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News and Events:

Supplier qualification

 

Here you will find answers to the following questions:

  • What is the difference between manufacturers and suppliers?
  • Who must select and approve the supplier who delivers starting materials to the contract acceptor on behalf of the contract giver?
  • May several suppliers be qualified for one starting material?
  • Which criteria are used to select suppliers?
  • How is a supplier approved?
  • What must be observed when changing a supplier?

Qualifications for suppliers of starting materials (especially active pharmaceutical ingredients and packaging materials) are specified by GMP regulations. According to Appendix 8 of the EU GMP sampling guideline (see chapter C.6.8 Annex 8 Sampling of Starting and Packaging Materials), the scope of the goods receipt analysis may be reduced if proper manufacturing, the QM system and handling of goods by the manufacturer have been verified beforehand. This can take the form of an audit or be carried out using a questionnaire. The supplier qualification is generally accompanied by increased safety and also reduced costs.

18.I.1 Suppliers (traders) and manufacturers of raw materials

A general difficulty associated with the procurement of starting materials, particularly in the area of active pharmaceutical ingredients and excipients, is that the difference between an original manufacturer who carries out the actual production and a trader is not entirely clear (see figure 18.I-1). Traders normally only carry out the procurement of starting materials in accordance with scheduled deadlines. In doing so, they take delivery of starting materials from the original manufacturer and forward them to the supplier, sometimes storing them provisionally beforehand. The classic approach to manufacturing a starting material is not taken. Sometimes repackaging and relabelling - also considered to be a part of production according to Annex 18 of the EU GMP Guideline (identical to ICH Q7A, see chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients) - is carried out. The requirements for the repackaging and relabelling of active pharmaceutical ingredients are set out in chapter 17.4 Repackaging, Relabelling and Holding of APIs and Intermediates of document ICH Q7A (see chapter 17.4 Repackaging, Relabelling and Holding of APIs and Intermediates , Section chapter 17.4 Repackaging, Relabelling and Holding of APIs and Intermediates ).

Figure 18.I-1 Original manufacturers and traders

Original manufacturers and traders

Original manufacturer with own manufacturing site

  • must be audited according to ICH Q7A.
  • frequently not identical with the trader/broker/supplier

Trader/broker/supplier

  • partially sells the original manufacturer's product without additional tampering.
  • carries out repackaging and relabelling that must be qualified according to ICH Q7A, chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients, chapter 17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers (traceability, QM system, stability, complaints and recalls, returns)

This means that in the first instance for the purposes of supplier qualification, the original manufacturer and corresponding manufacturing site must always be approved and not the trader. An exception to this is where the trader tampers with the starting materials in any way, e. g. by opening containers for the purposes of repackaging in other dosage forms or relabelling. In this case, additional qualification of the trader will be necessary. By the same token, containers may also be opened by the trader or supplier in order to add another component to the container. In these cases, auditing of the trader or supplier is always recommended to prevent impurities, mix-ups, dosing errors or similar.

In practise, this poses a problem for pharmaceutical manufacturers as only the data of an original manufacturer and not the data of a trader may be provided in a application file for marketing authorisation. Starting material can, on the other hand, very often only be obtained or ordered from a trader. This trader normally represents several manufacturers - also known as principals. The recipient of the raw materials is now confronted with the problem of having to approve an original manufacturer and not a trader. For this reason, it must be ensured by means of a workable quality assurance system that, where starting materials are ordered from a trader, the materials are only supplied by approved original manufacturers.

In practise, problems regularly crop up. The trader confirms the availability of a particular material in response to a request for a specific starting material. When the delivery arrives, it turns out that although it is in fact the material that was ordered, it has not come from a manufacturer that conforms with the requirements of the application file for marketing authorisation. As a precaution, this should be indicated by an additional check item on the delivery note or goods receipt slip so that a further check can be directly carried out with respect to the approved manufacturer as part of the goods receipt analysis.

18.I.2 Selection of manufacturer or supplier

Weaknesses often become apparent during the day-to-day selection of manufacturers or suppliers. Aspects such as delivery dates, price quoted and quality systems are foregrounded here. Although it will always be possible for the purchasing department to obtain a required starting material, but the question of conformity with the application file for marketing authorisation still remains an issue at this point. The application file for marketing authorisation is the only document source that states whether the material in question (excipient, active pharmaceutical ingredient or primary packaging material) is linked to one manufacturer. If this is the case, only the material by this manufacturer may be used in the formulation.

