organisation of sampling programmes background information richard wanko interregional seminar for...

Organisation of Sampling Programmes

Background InformationRichard Wanko

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

OutlineOutline

Some definitions…

Why sampling?

For which purpose should be sampled?

Where can / should be sampled?

Who can sample test material?

What should be sampled?

How should be sampled?


What is a Sample?What is a Sample?

A portion, piece, or segment that is representative of a whole.

In the context of medicines “a portion/piece/segment” means:

x g/ml active pharmaceutical ingredient / excipient / bulk material… or

x units of the finished dosage form (tablet, bottle,…)

representative of a batch Reference: http://www.thefreedictionary.com/


What is a Batch (Lot)?What is a Batch (Lot)?

In the context of medicines:

A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

Reference: Eudralex Vol 4 – Medicinal Products for Human and Veterinary Use: GMP, Part II


What Does Sampling Mean?What Does Sampling Mean?

The act, process, or technique of selecting an appropriate sample.

In the context of quality control of medicines “an appropriate sample” means:

representative sample to evaluate the quality of the whole batch

Reference: http://www.thefreedictionary.com/


Reference Sample / Retention SampleReference Sample / Retention Sample

Reference sample

provides a sample for analytical testing

A sample of a batch of starting material, packaging material or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned. Where stability permits, reference samples from critical intermediate stages (e.g. those requiring analytical testing and release) or intermediates, that are transported outside of the manufacturer’s control, should be kept.

Reference: EU Guidelines to GMP, Annex 19



Retention sample

provides a specimen of the fully finished product

A sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes. For example, presentation, packaging, labelling, patient information leaflet, batch number, expiry date should the need arise during the shelf life of the batch concerned. There may be exceptional circumstances where this requirement can be met without retention of duplicate samples e.g. where small amounts of a batch are packaged for different markets or in the production of very expensive medicinal products.

Reference: EU Guidelines to GMP, Annex 19



Reference sample

e.g. in cases where Out-of-Specification (OOS) results need to be verified

Retention sample

e.g. in cases where the authenticity of a product needs to be confirmed (e.g. counterfeit identification)


Common/Control Test SampleCommon/Control Test Sample

Common Test Sample

Used in the context of the General European OMCL Network (GEON) in Market Surveillance Studies (MSS). Sample acts as “unifier” and is tested by all participants of a post-marketing surveillance testing campaign (= study covering – as a rule - a group of products on the different national markets) to get an idea about the comparability of performance of the different laboratories.


Common/Control Test SampleCommon/Control Test Sample

Control Test Sample

This term is used in the sampling and testing programme for Centrally Authorised Products (CAPs) of the CAP Network, which is organised jointly by the European Medicines Agency (EMEA) and EDQM. The purpose of the sample is to compare a new, recently released batch with test samples drawn along the distribution chain.


Why is Sampling Possible/Necessary?Why is Sampling Possible/Necessary?

Homogeneity of test material; production under GMP conditions should guarantee standardised / controlled processes and should lead to homogeneous products within defined specification limits

Capacity restrictions; representative spot testing instead of checking the whole of a batch

Many quality control tests are destructive methods; thus as a rule it is not possible to test the whole of a batch, but only a representative portion in order not to consume the complete material before use


Example for 100% Sample CheckExample for 100% Sample Check

Ph.Eur. 2.9.20 Particulate contamination: visible particlesOn-line analysis in parenteralia


For Which Purpose?For Which Purpose?

Routine batch release by QC laboratory at manufacturing site

Routine Official Control Authority Batch Release (OCABR) of immunological medicinal products and medicinal products derived from human blood or plasma

Routine market surveillance testing (post-marketing surveillance)

During routine GMP inspection / Quality assessment to complement “paper work” 1/3



Pre-qualification

Inspection for customs clearance

Suspicion of inferior quality / safety or efficacy issue

– Suspicion of deterioration; product suspected to be responsible for adverse clinical reactions or ineffective

Suspicion of counterfeited (falsified) / illegal material– Suspicious of (deliberate) contamination, falsification or

adulteration2/3



Confirmation of quality defect

Confirmation of OOS result

Stability testing

Development and research within the regulatory frame work of medicinal products

3/3


At Which Time Point of Production?At Which Time Point of Production?

