1. World Health Organization
Pharmaceutical Development
6 April, 2017
Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations
Tallinn
15-19th October 2007

2. Pharmaceutical Development
World Health Organization
Pharmaceutical Development
6 April, 2017
Pharmaceutical Development of Finished Pharmaceutical Products (FPPs)
Presenter: Susan Walters

3. The Australian view of the world
World Health Organization
6 April, 2017
The Australian view of the world
We are here!
This place isn’t too bad either!

4. What Australia gave to the world (1)
World Health Organization
6 April, 2017
What Australia gave to the world (1)

5. What Australia gave to the world (2)
World Health Organization
6 April, 2017
What Australia gave to the world (2)

6. Pharmaceutical Development of FPPs
World Health Organization
Pharmaceutical Development of FPPs
6 April, 2017
Outline of presentation
We will:
Look at the development process as a whole & consider its objectives
Review relevant guidelines
Review sources of information
Go through a worked example

7. Objectives of Pharmaceutical Development : What is the purpose?
World Health Organization
6 April, 2017
Objectives of Pharmaceutical Development : What is the purpose?
From the perspective of a generic manufacturer, the objective is to develop a product that is:
of appropriate quality &
interchangeable with the innovator brand (so we can avoid expensive & time-consuming studies of safety & efficacy)

8. Objectives of Pharmaceutical Development : What is the purpose?
World Health Organization
6 April, 2017
Objectives of Pharmaceutical Development : What is the purpose?
From the perspective of the manufacturer of a new dosage form &/or strength (eg a paediatric dosage form), the objective is to develop a product that is:
Of appropriate quality, &
Of appropriate dosage form & strength, &
Either has been shown to be safe & effective for the claimed indications & patient population or has been shown to pharmacokinetically interchangeable with a brand that has been shown to be safe & effective for the claimed indications & patient population
However safety & efficacy is outside the scope of this presentation so I will deal only with generics that contain the same API in the same dosage form & strength as the innovator

9. World Health Organization
6 April, 2017

10. World Health Organization
6 April, 2017
Product & process development (sorry don’t know the source of this diagram)
CONTINUOUS IMPROVEMENT

11. Terminology – from ICH Q1A(R2) 2003 (stability)
World Health Organization
Terminology – from ICH Q1A(R2) 2003 (stability)
6 April, 2017
Production batch:
A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified
Pilot scale batch:
A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.
Laboratory scale batch [not an ICH definition]
A batch smaller than pilot scale that is manufactured for development purposes
Remember that scale-ups must be validated – batch characteristics may change during scale-up

12. Relevant non-WHO guidelines
World Health Organization
Relevant non-WHO guidelines
6 April, 2017
ICH Q8 Pharmaceutical Development (2005)
ICH Q9 Quality Risk Management (Nov 2005)
ICH Q10 DRAFT Pharmaceutical Quality System (May 2007)
Note for guidance on Process Validation CHMP/QWP/848/96 (EU 2001)
An elderly guideline but informative & helpful

13. Relevant WHO guidelines
World Health Organization
Relevant WHO guidelines
6 April, 2017
Pharmaceutical Development, Section 3.2 of Guideline on Submission of Documentation for Prequalification of Multi- source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis, WHO PQP (2005)
Extension of the WHO List of Stable (not easily degradable ARV) APIs, Supplement 2 (Rev 1) to Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis, WHO PQP (2005)
Supplementary guidelines on Good Manufacturing Practices: Validation, Annex 4 to WHO TRS 937 (2006)

14. Some relevant journals
World Health Organization
Some relevant journals
6 April, 2017
Pharmaceutical Technology
Pharmaceutical Technology Europe
Pharmaceutical Industry
Pharmaceutical Development and Technology
Drug Development & Industrial Pharmacy
Pharmaceutical Manufacturing
Dissolution Technologies - A free on-line journal at
European Journal of Pharmaceutics and Biopharmaceutics
Pharmazie in Unserer Zeit (often in German)
S.T.P. Pharma Pratiques (often in French)
Pharmaceutisch Weekblad (often in German)
It is often possible to obtain access to journals via university on-line databases

15. Some relevant websites
World Health Organization
Some relevant websites
6 April, 2017
WHO medicines program.
WHO prequalification program.
ICH website
htm
European guidelines for human medicines
international Pharmaceutical Federation: Pharmaceutical Sciences section
Dissolution methods for drug products

