Preparing Workshop on Pharmaceutical Development with spotlight on Pediatric Formulations Tallinn 15-nineteenth October

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Pharmaceutical Development Training Workshop on Pharmaceutical Development with concentrate on Pediatric Formulations Tallinn 15-nineteenth October 2007

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

The Australian perspective of the world This place isn't too terrible either ! We are here !

What Australia provided for the world (1)

What Australia provided for the world (2)

Pharmaceutical Development of FPPs Outline of introduction We will: Look at the advancement procedure in general & consider its goals Review pertinent rules Review wellsprings of data Go through a worked illustration

Objectives of Pharmaceutical Development : What is the reason? From the viewpoint of a nonexclusive producer, the goal is to build up an item that is: of fitting quality & compatible with the pioneer mark (so we can stay away from costly & tedious investigations of security & adequacy)

Objectives of Pharmaceutical Development : What is the reason? From the point of view of the producer of another measurement frame &/or quality (eg a pediatric dose shape), the goal is to build up an item that is: Of suitable quality, & Of proper dose frame & quality, & Either has been appeared to be protected & viable for the guaranteed signs & tolerant populace or has been appeared to pharmacokinetically compatible with a brand that has been appeared to be sheltered & compelling for the asserted signs & understanding populace However wellbeing & adequacy is outside the extent of this introduction so I will bargain just with generics that contain similar API in a similar dose shape & quality as the trailblazer

Product & prepare advancement (sorry don't have a clue about the wellspring of this graph) CONTINUOUS IMPROVEMENT

Terminology – from ICH Q1A(R2) 2003 (soundness) Production cluster: A group of a medication substance or medication item made at creation scale by utilizing generation gear in a creation office as determined Pilot scale clump: A bunch of a medication substance or medication item fabricated by a strategy completely illustrative of and recreating that to be connected to a full generation scale clump. For strong oral dose frames, a pilot scale is by and large, at the very least, one-tenth that of a full creation scale or 100,000 tablets or containers, whichever is the bigger. Research facility scale cluster [not an ICH definition] A bunch littler than pilot scale that is fabricated for improvement purposes Remember that scale-ups must be approved – group attributes may switch amid scale-up

Relevant non-WHO rules ICH Q8 Pharmaceutical Development (2005) ICH Q9 Quality Risk Management (Nov 2005) ICH Q10 DRAFT Pharmaceutical Quality System (May 2007) Note for direction on Process Validation CHMP/QWP/848/96 (EU 2001) An elderly rule however enlightening & accommodating

Relevant WHO rules 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 effortlessly 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 rules on Good Manufacturing Practices: Validation, Annex 4 to WHO TRS 937 (2006)

Some important diaries Pharmaceutical Technology Pharmaceutical Technology Europe Pharmaceutical Industry Pharmaceutical Development and Technology Drug Development & Industrial Pharmacy Pharmaceutical Manufacturing Dissolution Technologies - A free on-line diary at http://www.dissolutiontech.com/European Journal of Pharmaceutics and Biopharmaceutics Pharmazie in Unserer Zeit (regularly in German) S.T.P. Pharma Pratiques (regularly in French) Pharmaceutisch Weekblad (frequently in German) It is regularly conceivable to acquire access to diaries by means of college on-line databases

Some pertinent sites http://www.who.int/meds/en/. WHO medications program. http://mednet3.who.int/prequal/WHO prequalification program. http://www.ich.org ICH site http://www.emea.europa.eu/htms/human/humanguidelines/background.htm European rules for human medications http://www.fip.org/www2/sciences/index.php worldwide Pharmaceutical Federation: Pharmaceutical Sciences segment http://www.accessdata.fda.gov/scripts/cder/disintegration/index.cfm Dissolution strategies for medication items

