Advanced pharmaceutical formulation approaches

Nadeem Irfan BukhariUniversity College of Pharmacy, University of the Punjab, Lahore

The current approach

• Experience-based• Produces product above

minimum acceptable but below desired quality level

• Produces compromised products (usually)

• One factor at a time (OFAT) approach

Minimum Level

Aspirational Level

Qu

alit

y at

trib

ute

s

The advanced approaches• Computer-aided• Simultaneous manipulation of all factors• Effective• Maximize information with minimum

experimentation• Simultaneously optimize factors and responses• Reveal factor interactions (synergistic or

otherwise)• Recommended by FDA/other regulatory/ or

standard-setting organizations

The advanced approaches• Produce formulations:

– with optimized properties - meeting stringent quality requirements

– robust - maintains desired quality attributes after small external changes

– knowledge-based – understood ‘factor-response relationships’

– prepared by understood method (PAT)– with quality (achieved) by design (QBD)

The advanced approaches• Quality by design (QBD) – a structured and

organized method for determining relationship between factors affecting a process and the response(s) of that process

• PAT - system for designing, analysing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw materials and processes with the goal of assuring final product quality

The advanced approaches

Development efforts

Minimum Level

Aspirational Level

Acceptable

Qu

alit

y at

trib

ute

s Maximally achievable

ByOFAT

By DoE/ANN

• Require less effort in product development

Design-Expert® SoftwareFactor Coding: ActualOverlay Plot

Conversion CI LowActivity CI Low CI High

X1 = A: TimeX2 = B: Temperature

Actual FactorC: Catalyst = 2.68

40.00 42.00 44.00 46.00 48.00 50.00

80.00

82.00

84.00

86.00

88.00

90.00Overlay Plot

A: Time

B: T

em

pe

ratu

re

Conversion: 82.000

Conversion CI: 82.000

Activity: 60.000Activity CI: 60.000

Conversion: 91.314 CI Low: 87.676Activity: 63.000 CI Low: 62.340 CI High: 63.659X1 47.02X2 90.00

Design space –another advantage

• FDA defined “Design Space” as:– Multidimensional combination and interaction

of input variables that provide assurance of optimum quality

– Design space is declared for regulatory assessment and approval

– Working within the design space is not considered as a change

– Otherwise requires approval

The advanced approaches

• Advantages and applications

The advanced approaches• Prepared by any of the advanced formulation

approaches– Experiment by design – borrowed from QBD -

an experiment performed in structured and organized (designed) way to find relationships between factors and response

– Artificial Neural Network – a biologically inspired mathematical system which finds the relationships between factors and properties

The advanced approaches• DoE

– Principal component analysis– Factorial analysis (ANOVA)– Multiple regression– Response surface methodology

• ANN

The advanced approaches

• ANN

The advanced vs OFAT approach

• OFAT– can improve but never

approaches optimal settings cannot estimate each factor effect independent of existence of other factor effects

– takes more time to reach the same conclusions

– fail to relate multiple responses to different factors

– quality by testing

• Advance approaches– conceptual –

require knowledge– efficient,

economical– reveal interactions– quality by design

…. – a case study

• Now for granulation– Factors

• X1 Impeller speed• X2 Fluid addition rate

– Responses for granulation• Y1 Fines• Y2 Overs• Y3 Yield

Factors (Units) Low HighImpeller Speed (RPM) 120 180Addition Rate G/M 65 85

…. – a case study

…. – a case study

Design-Expert® SoftwareFactor Coding: ActualFines

Design points above predicted valueDesign points below predicted value26

0

X1 = A: Impeller SpeedX2 = B: Addition Rate

65.00

70.00

75.00

80.00

85.00

120.00 126.00

132.00 138.00

144.00 150.00

156.00 162.00

168.00 174.00

180.00

0

5

10

15

20

25

30

F

ines

A: Impeller Speed B: Addition Rate

Design-Expert® SoftwareFactor Coding: ActualYield

Design points above predicted valueDesign points below predicted value88

60

X1 = A: Impeller SpeedX2 = B: Addition Rate

65.00

70.00

75.00

80.00

85.00120.00 126.00

132.00 138.00

144.00 150.00

156.00 162.00

168.00 174.00

180.00

50

60

70

80

90

Y

ield

A: Impeller Speed B: Addition Rate

…. – a case studyDesign-Expert® SoftwareFactor Coding: ActualOverlay Plot

Fines CI HighOvers CI HighYield CI Low

Design Points

X1 = A: Impeller SpeedX2 = B: Addition Rate

120.00 126.00 132.00 138.00 144.00 150.00 156.00 162.00 168.00 174.00 180.00

65.00

70.00

75.00

80.00

85.00Overlay Plot

A: Impeller Speed

B:

Ad

ditio

n R

ate

Fines: 20.000

Fines CI: 20.000

Overs CI: 13.968

Yield: 65.000

Yield CI: 65.000

3

Fines: 3.417 CI High: 10.475Overs: 9.33333 CI High: 15.384Yield: 88.500 CI Low: 78.355X1 120.00X2 65.00

Should we adopt new approaches??

• Drug products are of good quality and end product quality is not the issue

• But ...........– The problem is uncontrolled variability (e.g., in

properties of starting materials or manufacturing process) which affects quality

– Products and processes could be improved– Opportunity for improvement offered by new

technologies are often missed

Should we adopt new approaches??

• All manufacturing operations are either already at 6 sigma or moving toward a 6-sigma process– 99.99966% of products

manufactured are statistically expected to be free of defects (3.4 defects per million)

Should we adopt new approaches??

• 6 Sigma:– Originally developed by Motorola, USA in

1981.– Seeks to improve the quality of process

outputs by identifying and removing the causes of defects (errors) and minimizing variability in process

– uses a set of quality management methods, including statistical methods, etc

Should we adopt new approaches??

0,01

0,1

1

10

100

1000

10000

100000

1000000DPMO(defects permillionopportunities)

2σ 3σ 4σ 5σ 6σ 7σ

Best-in-class

Airlines baggage check in

Restaurant bills

Lufthansa (6,6σ )

Quantas, SAS

Air India (5,8)Egypt Air (5,8σ )

Quelle: Motorola, Air Safety Online…Then why not for medicines??

Should we adopt new approaches??

• Our patients deserve safe, efficacious and innovative medicines, that make a positive difference to their lives, each and every time they need them.

Should we adopt new approaches??

• With good design & control strategies

• Good risk management strategies

• Good quality system

• Reduced regulatory burden• Reduction in submissions on

modifications• Inspection of quality system

Existing GMP1970s

’s

Quality by Design

Q82000s

Quality risk management (Q9) 2000s

Regulatory

Quality System

Quality Systems (Q10) 2000s

Should we adopt new approaches??

Lower Risk OperationsInnovation and Continual Improvement

Optimized Change ProcessFlexible Regulatory Approaches

Pharmaceutical Development:

Quality byDesign

Q8

Quality RiskManagement

Q9

Modern Effective PharmaceuticalQuality Systems

Q10

+ +

Our imagination is the limitation..

References• Colbourn E. Spotlight on Intelligensys. Controlled release

society Newsletter. Vol 21 (3): • Ibrić, S, Djurić, Z., Parojčić J., Petrović, U. Artificial

intelligence in pharmaceutical product formulation: Neural computing. Chemical Industry & Chemical Engineering Quarterly 15 (4) 227−236 (2009)

• Rowe, R. C. Roberts, R. J. Intelligent software for product formulation, Taylor and Francis, London, 1998.

• Smith G. (2011). QBD, lecture delivered at DeMontfort University, UK