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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007 Slide 1 Training Workshop on Pharmaceutical Development.

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Presentation on theme: "Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007 Slide 1 Training Workshop on Pharmaceutical Development."— Presentation transcript:

1 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 1 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn 15-19th October 2007 Pharmaceutical Development

2 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 2 Pharmaceutical Development Pharmaceutical Development of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters

3 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 3 The Australian view of the world We are here! This place isn’t too bad either!

4 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 4 What Australia gave to the world (1)

5 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 5 What Australia gave to the world (2)

6 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 6 Pharmaceutical Development of 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 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 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 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 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 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 9

10 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 10 Product & process development (sorry don’t know the source of this diagram) CONTINUOUS IMPROVEMENT

11 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 11 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

12 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 12 Relevant non-WHO guidelines ICH Q8 Pharmaceutical Development (2005) ICH Q9 Quality Risk Management (Nov 2005) ICH Q10 DRAFT Pharmaceutical Quality System (May 2007) Note for guidance on Process Validation CHMP/QWP/848/96 (EU 2001) –An elderly guideline but informative & helpful

13 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 13 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) to 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) Supplementary guidelines on Good Manufacturing Practices: Validation, Annex 4 to WHO TRS 937 (2006)

14 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 14 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 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

15 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 15 Some relevant websites –WHO medicines program. –WHO prequalification program. –ICH website htm htm –European guidelines for human medicines –international Pharmaceutical Federation: Pharmaceutical Sciences section –Dissolution methods for drug products

16 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 16 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

17 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 17 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 for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

18 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 18 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

19 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 19 What literature should we look for? Look for…… A WHOPAR, if one is available for your product –See Look for WHO Public Assessment Reports under Quick Links on the RH side of the pagehttp://mednet3.who.int/prequal/default.htm 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 An EPAR (European Public Assessment Report) An official monograph in the Ph Int A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press (latest edition 2004). A monograph in The Merck Index, published by CambridgeSoft (latest edition 2001). Regulatory information –See for example the WHO information line

20 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 20 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

21 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 21 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.

22 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 22 What useful sources of information did we find? An EPAR at A drug approval package (DAP) at 933_20-636S009_Viramune.htmhttp://www.fda.gov/cder/foi/nda/98/ _20-636S009_Viramune.htm A letter of approval at An official monograph in the Ph Int. A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press A monograph in The Merck Index, published by CambridgeSoft Regulatory information concerning a possible impurity in the API. See

23 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 23 What useful information did we find? - 1 Nevirapine is lipophilic (partition coefficient 83) & is essentially nonionized at physiological pH As a weak base (pK a 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

24 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 24 What useful information did we find? - 2 There are two crystal forms of the API No polymorphic changes were observed under stressed conditions The API (hemihydrate) is non-hygroscopic The synthesis of the two crystal forms is similar until the final drying step The impurity profile is well characterised Impurities arising from the synthesis have been toxicologically qualified No degradation products were detected during stability testing of the API The API is milled in order to obtain an acceptable particle size distribution for the suspension Nevirapine is official in the Ph Int Batch analysis data confirmed that nevirapine hemihydrate complies with the specifications

25 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 25 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 mg/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, polysorbate 80, 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

26 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 26 What useful information did we find? - 4 The innovator’s container is a white HDPE bottle with two piece child-resistant closure (outer shell white 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 A monograph (Ph Int) is being developed for the FPP, nevirapine oral suspension –NB check the WHO website for the latest information

27 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 27 What useful information did we find? - 5 The HDPE bottle is inert & has been shown to be compatible with the active substance & other ingredients of the innovator’s formulation. % content of antimicrobial preservatives has been correlated with antimicrobial effectiveness when tested according to Ph Eur methodology Acceptable data are available to demonstrate the precision & 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 well described. Validation data presented for three production batches manufactured using three different lots of nevirapine demonstrated that the process is under control & ensures both batch-to-batch reproducibility & compliance with standard specifications. Tests at release are typical & ensure reproducible performance of the product.

