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Process Drift: When Do We Detect


Richard L. Friedman
Director, DMPQ
CDER/Office of Compliance
PQRI Process Drift Workshop
December 1, 2010

Goal of Manufacturing
Central Question: Why is process output not
always predictable?

Problem detection on stability program...Too late!

Examples: Why did the failures occur?
Poorly understood processes = uncontrolled variability

Testing Reliability

Goal of a Manufacturing Organization

Provide a consistent, defect-free product to the
marketplace via consistent manufacturing operations

For a Drug Manufacturer, this means

Assure safety & efficacy every day, every dose.

But not every company has established adequate quality

practices, or achieved this predictable output. Some
companies, products, or processes make more mistakes
and defective units than others. Why?

More questions
Why due routine stability studies find
defects and result in recalls?
This includes:
Content Uniformity
Physical characteristics (e.g., viscosity of

What is the risk to the patient if a lot must be
Incorrect dose, poorly dissolved product, high
ineffective or unsafe
product not available

What are the possible root causes?

What is the conventional wisdom?

What are other possible reasons?

Two Overall Root Causes

1. The classical stability issue is chemical and
physical degradation during storage.

Some products are by nature unstable and have a shorter

shelf life, but are expected to be able to meet their labeled
expiration dating as supported by previous

2. The second issue to be considered is the

inherent manufacturing/process variability

due to inadequate process design and manufacturing.


Importance of Excipients:
Some Examples of Recalls Involving Excipients (2002-2008)




Root Cause

Malt Syrup

Oral Powder


Long excipient storage




OOS Stability

Different excipient supplier

5, 10, 15, and 30

mg Tablet Product

Dissolution Failures

Rendered drug
hydrophobic due to nonuniform mix issues
(excipient itself was not

Release Tablet

Dissolution Failure
(Drug release rate
too rapid)

Excipient functionality led

to this Recall



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)

Dissolution testing on stability ultimately detected the

only 1 batch/year placed on stability, but extra testing
done after the failure
3 batches failed

Case Study #2
Subpotency (multivariate cause?)
Tablet product
Assay failure on Stability (9 months)

Firms investigation concludes that product

stability needs to be improved by:
1.changing to a different API source
2.modification of formula

3.improved container/closure system

Case study #3
Assay, Appearance
Ointment drug product
NDA sold, and product now being made by contract manufacturer

Firm receives numerous complaints of product being

thinner consistency, watery, or liquidy.
Intermittent failures to meet specification for assay,
appearance and/or propylparaben content
Process involves complex set of process steps:
melting and mixing, dispersion, dissolving, heating, cooling for
specified times/temps. Transfer of materials to and from 5 different
Product and Process Design flaws. Firm issued WL.


Have sources of variability been identified
and minimized?
API, Excipients
Container-Closure System
Sampling and Measurement methods

Do companies collect enough data, within and
between batches, to really understand the
stability profile, and transition to typical one
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?

1975 journal article used DOE for preformulation

excipient compatibility.
Studied 5 factors and 10 two-factor interactions to get the best

Do companies follow the QbD concepts in ICH

Q8 for formulation design?
Is DOE used routinely?

Raw Material Variability

Have firms routinely identify all of the raw
material attributes that are important?
How has the variability been identified,
measured and minimized?
Many excipients (e.g., cellulose-based) are natural
materials, with unmeasured variability...

Are incoming ingredient batches sufficiently

analyzed using adequate tests?
e.g., HPMC

Raw Material Variability

Changes in particle size of some
excipients, for example, may affect content
uniformity. In other cases, a change in the
supplier of an excipient or lubricant may
affect dissolution or bioavailability.
The failure to specify the amount of
granulating solution, resulting in over
wetting and dissolution failures of aged
FDA Guide to Pre/Post-Approval Inspections of Solid Oral Dosage Forms (1994)

Excess Manufacturing Variability?

The root cause of root causes is often the failure
of management to focus on minimizing
unwanted variability, differences, and
discrepancies throughout the product life cycle.
There is a need to fully implement 211.110(a).
to validate the performance of those
manufacturing processes that may be
responsible for causing variability

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.

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

Testing After Distribution:

How Much is Enough?
Normally, 3,6,9,12,18,24...
But based on experiences with some products,
some firms have had to test more often than the
usual intervals.
Major Migraine drug: was tested every month.

Female Hormone Product: put every fifth lot on

stability due major dissolution problems, then
ultimately every lot pending reformulation. (Not
the only such example)

Stability Studies and Variability

As number of tested samples increases...
More tests lead to higher probability of failure
for unstable processes or products.
Excessive variability in batches results in
higher probability of failure.

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.

E11 2709: Probability of Passing

So instead of a pass/fail response from using the USP
Standard as a specification, this statistical method gives
a probability.
For example, we would be able to say:
we are 99% confident that the probability of the batch passing
the USP Standard in the future is 99% or better.

If a batch just barely passes the dissolution or content

uniformity criteria once (e.g., the USP Standard), what is
the probability of passing 1 to 9 more times?
Depending on the overall inherent batch variability, it can range
from circa 1% to 100%!

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

Passing the specifications once often

gives little assurance that it will pass again
The batch has to be robust to be assured of
passing repeatedly on a stability program

1. Preformulation DOE and history

Learn and routinely use DOE in formulation

2. Process/product control

Learn and adjust under Quality System

3. Raw material change control

4. Follow GMPs to assure representative
5. Minimize variability
6. Batch history
7. Process capability

Building Knowledge
Process Validation Lifecycle
Replication at full scale provides initial
assurance of commercial process





Validation includes lifecycle monitoring.

Post-market information gathering,
promotes maintenance of a stable
process and identifies areas for
continual improvement and adaptation.
Our Compliance Policy Guide on
Process Validation, and the draft
Process Validation Guidance,
recognize the value of advanced
engineering principles and control

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.

Six Sigma in the Pharmaceutical Industry:
Understanding, Reducing, and Controlling
Variation in Pharmaceuticals and
By Brian Nunnally and John McConnell
CRC Press, 2007

Lynn Torbeck

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