Sampling, Identification and

Testing(S.I.T.)

Introduction• Define basic principles for applying

sampling, identification and testing requirements

1) Systems and procedures ensuring that samples are representative of the batch

when sampled Correctly identified Tested

2) Systems and Procedures in accordance with regulatory and Safety requirements

Scope

• Applies to all manufacturing sites• Applies to all sub-contractors • Applies to all Affiliates• Applies to Raw-materials, isolated

intermediates, APIs, excipients, medical devices, packaging materials, inprocess materials, bulk and packaged drug products

• Does not apply to environmental samples and Reference and Retention samples

Reference Documents• ICH Q7 : Good Manufacturing Practice for Active Pharmaceutical

Ingredients

• EU GMP Part I Chapter 6 : Quality Control

• EU GMP Annex 8 : Sampling of Starting and Packaging Materials

• US CFR : Subpart E-Control of Components and Drug Product Containers and Closures : §211.80 : General requirements ; §211.84 Testing and approval or rejection of components, drug product containers, and closures ; §211.110 Sampling and testing of in-process materials and drug products, Subpart G-Packaging and Labelling Control : §211.122 Materials examination and usage criteria

Sampling General Requirements (1)

• Composite sample : justify the number of individual samples

• Sampling operations recorded with specific items. Records available for evaluation as condition of batch release

• Additional sampling may be considered in case of OOS/OOT - Based on approved re-sampling protocol

• Sterile materials sampled aseptically in environmental zone A.

Sampling General Requirements (2)

• Sampling personnel initially trained and retrained on regular basis

• Only qualified and authorised personnel can sample

• Any anomaly/irregularity during sampling has to be notified and recorded.

Sampling General Requirements (3)

• Sampling areas designed to protect product from environment and cross contamination and protect personnel from the product

• Appropriate areas in case of high potency, sensitizing material, antibiotic, etc

• Gowning instructions and personnel protective equipment must be available

• Material Safety Data Sheet (MSDS) available before sampling.

Sampling General Requirements (4)

• Sampling equipment and tools : specified, stored appropriately

protected from contamination, cleaned after use and cleaning

validation performed

• Cleanliness status of equipment identifiable

• Containers carefully opened and closed

• Containers marked when sample taken

• Identification of person who performs sampling

• Date of sampling recorded.

Sampling General Requirements (5)

• Containers in which samples are placed must be clean and clearly labelled

• Sampled samples must not be returned to the batch

Identification General Requirements

• Identification method : described in the current locally applicable Pharmacopoeia (e.g. USP, EP, JP) or approved Regulatory File

• For material identification, a NIR validated method can be applied even if not registered in the Regulatory File; for countries where the practice is allowed.

Sampling and Identification Operations (1)

• Samples must be representative of the batch of materials or products from which they are taken

• Pre-samples allowed only from approved or certified suppliers with written agreement on sampling delegation

• Place(s) where samples need to be taken or identification : detailed in SOP

• Sampling must not be the cause of contamination or cross-contamination

• Cleaning operation in case of outer dirty container.

Sampling and Identification Operations (2)

• Hazardous or highly toxic materials, processing aids (solvents) or other special material may not be sampled or tested

• CoA needed from supplier : results conform to established specifications

• Practice to be justified and approved.

Sampling and Identification Operations (3)

• Each batch of incoming material for API product : subject for identity, except in case of risk for health and safety

Such kind of materials to be listedCoA obtained from supplier for

each batch.

Sampling and Identification Operations (4)

• Sampling plans or procedures minimum information

Version, approver’s name, date of approvalName of material, amount to be sampledSample packaging and labelling, storage

conditionsSampling equipment, safety/handling

precautions : sterile, noxious product, pyrogens.

Sampling and Identification Operations (5)

• Sampling plans or procedures minimum information (cont.)Number of containers to be sampledNumber of samples to be takenSampling/Identification location within

the container :Supplier pre-samples or identification

location when direct NIR identificationMeasurement units : quantity (g, ml,

mg,…)

Sampling and Identification Operations (6)

• Sampling plans or procedures minimum information (cont.)Composite sample (number of sample

for a composite)Sub-division of sampleDepartment/person - the sample is to be

sentInstructions for cleaning and storage of

sampling equipment.

Sampling and Identification Specific Rules (1)

• Materials used for Manufacture of APIs: Starting Materials, Raw Materials and Synthesis Intermediates

Manufacturers of SM, RM, SI must be identifiedIf Manufacturer is certified, reduced testing is

allowedReduced testing on hold in case of investigation

and return to reduced testing only if supported by conclusion of investigation and approval from Quality operations.

Sampling and Identification Specific Rules (2)

• Materials used for Manufacture of APIs (cont.) Starting Materials, Raw Materials

1) Manufacturer within « ICH » Region*: A justified sampling and identification plan based on criteria such as :

– Criticality of material– Material variability– Supplier past quality history– Manufacturing factory dedication– Certification of Supplier

At least one test for Identity of each batch (except in case of health and safety risk sample each container)

* « ICH » = European Union, North America, Japan + EFTA:Switzerland, Norway, Iceland and Liechtenstein.

