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
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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”
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Sampling process
I. Preparation for sampling
II. Sampling operation
III. Sample storage and retention
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Examples of types of sampling tools (Appendix 1 of WHO guideline)
Spatulas
for solids
Dip tubes
for liquids
Sample thieves
for solid samples in
deep containers
Bag-sampling
spears for taking
samples from bags
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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....
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Example of sample collection form
(Appendix 2 of WHO guideline)
Page 1
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Page 2
II - Sampling operation (cont.)

Pay attention to any signs of non-uniformity of the material:






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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.
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:







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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.
Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Screw-top containers
Sampling for regulatory issues
I.
Drug quality surveillance programmes
II. Inspections
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
I - Drug quality surveillance programmes

The extent of the routine surveillance programmes for drug quality, carried out by
National Drug Regulatory Authorities will depend on:




capacity of the national drug QC lab
extent to which the quality of the product has been assessed prior to registration
extent to which the requirements for GMP are implemented
number of products imported from abroad

The programme should include marketed products, whether registered for sale or
prepared in pharmacies.

Each product should be assessed regularly (every 2-3 years).

Particular attention to products of prime importance to public health programmes or
potentially dangerous, unstable or difficult to formulate properly.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
I - Drug quality surveillance programmes (cont.)

The responsible laboratory should prepare the sampling programme (if needed
under the guidance of the drug regulatory authority) every year or half a year.
 Sampling programme:






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Lists the products to be sampled during a given period
Specifies the sampling procedure
Specifies the size of the samples to be collected (including retention sample)
States to what extent each brand of a given product will be sampled
States which local authority or inspector will be responsible for sampling
Indicates to which laboratory each sample should be sent (if more than 1)
Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
II - Inspections
 Inspectors may take samples from:
 retail or hospital pharmacies (including preparations manufactured in bulk in
the premises)
 industry
 wholesalers
 In case of a complaint received about a product, the sample should
include the original container and if possible 1 or 2 unopened containers
with the same batch number.
 In case of deteriorated dosage forms, the sample should consist of one or
more containers showing visual signs of deterioration.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Sampling for acceptance
I.
Starting materials
II. Intermediates in manufacturing and bulk products
III. Finished products
IV. Packaging materials
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
III - Sampling of finished products

Uniformity : a single consignment* of a product from a single manufacturer and
labelled with a single batch number may be assumed to be uniform.

The minimum size of the samples to be taken is determined by the requirements
of the analytical procedure used to test the product (tests of unit dosage forms for
uniformity of weight, volume or content, or sterility tests can require a large
number of samples).

Sampling and testing may be adjusted according to the experience with the
source of the product, e.g. manufacturer or supplier.
*Consignment: quantity of a bulk starting material or drug product, made by one manufacturer or supplied by
one agent, supplied at one time in response to a particular request (1 or more containers, 1 or more batches).
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
IV - Sampling of packaging materials
 Pay attention to mixing up printed packaging materials during sampling
 only 1 material should be handled at a time.
 adequately protect and identify the sample.
 Samples of packaging materials should never be returned to the
consignment.
 During sampling, primary packaging materials should be protected
against environmental contamination (e.g. special measures when
sampling parenteral ampoules).
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
IV - Sampling of packaging materials (cont.)
 A consignment of packaging materials may NOT be considered
homogeneous if:
 Materials manufactured on different days or machines
 Materials manufactured on one machine, but different stations (e.g. printing
stations, moulding stations)
 Packaging manufactured with different source materials
 Change in quality during the process (colour variation, text legibility or
change of printing plate, container-wall thickness...)
 Important to take random samples from across the consignment.
 Consider focus sampling based on the abovementioned risk factors.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Sampling plans
I. Starting materials
II. Finished products
III. Packaging materials
Note: guideline primarily addressed to Drug Regulatory Authorities, these
sampling plans might not be appropriate for manufacturers.
The following plans are examples
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
Calculate “n” (n = units to be sampled).
Select at random “n” units from N.
Take a sample from these units.
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”.
1.
2.
3.
4.
e.g. N=40 => n=7 (units to be sampled)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
individual package, drum or container)
1. Sample each of the N sampling units.
2. QC lab checks appearance + identity of
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
individual package, drum or container)
1. Sample each of the N sampling units.
2. QC lab checks appearance + identity of
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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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Sampling plans for packaging materials
 Should be based on defined sampling standards such as:
 ISO 2859
 British Standard BS 6001-1
 ANSI/ASQ Z1.4-2008 (American National Standards Institute/American
Society for Quality)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Sampling plans for finished products
 Should be based on defined sampling standards such as :
 ISO 2859
 British Standard BS 6001-1
 ANSI/ASQ Z1.4-2008 (American National Standards Institute/American
Society for Quality)
 In some cases a visual inspection might be sufficient.
 However, if physical and chemical testing is required, the sampling units
should consist of whole packs (individual packs should not be broken open).
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
ISO 2859 series - Sampling procedures for inspection by attributes

