Process Capability, cGMP, and Product

Quality

Lawrence X. Yu, Ph.D.

Deputy Director
Office of Pharmaceutical Quality
Center for Drug Evaluation and Research
Food and Drug Administration

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What is Pharmaceutical Quality?

Janet Woodcock
A high quality drug product as a product free of
contamination and reproducibly delivering the therapeutic
benefit promised in the label
Free of contamination: CGMP focus
Reproducibly delivering the therapeutic benefit promised in the
label: QbD focus
Therefore, Pharmaceutical Quality = QbD + CGMP?

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What is Quality by Design?
ICH Q8(R2)
The pharmaceutical Quality by Design (QbD) is a
systematic approach to development that begins with
predefined objectives and emphasizes product and
process understanding and process control, based on
sound science and quality risk management
Quality by Design Tools
Design of experiments (DoE)
Risk assessment

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 Overview of QbD
Labeled Use
Safety and Efficacy

DEFINE Quality Product Design and

Target Product Profile Understanding

Process Design and Control

Understanding Strategy

L. X. Yu. Pharm. Res.

25:781-791 (2008) Continual
Improvement

DESIGN and
TARGET IMPLEMENTATION
UNDERSTANDING
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Quality by Testing vs. Quality by Design

Quality by Testing
Specification acceptance criteria are based on one or
more batch data
Testing must be made to release batches
Quality by Design
Specification acceptance criteria are based on
performance
Testing may not be necessary to release batches

L. X. Yu. Pharm. Res. 25:781-791 (2008)

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Pharmaceutical QbD Objectives
Achieve meaningful product quality specifications
that are based on assuring clinical performance
Increase process capability and reduce product
variability and defects by enhancing product and
process design, understanding, and control
Increase product development and manufacturing
efficiencies
Enhance root cause analysis and post-approval
change management
L. X. Yu et al. AAPS J. 16:771-83 (2014)

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Concept of Process Capability
First introduced in Statistical Quality Control
Handbook by the Western Electric Company (1956).
Process capability is defined as the natural or
inherent behavior of a stable process that is in a
state of statistical control
ISO, AIAG, ASQ, ASTM .. published their guideline
or manual on process capability index calculation

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Process Capability Index
Cp: process capability index
USL LSL
Cp
6 ST
where ST is the inherent variability of a stable process, USL = upper
specification limit, and LSL = lower specification limit.

Cpk: minimum process capability index

Cpk = min (Cpku, Cpkl)
USL Mean
Cpku
3 ST

Mean LSL
Cpkl
3 ST

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Cpk Values and its
Corresponding non-Conforming Rate
Area under normal Non-conforming parts per
Sigma distribution curve million (ppm) Capability
Cpk Value
Value (% Conforming Unilateral Bilateral Rating
level*) Specification specification*
0.333 1 68.27 158650 317300 Terrible

0.667 2 95.45 22750 45500 Poor

Marginally
1.0 3 99.73 1350 2700
capable

1.333 4 99.9936 32 64 Capable

1.667 5 99.99994 0.3 0.6 Good

2.0 6 99.9999998 0.001 0.002 Excellent

* Process mean is centered at middle of the specification limits and has normal distribution

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Process Performance Index
Process performance is a statistical measure of the
overall variability of a measured quality attribute
from a process that may not have been
demonstrated to be stable
USL LSL
Pp
6 SD
Ppk= min (Ppku , Ppkl )
USL Mean
Ppku=
3SD
Mean LSL
Ppkl=
3SD

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Difference between Cpk and Ppk
Cpk represents the potential process capability (i.e.
how well a given process could perform when all
special causes have been eliminated).
Ppk addresses how the process has performed
without the demonstration of the process to be
stable.
Forecast future batch failure rate
Cpk (Yes) ; Ppk (No)

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Process Capability Requires a Stable Process
That is in a State of Statistical Control
A state of statistical control (i.e. stable state) means
that the process exhibits no detectable patterns or
trends and hence the variation seen in the data is
due to random causes and inherent to the process
Generally use Control Charts to determine if the
process is in state of control

