25oC): 1,150 cPs • pH: 5.80

  31. Benchmarking the innovator - 2 The qualitative composition suggests that: Sucrose and sorbitol are used to adjust the density of the medium Carbomer 934P is used to adjust viscosity Polysorbate is a wetting agent Sodium hydroxide is used to adjust the pH to 5.8

  32. Benchmarking the innovator – 3Our tests show….. • Dissolution profile (% labeled strength) • Apparatus: USP II (paddle, 25rpm) • Medium: 0.1N HCl • Volume: 900ml See http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March 2007

  33. Benchmarking the innovator - 4 Our tests show….. Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated

  34. Pharmaceutical development protocol API experiments • Particle size distribution • Formulation experiments • Screening laboratory batches with different proportions of excipients to match innovator dissolution • Stress testing of the selected composition • Compatibility with excipients • Antimicrobial effectiveness test accordingto PhEur • Packing materials • Dimensions and tolerances of packing components • Precision & accuracy of the dosing syringe

  35. Product-specific API properties • PhInt specifications + limits on residual solvents from API manufacture • Product-specific physical properties depend on crystallization and subsequentphysical processing. Density and particle size distribution of nevirapine hemihydrate are critical quality attributes. Acceptance criteria are established by measurement of particle size of innovator’s API in suspension & through the similarity of dissolution profiles of innovator and generic products.

  36. Undertake stress testing of the APIif not already available in existing documentation

  37. Solubility of nevirapine hemihydrate at 37oCIf not already available in existing documentation Note: • Nevirapine hemihydrate belongs to BCS2 (low solubility, high permeability) • See Annex 8 to WHO TRS 937 (2006) • Solubility data are also important for cleaning validation

  38. Dissolution profiles of innovator & generic FPPsHypothetical data M e a n % A P I d i s s o l v e d ▀innovator ▀generic Similarity factor f2=73 Time (minutes)

  39. Selected generic composition Hypothetical numbers Ingredientsmg/5ml • Nevirapine hemihydrate 51.7 • Excipients • Carbomer 934P 7.0 • Methyl parahydroxybenzoate9.0 • Propyl parahydroxybenzoate0.9 • Sorbitol900.0 • Sucrose (!)500.0 • Polysorbate804.0 • Sodium hydroxide q.s. • Purified water to make 5.0 ml

  40. Proposed FPP specificationsA hypothetical set of limits • Description: including at least colour, texture, odour • Identification (HPLC) • Dissolution (UV): Q = 70% in 45 minutes • pH = 5.0 – 6.1 • Deliverable volume • Average fill volume: NLT 240 ml • Fill volume variation: Meets PhInt requirements • Related substances: NMT 0.1% of any one imp & NMT 0.3% total imps • Preservative content (HPLC) • Methylparaben: 98 to 102% of labeled strength • Propylparaben: 98 to 102% of labeled strength • Assay: 95.0 to 105.0% of labeled strength

  41. Compatibility with excipientsMay not need to do this if use only the same excipients as the innovator Nevirapine hemihydrate in solid state – illustrative example: heat

  42. Development of manufacturing process • Select a standard process for oral aqueous suspensions, if possible using our existing method • Manufacture a lab scale batch • If necessary make adjustments & manufacture another lab scale batch • When satisfied with the formulation, manufacture a pilot scale batch • If necessary make adjustments & manufacture another pilot scale batch • Recollect that a pilot batch is manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch • Manufacture primary* batches in the proposed container & closure systems for: • Bioequivalence & dissolution studies • Regulatory stability studies • Iincluding an in-use stability study &a stress study under freeze-thawconditions • Validation of bioequivalence, dissolution & stability batches *Primary as defined in WHO/ICH guidelines

  43. Development of manufacturing process Note that the progress from pre-formulation to formulation to pilot manufacture to production scale manufacture should be described in the PQP dossier & shown to be logical, reasoned & continuous

  44. Scale up activities • Test a large number of samples from pilot scale batches to establish provisional acceptance limits for the control of critical process parameters (prospective validation, in-process control limits) in order to define the design space*&a control strategy that encompasses batch scale, equipment, packaging, as well as final product stability. The process will be well understood when: • all critical sources of variability have been identified & explained • variability is managed by the process • product quality attributes can be accurately & reliably predicted • A validation protocol is written * See ICH Q8, Q9 & draft Q10 for further explanation

  45. Dissolution & bioequivalence testing Generic FPP Innovator FPP Conduct a dissolution test on at least 3 batches Select a production batch, or one NLT 1/10thof final size Select a batch showing intermediate dissolution Test product Reference product Dissolution profile Bioequivalence study

  46. Pharmaceutical DevelopmentSummary and conclusion The probability of producing a product that is: • Of high quality • Stable • Consistent from batch to batch, & • Bioequivalent to the innovator can be significantly improved by employing a planned & systematic approach to product development, & using all the information that has been published

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