GlaxoSmithKline GLOBAL QUALITY GUIDELINE 7211

Laboratory Controls: Control Processes SAMPLING AND TESTING

JULY 2006

RATIONALE

Sampling, inspection and testing is required to assess the quality critical attributes of materials and product, and to verify that the correct specifications and standards have been met.

PURPOSE

GQP 7211 defines the minimum standards for sampling and testing. This guideline gives specific guidance, and examples illustrating the minimum requirements.

SCOPE

This guideline applies to all sites and companies manufacturing materials or products for sale by, or for, GSK. The principles apply to non-manufacturing sites analysing products for distribution.

SUMMARY OF REVISIONS

This replaces GQG 5204 dated June 2003, with the following revisions:

• Guideline has been renumbered from GQG 5204 to GQP 7211 due to changes in QMS sections and numbering.

• In Section 7.6, the word ‘must’ has been replaced with ‘are required to’ in the sentence ‘Features inherent in the manufacturing process are required to prevent defects of this type.’

• In Appendix 3, the word ‘must’ has been replaced with ‘should’ in the sentence ‘If the BS tables are used to provide the basis for a scheme, the need to interpret the curves to ensure the correct level of protection of individual batches should be understood.’

• In Section 3 and References GQP 5303 Retained Samples of Materials and Products has been renumbered GQP 7218 due to changes in QMS sections and numbering.

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1. General

The system of procedures and methods for sampling and testing, prior to dispositioning materials or product for use at the site and for despatch, should include:

• For each material or product, the definition of a batch for sampling and testing purposes (see GQP 5107).

• Adequate procedures, to ensure that the content of each container of each delivery of each batch of each material or product is verified against the ordered material or product. This would normally be by sampling and testing. For materials or products supplied from, and tested at, a GSK supplying site or from a certified external supplier, this verification may be by label verification at the receiving site.

• Adequate procedures for the appropriate sampling and testing for materials and products at all stages (e.g. delivered, received, in process, and despatched).

• Assigned responsibility for sampling including, where appropriate, the provision of pre-delivery or accompanying samples by the supplying site.

• Assigned responsibility and location for testing (e.g. whether testing is performed at the supplying site, at the receiving site or by an approved contract testing laboratory). If a contract laboratory is used, some regulators require the laboratory to be included in the manufacturer’s licence for the site responsible for the disposition, or in the marketing licence for each product.

• Defined methods for the sampling, testing and defined specifications for each material and product.

• Any provisions for reduced testing, e.g. when materials or product are received from a certified supplier with a certificate of analysis (C of A) or certificate of conformance (C of C) (see GQP 5215). Full analysis should be carried out on at least three batches, before any reduction in testing is considered. As a minimum, full testing should be performed at regular intervals, and compared to current quality information.

• The procedures and authorisation necessary to allow use or despatch of materials and products before testing is complete (see Sections 5 and 6).

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2. Confirmation of Identity for Supplied Materials and Products

Written policies and procedures should be defined to confirm the identity of supplied materials and products.

Finished product in a market pack does not usually require identity testing following receipt by the marketing company, unless required by local regulators.

Active pharmaceutical ingredients (APIs) may be sampled at either point of receipt or point of use and subsequently tested. Alternatively, if the testing of the resulting product provides data that confirms the identity of the API, that data may be used instead of an identity test on the API batch.

In some circumstances, particularly where hazardous materials or product are being handled, it may be more appropriate to assure the identity by application of rigorous quality systems. These cases should be justified on an individual basis.

In all cases where every container is not subject to an identity test, secure systems for confirmation by container label verification only, rather than by physical or chemical testing, should include:

• Secure label generation and application procedures at the supplying site.

• Use of identifiable security seals or other tamper evidence devices on shipping containers.

• Secure label recognition system at the receiving site.

• Definition of the data to be provided by the supplying site. This will depend on the nature of the material and product, and the relationship with the supplier. The format and content of the data should be agreed between the supplying and receiving sites. Data may be conveyed by any secure means, e.g. electronic or hard copy.

3. Sampling Schemes

All materials and product should be sampled according to a defined sampling procedure, and tested against approved specifications. The sampling and testing results, including disposition and any other conclusions, should be recorded. Further definition of the classification of defect types is given in Section 7.