Depending on the application file for marketing authorisation, the option of choosing a second manufacturer may be provided as an alternative to the first manufacturer. If, however, a material from an unnamed manufacturer is then used and the preparation becomes available on the market, conformity with the application file for marketing authorisation can no longer be guaranteed thus rendering the relevant batch unmarketable. The purchaser must comply with the specifications in the application file for marketing authorisation, even if this means that the options available become more limited. Several application files for marketing authorisation are therefore not directly linked to one manufacturer but rather refer to a corresponding pharmacopoeial monograph. This provides the purchasing department with a much greater degree of freedom with regard to the selection of manufacturers.

When manufacturing small-scale development batches or pilot batches on the same scale as subsequent production batches, the physical and technical differences of active pharmaceutical ingredients and exipients from various manufacturers or suppliers are normally checked in addition to the physical and analytical results (see chapter 16 Research and Development). The evaluation of development and/or pilot batches culminates in the approval of one or several manufacturers. In addition to the manufacturing of validation batches and implementation of audits at the manufacturer's premises, the manufacturer specified in the application file for marketing authorisation must be known to the purchasing department. If the manufacturer is linked to a specific starting material in an IT system, this guarantees that the acquisitions department can only order a required starting material from a manufacturer that has been tested and approved by means of quality assurance.

A revalidation will be necessary (see chapter 7.D.2 Incidences requiring revalidation) in cases where the intention is to use a starting material by a manufacturer who has not been tested as part of the process validation.

The purchasing department must regularly address the following question when sourcing starting materials: Should the order be placed with the supplier who is offering the lowest price? The interests of the purchasing and quality assurance departments often correlate in this regard. The requirements that are contained in the application file for marketing authorisation and that emerge from the results of the process validation must be observed as a priority. Otherwise, a supplier who complies with the specifications of the pharmacopoeial monographs may be selected.

The first three deliveries received for this starting material from a new manufacturer must, however, always be subjected to a comprehensive range of tests in accordance with the monograph. Under no circumstances should the certificate of analysis be accepted in isolation or only one identity test carried out. In addition, the batches containing the starting material produced by the new manufacturer must be subjected to special analysis and evaluation within the scope of a revalidation. If the result is positive, an audit must then be carried out at the manufacturer's premises by this point at the latest (see chapter 18.I.3 Audit of active pharmaceutical ingredient manufacturers) - only then can the manufacturer be formally approved and the starting material ordered from this manufacturer or (possibly) bought in via a trader.

Traders should also be subjected to an approval procedure as certificates can also be falsified, for example. While this is in essence a fairly minor matter, it is nonetheless extremely difficult for the contract giver and the contract manufacturer to get hold of this information. The following table shows the various aspects that are relevant to the selection of suppliers.

Figure 18.I-2 Selection of a supplier

Criteria for the selection of a supplier

  • Price comparison
  • Fast delivery time
  • Long-term delivery contracts
  • Quality
  • Goods correspond with the monograph
  • Manufacturer is specified in the dossier
  • Experiences

18.I.3 Audit of active pharmaceutical ingredient manufacturers

Appendix 18 of the EU GMP Guideline "GMP for manufacturers of active pharmaceutical ingredients" (see chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients) is used as the basis for the inspection of active pharmaceutical ingredient manufacturers. This document is a guideline entitled chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients which was published in November 2000 following long and intensive collaboration between the three parties - USA, Japan and Europe.

This guideline deals with the manufacturing of active pharmaceutical ingredients for human medicinal products. It applies to the manufacturing of sterile active pharmaceutical ingredients only up to the point directly before sterilisation and covers the manufacturing of active pharmaceutical ingredients manufactured using processes such as chemical synthesis, extraction, utilisation of natural resources or combinations of these. Vaccines, whole cells, blood and plasma derivatives (plasma fractioning) and active pharmaceutical ingredients used for gene therapy are excluded from this guideline. This document does however include active pharmaceutical ingredients that are manufactured using blood or plasma as raw materials. When preparing an inspection of the manufacturer of the active pharmaceutical ingredient, it is practicable to find out the extent to which the scope of the ICH Q7A guideline applies for the manufacturer in question or whether it can be regarded as a state-of-the-art guideline.

18.I.3.1 Preparation

The manufacturer's specifications are often handed over by company development or purchasing departments to the quality assurance units within a pharmaceutical company responsible for supplier qualification and inspections. Often at this stage, no information apart from the manufacturer's designation and address is available to the quality assurance units. The questions listed in the following table should therefore be addressed to make preparations for the inspection more efficient.

