Pharmaceutical Development: Training Workshop On

Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on

Paediatric Formulations Tallinn

15-19th October 2007

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

Pharmaceutical Development

Pharmaceutical Development of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters

Email: [email protected]

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

The Australian view of the world We are here!

This place isn’t too bad either!

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

What Australia gave to the world (1)

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

What Australia gave to the world (2)

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

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

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

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, and  interchangeable with the innovator brand (so we can avoid .....expensive & time-consuming studies.....of safety & efficacy)

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

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.

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

Development of a paediatric dosage form

Define drug & dosage regime for the paediatric indication

Consider: · Suitable routes of administration · Suitable dosage forms

Review literature data &/or conduct own studies

Consider pharmacokinetic characteristics of API including: · Half life, Cmax, AUC · BCS classification if oral route is intended Determine & prepare for studies likely to be required relating to BABE

Determine: · Relevant physicochemical characteristics of API · Stability of API under stress conditions · Compatibility of API with common excipients

Review literature data &/or conduct own studies

Select a dosage form & strength

Sources of possible formulations & manufacturing procedures: · Innovator excipients · Your company’s prior experience · Commercially available formulations & manufacturing procedures · WHO ‘starting-point’ formulations

Consider suitable, formulations & manufacturing procedures

Prepare draft prescribing information

Prepare early batches & test relevant characteristics including: · Dissolution rate · Stability · Pilot BE study if necessary

Define design space

Apply optimization techniques/validate formulation & method of manufacture

Decide final formulation, method of manufacture & packaging

Conduct: · Confirmatory stability studies · Confirmatory dissolution studies · Final BE study if needed

Submit application for prequalification

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

Finalise prescribing information

DEVELOPMENT OF A DOSAGE FORM Define drug & dosage regime for the indication Consider : - Suitable routes of administration - Suitable dosage forms

Review literature data and/or conduct own studies

Consider pharmacokinetic characteristics of API : - Half life, Cmax, AUC - BCS classification (if oral route) Determine & prepare for studies likely to be required relating to BA/BE

A

Determine: - Relevant physicochemical characteristic of API - Stability of API under stress conditions - Compatibility of API with common excipients

SELECT A DOSAGE FORM & STRENGTH

B

Review literature data and/or conduct own studies

DEVELOPMENT OF A DOSAGE FORM Source of possible formulations & manufacturing procedures: - Innovator excipients - Your company’s prior experiences - Commercially available formulations & manufacturing procedures - WHO ‘startpoint’ formulation

Define design space

A

B

Consider : - Suitable formulation & manufacturing procedures

Prepare draft prescribing information

Prepare early batches & test relevant characteristics including: - Dissolution rate - Stability - Pilot BE study, if necessary

Apply optimization techniques / validate formulation & method of manufacture C

D

DEVELOPMENT OF A DOSAGE FORM

C

Conduct: - Confirmatory stability studies - Confirmatory dissolution studies - Final BE study, if needed

Submit application for qualification

D

Finalise prescribing information

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

Qualification Stage

Validation Stage

Key elements

Design & C Installation Operation

Facilities and Equipment

Engineering phase

(Validation Protocols) Preparatory phase ( Validation of analytical methods )

Design (laboratory) ( Critical attributes & formula screening )

Prospective Concurrent

Manufacturing Start-Up

(Batch Records & Validation documentation) Scale-Up (pilot plant) ( process optimization & stability batch biobatch )

Product and process development

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

Production ( final batch size, reproducible quality)

CONTINUOUS IMPROVEMENT

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 Slide 14

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

Relevant non-WHO guidelines  ICH Q8 Pharmaceutical Development (2005)  ICH Q9 Quality Risk Management (Nov 2005)

 ICH Q10 Pharmaceutical Quality System (May 2007)  Note for guidance on Process Validation CHMP/QWP/848/96 (EU 2001) – An elderly guideline but informative & helpful

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

Relevant WHO guidelines  Pharmaceutical Development, Section 3.2 of Guideline on Submission of Documentation for Prequalification of Multisource (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 Multisource (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) Slide 16

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

Some relevant journals  Pharmaceutical Technology  Pharmaceutical Technology Europe  Pharmaceutical Industry  Pharmaceutical Development and Technology  Drug Development & Industrial Pharmacy  Pharmaceutical Manufacturing  Dissolution Technologies - A free online journal at http://www.dissolutiontech.com/

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 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

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

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 Slide 18

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

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, and 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 Slide 19

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

How can we optimise the possibility of developing an acceptable product? - 2  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

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

How can we optimise the possibility of developing an acceptable product? - 3 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

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

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

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

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) Slide 23

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

What literature should we look for?

Look for……

 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 [email protected].