Where a small, though finite, level of defects within a batch is permissible, assessment usually relies on use of a sampling scheme. Unacceptable defects, for which even the presence of a single defect renders the batch unacceptable, cannot be controlled by sampling schemes (see Section 5).

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Within any category of defect where a finite level is permissible (see Section 4), the sampling schemes should be designed to ensure that individual batches released by the supplying site have a high probability (p = 95%) of containing:

Either: A level of defects less than that specified in this guideline.

Or: A level of defects less than that which has been specifically agreed between the supplying and receiving factory as being appropriate to meet product and/or regulatory requirements. Samples taken for identity testing should not be pooled.

For all sampling schemes, the methodology used should have a written, valid, statistical rationale.

Approved procedures should include:

• The method of sample selection.

• A justified sampling plan, which includes the number of containers to be sampled, the number of samples to be taken and the quantity required, and whether or not samples should be pooled. Samples taken for checking homogeneity throughout the run should be retained as individual samples, with the sample source clearly identifiable. This should include samples for retention purposes (see GQP 7218). Sample size should be justified by the required use.

The sampling plan is defined by:

• The testing required.

• Any legal or regulatory requirements.

• Any known non-homogeneity of the material or product on receipt.

• The origin of the material or product.

• The method and route of transport.

• The type of packaging.

• The historical variation within and between containers and batches.

• The permissible limits of variation of results of critical tests.

• The methods for the sampling of material and products, including tools and containers to be used, and the methods for the cleaning of the sampling tools and containers.

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Sampling facilities should be designed to:

• Prevent contamination of the opened container, the sample and the operator.

• Prevent contamination of other materials and products.

Sampling should be performed in an area or booth, designed for and dedicated to sampling. This may be located in the warehouse, dispensary, laboratory, or at the point of use in production.

Special precautions should be applied when taking samples for microbiological testing, when handling materials or product affected by light or humidity, or when handling materials or product of high potency or high physiological activity.

Sampling personnel may report to the manufacturing or the quality organisation. There may be specific local regulatory requirements.

Sampling personnel should be trained and assessed and the training system should be approved by the site quality organisation (see GQP 2201).

4. Testing

Where materials or product have been transferred within the GSK supply network, including contracting sites, testing and evaluation of samples should take place in the supplying company and should not normally be re-evaluated by the receiving company. Testing and evaluation is carried out at the supplying company, or by contractual agreement at another company or the receiving site.

The receiving company should, however, be aware of any damage which may have been caused by adverse events during shipment and which could affect the quality of the material being shipped (and therefore invalidate the evaluations made by the supplying company).

If the test methods are registered, then these should be followed exactly. New or improved and validated test methods should be introduced under change control to manage any regulatory impact, and to match Corporate Product Standards (CPS) requirements (see GQP 5101). All new methods should comply with Compendium of Analytical Procedures (CAP) requirements.

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Test methods should be derived from available GSK master documents and should include:

• Method of sample selection, e.g. composite, random, stratified.

• The minimum number of test replicates to be performed on each sample.

• The permitted variation between replicates and between samples.

4.1. Testing should assure compliance with any regulatory requirements of the country of manufacture, as well as of all markets to be supplied with that material or product.

4.2. Testing should also assure compliance with any additional requirements of GSK for that material or product.

•

•

•

•

Ιn the case of finished product, all mandatory tests defined by the CPS should be performed.

In the case of other materials and products reduced testing (and ‘if tested, will pass’) may be applied where supported by satisfactory historical data and justified in accordance with local/corporate quality management systems.

C of As may be acceptable in certain circumstances for incoming materials and products (see Appendix 1 and GQP 5215).

4.3. Testing of materials and products received from other GSK sites should be defined in procedures.

4.4. Tests performed at the supplying site do not normally have to be repeated. However, there are situations which require additional testing at the receiving site. For example:

If there is a known risk that the material or product may have become non-homogeneous, e.g. by the stratification of bulk blended powders in transit. Usually, such materials or product would be blended before use at the receiving site using a validated blending procedure.

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•

•

•

•

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If there is a risk of physical change, e.g. change of particle size due to attrition or agglomeration. As above, the extent of such change, and the actions to be taken would normally have been established during development and subsequently validated. If the potential change is due to abnormal circumstances, then the material should be quarantined until its fate has been established. Further testing should be performed to verify the acceptability of the material and product.