Figure 18.I-3 Organisational preparations

Organisational preparations

  • Can information on the active pharmaceutical ingredient manufacturer be obtained from the Internet?
  • Are the names of contact persons at the company already known?
  • Can company brochures be ordered?
  • Does the pharmaceutical manufacturer provide a questionnaire that can be completed by the active pharmaceutical ingredient manufacturer prior to the inspection?
  • Does the company currently have information on specific products in a Drug Master File?
  • Is the active pharmaceutical ingredient manufacturer represented by a broker or trader? If necessary, would it be possible to carry out the inspection jointly with the brokers or traders?
  • From the point of view of the active pharmaceutical ingredient manufacturer and the pharmaceutical manufacturer, who will be taking part in the inspection?
  • Do alternative dates/times for the inspection exist?
  • Does the active pharmaceutical ingredient manufacturer produce other starting materials?
  • Are other starting materials - particularly active pharmaceutical ingredients - manufactured at the company site?

18.I.3.2 Type of inspection

In order to clearly establish the scope of the inspection and time required for this, it is useful to know at the early planning stages exactly which kind of inspection is to be carried out.

  • System inspection: Qualification of areas and procedures relevant to the functionality of the system. In this case, the procedures and organisations at the company are checked.
  • Product inspection: In this case, the development of the active pharmaceutical ingredient is inspected - from delivery of the starting materials followed by the manufacturing process and culminating in the approval inspection in the laboratory.
  • Procedure inspection: Is the required active pharmaceutical ingredient obtained using the procedure described in the manufacturing and testing instructions? Are the requirements in the directions adequately described?
  • Area inspection: This inspection is carried out in specific parts of the manufacturing, engineering, warehouse and packaging or changing and washroom areas.

The assessment regarding the kind of inspection that is ultimately to be carried out is largely dependent on whether this is the first inspection of the active pharmaceutical ingredient manufacturer by the contract giver or whether this inspection has come about, for example, due to shortcomings in the quality of the active pharmaceutical ingredient. If the active pharmaceutical ingredient manufacturer is being inspected for the first time, a system inspection is recommended. The procedures and organisation systems tested during this inspection provide a sound basis for gaining an overall impression of the company. If an inspection of the manufacturing and testing procedures for only one active pharmaceutical ingredient is required independently of all other organisations at the company, a product inspection should be carried out. If there are shortcomings in the active pharmaceutical ingredient, a procedure inspection can check the extent to which the requirements of the manufacturing and testing procedure are complied with. Alternatively, checks can be carried out using existing manufacturing and test protocols to establish how operational deviations are dealt with. If shortcomings are apparent in the area of manufacturing or control, this area is largely the focus of a critical examination carried out during the area inspection.

Frequently, straightforward classification of inspections according to fixed types is not possible. This makes it perfectly acceptable not only to inspect the procedure for manufacturing an active pharmaceutical ingredient during production (in this case, a product inspection) but also to check the quality assurance system at the same time (in this case, a system inspection). You will find more information about this in chapter 18.D Organisation of inspections and chapter 18.G Inspection of suppliers.

18.I.3.3 Questions for opening discussion

Following arrival at the active pharmaceutical ingredient manufacturer's premises, the qualification normally starts with a meeting for introduction and coordination purposes. The details and organisational aspects listed in the table below should be addressed at this meeting.

Figure 18.I-4 Details and organisational aspects

Opening discussion

  • Have all participants introduced themselves by name and explained what their responsibility is?
  • Has an agenda with topics and a schedule been agreed?
  • Will the start and end times of the inspection be determined?
  • Is a social event planned for the evening?
  • Should a closing meeting take place at the end of each day?
  • Will the topics and documents required for the following day be named?
  • Would it be possible to see a company presentation?

Questions on the manufacturing process

  • Does a flow chart for the synthesis process exist?
  • Is a diagram available that shows the organisational structure?
  • Are the responsible persons clearly identified?
  • Is it perfectly clear when the starting materials for the active pharmaceutical ingredient are fed into the process?
  • Would a presentation of the basic principles of the quality management system be possible?