How would we be able to enhance the likelihood of building up a satisfactory item? - 1 Form an advancement group Include staff with involvement in definition, fabricating, quality control, solidness testing Prepare an improvement arrange, set objectives & courses of events, & screen advance with standard gatherings (eg week after week in the principal example) Make utilization of experienced staff inside your organization, particularly in connection to assembling gear & techniques Review the writing for data on: Chemical & physicochemical properties of the API(s) Information on the trailblazer item Conduct analyses to fill in the crevices in data, Especially concerning API properties & compatibilities If conceivable, utilize an indistinguishable excipients from the pioneer. More averse to experience issues with similarity, solidness, bioequivalence If conceivable, utilize standard assembling systems with which your organization has encounter More liable to accomplish appropriate disintegration properties & reproducible assembling

How would we be able to streamline the likelihood of building up a worthy item? - 2 BOTTOM LINE: Ensure our item meets WHO criteria for quality, steadiness & compatibility Ensure our item has comparative disintegration attributes as the trend-setter at different pH May need to affirm bioequivalence with the trailblazer See Annex 8 to WHO TRS 937 (2006) Proposal to forgo in vivo bioequivalence necessities for WHO Model List of Essential Medicines quick discharge, strong oral dose frames

What are the compound & physicochemical properties of API(s) that we have to know, or are in any event helpful? Solvency at different pH Acid or base? pKa & parcel coefficient Stability under anxiety (eg oxygen, dampness, corrosive and so on) Compatibility with normal excipients

What writing should we search for ? Search for… … A WHOPAR, in the event that one is accessible for your item See http://mednet3.who.int/prequal/default.htm . Search for WHO Public Assessment Reports under Quick Links on the RH side of the page Innovator documentation. Can frequently be found on the pioneer site. The recommending data is particularly valuable & frequently incorporates a rundown of excipients. A medication endorsement bundle (DAP) by means of http://www.fda.gov/cder/foi/nda/An EPAR ( European Public Assessment Report ) An official monograph in the Ph Int A m onograph in Clarke's Analysis of Drugs and Poisons , distributed by The Pharmaceutical Press (most recent release 2004 ) . A m onograph in The Merck Index , distributed by CambridgeSoft ( most recent version 2001). Administrative data See for instance the WHO data line e-drug@healthnet.org .

Case ponder: another brand of Nevirapine 50mg/5 ml oral suspension - 1 Why do we have to know the synthetic structure? To figure out if the dynamic is a corrosive, base or impartial To help with concocting test methodology To decide likely compatibilities/incongruencies Based on a learning of natural science To advise different choices & forecasts that depend on science

Case ponder: another brand of Nevirapine 50mg/5 ml oral suspension - 2 We plan to build up a pediatric item that contains a similar dynamic in a similar measurement & dose shape as a current pediatric item. The trend-setter is Boehringer Ingelheim. The trend-setter brand name is Viramune® 50 mg/5mL oral suspension. The item being worked on is a multisource (non specific) item. The quality, security & adequacy of the current item have been built up. The item will be an oral suspension containing 50mg of nevirapine in each 5mL. The medication is available as a comparable amount of the hemihydrate API. Take note of that the API is frequently a salt or solvate of the dynamic fixing. For this situation the API is the hemihydrate of nevirapine.

What valuable wellsprings of data did we discover? An EPAR at http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf A medication endorsement bundle (DAP) at http://www.fda.gov/cder/foi/nda/98/20-933_20-636S009_Viramune.htm A letter of endorsement 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 , distributed by The Pharmaceutical Press 2004. A monograph in The Merck Index , distributed by CambridgeSoft 2001. Administrative data concerning a conceivable debasement in the API. See http://www.medicalnewstoday.com/articles/82050.php

What helpful data did we discover? - 1 Nevirapine is lipophilic (parcel coefficient 83) & is basically nonionized at physiologic al pH As a feeble base (pK a 2.8), n evirapine demonstrate s expanded solvency at acidic pH The a queous dissolvability ( of the anhydrate) is 90μg/ml at 25°C Nevirapine is by and large stable when focused on

What helpful data did we discover? - 2 There are two precious stone types of the API No polymorphic changes we