GMP Handling of Out of Specifications Results

Handling of Out of Specifications Results within GMP
A Scientific & Regulatory Perspective
Roohi B. Obaid
Karachi, the Nov10th 2018

It reflects the views and understanding of presenter
& may not be construed to represent the views or
policies of organization or association to which
speaker has ties
Documents of US-FDA, Papers from
Pharmaceutical Technology & Review Scientific
Articles are used to construct presentation
Disclaimer
Reference

OOS History (Barr Case)
Scientific & Regulatory Perspective
Phenomena, Scenario & Case Study
Integrity Emergence & Aftermath

Group
Discussion
Case
Studies
Interactive
Exercise
Tutorial

105
95
Above the Line
Below the Line

105
95
Above the Line
Below the Line
Within the Line

105
95
Above the Line
Below the Line
Within the Line Standard

105
95
Above the Line
Below the Line
?

105
95
Above the Line
Below the Line
?
?

95 to 105 %
Standard Line of Limit

95 to 105 %
94%
Standard Line of Limit

95 to 105 %
94%
106%Standard Line of Limit

95 to 105 %
94.44%
105.49%Standard Line of Limit

Sub-Standard Below Standard
Super-Standard Above Standard

94.45 94.44
0.01 mg
Uncertainty
?

NLT< 90.05
90.044
4
5
4th digit will decide the case

Make two groups
Group A will discuss related to laboratory affairs
Group B will discuss manufacturing affairs
It is half hour exercise
Every individual has to built his or her own case
Construct any real or imaginary scenario
where OOS is obvious

If outer color scheme of immediate container deviates from standard would
it be OOS? Would it be investigated? Would in any case be approved?

If strength of drug got wrongly printed & drug exists in only one strength,
would it be OOS? Would it be investigated? Would in any case be
approved?

If an approved label identified after dressing in finished good with slight
change in color due to exposure of light, would it be OOS? Would it be
investigated? Would in any case be approved?

If spelling of drug name got wrongly printed, would it be OOS? Would it be
investigated? Would in any case be approved?

It is nothing but results
that go outside
If it is regulatory specification,
it requires mandatory
investigation
If it is within specification, but
out of line from history, it
require justification of not
opting investigation … OOTOOS

Inspector’s
Perfect Menu
It is a mandatory requirement
to conduct & document
Root cause, CA & PA, as well as
efficiency of PA within Quality
System are the regulatory
expectationsOOS Investigation

Voluntary Compliance
OOS Investigation

Testing into Compliance
Retesting without proper
investigation is unscientific &
objectionable
It has potential to impact batch
quality & may release a
compromised batch
OOS Headache

Testing into Compliance
OOS procedures are expected
to be GMP compliant
Explained product failure &
method deviations are fundamental
outcomes
US - Draft Guidance document
finalized in 2006OOS Headache

In-process OOS would not
require investigation
If it is outside the established
specifications,
it will be required
It is a Myth

Biological assays come under
this guidance document
It is not applicable to
biological products due to high
variability and complexities
It is a Myth

During adjustment or
suitability exercise of machine,
OOS is not required to be
investigated
It is you, who have to decide
the potential knowledge &
reasonability of doing
investigationMachine
Adjustment

How to investigate
Responsibility of laboratory
personnel
Laboratory phase of investigation
Additional testing
Expanding investigation outside the
laboratory
Final evaluation of all test resultsScope Dots

Components
Containers
Closures
In-process materials
Finished products
With established specifications
Testing is necessary
to conform

Performance of scientifically
sound …
Raw Material Testing
In-process monitoring
Release & stability testing
Process Validation
Investigation of OOS
Also part of ICH Q7GMP Obligations

Real time investigation
Purpose is to determine the
cause, not to pass the batch
So be focus, you are pursuing
for information, knowledge to
enhance understanding
Phase I
Laboratory Investigation

Aberration of measurement
process
Aberration of manufacturing
process
Two Options
Investigation is mandatory, no
matter the batch is rejected

