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WHO Technical Report Series, No. 929, 2005

WHO guidelines for sampling of pharmaceutical

products and related materials

SAMPLING AND SAMPLING

PLAN

SAMPLING

The process of removing an appropriate number of items from a

population in order to make inferences to the entire population.

Population is the total of all actual or conceivable

items of a certain class under consideration

A sample is a finite number of objects selected

from a population

A random sample is a sample chosen in such a

manner that one object has a good chance of

being selected as another

MATERIALS FOR SAMPLING

Representatives of materials to be sampled are:

Raw materials, Packaging and printed

materials;

Intermediate products/ Bulk products

Final products

INSPECTION

The comparison of certain attributes and

dimensions of a product against specifications

to find out if the product is within the

prescribed limits.

An inspection is, most generally, an

organized examination or formal evaluation

exercise.

INSPECTION

Objectives of an inspection process:

- to conduct physical test

- to conduct periodic examination

- to look for any defects

TYPES

100% Inspection

1. If the acceptable percentage for non-conforming is

zero; expensive

Why sampling inspection is preferred?

100% inspection is tiring and the probability that

the inspector will commit errors is high.

The inspection operation may involve destructive

testing. The cost of 100% inspection is

prohibitive.

A statistical sampling plan well applied may give

better quality assurance than 100% inspection.

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SAMPLING PLAN

A sampling plan is a definite working rule regarding size and

frequency of sample and the basis for acceptance or rejection

Sampling plans can be designed and applied in such a manner as to reduce

the risks to a minimum and over a period of time, give assurance of

quality products

SAMPLING PLAN

In sampling, one must consider the laws of

probability.

Risks of error:

Producer’s risk ( ∞ ) is the probability of

rejecting a good batch

Consumer’s risk ( β ) is the probability of

accepting a bad batch

SAMPLING PLAN

AQL – Acceptance Quality Level

maximum percent defective

- the maximum number of defects per 100

units.

- trivial defects – AQL value is high

- serious defects- AQL value is low

SAMPLING PLAN

The percentage of defects at which a

consumer(buyer) is willing to accept lots as

“good.”

If the supplier’s process average nonconforming is

below the AQL, the consumer will accept all the

shipped lots.

If the supplier’s process average nonconforming is

above the AQL, the consumer will reject all the

shipped lots.

SAMPLING PLAN

It requires that three numbers be specified:

number of items (N) in the lot or batch from which

the sample is drawn

number of items (n) in the random sample drawn

from the lot

acceptance number (c).

Example, if N = 50, n = 5, c = 0

“Take a random sample of 5 from a lot of 50. If the sample contains

more than 0 defects, reject the lot; otherwise, accept the lot

SAMPLING PLAN FOR STARTING MATERIALS

Square root system: n plan uses the formula: n = 1 + √N

1927, AOAC (Assoc of Official Agricultural

Chemists) adopted this as a convenient,

memorizable rule for sample-size determination

Use to determine the number of containers to

inspect

Number of units to inspect, where Ac=0 or for

variables, ave is within the specification

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SAMPLING PLAN FOR STARTING MATERIALS

p-plan

The “p plan” may be used when the material is

uniform;

is received from a recognized source;

and the main purpose is to test for identity.

p = 0.4√N

SAMPLING PLAN

“r plan”

used when the material is suspected to be non-

uniform

and/or is received from a source that is not

well known.

Also used for herbal medicinal products

r = 1.5√N

GOVERNMENT SAMPLING PLAN

It consists of master tables first developed in

1942 by a group of engineers from the Bell

Telephone Laboratories

These tables were further developed and

adopted by the US Department of Defense.

Thus, they are now known as the military

standards

SAMPLING PLAN

Attributes:

MIL-STD-105A - 1950

MIL-STD-105E ANSI Z1.4 – 2008 /ISO 2859/ British Standard BS 6001-1

Variables: MIL-STD-414D ANSI Z1.9 – 2008/ISO 3951/ British Standard BS 6002-1

AT THE START OF THE INSPECTION

To correctly use Z1.4, Identify 5 things:

Inspection Level – lot history

Lot Size

Sample size code letter

Single, Double, or Multiple Sampling

AQL

17

Lot Size

Inspection

Level

Code

Letter

(Tbl. I)

INSPECTION LEVELS

General Inspection Levels are usually used for

non destructive inspection

I, II, III

II – for more than 90% of inspections

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Start Normal

Tightened

Reduced

Discontinue

10 of 10

Acc

1 of 1

Rej

2 of 5

Rej

5 of 5

Acc

10 of 10

Rej

Substandard or unknown

quality

Consistent good quality

TIGHTENED INSPECTION

ISO – Tightened inspection is the use of a

sampling plan with an acceptance criterion that

is tighter than that for the corresponding plan

for normal inspection

INSPECTION LEVELS

Special Levels are used where relatively small

sizes are necessary or large sample risks are

taken.

Inspection often is destructive and costly

Inspection is time consuming

;

AQL

Objective Limit

Types of defects

Critical – harm the user, cause the products to be

disapproved

Major – not acceptable my MOST of the consumers

Minor – contains non-conformities but SOME will

still buy

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SAMPLE

TYPES OF DEFECTS

Defect

Class Definition Description AQL

Critical A defect that can compromise product safety, purity, or identity that may be harmful to the consumer.