16. World Health Organization
How can we optimise the possibility of developing an acceptable product? - 1
6 April, 2017
Form a development team
Include staff with experience in formulation, manufacturing, quality control, stability testing
Prepare a development plan, set goals & timelines, & monitor progress with regular meetings (eg weekly in the first instance)
Make use of experienced staff within your company, especially in relation to manufacturing equipment & procedures
Review the literature for information on:
Chemical & physicochemical properties of the API(s)
Information on the innovator product
Conduct experiments to fill in the gaps in information,
Especially concerning API properties & compatibilities
If possible, use the same excipients as the innovator.
Less likely to encounter problems with compatibility, stability, bioequivalence
If possible, use standard manufacturing procedures with which your company has experience
More likely to achieve suitable dissolution properties & reproducible manufacturing

17. World Health Organization
How can we optimise the possibility of developing an acceptable product? - 2
6 April, 2017
BOTTOM LINE:
Ensure our product meets WHO criteria for quality, stability & interchangeability
Ensure our product has similar dissolution characteristics as the innovator at various pH
May need to confirm bioequivalence with the innovator
See Annex 8 to WHO TRS 937 (2006) Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

18. World Health Organization
What are the chemical & physicochemical properties of API(s) that we need to know, or are at least useful?
6 April, 2017
Solubility at various pH
Acid or base?
pKa & partition coefficient
Stability under stress (eg oxygen, moisture, acid etc)
Compatibility with common excipients

19. What literature should we look for?
World Health Organization
What literature should we look for?
6 April, 2017
Look for……
A WHOPAR, if one is available for your product
See Look for WHO Public Assessment Reports under Quick Links on the RH side of the 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
An EPAR (European Public Assessment Report)
An official monograph in the Ph Int
A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press (latest edition 2004).
A monograph in The Merck Index, published by CambridgeSoft (latest edition 2001).
Regulatory information
See for example the WHO information line

20. Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 1
World Health Organization
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 1
6 April, 2017
Why do we need to know the chemical structure?
To determine whether the active is an acid, base or neutral
To assist in devising assay procedures
To determine likely compatibilities/incompatibilities
Based on a knowledge of organic chemistry
To inform other decisions & predictions that are based on chemistry

21. Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 2
World Health Organization
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 2
6 April, 2017
We plan to develop a paediatric product that contains the same active in the same dose & dosage form as an existing paediatric product.
The innovator is Boehringer Ingelheim. The innovator brand name is Viramune® 50 mg/5mL oral suspension.
The product under development is a multisource (generic) product.
The quality, safety & efficacy of the existing product have been established.
The product will be an oral suspension containing 50mg of nevirapine in each 5mL. The drug is present as an equivalent quantity of the hemihydrate API.
Note that the API is often a salt or solvate of the active ingredient. In this case the API is the hemihydrate of nevirapine.

22. World Health Organization
What useful sources of information did we find?
6 April, 2017
An EPAR at
A drug approval package (DAP) at 933_20-636S009_Viramune.htm
A letter of approval at
An official monograph in the Ph Int.
A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press 2004.
A monograph in The Merck Index, published by CambridgeSoft 2001.
Regulatory information concerning a possible impurity in the API. See
Defined “In-use” stability earlier today.
EXERCISE:
What other examples might there be of in-use stability that should be addressed in stability studies?
[Possible answers:
- Pdr for injn reconstituted before use
- Mixing of injectable with LVPs
- Heating of injectable with solid particles before use (see fluorouracil injection DBL “If a ppt has formed as a result of exposure to low temperature, redissolve by heating to 60degC accompanied by vigorous shaking. Allow to cool to body temperature prior to use”. )
Antibiotics po lqds for reconstitution by a pharmacist prior to use
Issue of separate labelling after reconstitution]

23. What useful information did we find? - 1
World Health Organization
6 April, 2017
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 90μg/ml at 25°C
Nevirapine is generally stable when stressed

24. What useful information did we find? - 2
World Health Organization
6 April, 2017
What useful information did we find? - 2
There are two crystal forms of the API
No polymorphic changes were observed under stressed conditions
The API (hemihydrate) is non-hygroscopic
The synthesis of the two crystal forms is similar until the final drying step
The impurity profile is well characterised
Impurities arising from the synthesis have been toxicologically qualified
No degradation products were detected during stability testing of the API
The API is milled in order to obtain an acceptable particle size distribution for the suspension
Nevirapine is official in the Ph Int
Batch analysis data confirmed that nevirapine hemihydrate complies with the specifications

25. What useful information did we find? - 3
World Health Organization
6 April, 2017
What useful information did we find? - 3
The innovator markets an oral suspension (Viramune ® 50 mg/5 ml) containing nevirapine (present as the hemihydrate at mg/ml).
That is….the active is nevirapine & the API is nevirapine hemihydrate
Excipients in the innovator formulation are:
Carbomer 934P (synthetic high molecular weight crosslinked polymers of acrylic acid), methyl & propyl hydroxybenzoates, sorbitol, sucrose, polysorbate 80, NaOH, purified water.
The shelf life of the innovator is 3 years.
The product should be used within 2 months of opening (‘in-use’ stqbility).
The innovator has no special precautions for storage

