sampling according to who guidelines for sampling of pharmaceutical products and related materials...

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

2-6

Sampling and testing for Quality Control Laboratories, Nairobi, September 20092 |

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

WHO sampling guideline - IntroductionWHO sampling guideline - Introduction


Before samplingI. 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


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.

I - Preparation for sampling


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


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


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....

II - Sampling operation (cont.)


Example of sample collection form

(Appendix 2 of WHO guideline)

Page 1 Page 2


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.

II - Sampling operation (cont.)


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


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.

III – Sample storage and retention (cont.)


Examples of types of containers used to store samples of starting materials and bulk products (Appendix 4 of WHO guideline)

Bag for storage of samplesScrew-top containers


Sampling for regulatory issues

I. Drug quality surveillance programmes

II. Inspections


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.

I - Drug quality surveillance programmes


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: 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)

I - Drug quality surveillance programmes (cont.)


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.

II - Inspections


Sampling for acceptanceI. Starting materials

II. Intermediates in manufacturing and bulk products

III. Finished products

IV. Packaging 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.

I – Sampling of starting materials


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

II - Sampling of intermediates in manufacturing and bulk products


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.


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).

III - Sampling of finished products


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).

IV - Sampling of packaging materials


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.

IV - Sampling of packaging materials (cont.)


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


I.“n-plan”

II.“p-plan”

III. “r-plan”

Sampling plans for starting materials

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


Only used when material is considered uniform and from a recognised source.

I – The “n-plan”

Nn 1 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”

Np 4.0

May be used when material is considered uniform, from a recognised source and the main purpose is to test for identity.

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)

N = sampling units in the consignment (e.g. individual package, drum or container)


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.

Nr 5.1

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)

N = sampling units in the consignment (e.g. individual package, drum or container)


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)

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)

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).

Sampling plans for finished products


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

ISO 2859 series - Sampling procedures for inspection by attributes


Sampling documentation used in the Austrian Food and Drug Agency “AGES” (Vienna, Austria

http://www.ages.at

Practical example


1: ordering department

2: date / name of scientific advisor

3: urgent / planned beginning of analysis

4: requested sampling site

5: on site sampling necessary

6: specific information for transport/storage

7: name of sample

8: MA-number

9: batch number

10: quantity

11: unit

12: signature of head of dep.

1 423

10

56

987 11

12

Step 1: Sampling order from a scientific advisorStep 2: Verification and authorization of orderStep 3: Assignment to authorized sampling staff


Step 4: Sampling request sent by fax


1

2

3 5

4 6

7

8

1: sample (name, strength, dosage form)

2: number of packages, units, quantity of samples

3: batch number

4: expiry date

5: MA-number

6: manufacturing date

7: place of withdrawal (company, wholesaler, pharmacy, others)

8: sampling by: company; official expert; official inspector; public health officer

Part 1

… sampling performed onsite


1: found storage conditions

2: light protection

3: temperature

4: cause for suspicion

5: prohibition of sale

6: crosscheck

7: sealing executed

8: certificate of analysis

9: composition/formulation

10: date of withdrawal/signature

1

23

4

5

6

7

8

9

10

Part 2


1: general information: name, MA-number, date of receipt,…

2: receipt control - temperature

3: storage conditions

4: sample damaged (yes/no)1

2

3

4

Step 5: Arrival of sample


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.

References


http://www.edqm.eu http://www.edqm.eu

Thank you for your attention

Marta MiquelScientific OfficerCouncil of EuropeEuropean Directorate for the Quality of Medicines and HealthCare (EDQM)Biological Standardisation, OMCL Network & HealthCare Department (DBO)7 Allée Kastner, CS 30026F- 67081 Strasbourg, FranceTel.: + 33 (0) 3 90 21 42 41Fax: + 33 (0) 3 88 41 27 71E-mail: [email protected]

sampling according to who guidelines for sampling of pharmaceutical products and related materials...

Documents

sampling slide

purpose of sampling

respective sampling

sampling operation

sampling plan

sampling process

sampling area

sampling tools appendix