18.I.3.4 Inspection sequence: Documents versus site visit

The differences in the legal requirements between a pharmaceutical manufacturer and an active pharmaceutical ingredients manufacturer also have a major impact on the course of the inspection. If the opening discussion compares favourably with the company approach, this makes a considerable difference to the on-site inspection. The classic approach to the manufacturing of batches in pharmaceutical companies as such - i.e. separate manufacturing steps carried out on different equipment and machines in separate premises - is not taken by a manufacturer of active pharmaceutical ingredients. The processes and procedures involved in the chemical manufacturing of active pharmaceutical ingredients are carried out using closed equipment and systems. Reactors are provided for the synthesis steps and closed piping systems are provided for the transportation of materials. A tour of the company will therefore reveal very little about the manufacturing operation for the purposes of assessment and evaluation.

In contrast to pharmaceutical manufacturers, active pharmaceutical ingredient manufacturers generally take a different approach to the frequent handling of open products in the hygiene area. Depending on the active pharmaceutical ingredient manufacturer, the material (in this case starting material and finished product) is only exposed to environmental conditions in the areas where the initial weight is determined, starting materials for the process are added and transport containers are filled with the active pharmaceutical ingredient. In the case of a pharmaceutical manufacturer, the relationship between the analysis of company processes and compliance with the requirements in the documentation is more or less equal. The inspection processes for an active pharmaceutical ingredient manufacturer on the other hand are geared much more strongly towards the area of document analysis and general conditions. During the course of the inspection, the existing documents often represent the only opportunity to inspect and evaluate the active pharmaceutical ingredient manufacturer accordingly. The inspectors should modify their approach accordingly in the run up to the inspection.

The initial inspection at the works of an active pharmaceutical ingredient manufacturer will demonstrate that familiar pharmaceutical requirements and rules learned do not apply here and only vaguely correspond with state-of-the-art pharmaceutical companies. It is therefore hardly surprising to find that while entire manufacturing processes are in fact carried out at a defined business premises, they take place more or less outside or in buildings that are open to the elements. This applies right from the outset with starting materials frequently being stored in open-sided corrugated metal sheds.

18.I.3.5 Inspection questionnaire

In figure 18.I-5, a catalogue of questions covering the most important inspection topics has been compiled that may be of assistance when structuring an inspection. A questionnaire is only useful to the extent that the most important topics are covered for the purposes of preparing for or carrying out an inspection. Inexperienced inspectors cannot achieve satisfactory results simply by using a questionnaire as these results generally depend on how the answers to the questions are evaluated.

We thank the APIC for granting reprinting the following questionnaire.
© APIC "Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged."

The present publication may have been updated. For the latest available edition, see http://www.apic.cefic.org/publications/publications.html.

Figure 18.I-5 Catalogue of questions (part 1 of 50)

Questionnaire for auditing API manufacturers

Reference
ICH Q7a

Topics/Issue

Applicability

Compliant

Kind of
Documentation

Commentary

Question posed

Yes

No

Yes

tbi

No

1

Introduction

1.3

Scope

 

Has the company designated the point at which the production of the API begins?

Can a rationale be provided for this decision?

Has the decision been discussed with the respective authority?

Are the critical steps identified?

               

2

Quality Management

2.1

Principles

2.11

A Quality Management System (e.g. ISO 9000) is implemented?
(if yes, see chapter 20)

               

2.12

Is there a quality policy?

How is it brought to the attention of the employees?

               

2.13

Is the Quality Unit (QU) independent of production?

               

2.14

Is there an authorized person for the release of IM and APIs?

Who are the person(s)?

               

2.16

Are all deviations are documented and explained?

Are critical deviations investigated in a timely manner?

Is there a written procedure for handling investigations (6.53)?

Average days for completion?

               

2.17

How is ensured that materials are not released or used before completion of evaluation by the QU?

If not done by QU: appropriate system in place?

               

2.18

How is management notified of serious GMP deficiencies and/or product defects?

Average time needed for information?

               

2.2

Responsibilities of the QU

2.21

Procedures that ensure that QU reviews and approves all quality related documents in place?

               

2.22

Non-transferable responsibilities of QU:

  • release/rejection of APIs and IM (to be sold)
  • establish system to release/reject materials and labels
  • review of critical process steps batch records
  • ensure critical deviations are investigated
  • approving specifications and master instructions
  • approving all quality related documents
  • ensuring conduction of internal audits
  • approving contract manufacturers
  • approving changes with quality impact
  • approving validation documents
               
 
  • ensure complaints are resolved
  • ensuring calibration is executed
  • ensuring that stability data is generated
  • performing product quality reviews
               

2.3

Responsibilities for Production Activities

 
  • procedure for preparing, reviewing and approving instructions
  • reviewing batch production records
  • ensure all deviations and investigations are handled
  • cleaning of facilities
  • calibrations performed
  • validation documents generated
  • evaluation of proposed changes
  • ensure that facilities and equipment is qualified
               

2.4

Internal Audits

2.40

Are regular audits performed?