If there is evidence of environmental damage (e.g. light or moisture) to the outer casing of the container (material or product should not have been exposed).

5. Use Before Test (Process Before Full Approval)

5.1. This is a business risk decision. It is essential that sites justify the decision to operate in this way by performing an analysis of the risk of a test, or material or product failure and the consequent loss of process material and time. GSK contractor sites should not adopt this procedure without prior written approval from GSK.

5.2. Procedures should define:

The criteria agreed by the supplying and customer site for release for processing before full approval. For example:

− Supplier quality data and sample received (or, for transfers within a single site, previous stage in-process sampling and testing satisfactory).

− Containers secure and in good condition.

− Receiving site samples taken.

That each batch of a material or product is released for processing, using data which includes knowledge of the material or product source and the history of previous batches.

The actions that will be taken if an input material or product fails test requirements, after the material or product has been processed.

6. Despatch Before Test (Release Before Full Approval)

This is a business risk decision (see Appendix 2) for flowchart.

It is essential that sites justify the decision to operate in this way by performing an analysis of the risk of a test, or material, failure, and the consequent loss of despatched material, time, and effect on the customer.

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Procedures should include:

6.1. That the supplying and receiving sites are both GSK sites.

6.2. That the supplying site has:

6.2.1. Identified products and markets where there would be a business benefit to routinely ‘Despatch Before Full Approval’. This should be done jointly with the customer site to ensure product supply chain benefits are secured.

6.2.2. Quantified business benefits.

6.2.3. Validated and maintained the validated status of the manufacturing process and retained documented evidence to show it is in a continual state of control.

6.2.4. Reviewed product history, e.g. rejections, reworks, test failures, process deviations. Where a test gives frequent problems, it should be defined as ‘Must Comply Before Release’.

6.3. That the receiving site has adequate systems in place to receive and handle goods in a ‘Not Yet Passed’ condition.

6.3.1. The ability to store materials and products having different QA status. Current distribution outlets handling only ‘Passed’ stock, would not be suitable sites for receiving ‘Despatch Before Full Approval’ materials and products, without significant system changes.

6.3.2. The ability to book in quarantine materials and products, including the ability to:

• Inspect for tampering/damage in transit.

• Confirm correct goods received (label and container verification).

• Notify the quality organisation of goods arrival, and enable them to amend status, or to approve further use, as required.

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6.3.3. The ability to perform sampling and testing of received materials and

products, as agreed with the supplying site, or as required by regulatory agencies.

6.3.4. The ability to prevent any materials and products received under ‘Despatch Before Full Approval’ conditions from being despatched from the receiving site, without explicit quality organisation approval.

6.4. That the supplying and receiving sites have a jointly agreed procedure, which defines the process to be used to manage ‘Despatch Before Full Approval’. This should define agreements for both routine and ‘one-off’ arrangements, and should also define the criteria for ‘Authorisation for Despatch Before Testing is Complete’. This agreement should be recorded in the technical terms of supply (see GQG 1302) for routine arrangements, or by individual agreement with the receiving site, if it is a single consignment.

6.4.1. Procedures should also define the products for which ‘Despatch Before Full Approval’ will be used and the tests to be conducted by the supplying site, before release.

6.4.2. The criteria for ‘Authorisation for Despatch Before Testing is Complete’ should include:

• Satisfactory status of supplier quality data (e.g. C of A/C of C).

• Satisfactory completion of any required identity testing of material or product used in manufacture.

• Any other testing as agreed between supplying and receiving sites, including some defined testing of the material or product for despatch, for regulatory or business reasons.

• Review of batch records, for non-routine issues, which might impact on the release decision. For example:

− GMP deviations.

− Critical environmental requirements.

− Critical in-process results.

− Process deviations (including in-process control failures).

• All the testing performed should have given satisfactory results, with all agreed tests completed and reported. If any of the agreed tests have not been completed by the supplying site, the batch should not be despatched, except by written agreement

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of the quality organisations on both sites. This would be an exceptional case, and may require different handling on receipt.

6.4.3. That the supplying site has a procedure agreed with the receiving site, defining the actions that will be taken if despatched material or product fails its test requirements. These actions will be dependent on the feasibility and desirability of return, or destruction, of the faulty goods.