Performance of investigation
Written record of investigation
Conclusion
Follow up
Requirements

Timely
Unbiased
Well-documented
Scientifically sound
Meaningful Investigation

Initial assessment of accuracy
of lab data, preferably before
the test preparation solutions
are discarded
Laboratory error or instrument
malfunction can be spotted
Phase I

Full scale investigation as
assessment didn’t close the
OOS
Contract laboratory should
convey the data & findings to
the firm, who should then
conduct full scale OOS
investigation
Expand

Analyst
Remember,
Analyst must be aware by
qualification, of potential
problems that could occur
during testing process
&
of potential problems that
could create inaccurate resultsResponsibilities

Analyst
Reporting time is important
Report soon after OOS
occurrence, but first check
himself & document any
obvious cause
Responsibilities

Supervisor
Objective & timely assessment
No pre-conceived assumptions
Act promptly to ascertain
attribution of result with
laboratory error or manufacturing
problem
Re-examine the actual solutions,
test units & glassware used
Responsibilities

Supervisor
1. Discuss the test method with
the analyst; confirm analyst
knowledge of and performance of
the correct procedure
2. Examine the raw data obtained
in the analysis, including
chromatograms and spectra, and
identify anomalous or suspect
informationStep by Step

Supervisor
3. Verify that the calculations used
to convert raw data values into a
final test result are scientifically
sound, appropriate, & correct;
also determine if unauthorized or
unvalidated changes have been
made to automated calculation
methods
4. Confirm the performance of the
instruments
Step by Step

Supervisor
5. Determine that appropriate
reference standards, solvents,
reagents, and other solutions were
used and that they met quality control
specifications
6. Evaluate the performance of the
test method to ensure that it is
performing according to the standard
expected based on method validation
data and historical dataStep by Step

Supervisor
7. Fully document and preserve
records of this laboratory assessment
Step by Step

When a transient equipment
malfunction is suspected
It will provide strong evidence
to link with equipment
Re-Injection

From master solution of
sample to confirm extraction
Incomplete extraction can be
proven by re-extraction
But, it will put a question on
analytical method validation
Re-Extraction

Production process review &
Additional laboratory work
To identify root cause
For CAPA ….
Highest PriorityPhase II
Full Scale

Please remember,
Extension to other marketed
batches will be considered &
justified if not extended
Phase II
Full Scale

Conducted by Quality Unit
Every concerned department
will be engaged
Timely
Thorough
Well-documented review
Review of Production

Clear statement of the reason
of investigation
Summary of the aspects of
manufacturing process that
may caused the problem
Written Record of
Review

Results of documentation
review with the assignment of
actual or probable cause
Result of review made to
determine if the problem has
occurred previously
Description of corrective action
takenWritten Record of
Review

Upon confirmation, batch will
be rejected & investigation will
be terminated
Failure investigation may
extend to other batches
In case of re-process, after
additional testing detailed
comments will be recorded that
constructed the decisionDecision

If lack of robustness in product
formulation
If inadequate raw material
characterization or control
If substantial variation introduced by
one or more units of operation of the
manufacturing process or if
combination of these factors
Cause of inconsistent
product qualityRedesign the Product

It may be used during full
scale investigation.
Retesting of original sample &
re-sampling are practiced.
Additional
Lab Testing

Retesting may include
resampling but from the same
homogenous material
Suspected diluent error after
instrument (Phase I)
Retest may be performed by
other analyst (equally
qualified)Retesting

Remember
Establishment of specifications,
standards, sampling plan, test
procedures & laboratory control
mechanism are GMP regulations
Retesting

Remember
One cannot disregard OOS results
without justification
Practice of “Testing into
Compliance” is unscientific
and objectionable under GMP
Retesting

Remember
Maximum number of retest
should be specified in SOP
Number depends upon variability
of the particular test method
Number should be based on
scientifically sound principles
Retesting

Remember
Number of retest should not be
adjusted on the basis of result
obtained
SOP should specify point when
additional testing ends & batches
evaluated
Retesting