Sampling and Identification Specific Rules (3)

• Materials used for Manufacture of APIs (cont.)Starting Materials, Raw Materials

2) Manufacturer outside « ICH » Region:

Sampling of each container, identification on

composite sample and full testing (Identification on each container not required, in case of

deviation/OOT: investigation to be performed and concluded).

Sampling and Identification Specific Rules (4)

• Materials used for Manufacture of APIs (cont.)Intermediates Synthesis – external manufacturer

3) Regardless of geographical origin: Sampling on each container to make a

composite sample– For identification– For full testing

(Identification on each container not required, in case of deviation/OOT :investigation to be performed and concluded).

Sampling and Identification Specific Rules (5)

• APIs and ExcipientsAPI produced within company: sampling

and identification limited to one container (process validation demonstrates homogeneity, container integrity)

API not produced within company and excipients with origin outside the ICH region

– Identification of material on each container– Composite sample for later full testing.

Sampling and Identification Specific Rules (6)

• APIs and ExcipientsAPI not produced at company

manufacturing site and excipients with origin from the ICH Region: sampling and identification depend upon following parameters:

– Supplier nature and status : when supplier is certified

– Supplier quality assurance system– Manufacturing and control conditions– Nature of API, excipient and drug product in which

they are used.

Sampling and Identification Specific Rules (7)

• APIs and Excipients (cont.)

– API or excipient coming from single product manufacturer or plant

– API, excipient coming directly from manufacturer in sealed containers and manufacturer regularly audited

• In such case : Sampling and Identification performed on a reduced number of containers according to justified sampling plan

• If previous conditions not fulfilled : identification on each container

• APIs and Excipients used for Parenterals : EACH container must be identified.

Sampling and Identification Specific Rules (8)

• Packaging MaterialsSampling plan based on quantity received and

required, nature and criticality of material (geographical origin, primary packaging, printed packaging), production methods, quality assurance of manufacturer

Sampling place/location is dependant on supplier status :

– Approved or certified supplier > sampling possible by supplier : written sampling delegation and justified sampling plan are mandatory

– Supplier with no quality agreement > sampling by own company manufacturing site : justified sampling plan.

Sampling and Identification Specific Rules (9)

• Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products Intermediates and Bulk drug product produced by

same company and received at another site :– sampling and identification limited to one container (due to

homogeneity demonstrated by process validation and by transport validation)

– Each container perfectly sealed at receipt

Intermediates and Bulk drug product not produced by same company:

– Sampling depending upon parameters : criticality of product, manufacturing in a dedicated facility, quality of sealing, experience with sub-contractor

– Each individual container sampled and tested for identity.

Sampling and Identification Specific Rules (10)

• Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products (cont.)Intermediates and Bulk drug product not

produced by same company:– Tests other than identity, sampling can be reduced or

performed on each container, based on justified sampling plan

In-Process Materials and Drug Products :– If relevant, sampling and identification performed

according to marketing autorisation requirements or site sampling plan.

Testing Operations Requirements (1)

• Control operations of received goods - for each container check/perform and document

Container status and cleanlinessCorrect storage conditionsDamages, closures integrity, potential tempering,

homogeneity of containersLabelling in comparison with delivery

documentationNumber of containersMaterials reconciliation and weight discrepancies1 lot per pallet.

Testing Operations Requirements (2)

• Analytical Methods validated• Results obtained recorded and checked, calculation critically

examined• Tests performed must be recorded with following data:

Material name, dosage form Batch number, Manufacturer/Supplier if appropriate References of specifications and testing procedures Results, calculations, Supplier’s CoA Testing date(s) Initials of personnel who performed testing and verification Release or rejection decision and signature of manager Tests records and raw data archived

• All IPC must be performed and recorded with QC approval• Raw materials tested in accordance with written procedures and

specifications in respect with current pharmacopeias and/or approved dossiers.

Testing Operations Requirements (3)

• Packaging Materialsmost frequent defects and degree of criticality listed

• Tests reduced if certified supplier raw materials, intermediates, synthesis

intermediates and drug products manufactured within company regardless of origin

• Reduced testing not allowed raw materials used in manufacture of parenterals

products raw materials, intermediates, synthesis intermediates

and drug products with origin outside ICH region.

Testing Operations Requirements (4)

• GLYCEROL and Diethyleneglycol testing sites are required to:

Evaluate traceability of manufacturers/distributors Define manufacturer’s location : ICH or not ICH Declare manufacturer’s status certified or not certified Evaluate the risk and decide on the need for DEG testing on each container

taking into account the following:– Regular audits, no critical observation, no major related to traceability– Manufacturing & packaging conditions– Traceable distribution channels– Transportation– Good quality history– Containers sealing integrity– Containers aspect/integrity and labelling– Use for parenteral (note : If yes, then high risk)– Good service history

Evaluate the risk of fraud Decide on the DEG testing.

Testing Operations Requirements (5)

• The decision tree diagram below determines the extent of DEG testing required:* Composite sample size: 1 composite sample derived from no more than 5 individual samples

Glycerol

Directly Supplied by Manufactur

er

Supplied from ICH Location

Certified Supplier?

Risk Assessme

nt

DEG Testing

on Composit

e Samples*

DEG Testing on Each Container

YES YESYES

NONO

NO

HIGH RISK

LOW RISK

Thank You

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