26. What useful information did we find? - 4
World Health Organization
6 April, 2017
What useful information did we find? - 4
The innovator’s container is a white HDPE bottle with two piece child-resistant closure (outer shell white HDPE, inner shell natural polypropylene) with LDPE foam liner. Each bottle contains 240 ml of oral suspension.
Included with the innovator product is a clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber piston seal, & a clear low density polyethylene bottle-syringe adapter.
See
A monograph (Ph Int) is being developed for the FPP, nevirapine oral suspension
NB check the WHO website for the latest information

27. What useful information did we find? - 5
World Health Organization
6 April, 2017
What useful information did we find? - 5
The HDPE bottle is inert & has been shown to be compatible with the active substance & other ingredients of the innovator’s formulation.
% content of antimicrobial preservatives has been correlated with antimicrobial effectiveness when tested according to Ph Eur methodology
Acceptable data are available to demonstrate the precision & accuracy of the innovator’s dosing syringe
None of the synthesis impurities are degradants
The method of preparation of the oral suspension is standard for this dosage form & has been well described. Validation data presented for three production batches manufactured using three different lots of nevirapine demonstrated that the process is under control & ensures both batch-to-batch reproducibility & compliance with standard specifications. Tests at release are typical & ensure reproducible performance of the product.

28. What useful information did we find? - 6
World Health Organization
6 April, 2017
What useful information did we find? - 6
Stability data are available for up to 18 months for the innovator. Long-term stability data have been promised on an ongoing basis.
An in-use stability study has been performed that mimics delivery of a 2mL dose, representing one of the lowest projected doses using the delivery device intended for marketing
An additional study has been conducted on the stability of the product exposed to freeze-thaw conditions
On the basis of results from these studies, an in-use shelf life of 60 days with no special storage precautions is claimed

29. What useful information did we find? – 7
World Health Organization
6 April, 2017
What useful information did we find? – 7
In vivo data provided by the innovator included the following :
Nevirapine is readily absorbed (> 90 %) after oral administration in healthy volunteers & in adults with HIV-1 infection.
A 3-way crossover study comparing the bioavailability of three production/commercial scale batches that had varying dissolution profiles showed that all three batches were bioequivalent with respect to systemic exposure (AUC). The statistically significantly different values for Cmax and tmax were considered not to be clinically relevant.
In studies in which the suspension was administered directly using a syringe, it was demonstrated that the suspension & tablet formulations were comparably bioavailable with respect to extent of absorption.
In a study in which the suspension was administered in a dosing cup without rinsing, the suspension intended for marketing was bioequivalent to the suspension used during clinical trials but was not bioequivalent to the marketed tablets. This was attributed to incomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.

30. What useful information did we find? – 8
World Health Organization
6 April, 2017
What useful information did we find? – 8
Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatric population. A 4 mg/kg dose is proposed for all children regardless of age. Although no particular study has been performed to find the optimal lead-in dose, this dose was considered acceptable considering the enzyme induction to achieve initial antiretroviral activity.
The following doses were approved:
Patients from 2 months to 8 years, 4mg/kg once daily for 2 weeks followed by 7mg/kg twice daily
Patients from 8 years to 16 years, 4 mg/kg once daily followed by 4mg/kg twice daily

31. World Health Organization
6 April, 2017
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

32. Benchmarking the innovator - 2
World Health Organization
6 April, 2017
Benchmarking the innovator - 2
The qualitative composition suggests that:
Sucrose and sorbitol are used to adjust the density of the medium
Carbomer 934P is used to adjust viscosity
Polysorbate is a wetting agent
Sodium hydroxide is used to adjust the pH to 5.8

33. Benchmarking the innovator – 3 Our tests show…..
World Health Organization
6 April, 2017
Benchmarking the innovator – 3 Our tests show…..
% API dissolved (hypothetical figures)
Time (minutes) 27 5 42 10 55 15 65 20 76 30 88 45 92 60
Dissolution profile (% labeled strength)
Apparatus: USP II (paddle, 25rpm)
Medium: 0.1N HCl
Volume: 900ml
See olution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March 2007

34. Benchmarking the innovator - 4 Our tests show…..
World Health Organization
6 April, 2017
Benchmarking the innovator - 4 Our tests show…..
% API dissolved (hypothetical figures)
pH 6.8 buffer
pH 4.5 buffer
pH 1.2 buffer
Time (minutes) 22 15 27 5 25 42 10 35 36 55 65 20 49 48 76 30 57 88 45 92 60 50
100 90
Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated

