2005.03.01 Dr. Pogány - WHO, Shanghai 1/56 Workshop on Quality Assurance and GMP of multisource...

2005.03.01 Dr. Pogány - WHO, Shanghai 1/56

Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines

János Pogány, pharmacist, PhD, consultant to WHO

Shanghai, 01 March 2005E-mail: [email protected]

PharmaceuticalResearch and Development

Quality by design


Abbreviations and NotesAPI Active pharmaceutical ingredientFDC(s) fixed-dose combination(s)FPP(s) Finished pharmaceutical product(s)R+D Research and developmentText in green refers to WHO documents or requirementsText in yellow indicates a quality assessment issueText in light blue highlights key words


Subjects for Discussion1. Desk research — Indinavir2. Submission of pharmaceutical R+D data3. Research (Laboratory scale)

API (specifications, stress stability testing, etc.) FPP (

4. Development (Pilot scale)5. Manufacture (Production scale) 6. Conclusions

What can we learn from the European Public Assessment

Report(s) [EPAR(s)]?

DESK RESEARCH INDINAVIR


Indinavir


Indinavir - Chemistry Indinavir is a chiral molecule with 5 stereogenic centers and is

used as a single isomer, the 4-(R)-epimer. The primary degradation pathway for indinavir sulfate for both

solid state and solution is amide bond hydrolysis to form lactone and aminoindanol. The degradation is humidity and temperature dependent.

Indinavir is highly hygroscopic at relative humidities above 60 %. Indinavir Sulfate monoethanolate converts to hydrate with the loss of ethanol upon exposure to moist air.


Indinavir – Physicochemistry

It has two pKb values: 6.2 and 3.8

Aqueous solubility is 100mg/ml at room temperature but the solubility decreases at higher pH.

Partition coefficient octanol/water (log P) is 2.7 at pH 7.


Indinavir - Biology Early clinical studies revealed a more reproducible

absorption when indinavir was administered as the sulfate salt compared with the free base.

The bioavailability of indinavir is good (approximately 60 %, peak plasma concentration is 0.8 ± 0.3 hours), which facilitates pre-formulation and formulation research.

Toxico-pharmacological information suggests that indinavir pharmaceutical forms may be manufactured in multiproduct plants.


Indinavir - Preformulation In view of indinavir sulfate’s moisture and temperature

sensitivity, poor flowability and relatively loose bulk density, a dry granulation formulation with acceptable compressibility and consistent fill volume during encapsulation was developed.

Anhydrous lactose was selected as a filler and binding aid because of its low moisture content, non hygroscopicity and good compactibility.

Magnesium stearate provides the lubrication required for machinability.


Quality of inactive ingredients Both capsule manufacturers have provided

assurance that gelatin used will be obtained only from BSE-free countries (BSE = bovine (animal) spongiform encephalopathy).

The same assurance could be required for magnesium stearate, or stearic acid and its derivatives in general.


Crixivan™ Capsules Indinavir, as sulfate 100mg 200mg Lactose, anhydrous 37mg 74mg Magnesium stearate ? ?

Indinavir, as sulfate 333mg 400mg Lactose, anhydrous 124mg 149mg Magnesium stearate ? ?


Indinavir – Packing Materials

CRIXIVAN™ 100 mg: hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil induction cap.

CRIXIVAN ™ 400 mg: hard capsules are supplied in all-aluminium blisters.


Indinavir – Labeling HDPE bottles: keep the container tightly

closed in order to protect from moisture. Do not remove the desiccant canister from the bottle.

Blister packs: store in the original package in order to protect from moisture.

Note that the storage temperature is not indicated.


Indinavir – Stability of Capsules No degradation other than the lactone and the

aminoindanol were observed in any of the stressed capsules. The aminoindanol is produced in equimolar amount to the lactone.

Shelf life 24 months for CRIXIVAN™ capsules in blisters. 36 months for CRIXIVAN™ capsules in HDPE

bottles.


