Compliance to Good Laboratory Practice; OOS

results

“Getting prepared for FDA or PIC

inspections”

APV/IKEV Seminar on Good Manufacturing

Practice: Compliance and Inspection, Istanbul,
June 10/11, 2004

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 1

Table of contents

•Compliance to GMP in laboratories

•How to handle out-of-specification results,
“OOS”

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 2

Laboratory GMP: Regulatory
Guidelines

EEC Guide to Good 21 CFR 210/211 (cGMP for

Manufacturing Practice for finished pharmaceuticals)
medicinal products • Subpart I Laboratory
• Chapter 6 Quality Control Controls
• 6.1 – 6.4 General • § 211.165 Testing and
• 6.5 – 6.6 Good Quality release for distribution
Control Laboratory • § 211.166 Stability testing
Practice • § 211.167 Special testing
• 6.7 – 6.10 Documentation requirements
• 6.11 – 6.14 Sampling • § 211.170 Reserve samples
• 6.15 – 6.22 Testing • § 211.173 Laboratory
animals
• § 211.176 Penicillin
contamination

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 3

EEC GMP Guide

Chapter 6: “Quality control” Also see:

• General (6.2) • Chapter 2, Personnel
• Good quality control • Chapter 3, Premises and
laboratory practice (6.5, equipment (quality control
6.6) areas)

• Documentation (6.7 – • Chapter 4, Documentation

6.10) “sampling” and “testing”
are not mentioned in other
• Sampling (6.11 – 6.13) chapters
• Testing (6.15 – 6.22)

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 4

Personnel (chapter 2)

• General
• adequate number
• necessary qualification
• practical experience
• organisation chart
• job descriptions
• Key personnel (besides “head of production”)
• head of quality control
• Training
• Personnel hygiene

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 5

Premises and equipment (chapter
3)

• 3.26 – 3.29 Quality control areas

• 3.26 Quality control laboratories should be separated
from production areas
• 3.27 Mix-ups and cross-contamination are to be
avoided (also see chapters 5.18 – 5.20 and 5.44)
• 3.28 Sensitive instruments are to be protected from
vibration, electrical interference, humidity, etc.
• 3.29 Special requirements are needed in laboratories
handling particular substances, such as biological or
radioactive samples

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 6

Documentation (chapters 4 and 6)

• Chapter 4 • Chapter 6
• Specifications • Specifications
• Manufacturing formulae • Sampling
• Processing and packaging • Records
instructions • Certificate of analysis
• Procedures • Monitoring data (reports)
• Records • Validation records (testing
• Sampling methods)
• Testing • Procedures
• Testing

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 7

Testing (chapter 6)

Chapters 6.15 – 6.22 deal with the testing and

documentation of quality control results
Points to consider:
• In-process-control (IPC; 6.18): The EEC GMP Guide
leaves the responsibility for IPC open:
• production or
• quality control personnel ?
It is only mentioned that the IPC procedure has to be
approved by QC.
In general it is agreed that – if the procedure(s) for
IPC does/do not bear a risk for the manufactured
drugs – the IPC may be performed by production
personnel.
Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 8
Conclusions

In several sections of Chapter 6 of the EEC GMP Guide

reference is made to earlier chapters.
It can therefore be concluded that testing of
pharmaceuticals is to be performed with the same level
of safety as in production; e.g. EEC GMP Guide Annex
1.3 and Chapter 2.6.1, test for sterility, in the European
Pharmacopoeia:
• Annex 1.3. requires a “class A” production area in a
“class B” environment for aseptically manufactured
drugs.
• the European Pharmacopoeia requires that a “test for
sterility” be performed in a “class A” LAF that is
located in a “class B” environment (or use of an
isolator).
Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 9
OOS Results

A result is considered OOS when – if generated

according to the valid testing procedure – it does not
comply with the requirements given in the
specification(s).

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 10

Definitions

1. Re-testing: Retesting of a portion of the original

sample.
2. Re-analysing: A new mixture from the original sample
is prepared.
3. Re-sampling: While re-testing refers to analysis of the
original sample, re-sampling involves analysing a
specimen from the collection of a new sample from the
batch.
4. Reference sample: Sample from a batch which is
known to deliver unobjectionable results.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 11

“Failure investigations I and II”

• Failure investigation I: refers to the test/laboratory

environment

• Failure investigation II: refers to

sampling/production/processing

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 12

Draft FDA Guideline (1998): OOS
Results

Failure investigation I, laboratory environment:

1. Re-testing the original sample
2. Re-analysing the original sample. The re-analysis
must be described in the relevant SOP.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 13

Evaluation of laboratory faults (1/3):
Responsibility of the analyst

• The analyst is responsible for:

• only using calibrated equipment
• only using equipment which meets the requirements
of the “system suitability test”
• informing the supervisor as soon as an OOS result
has been generated which cannot be blamed directly
on a laboratory error, before further tests are carried
out

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 14

Evaluation of laboratory faults (2/3):
Responsibility of the supervisor

The supervisor must check and evaluate the available

data within the scope of “failure investigation I” before
further tests are carried out. As a rule, the evaluation
includes the following steps (besides systematic testing
of the analytical procedure, including inspection of the
test run and sample preparation):
1. equipment calibration
2. review of equipment parameters
3. “system suitability test”
4. review of laboratory reagents
5. review of standards used
6. sample preparation
7. calculations

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 15

Evaluation of laboratory faults (3/3):
Responsibility of the supervisor (cont’d)

Depending on the results of “failure investigation I”

and of a possible subsequent test, it is incumbent on
the supervisor to decide whether:

1. a laboratory error has occurred

2. a laboratory error can generally be ruled out or

3. if the problem lies outside the laboratory environment

(-> failure investigation II)

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 16

Procedure in the event of an apparent
laboratory error

When the OOS result can be attributed to an apparent

laboratory error, re-testing takes place.

Keep in mind: OOS results should not always be blamed

on (a) laboratory/staff error(s)

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 17

Procedure in the event of a non-apparent
laboratory error

If the OOS result cannot be attributed to an apparent

laboratory error, a subsequent re-analysis is carried out
before “failure investigation II” is started.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 18

Failure investigation II

During “failure investigation II”, sampling and the entire

manufacturing process is systematically checked. This
also includes inspection of the quality of the raw
materials and excipients utilized.
The results of “failure investigation II” are to be
documented
– in addition to the results of “failure investigation I”.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 19

CFR 211.165 (Re-testing)

1. The FDA permits the release of a batch with an OOS

result without query if the subsequent result of the re-
test was o.k., but not necessarily if only the subsequent
results of the re-analysis were o.k. This is important to
know for microbiological tests, as the original sample
often is no longer available due to the long period of
time between sample handling and the final results.
2. If the OOS result is based on a clear-cut laboratory
error, it can be dealt with by performing a single
subsequent test. However, if the (laboratory) error
cannot be clearly defined, …extensive re-testing for
inconclusive failure investigation …* is expected.

*United States versus BARR laboratories, 2/93

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 20

Averaging

If the Standard Operating Procedure (SOP) doesn’t

explicitly say that the average and not the single
value(s) (is)are to be considered, all generated results
are indicated and evaluated individually.
Creating an average value is recommended if variability
and standard deviations are important to consider, e.g.
validation of the LAL test: if the labelled lysate
sensitivity must be confirmed in quadruplicate, the
standard deviation must not exceed a certain value.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 21

Parallel tests

Several parallel preparations of the same sample are

particularly suitable for tests that show a high level of
variability in the results, e.g. microbial count
determinations, due to the system inherent variability.
If the standard operating procedure, SOP, requires
parallel tests of a preparation, only the average value
received and not the single values are documented as
result.
Keep in mind: If the single and not the average value(s)
is/are required when reporting the result, one is not
permitted to “improve” the results by generating an
average value if an OOS result was obtained!

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 22

“Test for outliers”

The test for outliers is used when a result from a data

pool with mainly homogenous results differs so greatly
from the others that it is rather unlikely that the obtained
result relies on “real data”.
The “outlier” may result from a laboratory or production
error that was not identified and is thus not
representative.
Keep in mind: In the relevant USP chapter, “Outliers”
are only accepted as such if they can be proved
statistically
(e.g. > triple standard deviation) and only for biological
and not for chemical tests!

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 23

CFR 211.167 “special testing
requirements” (for microbiological tests)

• 211.167(a) Sterile products: Written test procedures for

sterility and …… testing….

• Interpretation: When drawing up a OOS SOP there

should be 2 SOPs: one for sterile and one for non-sterile
products.
Rationale: The procedure for sterile products in the case
of OOS results is completely different from that for non-
sterile-products.

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 24

CFR 211.167 “special testing
requirements” (for microbiological tests)

1. 211.167(a) Sterile products (interpretations*)

1. It is difficult to justify invalidation of an initial positive
sterility test result.
2. Presence of the same micro-organism in test sample
and lab environment does not automatically rule out
product contamination.
3. A “high threshold” of justification is needed to
invalidate a positive sterility test result.
4. A positive sterility test result rate above 0.5%
requires investigation (-> both false and correct
positive; trending over a 12-month period is
required).
* FDA Human drug GMP notes, 6/99

Dr. M. Pfeiffer, A_Quality Operations Istanbul, June 2004 25