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Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

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April 2007

Pharmaceutical Development
Developing formulation and manufacturing process
Presenter: Jnos Pogny, pharmacist, PhD
WHO expert

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April 2007

API EoI FDC FPP GMP ICH MA PQP TRS Active Pharmaceutical Ingredient Expression of Interest Fixed-Dose Combination Finished Pharmaceutical Product Good Manufacturing Practices International Conference on Harmonization Marketing Authorization PreQualification Project Technical Report Series of WHO
Green WHO Violet ICH region

Red emphasis

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April 2007

Pharmaceutical Development
Outline and Objectives of presentation
Objective, guidelines Literature and patent survey Generic pharmaceutical product and process development assessors view of a science- and risk-based approach
Laboratory scale Pilot plant Production plant Presentation of dossier for prequalification Continuous improvement

Main points again

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April 2007

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Objective, guidelines

Interchangeability (IC)


IC = PE + BE

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Pharmaceutical equivalence
Products are pharmaceutical equivalents1 if they contain the
same molar amount of the same active pharmaceutical ingredient(s) in the same dosage form if they meet comparable standards, and if they are intended to be administered by the same route

1 Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.

Pharmaceutical development equivalence, including stability equivalence (and packaging equivalence)

WHO-GMP (manufacturing process equivalence)

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Focus on paediatric dosage forms

Epivir (lamivudine) 10 mg/ml oral solution Retrovir (zidovudine) 100 mg/10 ml oral solution Sustiva (efavirenz) 30 mg/ml oral solution Viramune (nevirapine) 50 mg/5 ml oral suspension Zerit (stavudine) 200 mg powder for oral solution Powder for oral suspension, capsules, film-coated tablets and chocolate pastilles can also be considered

Once safe and effective doses are established, generic FPPs can be developed and bioequivalence demonstrated

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April 2007

Pharmaceutical development
Qualification Stage Key elements Design & C Installation Operation Validation Stage Prospective Concurrent

Facilities and Equipment

Engineering phase

Manufacturing Start-Up

(Validation Protocols)

(Batch Records and Validation documentation)


Preparatory phase (Validation of analytical methods)

Design (laboratory) (Critical attributes and formula screening)

Scale-Up (pilot plant) (process optimization and stability batch biobatch)

Production (final batch size, reproducible quality)

Product and process development

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April 2007

Guidelines used in PQP

Annex 6. Validation of manufacturing processes, in WHO TRS No. 863 (1996).
WHO 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. 3.2 Pharmaceutical Development

ICH Q8 Pharmaceutical Development (Nov. 2005) ICH Q9 Quality risk management

(E.g., FMEA might be used to analyze a manufacturing operation and its effect on product or process. It identifies elements/operations within the system that render it vulnerable.)

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April 2007

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Desk research

Nevirapine 50mg/5 ml oral suspension

Information on Nevirapine
The synthesis of the two crystal forms is similar until the final drying step Impurity profile is well characterised. Impurities arising from synthesis have been toxicologically qualified

The API is milled in order to obtain an acceptable particle size distribution

The API is non-hygroscopic No polymorphic changes were observed under stressed conditions

No degradation products have been detected during stability testing

Batch analysis data confirm that nevirapine hemihydrate complies with the specifications

Nevirapine is official in the PhInt

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April 2007

Information on Nevirapine
Nevirapine is lipophilic (partition coefficient 83) and is essentially nonionized at physiologic pH. As a weak base (pKa 2.8), Nevirapine is showing increased solubility at acidic pH values.

Source: Meck Index Aqueous solubility (anhydrate) (90g/ml at 25C). Nevirapine is highly stable

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April 2007

Viramune 50 mg/5 ml oral suspension

Oral suspension containing 10 mg/ml of nevirapine as 10.35 mg/ml Nevirapine Hemihydrate as the API. Excipients: Carbomer, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water. (FDA excipient list: Carbomer 934P). Shelf life: 3 years The product should be used within 2 months of opening. No special precautions for storage Nature and contents of container 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. Clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber piston seal. Clear low density polyethylene bottle-syringe adapter.

Nevirapine oral suspension monograph (PhInt) is being developed

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April 2007

Viramune 50 mg/5 ml oral suspension

The HDPE bottle material is inert and was shown to be compatible with the active substance and other ingredients of the formulation. The levels of preservatives have been correlated with antimicrobial effectiveness tested according to PhEur Acceptable data demonstrating the precision and accuracy of the dosing syringe were provided. Synthesis impurities are not degradants and not part of FPP specifications The method of preparation of the oral suspension is standard for this form and has been adequately described. Validation data presented on three production batches manufactured using three different lots of nevirapine anhydrous (?) were adequate to demonstrate that the process is under control and ensures both batch-to-batch reproducibility and compliance with standard specifications. Tests at release are standard and ensure reproducible clinical performance of the product.