Before start of manufacture (starting materials)

In-process control / Control of intermediates

Before batch release

After batch release, but before market launch

After launch along the distribution chain

QC

OMCL


Where is Sampled?Where is Sampled?

Manufacturing site

MAH warehouse

Wholesaler

Retail pharmacy (pharmacy shop)

Hospital

=> Control of legal environment1/2


Where is Sampled?Where is Sampled?

Airport / Harbour

Internet

Fitness (Body building) centres

Bars

Illegal laboratories / manufacturing sites

=> Investigation in illegal environment2/2


Who is Sampling?Who is Sampling?

Suitably trained and qualified persons within companies– e.g. QA department => written training records required

(GMP) inspectors– Normally without power of enforcement

Other trained persons of National Competent Authorities– e.g. OMCL staff members

Enforcement officers– Customs officers– Police force


What Kind of Test Material?What Kind of Test Material?

Active pharmaceutical ingredients (APIs)– e.g. comparison of impurity profiles (finger prints) from different

API sources

Excipients– e.g. quality control against compendial (pharmacopoeial)

standard

Intermediates (in manufacturing process)– e.g. in-process control

1/2


What Kind of Test Material?What Kind of Test Material?

Bulk material (before packaging)– e.g. assessment of stability during transit / shipment

Drug products (DP)– e.g. follow-up of complain

Packaging material including Patient Information Leaflet (PIL), label etc.– e.g. market surveillance campaign

Processing agents, cleaning agents, compressed gases– e.g. cleaning validation 2/2


What Kind of Supportive Material?What Kind of Supportive Material?

Reference material/standards– e.g. Pharmacopoeia RS, working standards

Reagents– e.g. product-specific not purchasable material (biological

testing)

Control/Common Test Sample (CTS)– e.g. used in EDQM OMCL Network market surveillance

programmes


What Kind of Accompanying Documents?What Kind of Accompanying Documents?

Certificate of Analysis (CoA)– For Control Test Sample (CTS) to have a comparison of the

performance of the batch releasing QC lab and the independently testing OMCL

Safety Data Sheets (SDS), where applicable– To allow lab staff taking necessary safety measures – e.g.

handling of cytostatic material

Valid Test Method (MA dossier, SOP)– To perform test for compliance against the Marketing

Authorisation 1/2


What Kind of Accompanying Documents?What Kind of Accompanying Documents?

Valid Shelf-life Specification– To perform test for compliance in post-marketing situation

Composition of DP– To allow the interpretation of observed impurity profile

(Analytical) method validation data– To support method transfer

Storage conditions for sampled material– To guarantee correct transport and sample storage 2/2


What to be Considered During Planning?What to be Considered During Planning?

For annual post-marketing working programme

Need to cover different climatic zone conditions?

Risk-based selection of material with a minimum of randomised sampling (about 5%)

e.g. use of risk-based models considering following aspects– occurrence-related (=risk of quality defect)– exposure-related (=extent of quality defect)– harm-related (=severity in case of quality defect)

1/3


RB Approach for OMCLsRB Approach for OMCLs

Example of a risk-based model used by the General European OMCL Network (GEON)

Reference: RB Model for Targeting Medicinal Products for MS Testing, PA/PH/OMCL (07) 87 6R




Sufficient amount of material; if possible from different batches– On basis of selected test parameters– On basis of used test method– To allow ideally more than one full test run and repetitions for a

sound statistical evaluation of the results– To enable repeated testing in case of OOS results– To cover a big quality range of the product

2/3




Availability of competence within the OMCL– Sub-contracting to private laboratories should be avoided, if

possible– Collaboration with other OMCL should be given priority

Replacement policy for sampled material– Voucher system for replacement of taken samples– Special treatment of orphan drugs (low market volumes)

Nevertheless: sampling plans should be made on scientific grounds and not be driven by budgetary considerations 3/3


Voucher SystemVoucher System

Example used in the CAP programme


What to be Considered During Sampling?What to be Considered During Sampling?

