Using Quality by Design (QbD) for Process

Optimization of a Novel Oral Solid Dosage

Form
by Joe Cobb, R. Justin Brett, Michael D. Ruff, Anthony Berry,
Robert Epps

OBJECTIVE
To improve robustness of a core tablet for a novel modified release oral solid dosage
form using Quality by Design (QbD) principles.

General Background
As stated in the International Conference on Harmonisation Harmonised Tripartite
Guidance on Pharmaceutical Development, ICH Q8 (R2), “The aim of pharmaceutical
development is to design a quality product and its manufacturing process to consistently
deliver the intended performance of the product.”1 Several tools are available as
guidance issued by FDA such as “Quality Systems Approach to cGMP Manufacturing”2
that includes ideas such as Quality by Design (QbD) in the development process. This
guidance, amongst others, lay the framework for expectations of regulatory reviewers in
their examination of client submittal documentation.

This project involved first the technical transfer of a formulation and process of a novel
modified release oral solid dosage form (i.e. an active core tablet with an a series of
coatings that modified the release and delivered additional quantities of the same active
ingredient) that was originally manufactured at a relatively small scale. The next step
was a scale-up of the process to commercial scale but due to time constraints not all of
the unit operations had been completely optimized. Upon discovering processing issues
such as relatively high friability and low breaking strength of the core tablets the client
agreed to proceed with optimization utilizing principles of QbD.

The first step of the QbD process was to establish a Quality Target Product Profile
(QTPP) for the core tablets. The second step was to determine the Critical Quality
Attributes (CQA) of the core tablets. The third step incorporated a risk assessment
exercise to identify the Critical Processing Parameters (CPP). The final step involved
drafting an informal Design of Experiments (DOE) to determine optimal settings of the
CPP’s for the critical high shear wet granulation process.

METHODOLOGY

Materials
Active Pharmaceutical Ingredient (API) X, (Supplied by client)
Microcrystalline Cellulose, NF/EP (Avicel ® PH 102 and PH 200, supplied by FMC)
Partially Pregelatinized Starch, NF (Starch 1500® supplied by Colorcon)
Croscarmellose Sodium, NF/EP (Ac-Di-Sol ® SD-711 supplied by FMC)

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Magnesium Stearate, NF/EP, (Non-bovine, supplied by Mallinckrodt)
Various reagent grade chemicals and solvents to execute required analytical testing

Manufacturing Equipment
TK Fielder PMA-100 High Shear Granulator w/ Pressurized Spray Pot
O’Hara FBDG-30 Dryer with 100 liter bowl
Fitzpatrick Fitzmill, Model M
15 ft3 Tote Blender
Manesty Unipress equipped with 0.25” round standard concave tooling

Analytical Equipment (Physical testing only)

USP <1216> Compliant Tablet Friability Tester
USP <1217> Compliant Tablet Breaking Force Tester

Background Formulation Information

The core tablet formulation listing ingredients, functionality and quantitative amounts is
given in Table 1 at the top of the next column.

Table 1 – Core Tablet Formulation

Amount per
Ingredient Functionality
Tablet (mg)
Active Pharmaceutical
X 10.00
Ingredient
Avicel PH102 Diluent (Intragranular) 53.00
Starch 1500 Diluent/Binding Agent 20.00
Super-Disintegrant (Intra
Ac-Di-Sol SD-711 4.000
and Extragranular)
Avicel PH 200 Diluent (Extragranular) 12.50
Magnesium Stearate Lubricant 0.5000
Total 100.0

Based on the relatively late stage in the development cycle, the client agreed that neither
the core tablet formulation nor the unit operations used in its manufacture could be
changed. See Figure 1 below for a flowchart of the core tablet manufacturing process.

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 Figure 1 – Flowchart for Core Tablet Manufacturing Process

In-process data gathered during the compression process indicated that the core tablets
had excellent weight control. However, even though the core tablets had satisfactory
friability to pass USP <1216> (Not more than 1.0% 3) the team agreed that they would
not be able to withstand the rigors of downstream coating in a standard side-vented
coating pan. The team further agreed that optimization on the entirety of the core tablet
manufacturing process was necessary using QbD principles.

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The first step of the optimization process using QbD principles was to establish a Quality
Target Product Profile (QTPP) for the core tablets themselves. Based on the phase of
work involved several elements of the QTPP had already been established, such as the
fact that the final dosage form was going to be a modified release product with a novel
coating scheme to allow for immediate and delayed release of X. However a more
formalized declaration of QTPP specific to the core tablet itself had not. See Table 2
below for the QTPP for the core tablets themselves.