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April 2007

Viramune 50 mg/5 ml oral suspension

Stability data up to 18 months for the newly recapped oral suspension and 24 months with the old pulpboard liner confirmed the physical and chemical stability of the oral suspension and the antimicrobial efficacy of the preservative. These results support a shelf life of 24 months. Long-term stability data will be submitted on ongoing basis. An in-use stability study designed to mimic the delivery of 2 ml dose, which represents one of the lowest projected doses, twice a day, using the delivery device intended for marketing has been performed. An additional study is presented on the stability of the product exposed to freeze-thaw conditions. On the basis of results from both studies, the claimed in-use shelf life of 60 days with no special storage precautions is supported.

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Clinical information
Nevirapine was readily absorbed (> 90 %) after oral administration in healthy volunteers and in adults with HIV-1 infection. A 3-way crossover study compared the bioavailability from three production/commercial scale batches with varying dissolution profiles. All three batches were bioequivalent with respect to systemic exposure (AUC). The significantly different values for Cmax and tmax were considered not to be clinically relevant. In studies 1100.1231 and 1100.896 in which the suspension was administered directly using a syringe, it was demonstrated that the suspension and tablet formulations were comparably bioavailable with respect to extent of absorption. In study 1100.1213 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 could be attributed to incomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.

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Clinical information
It has been later determined in a single dose study in 9 patients aged between 9 months and 14 years administered after an overnight fast (3 patients per dose level equivalent to 7.5 mg/m, 30.0 mg/m and 120.0 mg/m). 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 the 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 final recommended doses for the different ages are therefore the following: Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7 mg/kg bid Patients from 8 years to 16 years are 4 mg/kg once daily followed by 4-mg/kg bids.

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April 2007

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Generic pharmaceutical product and process development

Pharmaceutical development for generics

Product target profile (PTF) is different:
Innovator PTP is based on clinical studies Generic FPP targets the innovator FPP

Multisource FPP manufacturers must be highly skilled in product development

The chances of developing a bioequivalent generic product can be significantly increased by using the formulation of the innovator. The lowest risk strategy for the development of an interchangeable multisource FPP is to copy the innovator FPP.
Manufacturing processes are the same for innovators and generic manufacturers.

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April 2007

Innovator suspension bench marking (1)

Sample confirmation
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) Methylparaben (HPLC): 0.18% w/v Propylparaben (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

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April 2007

Innovator suspension bench marking (2)

The 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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April 2007

Innovator product bench marking (3)

Time (minutes) % API dissolved
(hypothetical figures)

Dissolution profile (% LA) Apparatus: USP II (paddle, 25rpm)




Medium: 0.1N HCl

Volume: 900ml olution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March 2007

30 45

76 88


April 2007

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Innovator product bench marking (4)

% API dissolved
(hypothetical figures)

% API dissolved
(hypothetical figures)

% API dissolved
(hypothetical figures)

Time (minutes)

pH 1.2 buffer 27

pH 4.5 buffer 15

pH 6.8 buffer 22

10 15 20 30 45 60 90

42 55 65 76 88 92 100

25 36 42 48 49 49 50

27 35 42 49 57 65 76

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

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Pharmaceutical development protocol

API experiments
Solubility at 37 oC Particle size distribution Density

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 PhEur

Packing materials
Dimensions and tolerances of packing components Precision and accuracy of the dosing syringe

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Product-specific physical API properties

Introduction of the API starting material(s) into process Physical processing and packaging

Production of intermediate(s)

Isolation and purification

PhInt specifications + residual solvents from APIMF. Product-specific physical properties depend on crystallization and subsequent physical processing. Density and particle size distribution of Nevirapine Hemihydrate are critical quality attributes of the API. Acceptance criteria are established by measurement of particle size of innovators API in suspension and through the similarity of dissolution profiles of innovator and generic products.

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April 2007

Stress stability testing - Nevirapine

Stress type Control 36% HCl 5N NaOH 30% w/w H2O2 Heat Light Water

Conditions 25o C 80o C, 40 min. 80o C, 2h 20 80o C, 2h 20 130o C, 49h 500W/m2, 68h 25o C, 92% RH, 91h

Assay (%) 99.8 72.0 98.6 98.6 101.5 101.7 101.2

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April 2007

Solubility of nevirapine hemihydrate at 37oC

1.2 2.1

Dissolved material (mg/ml)

(hypothetical figures)

2.75 0.28

3.0 4.5 6.8

7.2 8.0

0.08 0.06 0.06

0.06 0.06

Nevirapine Hemihydrate belongs to BCS Class 2 (low solubility, high permeability).