6.5. That the quality organisation at the supplying site provides a statement of ‘authorisation for despatch’, by paper or electronic means, confirming compliance with the agreed criteria for ‘Authorisation for Despatch Before Testing is Complete’. Each batch should be individually ‘Authorised for Despatch’ by the quality organisation at the supplying site.

Note: For GSK sites, the label details will provide access to full shipment details, including the batch status and current quality data.

Full quality data, or C of A/C of C, should be provided, if required, after despatch when full testing has been completed.

6.6. That the details of transport type, transport conditions and routes to be taken, have been agreed.

All shipping documentation conditions (e.g. for acceptance by the customs agency in the receiving country) conform to requirements.

6.7. When a receiving GSK site is the last site in a chain and where previous sites have been using the ‘Despatch Before Full Approval’ principle, it is essential that this final site is able to fully verify that all previous relevant tests and controls have been applied and approved.

6.7.1. All testing for all previous supplying sites should have been completed, and the quality organisation at the last site in the chain positively informed that all testing/GMP is in conformance with specifications and regulatory requirements.

Disposition documentation should only be received from the quality organisation at its direct supplying site. Specifically, release documentation should not be allowed to bypass any processing sites in the supply chain. This is to provide consistency with technical terms of supply requirements, to protect against assumptions, oversights, etc., and to preserve the critical relationship between each pair of supplier/receiver quality organisations.

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6.7.2. The final (receiving) site should have, for each product and pack

variant released, a checklist of all the documents required to enable final sign off, their source site, and what dispositioning statements are required on each document (see GQP 5208).

6.7.3. All testing on the final GSK site should be completed, documented and approved, before the batch is released outside GSK control.

7. Acceptance Sampling Schemes

7.1. Sampling based on the use of defined sampling standards (e.g. ISO 2859-1, BS6001, ANSI/ASQC Z1.4-1993) is in common use within the company to control acceptance of goods by receiving sites. These are commonly known as Acceptable Quality Level (AQL) plans. Their focus is that of ensuring that, over a series of batches, the receiving site will have a low probability of accepting stock whose average level of defects is worse than the specified AQL (see Appendix 3).

7.2. The sampling schemes defined in this guideline are not, and should not be described as, AQL schemes. They deal with the supplier site ensuring that it has a very low probability of dispatching individual batches with greater than a specified level of defects.

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7.3. The schemes proposed by this guideline are described as Limiting Quality (LQ) schemes. Whilst the ISO/BS/ANSI standards provide tables and operating characteristic curves which can be used as reference sources for setting up LQ sampling schemes to meet the purposes of this guideline, it is vital to note the differences between an AQL scheme and an LQ scheme. These differences can be summarised as follows:

Guideline schemes ISO/BS/ANSI schemes

Technical description

LQ scheme AQL scheme

Designed for use by

Supplying site Accepting Site

Type of control intended

Specific level of defects supplied within a specific batch

Average level of defects accepted over a series of batches

Meaning of AQL value

No direct link of AQL value to the level of defect controlled AQL in combination with sample size value merely provides a reference to the plan used

Equals the maximum acceptable average level of defects over a series of batches

7.4. A sampling scheme designed to ensure that there is less than a 5.0% chance of accepting a series of batches whose average defect level is <1.0% (i.e. an AQL scheme) is very different from a sampling scheme designed to allow a supplier to ensure that there is less than a 5.0% chance that any individual batch despatched to the receiving site contains <5.0% defects (an LQ scheme). The LQ scheme is much more demanding in both its sample sizes and its permitted level of defects in the sample.

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7.5. Classification of Defect Types

It is recommended that there should be four classes of defect. They are:

Level 1 Unacceptable defect - no such defect should exist in the batch (see Section 3.1)

Level 2 95% confidence that not more than 0.1% of the batch contains this type of defect

Level 3 95% confidence that not more than 0.65% of the batch contains this type of defect

Level 4 95% confidence that not more than 2.5% of the batch contains this type of defect

Definitions and illustrative examples of these defects are given in Appendix 4.

7.6. Defects of the Level 1 Unacceptable Defect type cannot be controlled by sampling schemes because:

•

•

The presence of even 1 defective unit in the batch makes it rejectable.

A sampling scheme, by definition, examines less than the whole of the batch and therefore has a finite probability of missing such defects.