Indinavir – Scale up The formulation intended for market has

remained unchanged throughout the development program. Studies showed that the quality of the finished product is not compromised by the scale-up in production.

Flowability and bulk density of granules are important/critical parameters for weight variation.


Indinavir – Scale up The manufacturing process is carried out under GMP at

controlled humidity of the air in the manufacturing areas associated with roller compaction, milling and encapsulating.

HVAC system should maintain a relative humidity of ≤33% at 25oC.

The result of the manufacturing process development is a stable product with low batch-to-batch variation with the finished product specification.


Indinavir – Quality control

The specifications of the FPP cover the Appearance of the capsules, Identity, Assay of drug substance, Dose uniformity, Dissolution test, Test on degradation product and Moisture content.


Indinavir – Quality control

At release, an assay limit of 95-105 % lactone impurity is not more than 0.3%. Batch analyses data for several pilot scale lots used

in clinical, safety and stability studies are submitted and demonstrate a consistent quality of the product and compliance with the stated specifications.


Indinavir – Quality controlAt the end of shelf life, an assay limit of 93-105 % and lactone impurity is not more than 1.5%. The stability studies of the FPP show that the drug

product is stable when stored in the original container, tightly closed and protected from humidity.

Submission of full time stability data on production batches of the finished product is part of the follow-up measures.


Indinavir – Literature

CPMP/589/96 —Committee for Proprietary Medicinal Products (CPMP) European Public Assessment Report (EPAR)— The European Agency for the Evaluation of Medicinal Products, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK

Additional sources of information:

United States patent No. 5,413,999

Literature search on chemistry of indinavir.

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 RESEARCH and DEVELOPMENT


Objective of Pharmaceutical R+D

The Pharmaceutical R+D section presents the knowledge gained through the application of scientific approaches, and risk management, to the development of a FPP and its manufacturing process. It is first submitted in the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product.

The studies described here are distinguished from routine control tests conducted according to specifications.

PREFORMULATION

Laboratory scale R + D


Physicochemical and physical properties of API

Physicochemical

hygroscopicity

solubility

water content

polymorphism

permeability

Physical

particle size

bulk density (g/100ml)

flowability

color, olor, taste

consistency


Equilibrium Moisture ContentAt relative humidities (RHs) <100%, a solid API (that does not form crystalline compounds with water) will loose some bound and all its unbound water until it is in equilibrium with the surrounding atmosphere. The sum of both these moistures is the free moisture of the API (granules) at the specified RH.


Rate of Water Absorption at Different RHs

0,20

0,25

0,30

0,35

0,40

0,451 4 7 10 13 16 19 22 25 28

Lg time, t (3 min. units)

Lg

RH

, %

35%

55%

75%

100%


Solubility of Zidovudine at 25oC

pH Dissolved material (mg/ml)

3.0 21

4.0 20

5.3 20

6.0 21

7.0 22

Distilled water 20

8.0 21


Relationship between Permeability Coefficient and Octanol-Water Partition

1 Prednisolone

...

3 Dexamethazone

...

9 Dexamethazone-acetate

...

11 Progesterone


NORVIR (Ritonavir) EPAR/CPMP /527/96

1. No polymorphism observed at the time of first submission (only form I : hard capsules and oral solution registered)

2. Failure in dissolution during stability studies for hard capsules

3. Emergence of form II (contamination of form I)

4. Production of hard capsules discontinued

5. Development and registration of soft capsules


Particle Size

When the solubility of an API is less than 0.1 mg/ml, the optimization of the particle size during preformulation may be critical to efficacy or pharmaceutical equivalence. Other researchers believe that particle size may be critical at a solubility of 1 mg/ml or less.