28 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 28 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 been performed that mimics delivery of a 2mL dose, representing one of the lowest projected doses using the delivery device intended for marketing An additional study has been conducted on the stability of the product exposed to freeze-thaw conditions On the basis of results from these studies, an in-use shelf life of 60 days with no special storage precautions is claimed

29 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 29 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 adults with HIV-1 infection. A 3-way crossover study comparing the bioavailability of three production/commercial scale batches that had varying dissolution profiles showed that all three batches were bioequivalent with respect to systemic exposure (AUC). The statistically significantly different values for Cmax and tmax were considered not to be 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 with respect to extent of absorption. In a study in which the suspension was administered in a dosing cup without rinsing, the suspension intended for marketing was bioequivalent to the suspension used during clinical trials but was not bioequivalent to the marketed tablets. This was attributed to incomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.

30 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 30 What useful information did we find? – 8 Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatric population. A 4 mg/kg dose is proposed for all children regardless of age. Although no particular study has been performed to find the optimal lead-in dose, this dose was considered acceptable considering 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

31 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 31 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 25 o C): –Viscosity (at 25 o C): 1,150 cPs –pH: 5.80

32 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 32 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

33 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 33 Benchmarking the innovator – 3 Our tests show….. % API dissolved (hypothetical figures) Time (minutes) Dissolution profile (% labeled strength) Apparatus: USP II (paddle, 25rpm) Medium: 0.1N HCl Volume: 900ml See olution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March olution/dsp_SearchResults_Dissolutions.cfm

34 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 34 Benchmarking the innovator - 4 Our tests show….. % API dissolved (hypothetical figures) pH 6.8 bufferpH 4.5 bufferpH 1.2 buffer Time (minutes) Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated

35 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 35 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 according to Ph Eur Packing materials –Dimensions and tolerances of packing components –Precision & accuracy of the dosing syringe

36 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 36 Product-specific API properties Ph Int specifications + limits on residual solvents from API manufacture Product-specific physical properties depend on crystallization and subsequent physical 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.

37 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 37 Undertake stress testing of the API if not already available in existing documentation Stress typeConditionsAssay (%) Control25 o C % HCl80o C, 40 min N NaOH80 o C, 2h 20’ % w/w H 2 O 2 80 o C, 2h 20’98.6 Heat130 o C, 49h101.5 Light500W/m 2, 68h101.7 Water25 o C, 92% RH, 91h101.2

38 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 38 Solubility of nevirapine hemihydrate at 37 o C If 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

39 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 39 Dissolution profiles of innovator & generic FPPs Hypothetical data Mean% APIdissolvedMean% APIdissolved Time (minutes) ▀ innovator ▀ generic Similarity factor f 2 =73

40 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 40 Selected generic composition Hypothetical numbers Ingredientsmg/5ml Nevirapine hemihydrate 51.7 Excipients –Carbomer 934P 7.0 –Methyl parahydroxybenzoate 9.0 –Propyl parahydroxybenzoate 0.9 –Sorbitol900.0 –Sucrose (!)500.0 –Polysorbate –Sodium hydroxide q.s. –Purified water to make 5.0 ml

41 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 41 Proposed FPP specifications A 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 Ph Int 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

42 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 42 Compatibility with excipients May not need to do this if use only the same excipients as the innovator Nevirapine hemihydrate in solid state – illustrative example: heat

43 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 43 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-thaw conditions –Validation of bioequivalence, dissolution & stability batches *Primary as defined in WHO/ICH guidelines

44 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 44 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

45 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 45 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

46 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 46 Dissolution & bioequivalence testing Innovator FPP Generic FPP Conduct a dissolution test on at least 3 batches Select a production batch, or one NLT 1/10 th of final size Reference product Test product Select a batch showing intermediate dissolution Dissolution profile Bioequivalence study

47 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines October 2007 Slide 47 Pharmaceutical Development Summary 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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