Storage requirements for samples during shipment and on-site storage– Cold chain – controlled transport with temperature recording

(data logger) for unstable products– Light and/or moisture protection, where applicable

Special sampling plan for samples intended for sterility testing– Sufficient number of samples to make a sound statistic

evaluation (according to pharmacopoeial requirements)– Time points and location of sampling 1/3



Suitable sampling equipment– Raw / Bulk material vs. finished product in marketed packaging

Storage location of retained samples– Storage under same condition as test samples, preferably at

testing site or in case of low market volume products (orphan products) at sampling location

Acknowledgement of Receipt procedure– In case of shipment of samples feedback to the sampler about

the receipt of sample and condition at receipt2/3


Acknowledgement of Receipt FormAcknowledgement of Receipt Form

Example used in the CAP programme



Immediate check of visual appearance– The visual appearance of the samples at time of sampling should

be recorded because it can provide valuable information about possible quality defects

Sample yourself and don’t let the company do it for you– To avoid manipulation– To select a representative sample– To guarantee independency

3/3


Specific PrecautionsSpecific Precautions

Sampling in warehouses (starting material, intermediates or bulk products):– Prevent contamination of the opened container, the materials

and the operator– Prevent cross-contamination by other materials and the

environment– Protect the operator (sampler) during sampling– Where possible, sampling should be performed in an area or

booth designed for and dedicated to this purpose– The area of sampling should be recorded in the sampling

record 1/2


Specific PrecautionsSpecific Precautions

Sampling in pharmacies/hospitals/at wholesalers (original sales package):

– As a rule keep the sample in the original outer package at the time of sampling and during transport

– Samples with different batch numbers and/or from different locations should be treated separately

Sampling via internet:– Purchase the material “incognito” in case of investigation for

illegal products

2/2


Conduct of SamplersConduct of Samplers

To be conscientious, meticulous and careful

To be alert to any signs of contamination, deterioration or manipulation, and record any suspicious sign

To be aware of relevant health/safety information (e.g. Safety Data Sheet)

To be trained in specific safety precautions, if required (e.g. respiratory equipment)

To wear appropriate protective clothing

Samplers should have safe access to get in and out from the sampling place


Consequence of Sampling for Testing?Consequence of Sampling for Testing?

Testing complements paperwork and helps to find an answer regarding

– the quality of a product against its Marketing Authorisation (MA) or other standards (e.g. Ph.Eur.)

– GMP findings– safety/efficacy issues (pharmacovigilance cases)

but in a strict sense test results alone only allow to draw conclusion for the tested batch(es) and not for the product in total


New ApproachNew Approach

Real Time Release Testing (RTR testing)

The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.

Parametric Release

One type of RTR testing. Parametric release is based on process data (e.g. temperature, pressure, time for terminal sterilisation) rather than the testing of a sample for a specific attribute.

1/2


New ApproachNew Approach

Shift from

Bench top analysis (batch analysis) – e.g. HPLC test to

In-line analysis (in-process control) – e.g. pH, NIR monitoring

Is this the end of classic punctual sampling? or

New challenge for post-marketing sampling and testing?

=>RTR testing is not the end of market surveillance and “classic” sampling will still be necessary 2/2


ConclusionConclusion

Sampling should be done – wherever possible - by trained staff

A careful planning is essential

A comprehensive sample documentation is important to guarantee smooth testing afterwards

The independency of sampling needs to be guaranteed

Quality control starts at the sampling stage


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

Thank you for your attention

Dr Richard WankoScientific OfficerCouncil of EuropeEuropean Directorate for the Quality of Medicines and HealthCare (EDQM)Biological Standardisation, OMCL Network & HealthCare Department (DBO)

7 allee Kastner, CS 30026F- 67081 Strasbourg, FranceTel.: + 33 (0) 3 90 21 40 13Fax: + 33 (0) 3 88 41 27 71E-mail: [email protected]

organisation of sampling programmes background information richard wanko interregional seminar for...

Documents

batch reference

representative sample

quality control laboratories

appropriate sample

batch number

batch of finished product

batch lot

batch size