Template ppt presentation

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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
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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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• Before sampling
• purpose of sampling?
• type of tests intended to be applied to the
  samples?
• type of products/materials to be sampled?
• are sampling facilities adequate?
• 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 process
• Preparation for sampling
• Sampling operation
• Sample storage and retention

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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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• Examples of types of sampling tools (Appendix 1
  of WHO guideline)

Dip tubes for liquids
Spatulas for solids
Sample thieves for solid samples in deep
containers
Bag-sampling spears for taking samples from bags
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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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II - Sampling operation (cont.)

• Sampling operations should be supervised and
  documented gt sample collection form gt 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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Example of sample collection form (Appendix 2 of
WHO guideline)
Page 2
Page 1
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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.

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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.

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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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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
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• Sampling for regulatory issues
• Drug quality surveillance programmes
• Inspections

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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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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
• 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)

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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 for acceptance
• Starting materials
• Intermediates in manufacturing and bulk products
• Finished products
• Packaging materials

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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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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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• 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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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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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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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 plans
• Starting materials
• Finished products
• 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 plans for starting materials

• n-plan
• p-plan
• r-plan

See examples of use of sampling plans in Appendix
5 of WHO guideline
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I The n-plan

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

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 gt combine samples into a
   single final sample.
6. Take analytical sample for full testing.
7. Keep the rest as retention sample.

e.g. N40 gt n7 (units to be sampled)
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• 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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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.

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 gt p final samples are
   formed by appropriate pooling.
4. Keep the p samples for retention (or full testing
   if required).

e.g. N40 gt p3 (final samples after
testingpooling)
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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.

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 gt r samples are randomly
   selected.
4. r samples individually fully tested.
5. If results concordant gt combine the r samples
   for the retention sample.

e.g. N40 gt r10 (randomly selected samples for
testing)
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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 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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ISO 2859 series - Sampling procedures for
inspection by attributes

• ISO 2859-11999 - Part 1 Sampling schemes
  indexed by acceptance quality limit (AQL) for
  lot-by-lot inspection
• ISO 2859-21985 - Part 2 Sampling plans indexed
  by limiting quality (LQ) for isolated lot
  inspection
• ISO 2859-3 - Part 3 Skip-lot sampling procedures
• ISO 2859-42002 - Part 4 Procedures for
  assessment of declared quality levels
• ISO 2859-52005 - Part 5 System of sequential
  sampling plans indexed by acceptance quality
  limit (AQL) for lot-by-lot inspection

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Practical example

• Sampling documentation used in the Austrian Food
  and Drug Agency AGES (Vienna, Austria
• http//www.ages.at

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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 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
4
2
5
3
6
10
9
8
7
11
12
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Step 4 Sampling request sent by fax
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sampling performed onsite
Part 1

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
1
2
3
5
6
4
7
8
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Part 2

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
2
3
4
5
6
7
8
9
10
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Step 5 Arrival of sample
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
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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 107252000 - 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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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. [phone]
42 41 Fax [phone] E-mail
marta.miquel_at_edqm.eu