AQL and LQ Schemes their use and

limitations in pharmaceutical quality

assurance
1 Introduction
Paolo as a prelude to answering the supplementary questions you asked (and I apologise in
advance if I repeat myself), it is worthwhile re-visiting some key facts about AQL and LQ
schemes. Where I refer to a Slide by number, it is one in the slide set to which I provided the link

2 Issues
1.1 Issue 1- the perceived magical properties of ISO 2859
schemes
The AQL schemes of ISO 28591 and the LQ schemes of ISO 2859-2 possess no magical
properties. which provide a level of protection beyond that statistically calculable from the
Binomial/Poisson statistics which underpin them for a given combination of sample size and
acceptance number. The standards merely provide a convenient, standard, sub-set of the
infinite possible sample size/acceptance number permutations, together with tabulated
details on the level of protection they supply for particular sample size/acceptance number
combinations.
1.2 Issue 2 the perception that the AQL value is the percentage
of defects within a single batch with a high probability of
rejection
The clue to the first problem with this fallacy of this perception lies in the name (Acceptable
Quality Level) that the acronym AQL represents.
The stated AQL value is the Average Level of Defects across a Composited Series of
Batches which you would be happy to have an approximately 95% chance of Accepting. An
individual batch can have a significantly higher proportion of defects (up to 12 times the
stated AQL) present.
The second problem comes from the words Composited Series of Batches and Average
Level of Defects which are critical, since they imply two things which are not acceptable for
many GMP purposes:
Compositing, eliminating batch based track and trace during the manufacture chain
Compositing of batches deliberately using the better batches which are part of the composite
to average out the effect of batches which are substantially worse than the composite average.
1.3 Issue 3 using ISO 2859-1 schemes for outgoing product
assessment
This standard is designed for incoming inspection. As is explicit in the background
information provided within the standard, they are designed for giving an Average Level of
Protection as measured over a Composited Bulk as a Series of Incoming batches. They are
identified as Specifically Not Designed to provide Individual Batch Protection on Single
Outgoing Batches.
An understanding of how Operating Characteristic curves (OC curves) work allows the
tabulated probabilities in the different code letter tables of ISO 2859-1 to be used to
 determine the level of defects which would give a high probability of rejection on a single
batch effectively, you are then looking at the performance of an LQ (Limiting Quality
Scheme) but when used in this way, the tabulated AQL value is meaningless (see 1.5 later).
This is why, for single batches, the Limiting Quality schemes of ISO 2859-2 are intuitively
clearer in the level of single batch protection they offer since, to paraphrase use the words
from a UK advert for wood protection paint which have passed into common UK usage
.they do exactly what it says on the label!..
1.4 Issue 4 using AQLs in the belief that they can control
critical defects or can deliver the mythical 0% AQL
Critical defects, by definition cannot be controlled by any form of sampling AQL schemes
do not possess any magic properties which allow control of critical defects.
A fundamental condition of the use of any sampling scheme, including these schemes, is
that there is a finite permissible level of defects which can be present in a batch. The level
may be very low but use of a sample requires it to be finite.
When the 0% AQL appears in a specification, in my experience, one or both of the
following is happening:
The author of the scheme is using 0%AQL to describe what is in reality a Critical Defect
An acceptance number of 0 is being confused with an assumption that 0 defects found in the
sample = 0 defects in the batch.
3 Your specific questions
1.5 Properties of Operating Characteristic (OC) curves.
The answers to the questions are so dependent on the properties of OC curves that I will deal
with this issue first, before answering the questions. Diagram 1 below is from ISO 2859-1
and shows the OC curves for a range of AQLs with a sample of 315 code M

In diagram 2 below, I have focussed on one of these curves sample 315 accept on 0 or 1
defects -reject on 2 or more.