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

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 Slide 25

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

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/5 mL 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 50 mg of nevirapine in each 5 mL. 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. Slide 26

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

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/98/20933_20-636S009_Viramune.htm  A letter of approval at http://www.fda.gov/cder/ogd/rld/20933s3.pdf  An official monograph in the Ph Int.  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 Slide 27

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

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 90 μg/ml at 25°C  Nevirapine is generally stable when stressed

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

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

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

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 10.35 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’ stability).  The innovator has no special precautions for storage

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

What useful information did we find? (4)  The innovator’s container is a white HDPE bottle with two piece childresistant 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, and a clear low density polyethylene bottle-syringe adapter. See http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697e n6.pdf http://www.fda.gov/cder/ogd/rld/20933s3.pdf  A monograph (Ph Int) is being developed for the FPP, nevirapine oral suspension – NB check the WHO website for the latest information Slide 31

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

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 (3) production batches manufactured using three (3) 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. Slide 32

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

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 2 mL 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

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

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 (3) production/commercial scale batches that had varying dissolution profiles showed that all three (3) 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. Slide 34

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

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 Slide 35

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

Benchmarking the innovator (these slides were taken from a presentation by János Pogány ) (1)  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 Slide 36

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

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

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

Benchmarking the innovator Our tests show….. (3) Time (minutes)

% API dissolved (hypothetical figures)

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5

27

10

42

15

55

20

65

30

76

45

88

60

92

 Dissolution profile (% labeled strength)  Apparatus: USP II (paddle, 25 rpm)  Medium: 0.1N HCl  Volume: 900ml

See http://www.accessdata.fda.gov/scrip ts/cder/dissolution/dsp_SearchResu lts_Dissolutions.cfm downloaded on 13 March 2007

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

Benchmarking the innovator Our tests show….. (4) % API dissolved (hypothetical figures) Time (minutes)

pH 1.2 buffer

% API dissolved (hypothetical figures)

% API dissolved (hypothetical figures)

pH 4.5 buffer

pH 6.8 buffer

5

27

15

22

10

42

25

27

15

55

36

35

20

65

42

42

30

76

48

49

45

88

49

57

60

92

49

65

90

100

50

76

Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated Slide 39

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

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

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

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.

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

Undertake stress testing of the API if not already available in existing documentation

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Stress type

Conditions

Assay (%)

Control

25o C

99.8

36% HCl

80o C, 40 min.

72.0

5N NaOH

80o C, 2h 20’

98.6

30% w/w H2O2

80o C, 2h 20’

98.6

Heat

130o C, 49h

101.5

Light

500 W/m2, 68h

101.7

Water

25o C, 92% RH, 91h

101.2

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

Solubility of nevirapine hemihydrate at 37oC If not already available in existing documentation pH

Dissolved material (mg/ml) (hypothetical figures)

1.2

2.75

2.1

0.28

3.0

0.08

4.5

0.06

6.8

0.06

7.2

0.06

8.0

0.06

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 Slide 43

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

Dissolution profiles of innovator & generic FPPs Hypothetical data M e a n % A P I d i s s o l v e d

120 100

▀ innovator ▀ generic

80 60 40

Similarity factor

20

f2=73

0 0

10

20

30

40

50

60

Time (minutes) Slide 44

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

70

80

90

Selected generic composition Hypothetical numbers Ingredients  Active – Nevirapine hemihydrate  Excipients – Carbomer 934P – Methyl parahydroxybenzoate – Propyl parahydroxybenzoate – Sorbitol – Sucrose (!) – Polysorbate 80 – Sodium hydroxide – Purified water to make Slide 45

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

mg/5 ml

51.7

7.0 9.0 0.9 900.0 500.0 4.0 q.s. 5.0 ml

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 Slide 46

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

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

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Stress Condition

Treatment

None

Initial values API

Heat

API is mixed with excipient, the mixture is wetted and a thin layer of the powder blend is kept at 60°C for 4 weeks in a Petri dish (open system)

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

Observations Assay: Impurity 1: Impurity 2: Total unspecified imps: Total impurities: Assay: Impurity 1: Impurity 2: Total unspecified imps: Total impurities:

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 (including an in-use stability study & a stress study under freeze-thaw conditions) – Validation of bioequivalence, dissolution & stability batches * Slide 48

Primary as defined in WHO/ICH guidelines

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

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 and continuous

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

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 Slide 50

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

Dissolution & bioequivalence testing Innovator FPP

Generic FPP

Conduct a dissolution test on at least 3 batches

Select a production batch, or one NLT 1/10th of final size

Select a batch showing intermediate dissolution

Reference product

Test product

Dissolution profile

Bioequivalence study

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

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 Slide 52

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