training workshop on pharmaceutical development with a focus on paediatric medicines 15-19 october...

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

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Tallinn

15-19th October 2007

Pharmaceutical DevelopmentPharmaceutical Development


Pharmaceutical DevelopmentPharmaceutical Development

Pharmaceutical Development of Finished Pharmaceutical

Products (FPPs)

Presenter: Susan Walters

Email: [email protected]


The Australian view of the worldThe Australian view of the world

We are here!

This place isn’t too

bad either!


What Australia gave to the world (1)What Australia gave to the world (1)


What Australia gave to the world (2)What Australia gave to the world (2)


Pharmaceutical Development of FPPsPharmaceutical 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


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)




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


Define drug & dosage regime for the paediatric indication

Development of a paediatric dosage form

Select a dosage form & strength

Consider:· Suitable routes of administration· Suitable dosage forms

Consider suitable, formulations & manufacturing

procedures

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

Sources of possible formulations & manufacturing procedures:· Innovator excipients· Your company’s prior experience· Commercially available formulations &

manufacturing procedures · WHO ‘starting-point’ formulations

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

Review literature data &/orconduct own studies

Consider pharmacokinetic characteristics of API including:· Half life, Cmax, AUC · BCS classification if oral

route is intendedDetermine & prepare for studies likely to be required relating to BABE

Submit application for prequalification

Determine:· Relevant

physicochemical characteristics of API

· Stability of API under stress conditions

· Compatibility of API with common excipients

Define design space

Prepare draft prescribing information

Review literature data &/orconduct own studies

Finalise prescribing information


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

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

CONTINUOUS IMPROVEMENT


Terminology – from ICH Q1A(R2) 2003 (stability)

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


Relevant non-WHO guidelinesRelevant 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


Relevant WHO guidelinesRelevant 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)


Some relevant journalsSome 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


Some relevant websitesSome 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


How can we optimise the possibility of developing an acceptable product? - 1How 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


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


What are the chemical & physicochemical properties of API(s) that we need to know, or are at least useful?

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


What literature should we look for?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 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].


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




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.


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


What useful information did we find? - 1What 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



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


What useful information did we find? - 3 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


What useful information did we find? - 4 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



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.



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


What useful information did we find? – 7What 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.


What useful information did we find? – 8What 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


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

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


Benchmarking the innovator - 2Benchmarking 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


Benchmarking the innovator – 3Our tests show…..

Benchmarking the innovator – 3Our tests show…..

Time (minutes)% API dissolved (hypothetical figures)

527

1042

1555

2065

3076

4588

6092

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


Benchmarking the innovator - 4 Our tests show…..

Benchmarking the innovator - 4 Our tests show…..

% API dissolved (hypothetical figures)



Time (minutes)pH 1.2 bufferpH 4.5 bufferpH 6.8 buffer

5271522

10422527

15553635

20654242

30764849

45884957

60924965

901005076Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated


Pharmaceutical development protocolPharmaceutical development protocolAPI 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


Product-specific API propertiesProduct-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.


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

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

Stress typeConditionsAssay (%)

Control25o C 99.8

36% HCl80o C, 40 min. 72.0

5N NaOH 80o C, 2h 20’ 98.6

30% w/w H2O280o C, 2h 20’ 98.6

Heat130o C, 49h 101.5

Light 500W/m2, 68h 101.7

Water 25o C, 92% RH, 91h 101.2


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

Solubility of nevirapine hemihydrate at 37oC 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

0.282.1

0.067.2

0.068.0

0.066.8

0.064.5

0.083.0

2.751.2

Dissolved material (mg/ml)

(hypothetical figures)

pH

0.282.1

0.067.2

0.068.0

0.066.8

0.064.5

0.083.0

2.751.2

Dissolved material (mg/ml)

(hypothetical figures)

pH


Dissolution profiles of innovator & generic FPPsHypothetical data

Dissolution profiles of innovator & generic FPPsHypothetical data

Mean % API

dissolved

Time (minutes)

▀ innovator

▀ generic

Similarity factor f2=73

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80 90


Selected generic composition Hypothetical numbers

Selected generic composition Hypothetical numbers

Ingredients mg/5mlNevirapine hemihydrate 51.7

Excipients– Carbomer 934P 7.0– Methyl parahydroxybenzoate 9.0 – Propyl parahydroxybenzoate 0.9– Sorbitol 900.0– Sucrose (!) 500.0– Polysorbate 80 4.0– Sodium hydroxide q.s.– Purified water to make 5.0 ml


Proposed FPP specificationsA hypothetical set of limits

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 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


Compatibility with excipientsMay not need to do this if use only the same excipients as the

innovator

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

Stress Condition

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

None Initial values API

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

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) Total impurities:


Development of manufacturing process 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


Development of manufacturing process 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


Scale up activitiesScale 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


Dissolution & bioequivalence testingDissolution & bioequivalence testing

Innovator FPP Generic FPPConduct a dissolution test

on at least 3 batchesSelect a production batch, orone NLT 1/10th of final size

Reference product Test product

Select a batch showing intermediate dissolution

Dissolution profile

Bioequivalence study


Pharmaceutical Development Summary and conclusion

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

training workshop on pharmaceutical development with a focus on paediatric medicines 15-19 october...

Documents

training workshop

development process

innovator slide

paediatric medicines

development purposes

informative helpful

paediatric dosage form

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