Remember
Upon unsatisfactory result of
the point established in SOP
suspected batch must be
rejected or
In some cases, held for further
investigation
Retesting

Remember
Deviation from the SOP
requires compliance of intent
of GMP regulations as well as
strong recorded justified
reason.
Retesting

If laboratory or calculation
error are not identified in first
test,
There is no scientific basis for
invalidating initial OOS result
in passing of retest result.
Report every result, (whether it
is pass or suspect) to help in
construction of release decisionKeep in mind

Use original sampling
procedure
Collect the sample & analyze
Predetermined procedures &
sampling strategy is required to
examine additional sampling &
sample
Resampling

Resampling should be
performed by the same
qualified validated method that
was initially used
Resampling

Upon evaluation of all data, it
may conclude
Sample was prepared
improperly & was therefore not
representative of batch quality
Conclusion

Improper sampling preparation
might be indicated as widely
varied result from several
aliquots of original sample
Conclusion

Investigation reaches to
conclusion that initial sampling
method was inherently
adequate,
A new accurate sampling
method should be developed,
documented, reviewed &
approved
Suppose

Averaging & Outlier
Both appropriate &
inappropriate uses of averaging
are there
Reporting of
Test Results

Appropriate Uses
Depends upon sample & its
purpose, e.g.
Sample for optical rotation
testing
Acceptance limit for variability
among the replicates should be
predefined
Averaging

Appropriate Uses
If acceptance criteria of
availability does not meet,
these result will be recorded
but not be used & the reason
will be documented.
Averaging

Remember
Averaging is allowed in OOS
investigation if it was used
during the original testing that
produced OOS result
Averaging

Inappropriate Uses
May hide variability among
individual tests
Report individual test results as
separate value
Use standard deviation or RSD
with individual results (e.g.
CU)
Averaging

Inappropriate Uses
May conceal variation among
different portions of batch
Powder blend, CU, Mixture
uniformity are the best
examples
Averaging

Establishment of acceptance &
rejection level is the GMP
requirement
Outliers are usually associated
with deviations or variability in
the sample.
Error of testing procedure
should never be assumedOutlier Tests

It is a statistical procedure for
identifying from an array those
data that are extreme
SOP should include specific
outlier test to be applied with
relevant parameters specified in
advance.
Minimum number of results
required to obtain a specifically
significant assessment will also be
specified
Outlier Tests

Evaluate the result
Determine the quality of batch
Construct the decision
Follow the SOP, don’t go outside
Concluding
Investigation

To continue investigation &
testing to determine the root
cause, there is no limit, you can
continue as long as you require if
you rejected the batch
It will help to plan CA &
strengthen knowledge bank
You are free

QU is responsible
Initial OOS does not necessarily
mean the batch is failed & must
be rejected
Findings of investigation, retest
results, should be interpreted to
evaluate the batch & decision of
release or rejection
Interpretation

QU is responsible
If an investigation has revealed a
cause to invalidate result, the
result should not be used to
evaluate the quality of batch
Interpretation

QU is responsible
If OOS is confirmed & batch does
not meet established standards or
specifications,
You know what will be the
decision … it will also be
extended for other batches that
may have associated with specific
failureInterpretation

QU is responsible
If investigation does not reveal
cause and/or does not confirm
OOS result, it is critical to decide
but it can be released in certain
scenario
Interpretation

90 – 110% limit, Initial result 89.5%
Next results 99.0%, 98.9%, 99.1%,
98.8%, 99.1% & 99%
No laboratory error found in Phase I
No production error was found
Manufacturing process &
manufacturing history was robust
In-process monitoring, CU,
everything was correctInterpretation

Some OOS
Some within specifications
All are within known
variability of the method
Careful decision will be taken
Caution

FDA
Disagreement
Validation of your
analytical method should
address robustness or
variability

FDA
Disagreement
System suitability is
designed to address
instrument variation
performance, which was
met in each of these
instances

FDA stance
The procedure is a
corporate directive that
may be in place in other
manufacturing and testing
facilities