Effect of Particle Size on DissolutionUSP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Nevipan MGS(1024)05 (90%LT81.12)Nevipan MGS(1024)60B (90%LT30.89)Viramune 992633B

0 10 20 300.00 50.80 73.80 83.980.00 80.00 92.00 96.000.00 83.30 96.60 97.70

% D

rug

Dis

solv

ed


Screening of Compositions Compatibility of an API with the excipients

and the APIs with each other in FDCs is studied in open system stress stability experiments, e.g., 60-80 oC, 100% RH.

Regulatory stability studies of the final composition are frequently initiated in the pharmaceutical R + D laboratory.


Compatibility of Acetylsalicylic Acid with Excipients

Time (week) Talc A Talc B

Salicylic acid, % Salicylic acid, %

0 0.10 0.10

4 0.32 5.85

8 0.41 13.00

12 0.80 28.50


Triomune - WHOPARExperimental „studies showed chemical incompatibility for the lamivudine with stavudine and nevirapine with stavudine combination. Lamivudine with nevirapine showed no change indicating that they are compatible. Stavudine was found incompatible with both the drugs, indicated by the brown colouration and increase in the impurities.Therefore it was decided to separate stavudine from the other two drugs. Hence the formulation was proposed to be bilayered tablet formulation, where stavudine is in one layer and lamivudine + nevirapine in other layer. Thus contact of stavudine with the other two drugs was minimised.”


Dissolution Test and Profile A (discriminating) dissolution test method should

be developed for the final composition of the FPP.

Limits should be set for each API in fixed-dose FPPs.

The dissolution method should be incorporated into the stability and quality control programs.

Multipoint dissolution profiles of both the test and the reference FPPs should be compared.


Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market

USP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Viramune B.No.992633BBrand C B.No.C00139Ranbaxy B.No.(1024)17

0 10 20 30 450.0 83.3 96.6 97.7 99.70.0 34.3 51.3 61.2 70.80.0 88.9 97.6 99.2 99.7

% D

rug

Dis

so

lve

d

F2

20

73


Hypothetical Dissolution Profile of a 2-FDC FPP

020406080

100120

0 15 30 45 60

minutes

% d

isso

lved Series1

Series2

Series3

Series4


Pivotal BatchesA tabulated summary of the compositions of the clinical, bioequivalence, stability and validation FPP batches together with documentation (batch number, batch size, manufacturing date and certificate of analysis at batch release) and a presentation of dissolution profiles must be provided. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.


Excipients – Lactose (L)Different grade, different physical properties: Angle of repose: 32- 47o (Specs.) Bulk density: 0.34 – 0.80 g/cm3 (Specs.) Bulk density (tapped): 0.41 – 0.95 g/cm3

Flowability (spray processed): 4.1 g/s (Specs.) Hygroscopicity: L monohydrate is stable in air at

room temperature. Anhydrous L may absorb humidity. Moisture content: L monohydrate contains approx.

5% w/w water of crystallization


Excipients – Lactose (L)Solubility in water 1 in 4.63 at 25 oC 1 in 3.14 at 40 oC 1 in 2.04 at 50 oC 1 in 1.68 at 60 oC 1 in 1.07 at 80 oC

Particle size distribution: depends on grade.

Stability: may develop brown colouration (≥ 80% RH)

Incompatibility: APIs with a primary amine group (base catalysed), aminophylline and amphetamines.


Packaging Materials Moisture-impermeable containers: glass ampoules,

vials closed with rubber stoppers and fixed with metal caps, aluminium/aluminium blisters, high density polyethylene (HDPE) or glass bottles fitted with metal metal or HDPE closures, etc.

Moisture-permeable containers: polyvinyl chloride (PVC) blisters, low density polyethylene (LDPE) bottles, HDPE bottles fitted with polypropylene closures.

Specifications of packaging materials should include thickness and permeability coefficient.

