2 6 Sampling WHO Guidelines

2-6
Sampling according to WHO guidelines

for sampling of pharmaceutical products
and related materials
Marta Miquel
Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling
and testing projects, Nairobi, Kenya, 23-25 September 2009
WHO sampling guideline - Introduction
 This guideline is primarily addressed to governmental organizations

such as drug regulatory authorities (including inspectorates), quality
control laboratories, customs and police officials, when surveying the
national markets for the quality of drug products.
 The guideline is available on the internet as Annex 4 of the WHO

Technical Report Series No. 929 (2005), issued by the WHO Expert
Committee on Specifications for Pharmaceutical Preparations.
http://apps.who.int/prequal/info_general/documents/TRS929/WHO_TRS_929.pdf
2| Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Before sampling
I. purpose of sampling?
II. type of tests intended to be applied to the samples?
III. type of products/materials to be sampled?
IV. are sampling facilities adequate?
V. are responsibilities of the samplers clear?
Note: these topics are dealt with in the presentation

“Organisation of sampling programmes – background information”
Sampling process
I. Preparation for sampling
II. Sampling operation
III. Sample storage and retention
I - Preparation for sampling
 Sampling tools should be available to the sampler, e.g. to open containers (knives,
hammers,...), material to reclose the packages (sealing tape), self-adhesive labels to
indicate that some of the contents have been removed, etc...
 Sampling tools should be made of inert materials (e.g. polypropylene or stainless steel;
avoid glass) and kept very clean. After use, thoroughly washed, rinsed with water or
suitable solvent, dried and stored in clean conditions.
 Disposable sampling materials can also be used.
 Washing facilities should be located in, or close to, the sampling area.
 Cleaning procedure should be documented and validated (= demonstrated efficiency).
 Sterile pharmaceutical products should be sampled under aseptic conditions.
Examples of types of sampling tools (Appendix 1 of WHO guideline)
Dip tubes
Spatulas for liquids
for solids Sample thieves
for solid samples in
deep containers
Bag-sampling
spears for taking
samples from bags
II - Sampling operation
 Written sampling procedure: operations to be performed on a defined material for a

specific purpose, including health/safety aspects (see Appendix 3 of WHO guideline:
Examples of steps to be considered for inclusion in a SOP).
 Sampling plan: description of the location, number of units and/or quantity of material that
should be collected, and associated acceptance criteria.
 Make sure that representative samples are taken in sufficient quantity. Representative
sample: sample obtained according to a sampling procedure designed to ensure that the
different parts of a batch or the different properties of a non-uniform material are
proportionately represented.
 Samples should never be returned to the bulk.
II - Sampling operation (cont.)
 Sampling operations should be supervised and documented => sample collection form
=> always kept together with the collected sample.
 Sample collection form: written record of the sampling operations, containing: batch
number, sampling date/place, reference to sampling protocol used, description of
containers and materials sampled, possible abnormalities, any relevant observations,
name/signature of the sampler...
 Store the sample in a properly labelled container: sample type, name of material,
identification code, batch number, code, quantity, date of sampling, storage conditions,
handling precautions, container number....
Example of sample collection form
(Appendix 2 of WHO guideline)
Page 1 Page 2
II - Sampling operation (cont.)
 Pay attention to any signs of non-uniformity of the material:

 Differences in shape, size, colour of particles in crystalline/granular/powdered subst.
 Moist crusts on hygroscopic substances.
 Solid deposits in liquids or semi-liquids.
 Stratification of liquids.
 In this case, sample portions of the material and test them separately from the material
with normal aspect.
 Take into account previous experience with the product and supplier.
10 | Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
III – Sample storage and retention
Containers
 Containers used to store a sample should comply with the storage directions for
the active pharmaceutical ingredient, excipient or drug product:
 should not interact with the sampled material.
 should not allow contamination.
 should protect the sample from light, air and moisture.
 should be sealed and adequately labelled.
 avoid mix-up when containers are opened (screw caps, separate lids).
 manipulations/unauthorised opening should be easy detectable.
 transported in such way as to avoid breakage.
III – Sample storage and retention (cont.)
Rooms for sample storage
 Security and adequate storage conditions (light, ventilation, safety requirements, and
any special requirements) should be ensured for the rooms in which samples are
stored.
 Samples should be stored according to the storage conditions as specified for the
respective API, excipient or drug product.
 Packaging materials similar to those in which the bulk is supplied should be used for
long-term storage.
Examples of types of containers used to store samples of starting materials and
bulk products (Appendix 4 of WHO guideline)
Bag for storage of samples