FDA stance
Ensure the corrective
and preventive actions
implemented throughout
your corporation to
address this deficiency

Case Study
Investigation of Microbial Contamination
Obaid Ali & Roohi B. Obaid

An Investigation of Microbial
Contamination
(CDER-FDA Case study; Ref: John W.Metcalfe 2017)
Bulkholderiia multivorans

Burkholderia Cepacia Complex (BCC) 1949 … 1950
Catalase producing Lactulose non-fermenting Gram -ve
More than 20 species including B. multivorans
Plant / water Moist environment Opportunistic
Pneumonia particularly in immuno-compromised patients

Please list down potential areas/ source from where
contamination can arise

Burkholderia Cepacia Complex (BCC)

BCC & Pharmaceutical Water System1

BCC & Biofilm Formation2

BCC & resistance to preservatives3

BCC & resistance to preservatives3
BCC & aqueous non-sterile drugs4

Control of Microbiological Contamination
Regulatory
Perspective

Control of Microbiological Contamination
Regulatory
Perspective
Appropriate written procedures, designed
to prevent objectionable
microorganisms in drug product not
required to be sterile shall be established
& followed

Testing & Release for Distribution
Regulatory
Perspective

Testing & Release for Distribution
Regulatory
Perspective
There shall be appropriate laboratory
testing, as necessary, of each batch of
drug product required to be free of
objectionable microorganisms

Field Alert / Intimations
Regulatory
Perspective

Field Alert / Intimations
Regulatory
Perspective
Information concerning any
bacteriological contamination,
or … one or more distributed batches of
drug product to meet specifications for it
in the application

Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist

Strongly
agree
1

Strongly
agree
Agree
1 2

Strongly
agree
Agree Neutral
1 2 3

Strongly
agree
Agree DisagreeNeutral
1 2 3 4

Strongly
agree
Strongly
disagree
1 2 3 4 5

Strongly
agree
Strongly
disagree
1 2 3 4 5
reason of remaining 4
one by one

Question
Does the presence of B. multivorans in the
drug product present a risk to patient
?

Question
?
Yes, this constitutes a patient risk
Does the presence of B. multivorans in the
drug product present a risk to patient

Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released

Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released
Additional expanded testing of 10 batches … 5 previously –ve are now +ve

How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

Is water system routinely tested for BCC
Steps of drug manufacturing process that were gone through test
What should be the plan for batches … both available & …

USP <62> Bile-Tolerant Gram –ve method
Pipe in purified water system not properly sanitized/engineered
Biofilm, but it was in control during manufacturing

Question
Do all 58 batches having valid shelf life
need to be recalled?
?
FDA Team

Are all batches subject to microbiological testing at release
If so, what methodology/strategy is used
The product is preserved: are the methods suitable for use with the
subject drug product

Regarding the 58 lots, they asked test methods, acceptance
criteria & data summaries from all microbiological testing
performed on the drug product at release.
They further asked data summaries demonstrating that
microbial test methods are suitable for the drug product
1

Regarding the 58 lots, they asked test methods, acceptance
criteria & data summaries from all microbiological testing
performed on the drug product at release.
They further asked data summaries demonstrating that
microbial test methods are suitable for the drug product
1
2

They continued and asked stability protocol & data
summaries for any microbiological testing that has been
performed till time on any particular lots of 58 batches that
are under question
3

Response
…
Firm

Routinely perform
microbial release
testing as per USP
<1111>
Acceptance Criteria for
Pharmaceutical Preparations &
Substance for Pharmaceutical Use
Microbiological examination of
non-sterile products

Routinely perform
microbial release
testing according to the
method described in
USP <61> & <62>
Enumeration Test and Test for
specified microorganisms
Microbiological examination of
non-sterile products

Assessment
…
FDA

Firm has satisfactorily testing to demonstrate that the
microbiological test method are suitable for use with drug
product, including in the recovery of Bulkholderia multivorans
The microbiological release test data on the 58 batches of
drug product meet acceptance criteria and are acceptable

