it?
Richard L. Friedman
Director, DMPQ
CDER/Office of Compliance
PQRI Process Drift Workshop
December 1, 2010
Overview
Goal of Manufacturing
Central Question: Why is process output not
always predictable?
Testing Reliability
Recommendations
More questions
Why due routine stability studies find
defects and result in recalls?
This includes:
Potency
Content Uniformity
Dissolution
Impurities
Physical characteristics (e.g., viscosity of
ointment)
Impact
What is the risk to the patient if a lot must be
recalled?
Incorrect dose, poorly dissolved product, high
impurity
ineffective or unsafe
Shortage
product not available
Examples
Importance of Excipients:
Some Examples of Recalls Involving Excipients (2002-2008)
Excipient
Product
Reason
Root Cause
Malt Syrup
Oral Powder
Product
(Granules)
Mold
Sorbitol
Syrup
OOS Stability
Dissolution Failures
Rendered drug
hydrophobic due to nonuniform mix issues
(excipient itself was not
defective).
Extended
Release Tablet
Dissolution Failure
(Drug release rate
too rapid)
Magnesium
Stearate
HPMC
Case Study #1
Dissolution Failure (multivariate cause?)
It was concluded that the cause of the dissolution failure
was a combination of factors, e.g.,
a formulation change, specifically a 1% increase in lubricant
a subtle change in the effective density of the tablets which was
apparently affected by the bulk density of microcrystalline
cellulose (another ingredient variable)
mixer change (different mixing principle)
Case Study #2
Subpotency (multivariate cause?)
Tablet product
Assay failure on Stability (9 months)
Case study #3
Assay, Appearance
Ointment drug product
NDA sold, and product now being made by contract manufacturer
Variability
Variability?
Have sources of variability been identified
and minimized?
API, Excipients
Formulation
Process
Container-Closure System
Sampling and Measurement methods
Development
Do companies collect enough data, within and
between batches, to really understand the
stability profile, and transition to typical one
lot/year?
Do companies truly understand first principles
the physicochemical reasons that contribute to
stability failure?
If so, why are batches vulnerable to stability
failure during shelflife not routinely identified
(prediction capability) prior to distribution?
Formulation Development
Do companies routinely do sufficient
preformulation studies of excipients and APIs to
understand their behavior?
Managements Role
It is good management to continually
reduce the variation of any quality
characteristic - Deming
This builds robustness and ruggedness
into the process and product, increases
product quality, and can reduce costs.
Representative Samples
The sample must represent the batch
physically. For example, beginning,
middle, end of the batch, and...
The sample must represent the variability
in the batch
This applies to all samples, whether raw
material, in-process, QC, or stability...
Representative Samples
This is a key concept and assumption in
the CGMPs.
210.3(b)(21)
Definitions
211.84(b)
Testing
211.122(a)
Materials
211.134(b)
Inspection
211.180(e)(1)
Review
Testing Programs
QC Release:
Quality System Detection of Variation & Defects
before Distribution
Test of a firms Quality System is if it will promptly catch a
problem in a batch vs. discovering only after it is marketed.
1. Mistakes are, in many cases, not caught by the
individual making the error, but instead through final
inspection or QC test!!
2. QC testing is of limited sample size intended to assess a
chemical, microbiological, or physical attribute.
3. To avoid detecting mistakes or defects only after a drug
product has been distributed:
Use Redundancy of Controls or PAT
E11 2709
One statistical approach for developing inhouse specifications for USP Standards
now gaining attention and acceptance is
ASTM E11 E2709 adopted in 2009
It is a statistical procedure that evaluates
the variability in the data and calculates
probability of passing the specification
(assay, content uniformity, dissolution)
with a specified confidence.
For Example
(E2709 Analysis)
A batch with a 90% probability of passing
(i.e. 10% fail) the test the first time, has
almost a 60% chance of failure if tested
eight times on a stability program.
A batch with a 99% probability of passing
the test the first time, still has almost a 9%
chance of failure if tested nine times.
Summary / Recommendations
Unwanted variability is the root cause!
raw materials, product stability, and process
stability
Summary/Recommendations
1. Preformulation DOE and history
2. Process/product control
Building Knowledge
Process Validation Lifecycle
Replication at full scale provides initial
assurance of commercial process
reliability.
Design
Confirm
Assess
Monitor
CGMP:
Every batch, Every day
We rely upon the manufacturing controls and
standards to ensure that time and time again, lot after
lot, year after year the same clinical profile will be
delivered because the product will be the same in its
quality We have to think of the primary customers as
people consuming that medicine and we have to think
of the statute and what we are guaranteeing in there,
that the drug will continue to be safe and effective and
perform as described in the label.
- Janet Woodcock, M.D.
Reference
Six Sigma in the Pharmaceutical Industry:
Understanding, Reducing, and Controlling
Variation in Pharmaceuticals and
Biologics
By Brian Nunnally and John McConnell
CRC Press, 2007
Acknowledgments:
Lynn Torbeck