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Control Chart
6.0
USL

UCL

Quality 5.0 CL
attribute
(unit)
LCL

LSL

4.0
30 40 50 60
Sample #

Definition: a graphical display of a product quality characteristic

Figure 1. Control chart. A control chart displays measurement of a quality attribute over time. When appropriate tools
detect the presence of special cause variation, continual improvements can be initiated to correct and/or prevent potential

that has been measured or computed periodically from a process

failures so that the process remains in a state of statistical control. Thus, the expected range of process outputs can be
reliably predicted and the well sought goal of product and process robustness is achieved and maintained. (USL, upper
specification limit; LSL, lower specification limit)

at a defined frequency
Every control chart consists of:
A set of data
A central line (CL) (mean)
Two statistical process control limits (UCL and LCL) (Is the process
Stable?)
Upper and Lower Specification Limits (USL and LSL)
Patients need ( Safety and Efficacy) (Is the process Capable?)
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 Sources of Variation
Variation can be categorized as
either:
Common causes of variation
Inherent to a system, random, always present and
hence predictable within statistical limits
Eliminate inherent variability (noise) is difficult
Special causes of variation
Exterior to a system, non-random, not always present
(intermittent)
can cause changes in the output level, such as a spike,
shift, drift, or non-random distribution of the output.
Are usually easier to be detected, controlled or
eliminated
What are GMPs?
GMP refers to the Current Good Manufacturing Practice
regulations... CGMPs provide for systems that assure
proper design, monitoring, and control of manufacturing
processes and facilities... This includes establishing strong
quality management systems, obtaining appropriate
quality raw materials, establishing robust operating
procedures, detecting and investigating product quality
deviations, and maintaining reliable testing laboratories.
This formal system of controls at a pharmaceutical
company, if adequately put into practice, helps to prevent
instances of contamination, mix-ups, deviations, failures,
and errors.

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CGMP: New Inspection
Protocol Project
Goal: To develop a new paradigm for inspections and
reports that will advance pharmaceutical quality
Standardized approach to inspection
Data gathering to inform quality intelligence of sites and
products
Risk based and rule based process, using expert questions
Semi-quantitative scoring to allow for comparisons within
and between sites
More common inspection report structure
Recognize and reward positive behaviors in cases where
facilities exceed basic compliance

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 NIPP Project Organization

New Inspection Protocols Project (NIPP)

CDER and ORA

Pre-Approval Surveillance For Cause Inspection

Inspection Subgroup Inspection Subgroup Subgroup
Observations to Observations on state Evidence of cGMP
Draft Protocol

inform premarket of quality in a facility violations to support

Draft Protocol

review decisions to assess quality risk enforcement

Escalation/ transition to For Cause when conditions indicate

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Quality System
Management Responsibilities
Quality Unit Responsibilities
Training and Personnel Development
Process Performance and Product Quality
Monitoring System (PPPQMS) &
Preventative Action
Investigations and Corrective Action
Change Management System
Data Integrity All Systems Oversight

Continuous improvement

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Quality Metrics
Vision
A more rigorous and comprehensive approach to quality
surveillance that allows for improved monitoring of
current status across the inventory of FDA-regulated
drug products and manufacturing sites

Goals: Objective measures

Quality of a drug product
Quality of a site
Effectiveness of systems associated with the manufacture
of pharmaceutical products
Draft Guidance published July 27, 2015
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegu
latoryInformation/Guidances/UCM455957.pdf
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FDA Draft Quality Metrics
Guidance, July, 2015
Metrics FDA Intends to Calculate
Lot acceptance rate
Product quality complaint rate
Invalidated Out-of-Specification rate
Annual product review or product quality review on time
rate

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FDA Draft Quality Metrics
Guidance, July, 2015 (continued)
Optional Metrics
Quality Culture
Senior management engagement
corrective action and preventive action effectiveness
percentage of your corrective actions involved re-training of
personnel
Process Capability/Performance
Process capability is a leading, useful indicator. However, its
calculation is relative complex

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Amgen

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Business Case

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Excuses not to Use Process
Capability, therefore, not to Improve
My specification acceptance criteria are too
narrow
Provide evidence and discuss with the FDA
Process capability requires 30 or more batches
You can always calculate process performance when
the number of batches is small or the process is not
stable.

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Summary

Process capability is a leading, useful indicator

although its calculation is relative complex
Quality standard should be clinically relevant and a
surrogate of clinical performance
Pharmaceutical Quality = QbD + CGMP

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