ISO 2859-1:1999 - Part 1: Sampling schemes indexed by acceptance quality limit
(AQL) for lot-by-lot inspection

ISO 2859-2:1985 - Part 2: Sampling plans indexed by limiting quality (LQ) for isolated
lot inspection

ISO 2859-3 - Part 3: Skip-lot sampling procedures

ISO 2859-4:2002 - Part 4: Procedures for assessment of declared quality levels

ISO 2859-5:2005 - Part 5: System of sequential sampling plans indexed by acceptance
quality limit (AQL) for lot-by-lot inspection
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Practical example
Sampling documentation used in the Austrian
Food and Drug Agency “AGES” (Vienna, Austria
http://www.ages.at
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Step 1: Sampling order from a scientific advisor
Step 2: Verification and authorization of order
Step 3: Assignment to authorized sampling staff
1: ordering department
2: date / name of scientific advisor
1
2
3
4
5
6
7
8
9
10
3: urgent / planned beginning of
analysis
4: requested sampling site
5: on site sampling necessary
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6: specific information for
transport/storage
7: name of sample
8: MA-number
9: batch number
10: quantity
11: unit
12
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
12: signature of head of dep.
Step 4: Sampling
request sent by fax
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
… sampling performed onsite
Part 1
1: sample (name, strength, dosage
form)
2: number of packages, units,
quantity of samples
3: batch number
1
4: expiry date
2
3
4
5: MA-number
5
6
6: manufacturing date
7: place of withdrawal (company,
wholesaler, pharmacy, others)
7
8: sampling by: company; official
expert; official inspector; public
health officer
8
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Part 2
1: found storage conditions
1
2: light protection
2
3
3: temperature
4
4: cause for suspicion
5
5: prohibition of sale
6
6: crosscheck
7
7: sealing executed
8
8: certificate of analysis
9
9: composition/formulation
10: date of withdrawal/signature
10
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
Step 5: Arrival of sample
1: general information: name,
MA-number, date of receipt,…
2: receipt control - temperature
3: storage conditions
1
4: sample damaged (yes/no)
2
3
4
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
References

WHO guidelines for sampling of pharmaceutical products and related materials. Annex 4 of
WHO Technical Report Series No. 929 (2005).

ISO 2859 - Sampling procedures for inspection by attributes.

British Standard BS 6001-1 - Sampling procedures for inspection by attributes.

ISO 10725:2000 - Acceptance sampling plans and procedures for the inspection of bulk materials.

Good Manufacturing Practices; Part I - Basic Requirements for Medicinal Products ; Part II - Basic
Requirements for Active Substances used as Starting Materials.

European Pharmacopoeia. Chapter 2.8.20. Herbal drugs: sampling and sample preparation.

ANSI/ASQ Z1.4-2008 Standard (American National Standards Institute/American Society for Quality)
- Sampling Procedures and Tables for Inspection by Attributes.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
http://www.edqm.eu
Thank you for your attention
Marta Miquel
Scientific Officer
Council of Europe
European Directorate for the Quality of Medicines and HealthCare (EDQM)
Biological Standardisation, OMCL Network & HealthCare Department (DBO)
7 Allée Kastner, CS 30026
F- 67081 Strasbourg, France
Tel.: + 33 (0) 3 90 21 42 41
Fax: + 33 (0) 3 88 41 27 71
E-mail: marta.miquel@edqm.eu
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009