Features inherent in the manufacturing process are required to prevent defects of this type. Detection of such defects by a sampling scheme is not only cause for rejection of a specific batch, but it is an indicator of failure of the process controls designed to prevent such defects. As such, this situation calls all other batches made by the same process into question, irrespective of the failure to detect defects in samples of specific batches.

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REFERENCES

GQP 1302 Technical Terms of Supply

GQP 2201 Role Competencies and Training

GQP 5101 Product Standard Management

GQP 5107 Batch Definition

GQP 5208 Batch Release

GQP 5215 Transportation of Bulk Sterile Filled Glass Ampoules and Vials for Final Packing

GQP 5216 Acceptance of Supplier’s Results on Certificate of Analysis

GQP 7218 Retained Samples of Materials and Products

FPG14, SECTION D Sampling

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Appendix 1

CERTIFICATES OF ANALYSIS FOR MATERIALS OR PRODUCT

1. In certain circumstances, and where national requirements permit, compliance with the raw material or product specifications may be demonstrated in part by possession of an acceptable C of A. For such a certificate to be considered acceptable, the senior quality executive, or the person nominated by him, in the purchasing company should be satisfied that:

• The quality assurance procedures for the manufacture or selection of the material concerned are of an acceptable standard.

• The organisation issuing the certificate is competent to do so, whether that organisation is part of the supplying company or is independent or it (e.g. is a contract analytical service).

A supplier outside GSK should be audited, before it is agreed to accept materials on the basis of a C of A, and at intervals of not greater than 2 years thereafter.

The certificate should:

• Ιdentify the organisation issuing it, be signed by a person competent to do so, and indicate the person’s qualifications.

• Name the material to which it refers and identify it by batch number.

• State the specification (e.g. ‘BP’) and methods with which the tests were performed (the methods used by the supplier may be included in a separate document).

• Give the test results obtained where the result is a specific value, or declare that the results obtained showed compliance with the stated specification.

• The certificate should also include the place of manufacture of the material.

Materials and APIs provided with a C of A should be checked for identity before being accepted for use. At regular intervals (e.g. one batch every ten deliveries, at least one batch per year) the accuracy of the supplier’s data should be verified by carrying out a full analysis of the material of API. Processing aids, hazardous or highly toxic raw material, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturers C or A is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels and recording of batch numbers should help in establishing the identity of these materials. The lack of on site testing for these materials should be justified and documented.

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Note: Possession of a C of A does not absolve the purchaser from ultimate responsibility for the correctness of the material to which it refers.

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Appendix 2

FLOWCHART FOR ‘DESPATCH BEFORE FULL APPROVAL’ (DBFA)

6.4.3 ‘Action in event ofFailure’ Procedure

6.1 Supplying and Receivingsites

6.2 Supplying Siterequirements

6.3 Receiving sitesystems adequate

6.2.1 Selection ofProduct suitable for

DBFA

6.2.2 Quantifiedbusiness benefit

6.2.3 ValidatedFacility/Process

6.2.4 Product historyreviewed

6.3.1 Ability to storegoods with different

QA status6.3.2 Ability to ‘book-

in’ Quarantinedgoods

6.3.3 Ability toperform Sampling

and Testing

6.3.4 Ability toprevent despatch

6.4 DBFA Procedure agreedbetween Supplying and

Receiving sites

6.5 Supplying QA providesstatement ‘Authorisation for

Despatch’

6.6 Transport details agreed

6.7 ‘Final Site’ Procedure

6.4.1 Agreed ProductsAgreed Tests

6.4.2 Received Materials/Components Quality Data

6.4.2 Received MaterialIdentity Test(s)

6.4.2 Received MaterialOther agreed Tests

6.4.2 Batch Records

6.4.2 GMP Records

6.4.2 EnvironmentalRecords

6.4.2 In-process Tests

6.7.1 All testing atprevious nodes

complete

6.7.2 Checklist ofrequired documents

6.7.3 Final sitetesting complete

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Appendix 3

ILLUSTRATION OF AQLs AND OPERATING CHARACTERISTIC CURVES

1. The AQL sampling schemes of ISO 2859-1, BS6001, ANSI/ASQC Z1.4-1993 are designed primarily to ensure that over a series of batches, the long term average of the percentage defectives does not exceed a specified value.