35. Pharmaceutical development protocol
World Health Organization
6 April, 2017
Pharmaceutical development protocol
API experiments
Particle size distribution
Formulation experiments
Screening laboratory batches with different proportions of excipients to match innovator dissolution
Stress testing of the selected composition
Compatibility with excipients
Antimicrobial effectiveness test according to Ph Eur
Packing materials
Dimensions and tolerances of packing components
Precision & accuracy of the dosing syringe

36. Product-specific API properties
World Health Organization
Product-specific API properties
6 April, 2017
Ph Int specifications + limits on residual solvents from API manufacture
Product-specific physical properties depend on crystallization and subsequent physical processing. Density and particle size distribution of nevirapine hemihydrate are critical quality attributes. Acceptance criteria are established by measurement of particle size of innovator’s API in suspension & through the similarity of dissolution profiles of innovator and generic products.

37. World Health Organization
6 April, 2017
Undertake stress testing of the API if not already available in existing documentation
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
Heat
130o C, 49h
101.5
Light
500W/m2, 68h
101.7
Water
25o C, 92% RH, 91h
101.2

38. World Health Organization
Solubility of nevirapine hemihydrate at 37oC If not already available in existing documentation
6 April, 2017
Note:
Nevirapine hemihydrate belongs to BCS2 (low solubility, high permeability)
See Annex 8 to WHO TRS 937 (2006)
Solubility data are also important for cleaning validation

39. Dissolution profiles of innovator & generic FPPs Hypothetical data
World Health Organization
6 April, 2017
Dissolution profiles of innovator & generic FPPs Hypothetical data M e a n % A P I d i s o l v
▀ innovator
▀ generic
Similarity factor f2=73
Time (minutes)

40. Selected generic composition Hypothetical numbers
World Health Organization
6 April, 2017
Selected generic composition Hypothetical numbers
Ingredients mg/5ml
Nevirapine hemihydrate
Excipients
Carbomer 934P
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
Sorbitol
Sucrose (!)
Polysorbate
Sodium hydroxide q.s.
Purified water to make ml

41. Proposed FPP specifications A hypothetical set of limits
World Health Organization
6 April, 2017
Proposed FPP specifications A hypothetical set of limits
Description: including at least colour, texture, odour
Identification (HPLC)
Dissolution (UV): Q = 70% in 45 minutes
pH = 5.0 – 6.1
Deliverable volume
Average fill volume: NLT 240 ml
Fill volume variation: Meets Ph Int requirements
Related substances: NMT 0.1% of any one imp & NMT 0.3% total imps
Preservative content (HPLC)
Methylparaben: 98 to 102% of labeled strength
Propylparaben: 98 to 102% of labeled strength
Assay: 95.0 to 105.0% of labeled strength

42. World Health Organization
6 April, 2017
Compatibility with excipients May not need to do this if use only the same excipients as the innovator
Nevirapine hemihydrate in solid state – illustrative example: heat

43. Development of manufacturing process
World Health Organization
6 April, 2017
Development of manufacturing process
Select a standard process for oral aqueous suspensions, if possible using our existing method
Manufacture a lab scale batch
If necessary make adjustments & manufacture another lab scale batch
When satisfied with the formulation, manufacture a pilot scale batch
If necessary make adjustments & manufacture another pilot scale batch
Recollect that a pilot batch is manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch
Manufacture primary* batches in the proposed container & closure systems for:
Bioequivalence & dissolution studies
Regulatory stability studies
Iincluding an in-use stability study & a stress study under freeze-thaw conditions
Validation of bioequivalence, dissolution & stability batches
*Primary as defined in WHO/ICH guidelines

44. Development of manufacturing process
World Health Organization
6 April, 2017
Development of manufacturing process
Note that the progress from pre-formulation to formulation to pilot manufacture to production scale manufacture should be described in the PQP dossier & shown to be logical, reasoned & continuous

45. World Health Organization
6 April, 2017
Scale up activities
Test a large number of samples from pilot scale batches to establish provisional acceptance limits for the control of critical process parameters (prospective validation, in-process control limits) in order to define the design space* & a control strategy that encompasses batch scale, equipment, packaging, as well as final product stability. The process will be well understood when:
all critical sources of variability have been identified & explained
variability is managed by the process
product quality attributes can be accurately & reliably predicted
A validation protocol is written
* See ICH Q8, Q9 & draft Q10 for further explanation

46. Dissolution & bioequivalence testing
World Health Organization
6 April, 2017
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

47. Pharmaceutical Development Summary and conclusion
World Health Organization
Pharmaceutical Development Summary and conclusion
6 April, 2017
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