Incorrect label, carton, insert, foreign tablet, incorrect code

0.01 %

Major A defect that jeopardizes the integrity or function of the package.

Missing band, deformed/cracked closure, no foil, short count/overfill, etc.

0.65%

Minor A defect that does not affect product safety, purity, or identity, or package integrity of function.

Grease on the bottle, double code on the label, flaps not glued on the carton.

4.0%

Critical – 0, Major 2.5%, Minor – 4.0%

EXAMPLE 1: LOT SIZE OF 40,000, AQL OF 2.5, NORMAL AND SINGLE SAMPLING PLAN

200 500 800 8 13 32 80

Level I II III S-1 S-2 S-3 S-4

Sample

size

Ac

number

200 500 800 8 13 32 80

L N P D E G J

SINGLE SAMPLING PLAN

The most common and the easiest plan

Inspect a sample of n pieces

If the number of defects in the samples exceed the

standard, reject, otherwise, accept.

DOUBLE SAMPLING PLANS

1. Take small initial sample

- If # of defectives < lower limit, accept

- If # of defectives > upper limit, reject

- If # of defectives are between limits, take a second

sample

2. Accept or reject a lot based on 2 samples

3. Less inspection than in sampling plan

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MULTIPLE SAMPLING PLANS

Advantage: uses a smaller sample size

Take initial sample

- If # of defectives < lower limit, accept

- If # of defectives > upper limit, reject

- If # of defectives are between limits, re sample

Continue sampling until accept or reject lot based

on all sample data

Sample

number

Sample

size

Cumul-tive n Ac

no.

Re

no.

DOUBLE

1st 50 50 1 4

2nd 50 100 4 5 MULTIPLE

Ist 20 20 - 3

2nd 20 40 0 3

3rd 20 60 1 4

4th 20 80 2 5

5th 20 100 3 6

6th 20 120 4 6

7th 20 140 6 7

DOUBLE SAMPLING PLAN

Disintegration Test

All of the tablets have disintegrated completely

If 1 or 2 tablets fail to disintegrate completely,

repeat test on 12 additional tablets

The requirement is met if 16 of 18 tablets tested

disintegrated

DISSOLUTION TEST

Dissolution Test

S Number Tested Acceptance Criteria

S1 6 Each unit is nlt Q + 5%

S2 6 Average of 12 is equal to or greater

than Q, no unit is less than Q - 15%

S3 12 Average of 24 is equal to or greater

than Q, not more than 2 units are less

than Q-15%, no unit is less than Q -

25%

Sampling Plans:

1. Fourteen drums of muriatic acid were received in the warehouse. Each drum has a capacity of 5L

a. if the shipment has the same batch number in all drums, how many drums should be sampled using square root system and military std tables

b. if the shipment consists of 2 drums with one batch number and 12 drums with another batch number, give the sample sizes using the 2 sampling plans.

2. In acceptance sampling under the ABC standard, single sampling is to be used with inspection level II, for a batch of 10,000 pieces of labels. Give the AQL for normal sampling.

3. True or False? A sample size of 5 units with an AQL of 6.5 can have an acceptance number of 1

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4. The following materials were delivered and received in the warehouse with a status of ready for sampling. Determine the number of samples to be taken (using both sampling plan) include the acceptance and rejection number.

Labels - 3 packs of 12 bundles by 500, another batch of 1 pack of 14 bundles by 500

Bottles, 30 mL cap – 210 shippers x 144

Inserts – 55 packs by 500, 1 pack by 300

Cartons – 100 packs by 250

A batch size of 25 was inspected, 3 defectives

were found during the inspection. The

acceptance limit is 2.5% defectives. Determine

the sample size code letter, sample size,

acceptance number and disposition using the

master table. Give the N if the sample size is 5

using square root system.

Sample

number

Sample

size

Cumulative n Ac

no.

Re

no.

DOUBLE

1st 50 50 1 4

2nd 50 100 4 5 MULTIPLE

Ist 20 20 - 3

2nd 20 40 0 3

3rd 20 60 1 4

4th 20 80 2 5

5th 20 100 3 6

6th 20 120 4 6

7th 20 140 6 7

1. Using a double sampling method, 3 defectives

were found during the first sampling. Give the

disposition

2. Total number of defectives after the 4th

inspection gave 4 defects. On the fifth

sampling, three more defectives were found. Is

the lot acceptable?

PERCENTAGE ACCEPTED

Percentage of lots to be accepted

= 100 - (n) (percent non conforming)

Ex. AQL of 0.40% non conforming with sample

size code letter G

Ans = 87.2% of the lot

Percent non-conforming

= (100 - Percentage of lots to be accepted) / n

1. Batch size using square root for a sample size of 317 bottles from a trusted supplier. Using military sampling plan, what is n? what inspection level to be used?

2. Total labels delivered were 6 packs of 20 bundles by 500, what is n using square root system? With AQL of 1.0, what is the Ac and Re no?

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Amount of Samples for RM: For total weight of sample is less than 100 Kg, the sample should be at least

250 g;

for total weight of drug greater than 100Kg, the sample weigh 125 g

For total weight of drug that is less than 10Kg, sample weight should be 125 g.

2/3 for complete analysis, 1/3 as retention sample

Company X acquired his supplies from Supplier Y, a new supplier. The following were delivered:3 drums, each containing 30 Kg of Chloramphenicol and 12 packs of MCC, 25 kg each pack.