Stability data till time meets acceptance criteria and are
acceptable
Microbiological testing of drug product sample in the
stability program is routinely performed

Rationale
…
Science

Firm’s Investigation
Evaluation of growth potential of the
contaminant in the drug product
The contaminant count decreases over first few days1
Day 3: Start of Log phase growth in the preserved drug2
Day 7: Counts > 10 CFU/ml of preserved drug3
5

Firm’s Investigation
Growth Kinetic Study:
BCC in Drug Product
Performing the study provided the firm with an understanding of this
organism in this product1
May explain picking up the organism using the “expanded” testing2
Provided the firm with an avenue for Corrective Actions regarding future
micro testing of this product3

Firm’s Investigation Expanded Testing Sequence
Initial: 10 batches tested & 5 batches found +ve1
Next: 25 marketed batches manufactured prior to original 102
None of these batches tested +ve3

Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

Review
…
FDA

Reviewer acknowledges
that end product release
testing presents limitations
with regard to predicting
quality of a given product
batch
However

The information provided does not
suggest that a product recall of 58
batches is warranted from the
standpoint of microbiological
contamination

Summary Recommendation / Decision
No
Recall
Corrective
Actions

No Recall
Corrective Action followed by
Investigation
Re-engineered the bad plumbing Improved sanitization
Eyes are wide open for BCC Expanded micro testing for 12 months
Modified start time of microbiological release testing based
on growth kinetic study

With scientific support to
present & demonstrate your
decisions driven by data
To have a question that how
would you respond when E.
coli hits the fan
You may hear any time …
please be ready …

Data and Data
Policies and Practices
Integrity above all

Complete Accurate Consistent
Safety
Quality

Trustworthiness / Integrity of Data
Data that is reliable
Data that is authentic
Data that is useable
Complete & Accurate
Proven to be what it say, it is
Can be located, retrieved, presented & interpreted

Data Integrity … Why?
It is an issue of
public safety
Efficacy & Quality of drug is
an obligation
Protection of public health is a
regulatory responsibility
Regulatory
actions may …

Drug may and would be
declared adulterated if
integrity issue is established

Make and keep your data

Reliable AccurateMake and keep your data

Detect
Prevent
Data Integrity
Issues
Flexible
Risk based
Strategies
Based on Process Understanding and Knowledge Management

Data Integrity
“Back up data are exact and
complete” and
“Secure from alteration, Inadvertent
erasures or loss” and that
“output from the computer”
“be checked for accuracy”

Data Integrity
Stored to prevent
deterioration or loss

Data Integrity
Certain activities be “documented
at the time of performance”
and that laboratory control be
“scientifically sound”

Data Integrity
Record be retained as “original
record”, “true copies” or other
“accurate reproduction of the
original record”

Data Integrity
Electronic signatures and
record keeping requirements
are defined everywhere and are
not choice but an emerging
obligation

Data Back up means …
True copy of the original data
that is maintained
Securely throughout the
Record Lifecycle
and Periodically Reviewed

Electronic cGMP data should
include relevant metadata

Data Exclusion
must be scientifically justified
with valid document, if it is used
in decision process of releasing
the product

Restrictions in Computer System
Appropriate control to assure only authorized personnel change in
computer (e.g. input of laboratory data into records)
Restricting the ability to alter
Specifications
Process parameters
Manufacturing or testing methods

Recommend system administrator
role including any right to alter files
and settings, be assigned to
personnel independent from those
responsible for the record content

Recommend maintaining a list of
authorized individuals and their
access privileges for each computer
system in use within GMP zone

Yes, it may not be practical
for small operation with
few employees BUT …

Share login account is a concern …
Do exercise appropriate control to
assure that only authorized personnel
make changes to computerized records
Do ensure actions are attributable to
specific individuals

Innocent mistakes in recording honest Data
A great challenge & deep concern on
the availability of the drug as well as
beta risk … hybrid phase needs careful
judgment which may not be necessarily
same in every case

GMP Handling of Out of Specifications Results

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