Development of a film-tablet manufacturing process

Pilot scale experiments


Justification of Film-coating

1. Mask bitter taste of the tablets

2. Reduce skin contact (risk of allergy)

3. Improve colour uniformity

4. Facilitate packaging


Results of API Stress Stability Testing

Initial assay 98.1%

Storage conditions Assay (%)

50oC 99.9

60oC 98.4

70oC 99.9

30oC/90%RH 100.2

40oC/90%RH 100.1

LIGHT 93.3


Preformulation API is soluble in water, it can be easily

granulated, compression results in good tablets with a rapid dissolution rate. There is no need for particle size reduction.

API is compatible with all excipients, including film-coating inactive ingredients.

Decomposition of API in UV and artificial daylight is not accelerated by the excipients.


Selection of Tablet MassComposition A B C

API (mg) 500 500 500

Excipients (mg) 200 125 56

Tablet mass (mg): 700 625 556

Granules, LOD (%) 0,9 0,8 0,8

Median diameter (μm) 194 186 189

Tablets, hardness (kp) 12.8 13.3 12.4

Friability (%) 0.7 0.5 0.5

Disintegration time 6’30’’ 7’40’’ 10’50’’

Dissolution (%, 15’) 96.6 95.6 96.7


Solvent Selection for BinderPovidone, water (W), ethanol (E) W-E W E

Granules

LOD(%) 0.8 0.9 0.8


Tablets

Average weight (mg) 626 624 628

Hardness (kp) 13.3 11.2 12.9

Friability (%) 0.5 0.5 0.4


Dissolution (%, 15’) 95.6 96.3 75.7


Compression SpeedTabletting machine BB3 BB3 β-Press

Granules, (Mg-stearate %) 0.25 0. 50 0.50

LOD (%) 1.5 1.5 1.5


Tablets

Average weight (mg) 605 607 599

Hardness (kp) 10.9 9.7 7.3

Friability (%) 0.3 0.5 0.8


Dissolution (%, 15’) 99.5 76.7 92.0


Film-coating Parameters

Spraying conditions Pilot batch 1 Pilot batch 2

Film-coater Manesty Manesty

Nozzle (mm) 0.8 0.8

Spraying pressure (psi) 40/25 40/25

Inlet temperature (oC) 81 71

Outlet temperature (oC) 45 44

Spray rate (g/min) 36 26

Drum speed (rpm) 8 10


Film-coating Results

Quality parameterPilot batch 1 Pilot batch 2

Core Coated Core Coated

Weight increase (%) 2.12 2.04

Appearance good good

Mean thickness (mm) 4.25 4.28 4.34 4.37

Hardness (kp) 9.2 14.7 8.7 10.8

Friability (%) 0.3 0 0.44 0

Disintegration time 3’40’’ 5’32’’ 1’44’’ 2’46’’

Dissolution (15’, %) - 93 - 98


Choice of Container

1. Amber glass bottles with LDPE snap-fitting caps, and

2. Amber PVC/aluminium foil blister packs

General principlePackaging should be selected to ensure thequality of the FPP throughout its shelf life.

Pharmaceutical R + D Process includes Transfer of Technology

to the Production Plant

Production scale experiments with validation batches


Validation protocol and report Data should be submitted in the application for

prequalification demonstrating the validity of a given process.

Formal studies of production scale batches (normally not less than three consecutive batches) are required before the product is placed on the market.

Where validation data on production scale batches are not provided with the application, the applicant should submit the validation protocol.

Following completion of the programme, a validation report should be generated for examination by WHO.


Main points again Pharmaceutical R + D is an essential part of

applications for Marketing Authorization. Desk research gives valuable information. Laboratory scale studies should identify critical

product quality attributes. FDCs require particular tests. Packing materials should also be selected through

documented experiments.


Main points again Pilot plant experiments should provide the basis

for process optimisation, process validation and process control requirements.

Validation batches at production scale should establish the critical process parameters (e.g., granulation end point, drying temperature) that should regularly be monitored or controlled to guarantee batch-to-batch consistency of quality.


THANK YOU

谢谢 !

2005.03.01 Dr. Pogány - WHO, Shanghai 1/56 Workshop on Quality Assurance and GMP of multisource...

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