Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Tallinn 15-19th October 2007

Slide 1 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: Email: Susan Walters [email protected]

Slide 2 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

!

Slide 3 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

What Australia gave to the world (1)

Slide 4 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

What Australia gave to the world (2)

Slide 5 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

Slide 6 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 &



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

Slide 7 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

Slide 8 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 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 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

Slide 9 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

Review literature data &/or conduct own studies Prepare draft prescribing information Finalise prescribing information

Product & process development

(sorry don’t know the source of this diagram) Key elements Facilities

and

Equipment Preparatory phase

(

Validation

of

analytical methods

)

Slide 10

(

Qualification

Stage Design & C Installation Engineering phase

Validation

Protocols) Operation

Validation

Prospective Manufacturing Start-Up (Batch Records and

Validation Design (laboratory)

(

Critical attributes

and

formula screening

)

Scale-Up (pilot plant)

(

process optimization

and

stability batch biobatch

)

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

Stage Concurrent documentation)

Production

(

final batch size

,

reproducible quality

)

CONTINUOUS IMPROVEMENT

Terminology –

from ICH Q1A(R2) 2003 (stability)

Slide 11

-

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

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

Relevant non-WHO guidelines

Slide 12



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

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 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)

Slide 13 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 European Journal of Pharmaceutics and Biopharmaceutics Pharmazie in Unserer Zeit S.T.P. Pharma Pratiques

- A free on-line journal at (often in French)

Pharmaceutisch Weekblad

(often in German) (often in German) http://www.dissolutiontech.com/

It is often possible to obtain access to journals via university on-line databases Slide 14 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

Some relevant websites

Slide 15



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 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, & 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

Slide 16 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

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

Slide 17 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

Slide 18 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

Quick Links

on the RH side of the page . Look for

WHO Public Assessment Reports

under  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 ( http://www.fda.gov/cder/foi/nda/

European Public Assessment Report

)   An official monograph in the (latest edition 2004).

Ph Int

A monograph in

Clarke ’s Analysis of Drugs and Poisons

, published by The Pharmaceutical Press   A monograph in

The Merck Index

Regulatory information – , published by CambridgeSoft (latest edition 2001). See for example the WHO information line [email protected]

.

Slide 19 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

Slide 20

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

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/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.

Slide 21 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/98/20 933_20-636S009_Viramune.htm



A letter of approval at

http://www.fda.gov/cder/ogd/rld/20933s3.PDF



An official monograph in the 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 22 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 (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

Slide 23 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

Slide 24 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’ stqbility).

The innovator has no special precautions for storage

Slide 25 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 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 http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.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 26 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 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.

Slide 27 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 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

Slide 28 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 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.

Slide 29 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 30 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

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 – – – – – – – 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): 1.150 Viscosity (at 25 o C): 1,150 cPs pH: 5.80

(hypothetical figures)

Slide 31 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

Slide 32 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

Slide 33

Benchmarking the innovator – 3 Our tests show…..

Time (minutes) 5 10 15 20 30 45 60 % API dissolved (hypothetical figures) 27 42  Dissolution profile (% labeled strength)  Apparatus: USP II (paddle, 25rpm) 55  Medium: 0.1N HCl 65  Volume: 900ml 76 88 See http://www.accessdata.fda.gov/scripts/cder/diss olution/dsp_SearchResults_Dissolutions.cfm

downloaded on 13 March 2007 92

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

Benchmarking the innovator - 4 Our tests show…..

% API dissolved

(hypothetical figures)

% API dissolved

(hypothetical figures)

% API dissolved

(hypothetical figures)

Time (minutes) 5 10 15 20 30 45 60 pH 1.2 buffer 27 42 55 65 76 88 92 pH 4.5 buffer 15 25 36 42 48 49 49 pH 6.8 buffer 22 27 35 42 49 57 65 90 100 50 76 Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated

Slide 34 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

Slide 35 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.

Slide 36 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

Slide 37

Undertake stress testing of the API

if not already available in existing documentation

Stress type Control 36% HCl 5N NaOH 30% w/w H 2 O 2 Heat Light Water Conditions 25 o C 80o C, 40 min.

80 o C, 2h 20 ’ 80 o C, 2h 20 ’ 130 o C, 49h 500W/m 2 , 68h 25 o C, 92% RH, 91h Assay (%) 99.8

72.0

98.6

98.6

101.5

101.7

101.2

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

Solubility of nevirapine hemihydrate at 37

o

C

If not already available in existing documentation

(

hypothetical figures)

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

Dissolution profiles of innovator & generic FPPs Hypothetical data Slide 39 M e a n % A P I l v e d d i s s o

120 100 80 60 40 20 0 0 10 20 30 40 50

Time (minutes) Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

60 70 80 90

▀ innovator ▀ generic Similarity factor f 2 =73

Selected generic composition

Hypothetical numbers

 Ingredients

Nevirapine hemihydrate

mg/5ml 51.7



Excipients

– Carbomer 934P – – – – Methyl parahydroxybenzoate Propyl parahydroxybenzoate Sorbitol Sucrose (!) – – – Polysorbate 80 Sodium hydroxide Purified water to make 7.0

9.0 0.9

900.0

500.0

4.0

q.s.

5.0 ml

Slide 40 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

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 41 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 Stress Condition None Heat Treatment Initial values API 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) Observations Assay: Impurity 1: Impurity 2: Total unspecified imps: Total impurities: Assay: Impurity 1: Impurity 2: Total unspecified imps: Total impurities:

Slide 42 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

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

Slide 43 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 & continuous

Slide 44 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 45 Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007

Dissolution & bioequivalence testing

Innovator FPP

Conduct a dissolution test on at least 3 batches Select a batch showing intermediate dissolution Reference product

Generic FPP

Select a production batch, or one NLT 1/10 th of final size Test product Dissolution profile Bioequivalence study

Slide 46 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 Slide 47 can be significantly improved by employing a planned & systematic approach to product development, & using all the information that has been published Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007