Table 2 – Core Tablet Quality Target Product Profile

Step in Manufacture Nominal Characteristics Rationale

Core tablets must not
Low Friability erode in standard side
vented coating pan
Core Tablet
Core tablets must not
Relatively High Breaking
break in standard side
Strength
vented coating pan

The next step of the optimization process using QbD principles was to utilize the QTPP
above to derive a set of Critical Quality Attributes (CQA) of the Core tablets. The CQA
would be based on empirical evidence derived from previous experimentation as well as
similar experiences with other products. See Table 3 below for the CQA of the core
tablets.

Table 3 – Core Tablet Critical Quality Attributes

Intermediate/
Attributes
Product Type
Minimum orifice flow diameter < 12 mm to allow for
compression on a high-speed tablet press
Final Blend
Uniformity must satisfy requirements given in relevant
guidance 4
Friability Specification < 0.3%, Target < 0.10%
Based on previous experimentation
Tablet Breaking Strength between 4.0 – 8.0 kp
Core Tablets
Ideal range based on previous experimentation
Uniformity must satisfy requirements given in relevant
guidance 4

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Using the attributes given above the team organized a set of Critical Process-
Parameters (CPP) utilizing a risk-based approach to all of the upstream unit operations.
This was based on previous experience with this project as well as other similar dosage
forms with equivalent or similar equipment trains. See Table 4 for CPP using a risk-
based model of potential effects on CQA from above.

Table 4 – Risk-based Model for CPP’s of Relevant Unit Operations

Unit Operation Parameter Relative Risk to CQA’s

Liquid Addition
Low (previously assessed)
Rate
Liquid Addition High (not thoroughly
High Shear Wet Granulation
Amount examined)
Post-Spray Wet High (not thoroughly
Mass Time examined)
Medium
Fluid Bed Drying Loss on Drying (range had been previously
specified by client)
Milling Type/Screen Low (previously assessed)
Uniformity had been
Blending Blend Time established previously, not to
be re-examined
Compression
Compression Previously assessed
Force

To build on previous experiments already performed, an abbreviated Design of

Experiments consisted of examination of only two of the CPP’s that had not been
already optimized. The two variables to be examined were granulating liquid amount
and post-spray wet-massing time. An full factorial experimental design based on two
factors with three settings (32) was agreed to, but with one experiment left out (Medium
Liquid Amount, Low Wet Mass Time) because that had been evaluated in previous work
and found to give unsatisfactory tablet physical characteristics. Factor levels were
defined as such:

Liquid Amount: Low = 8.500 kg, Medium = 9.000 kg, High = 9.500 kg

Wet Mass Time: Low = 2 minutes, Medium = 4 minutes, High = 6 minutes

See Table 5 below for factors for the abbreviated experimental design.

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 Table 5 – DOE Factors and Levels

Experiment #
Factor
1 2 3 4 5 6 7 8
Liquid
Low Low Low Med Med High High High
Amount (kg)
Wet Mass
Low Med High Med High Low Med High
Time (min)

RESULTS
CQA’s listed in Table 3 were evaluated for each experiment in the DOE and compared
to previously generated data for acceptability and improvement. See Table 6 below for a
summary of results from each experiment.

Table 6 – Results from Blend and Core Tablets DOE

Experiment #
Responses
1 2 3 4 5 6 7 8 Previous
Minimum
Orifice Flow
4 8 12 10 12 5 4 10 4
Diameter
(mm)
Friability
0.08 0.07 0.02 0.04 0.10 0.01 0.00 0.01 0.15
(%)
Avg. Tablet
Breaking
7.1 6.0 6.7 5.6 4.9 6.9 5.5 5.2 4.7
Strength
(kp)
Core Tablet
Uniformity
8.8 4.0 4.3 4.1 3.6 5.5 4.7 4.0 n/a
per USP
<905> AV(%)

Discussion
Based on the results, high liquid amount and low wet mass time (Experiment #6),
yielded the best blend and tablet characteristic responses. All experiments showed
acceptable flowability and uniformity of dosage units to satisfy the requirements as
stated in CQA. Based on these findings the conditions given in experiment # 6 are
considered optimal.

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CONCLUSION
Robustness of the core tablet was substantially improved by following QbD principles
and performing an informal DOE based on these findings.

1 – ICH Q8 (R2), Revision from August 2009. Page 1

2 – FDA Guidance Quality Systems Approach to CGMP Regulations, September 2006
3 – Current USP (35), General Chapter <1216> “Tablet Friability”
4 – Current USP (35), General Chapter <905> “Uniformity of Dosage Units

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