2. The plans define a total sampling and inspection system. In order to be used ‘as is’ and for the specified level of protection to be achieved, they depend on:

• Use of defined sampling levels.

• Use of agreed switching rules to tightened inspection when a series of batches fail.

• 100% inspection of defective batches.

3. The practical consequences of such sampling schemes are best illustrated by the operating characteristic curve of 2 typical schemes for an AQL of 0.65%. Both are designed to give a high probability of accepting batches, from a process whose long-term average is 0.65% defects (i.e. the upper left-hand portion of the curves). This presumes that the schemes are used in conjunction with the rules for switching to tighter inspection, and the requirement to 100% inspect all rejected batches.

Operating Characteristic Curves

AQL 0.65

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4. This guideline is concerned not with the average quality of a series of batches but

with the specific risks of accepting individual batches. This is defined by the lower right hand end of the curves. It is obvious that the two schemes, with an identical AQL, are offering very different protection of individual batches.

5. The scheme with a sample size of 315 allows not more than 5 defects in the sample and has a 95% chance of rejecting a batch with 3.3% defects. With a sample size of 20, which allows zero defects in the sample, the level of defects has to reach 13.9% for an equivalent probability of rejection.

6. If the BS tables are used to provide the basis for a scheme, the need to interpret the curves to ensure the correct level of protection of individual batches should be understood. The tables cannot be used ‘as is’ because they are primarily designed for control of average quality.

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Appendix 4

EXAMPLES OF DEFECTS

1. Level 1 Defects

A single defect with safety, identification, efficacy and/or regulatory implications which if found in a marketed batch would result in a high probability of a batch recall being instigated either by a GSK company or the regulatory authority.

1.1. Examples of a Level 1 defect (this is not an exhaustive list):

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•

•

•

•

•

•

Incorrect product.

Incorrect container/closure.

Incorrect size of metering valve on a metered dose inhaler.

Incorrect packaging component.

Empty pockets on a powder inhaler.

Expiry date exceeds registered life.

Pack detail not in compliance with registered detail.

2. Level 2 Defects

A defect which significantly detracts from the overall quality of the product and may:

• Significantly affect the ability of the receiving company to process the product in a cost efficient, effective manner.

• Result in the patient being unable to obtain the dose of a non-life saving medicine.

• Affect the confidence of the patient or healthcare professional in the individual container/dose of product.

• Examples of a Level 2 defect (this is not an exhaustive list).

• Missing primary container label within a correct outer patient pack.

• Missing/illegible batch/lot number or expiry date on primary container label.

• Crack in primary container of a sterile product.

• Broken or bent needle on an injection device.

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• Gross over or under fill of dry powder injection or granules for suspension.

• Glass or visible contaminants in injectable products.

• Missing or broken tamper evident seals.

• Twinned coated tablets.

• Tablet shape defects (too thick to run on feed mechanisms on packaging line).

• Missing container closure.

• Continuous spray metered dose inhaler.

• Slow recovering valve on a metered dose inhaler.

3. Level 3 Defects

A defect which detracts in a minor manner from the overall quality of the product and may:

• Marginally affect the ability of the receiving company to process the product in a cost efficient, effective manner.

• Have a relatively minor affect the confidence of the patient or healthcare professional in the individual container/dose of product.

3.1. Examples of a Level 3 defect (this is not an exhaustive list):

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•

•

•

•

•

•

•

•

Missing perforations on a blister.

Tamper evident seal which is difficult to break.

Broken tablets.

Incorrect number of units per pack (missing tablet in blister/carton missing from outer pack).

Missing leaflet.

Capped tablets.

Hole in suppository.

Poor quality imprint on tablets.

Grease spots on tablets.

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•

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•

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•

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Loose fitting metered dose inhaler in actuator.

4. Level 4 Defects

A defect which is cosmetic in nature:

• But does not affect the ability of the receiving company to further process the product.

• Which is unlikely to affect the confidence of the patient or healthcare professional in the individual container/dose of product.

4.1. Examples of a Level 4 defect (this is not an exhaustive list):

Poor but legible engraving or overprint on tablets.

Crooked labels.

Imperfect perforations.

Small portion of label not secured to container (flagging).

Double label.

Inkspots on cartons.