Screw-top containers
Sampling for acceptance
I. Starting materials
II. Intermediates in manufacturing and bulk products
III. Finished products
IV. Packaging materials
I – Sampling of starting materials
 Uniform material: sample can be taken from any part.
 Non-uniform material:
 Special sampling tools are needed.
 Alternatively, if applicable, restore uniformity before sampling (e.g. stratified
liquid may be stirred or a solid deposit in a liquid may be dissolved by gently
warming and stirring) – validated method !
 In these cases, in order to prepare representative samples, see ISO 2859.
 Partially processed natural products (animal, herbal and mineral) should be
treated as intrinsically non-uniform. For info, sampling of herbal drugs, see
European Pharmacopoeia chapter 2.8.20.
II - Sampling of intermediates in manufacturing and
bulk products
 Intermediates: liquids and semi-solid products; powdered solids or
granulates; unit dosages forms in bulk (tablets, capsules).
 Pay attention to the segregation of bulk materials during transportation.
 These products may be assumed as uniform if the transportation

process has been validated, AND:
 They are labelled with name of the manufacturer and a single batch number;
 They have been produced according to GMP; and
 They are supplied with a certificate, issued in the country of origin, according to
the WHO Certification Scheme on the quality of pharmaceutical products
moving in international commerce
WHO Certification Scheme for Products moving in International Commerce
is an international voluntary agreement, created to enable countries with limited
drug regulatory capacity to obtain partial assurance from exporting countries
concerning the safety, quality and efficacy of the products they plan to import.
http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/
On this website you can find information about:

 competent authorities participating in this certification scheme.
 model certificate of a pharmaceutical product.
 guidelines on the implementation of this certification scheme.
Sampling plans for starting materials
I. “n-plan”
II. “p-plan”
III. “r-plan”
See examples of use of sampling plans in Appendix 5 of WHO guideline
I – The “n-plan”
 Only used when material is considered uniform and from a recognised source.
n  1 N N = sampling units in the consignment (e.g.

individual package, drum or container)
1. Calculate “n” (n = units to be sampled).

2. Select at random “n” units from N.
3. Take a sample from these units.
4. QC lab checks appearance + identity of
each sample.
5. If results concordant => combine samples
into a single final sample.
6. Take “analytical sample” for full testing.
7. Keep the rest as “retention sample”.
e.g. N=40 => n=7 (units to be sampled)
NOTES:
• The “n-plan” is NOT statistically based and should be used only as a guiding
principle.
• The “n-plan” is NOT recommended for use by control laboratories of
manufacturers that are required to analyse and release or reject each
received consignment of the starting materials used to produce a drug
product.
II – The “p-plan”
 May be used when material is considered uniform, from a recognised source and
the main purpose is to test for identity.
p  0 .4 N
N = sampling units in the consignment (e.g.
1. Sample each of the N sampling units.

each sample.
3. If results concordant => p final samples
are formed by appropriate pooling.
4. Keep the p samples for retention (or full
testing if required).
e.g. N=40 => p=3 (final samples after testing+pooling)
III – The “r-plan”
 May be used when material is considered non-uniform and/or obtained from a not
well know source.
 Can be used for herbal medicinal products used as starting materials.
r  1.5 N N = sampling units in the consignment (e.g.

1. Sample each of the N sampling units.

each sample.
3. If results concordant => r samples are
randomly selected.
4. r samples individually fully tested.
5. If results concordant => combine the r
samples for the retention sample.
e.g. N=40 => r=10 (randomly selected samples for testing)

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2-6

Sampling according to WHO guidelines

 This guideline is primarily addressed to governmental organizations

 The guideline is available on the internet as Annex 4 of the WHO

II. type of tests intended to be applied to the samples?

III. type of products/materials to be sampled?

IV. are sampling facilities adequate?

V. are responsibilities of the samplers clear?

Note: these topics are dealt with in the presentation

II. Sampling operation

III. Sample storage and retention

 Disposable sampling materials can also be used.

 Cleaning procedure should be documented and validated (= demonstrated efficiency).

 Sterile pharmaceutical products should be sampled under aseptic conditions.

 Written sampling procedure: operations to be performed on a defined material for a

 Samples should never be returned to the bulk.

 Pay attention to any signs of non-uniformity of the material:

Rooms for sample storage

Bag for storage of samples

II. Intermediates in manufacturing and bulk products

III. Finished products

IV. Packaging materials

 Uniform material: sample can be taken from any part.

 Pay attention to the segregation of bulk materials during transportation.

 These products may be assumed as uniform if the transportation

On this website you can find information about:

See examples of use of sampling plans in Appendix 5 of WHO guideline

n  1 N N = sampling units in the consignment (e.g.

1. Calculate “n” (n = units to be sampled).

1. Sample each of the N sampling units.

e.g. N=40 => p=3 (final samples after testing+pooling)

r  1.5 N N = sampling units in the consignment (e.g.

1. Sample each of the N sampling units.

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