An OC curve (the blue line) is a graphical representation of the probability (vertical axis) of
accepting of a batch with a given percentage of defects (horizontal axis) and it is derived
 directly from the percent nonconforming = 2.5% column of table 10-M-1 of diagram 1.
Acceptance schemes technically follow Binomial statistics, though for large samples with
low percentages of defects expected, sampling schemes such as the ISO 2859 series use the
Poisson approximation to the Binomial distribution. The shape of the curve produced by
either distribution is solely dictated by two parameters the Sample Size and the Maximum
Acceptable Number of defects. For Diagram 2, the sample size is 315 and the maximum
acceptable number of defects is 1. The shape of the curve is the unaffected, whether the
curve is being used to predict the effect of an AQL scheme or a LQ scheme.
The curves in ISO 2859-2 are, in effect. a sub-set of the curves in ISO 2859-1 and I have
chosen in Diagram 2 a curve which appears in both standards. The difference between
ISO 2859-1 and ISO 2859-2 is the end of the OC curve on which each standard is focussed.
The AQL schemes of ISO 2859 are focussed on the left hand end of the curve (the green
bar) which is the chance of acceptance. The standard is focussed on a high probability of
accepting batches which, when composited into a bulk, would produce a composite-bulk,
whose average level of defects was close to or better than the AQL, good batches effectively
being used to dilute the effect of poorer batches. This is the reason, given the batch based
nature of most pharmaceutical manufacturing and GMP tracking, the stated AQL numbers
are meaningless in assessing the quality of an individual batch.
If you wish to ensure that there is a low probability of accepting an individual batch with a
level of defects greater than a specified number, you are looking at the right hand end of the
curve of diagram 2 (the red bar). This is the basis of focus for the ISO 2859-2 LQ schemes
and the example of Diagram 2 displays an ISO 2859-1 AQL of 0.15% which also
corresponds to an ISO 2859-2 LQ of 1.25% - i.e., the LQ is 8.3 times higher than the stated
value of the AQL. This is the origin of my comment in slide 12 of the presentation that the
common belief that the AQL value is the level of defects with a high chance of rejection is
wrong and leads to a vast overestimate of the protection offered.
As Diagram 2 indicates, if you are clear about the properties of the OC curves, it is perfectly
possible to use the right hand end ISO 2859-1 OC curves to define an LQ sampling scheme
for individual batches whose statistical properties are known and officially defined, however
such schemes should not be defined as AQL schemes.
1.6 Question 1) I wonder if you could indicate how a company should in
general select/define appropriate AQL values.
As I hope I have made clear in previous answers, AQLs, as defined in the ISO 2859-1
standard, with their focus on the average properties of a composited bulk where batch
identity is lost are typically inappropriate for batch related pharmaceutical GMP controls.
A focus on preventing acceptance of individual batches whose defect level exceeds a certain
percentage is, by its nature, an LQ scheme. To legitimately use such schemes, one pre-
condition must be met and three key decisions have to be made:
The precondition for using LQ sampling is that within a batch, there must be a finite tolerable
level of any defect selected for control by sampling the level may be small but it cannot be
zero.
What is the tolerable percentage for each defect where a proportion of such defects can be
allowed in the batch?
What constraints are there on sample size? Larger samples give better discrimination and
schemes with an acceptance number of zero have particularly poor discrimination (slides 24
and 25 of the presentation)?
Is there a defined scheme meeting the need in ISO 2859-2 or is it necessary to interpolate the
OC curves of ISO 2859 to find a more appropriate combination of sample size, acceptance
number and LQ?
 Examples of things which may be amenable to LQ sampling include, but are not limited to,
black specks on white tablets, smudged print on printed capsules, misaligned labels or non-
functional defects in plastic components such as mould lines.
Critical defects such as non-sterile injection vials, rogue labels or components or incorrect
print on labels cannot be controlled by any sampling scheme.
1.7 2) In one particular example, a company is using (for many years) a
unique AQL =2.5%. Nobody knows how this AQL was selected, and
the company would like to justify this value retrospectively. How
would you proceed to provide a rationale showing the pertinence
of the aforementioned value? Is a retrospective data analysis
possible? What kind of data sets would have in this case to be
analyzed?
Any justification would have to start with understanding the protection the existing scheme
has been delivering, and in assessing this protection, an AQL value in isolation is inadequate
the number of samples and the acceptance numbers are also needed as illustrated in
diagram 3 below.

Both the curves are for an AQL of 0.65, but the sample size and permissible number of
defects produce very different LQ values - ~3% for the 315 sample and ~15% for the 20
sample. The first stage of any analysis and justification starts with this understanding of the
level of protection which has been present.
This then needs to be subjected to the analysis of outlined in section 1.6 to confirm whether
the attributes allegedly controlled by the sampling are appropriate for control by sampling
and whether the actual level of protection delivered by the sample size and acceptance
number meet the identified control need.
As regards retrospective data analysis, if the average reject rate over large a sample of
batches, then using the sample size and acceptance number, it would be possible to use
Poisson statistics to estimate the probable LQ achieved and determine whether it was
possible to develop a rationale based, for example, on the basis of process performance,
customer complaints etc. that this LQ delivered an acceptable outcome.
1.8 3) I think I got confused with the difference between ISO 2859-1
and 2859-2. The first is intended for lot-by-lot inspection and the
second for isolated lot inspection. In my current understanding
lot-by-lot is applicable to a continuous production and the
second one for a discontinuous production at supplier am I
correct ? Does the continuous production refer to a single
production equipment (including, for example, one single mold)?
As I hope I was able to make clear in section 1.5, the difference between ISO 2859-1
and 2859-2 is not the type of production process it is applied to it is the fact that
ISO 2859-1 focusses on the assumption that recipient wishes to composite individual
batches into a pooled bulk, and you wish to manage the average properties of this
pooled bulk as you add new batches.
In most pharmaceutical applications where batches are being assessed on receipt, the
focus is typically on ensuring that the properties of individual batches are unlikely to
be worse than a stated percentage of defects of a type where a finite level of such
defects is permissible i.e., an LQ based sampling scheme of the type specifically
described in ISO 2859-2 or using the more comprehensive set of OC curves in ISO
2859-1 to find an acceptance number/sample size combination whose LQ fits the
need.
1.9 4) Is it correct to indicate that a Critical component is a
component having at least one critical quality attribute (out of
the various quality attributes it can have with the different
criticality degrees)?
Im not sure of the properties implied by different criticality degrees so I would answer the
question in this way:
Proposition 1 - A Critical Defect is a type of defect in a product or component for which no
acceptable level can be set for the presence of such a defect in a batch. Examples would be
non-sterile units in a batch of injection vials or a rogue label for one product in a batch of
labels for another product,
Proposition 2 - Such defects cannot be controlled by any form of sampling. They can only be
controlled by a manufacturing process designed to eliminate the possibility of such defects
Proposition 3 the detection of an instance of the type of defect defined in proposition 1
affects not just the batch in which it was found it indicates the system defined in proposition
2 has failed and calls into question other batches from the same source even if sampling has
not disclosed any instances of the defect.
Degrees of Criticality are not a concept defined in the terminology of these schemes. Either
a defect is Critical (no instances acceptable) or it is, within the Major and Minor categories
of defect recognised within the schemes.
It is often the case that there may be sub divisions (with different acceptable percentages of
defects) within the Major/Minor categories e.g., Major A, Major B, Minor A, Minor B.
The concept of ..degrees of criticality.. is, however alien to the terminology.

Peter Murray 14/9/2015

B.Sc., M.Ph.A., C.Chem, F.R.S.C