Solubility data are also important for cleaning validation


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Dissolution profiles of innovator and generic FPPs

M e a n % A P I d i s s o l v e d

120 100

80 60 40 20 0 0 10 20 30 40 50 60 70 80 90


Similarity factor, f2=73

Time (minutes)

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Selected generic composition (hypothetical figures)


Nevirapine hemihydrate Excipients


mg/5ml 51.7

Carbomer 934P Methyl parahydroxybenzoate Propyl parahydroxybenzoate Sorbitol Sucrose Polysorbate 80 Sodium hydroxide Purified water to make
April 2007

8.0 10.0 1.0 800.0 700.0 3.0 q.s. 5.0 ml

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Compatibility with excipients

Nevirapine Hemihydrate in solid state illustrative example: heat

Stress Condition None


Initial values API


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

Observations Assay: SI1: D1: Total unspecified: Total impurities: Assay: SI1: D2: Total unspecified: Total impurities:

To do: stress testing the dose-proportional mixture of the APIs in aqueous medium.

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Risk assessment matrix illustrative

Milling Wetting Weighing API API Dissolution Assay Degradation Content uniformity Stability physical microbial pH Vehicle Wet milling Filling Packing

Not critical to Q

Potentially critical to Q Monitoring strategy

Critical to Q Control strategy

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Process development
Selection of process: standard for oral aqueous suspensions The progress from pre-formulation formulation pilot manufacture (not less than 1/10th of production batch) production scale (approved batch size) manufacture should be shown in the dossier submitted for prequalification to be logical, reasoned and continuous. A pilot batch is manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. Manufacture of primary batches in the proposed container and closure systems for:
Bioequivalence and dissolution studies Regulatory stability studies ( including in-use stability study and an additional study under freeze-thaw conditions.) Prospective validation of bioequivalence, dissolution and stability batches

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Proposed FPP specifications

Description Identification (HPLC) Dissolution (UV): Q = 70% in 45 minutes pH = 4.8 6.2 Deliverable volume
Average fill volume: NLT 240 ml Fill volume variation: should meet PhInt requirements

Related substances: not tested Preservative content (HPLC)

Assay: 95.0 to 105.0% of LA

Methylparaben: 98 to 102% of LA Propylparaben: 98 to 102% of LA

[End of shelf life: 80 to 102% of LA] [End of shelf life: 80 to 102% of LA]

End-of shelf-life acceptance limits for assay should not be proposed at this stage.

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Scale up activities
Stability protocol is prepared A large number of samples is tested from pilot scale batches to establish provisional acceptance limits for the control of critical process parameters (prospective validation, IPC limits) in order to define design space (process knowledge) and control strategy (risk mitigation) that encompasses aspects of scale, environmental aspects of site, packaging, as well as final product stability. The process will be well understood when:
all critical sources of variability have been identified and explained variability is managed by the process product quality attributes can be accurately and reliably predicted

Validation protocol is written Dossier is submitted for prequalification


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High-shear batch mixer and in-line mixer

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Dissolution (and bioequivalence) batch

Innovator FPP Dissolution test 3 batches
Select a batch showing intermediate dissolution

Generic FPP Production batch, or NLT 1/10 of final size

Reference product

Test product

Dissolution profile

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Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Special features of FDCs

4-FDC antituberculosis FPP

Originator FPP in ICH region
None FPP in current (14th) List Essential Medicines Rifampicin Isoniazid Pyrazinamide Ethambutol 150 mg 75 mg 400 mg 275 mg

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4FDC-TB tablets exposed to 40C/75%RH for one week

Two different products. Bleeding may start after more exposure to stress testing without packing material. (Source: North-West University, South Africa) Control on left Control on left

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A typical incompatibility
Magnesium stearate is incompatible with salts of weak bases and strong acids, such as:
Amodiaquine hydrochloride Ethambutol hydrochloride Mefloquine hydrochloride

because the formed MgCl2 is highly hygroscopic (the hexahydrate is also deliquescent) and, as a result, the lubricant properties of magnesium stearate also change.

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Critical quality variables

1. The formulation is hygroscopic, sensitive to light and unstable (reaction between rifampicin and isoniazid). 2. Moisture content of FPP and intermediates (granules and uncoated tablets). 3. Ethambutol.2HCl provides acidic conditions to accelerate reaction between rifampicin and isoniazid. 4. Packing materials are critical for stability. 5. Compatibility of APIs with each other and with excipients 6. Stress stability testing of the final formulation 7. Control of temperature and RH during the manufacturing process 8. Heavy-duty compression machine. 9. Validation batches and annual product review reports. 10. Stability testing of the FPP to include visual inspection, assay, impurities and degradants (in particular isonicotinyl hydrazone), LOD, hardness, and other attributes.

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Main points again

Pharmaceutical development is an essential part of applications for prequalification. Desk research gives valuable information for generic pharmaceutical product and process development for paediatric formulations. FPP-specific quality and processability requirements are integrated into the API specifications during pharmaceutical development studies. A science- and risk-based pharmaceutical development of generic FPPs provides a high level of assurance for interchangeability with the innovator product. Manufacturing process design and optimization identifies the critical attributes whose control leads to the batch-to-batch consistency of quality.

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Science- and risk-based approach means:

There will be no weak eye in the pharmaceutical development chain

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