Is there an audit schedule?

Is the schedule followed?

               

2.41

Are audit findings and corrective actions documented?

Procedure to notify management of audit findings?

Are corrective actions completed within agreed time (delays!)?

               

2.5

Product Quality Review

2.50

Are regular Product Quality Reviews conducted for all products?

Frequency (dedicated, campaign)?

Content (at least):

  • review of critical IPC and API test results
  • review of all batches failed
  • review of all critical deviations
  • review of changes and impact on quality
  • review of stability programmes
  • review of returns, complaints
  • review of adequacy of corrective actions
               

2.51

Evaluation and assessment for need of corrective actions and/or revalidation

               

3

Personnel

3.1

Personnel Qualifications

3.10

Adequate number of personnel?

Qualification of personnel sufficient at different levels?

               

3.11

Are responsibilities of all personnel engaged in manufacture in APIs in writing available?

               

3.12

Is regular training conducted?

Are records of training maintained?

               

3.2

Personnel Hygiene

3.21

Personnel wears clean clothing suitable for activity?

Additional protective apparel where necessary (e.g. filling rooms)?

               

3.22

How is ensured that no direct contact with IM and APIs takes place?

               

3.23

How is ensured that no smoking, drinking, chewing and storage of food takes place?

               

3.24

How are personnel with infectious diseases identified?

Is there a procedure in place that these persons have no product contact?

               

4

Buildings and Facilities

4.1

Design and Construction

4.10

Cleaning and maintenance easily to be carried out?

               

4.11

Adequate space for placement of equipment available?

               

4.12

Outdoors equipment raise no concerns for contamination

               

4.13

Flow of materials and personnel raise no concerns for contamination

               

4.14

Defined areas for the following activities available:

  • receipt, identification, sampling of incoming materials
  • quarantine before release/reject
  • handling of rejected materials
               

4.15

Washing facilities and toilets available for personnel?

               

4.16

Laboratory areas separated from production?

               

4.2

Utilities

4.20

All utilities qualified?

               

4.21

Adequate ventilation, air filtration and exhaust systems in place?

               

4.22

Control of re-circulated air sufficient to avoid contamination?

               

4.23

Permanently installed pipework appropriately identified?

               

4.24

Drains designed to prevent back-siphonage?

               

4.3

Water

4.30

Water demonstrated to be suitable for intended use?

               

4.31

Process water meets drinking water quality (otherwise data available showing that lower quality is sufficient)?

               

4.32

Tighter specifications needed to ensure quality?

What are the specifications?

               

4.33

Validation of treatment of (higher) water treatment?

               

4.34

If claims are made for sterile use:

Monitor microbial counts, objectionable microorganisms and endotoxins

               

4.4

Containment

4.40

For highly sensitizing materials dedicated production areas (facilities, air systems, equipment) required

               

4.41

Dedicated production area for high pharmacological activity

               

4.42

Measures to prevent cross-contamination

               

4.43

Production of highly toxic, non-pharmaceutical excluded?

               

4.5

Lighting

 

Adequate lighting for e.g. cleaning and maintenance

               

4.6

Sewage and Refuse

4.60

Sewage to be removed timely

               

4.7

Sanitation and Maintenance

4.70

Buildings to be kept properly maintained, repaired and cleaned

               

4.71

Written procedures for cleaning for equipment and facilities in place

               

4.72

Procedures for pest control in place

               

5

Process Equipment

5.1

Design and Construction

5.10

Equipment suitably located, easy to clean and maintenance

               

5.11

Equipment surfaces do not alter product quality

               

5.12

Equipment only used within the qualified operation range.

               

5.13

Major equipment and permanently installed pipework identified

               

5.14

Lubricants can not contact IM and APIs otherwise food grade lubricants to be used

               

5.15

Precautions (measures) taken where equipment is opened.

               

5.16

P & ID schemes available.

               

5.2

Equipment Maintenance and Cleaning

5.20

Preventive maintenance programme in place?

Schedule followed?

               

5.21

Written procedures for the cleaning of equipment in place?

               

5.23

Continuous production or dedicated production: cleaned at appropriate intervals (frequency)?

               

5.24

Is equipment cleaned between production of different products?

               

5.25

Acceptance criteria for residues determined?

               

5.26

Equipment identified as to its content and cleanliness status?

               

5.3

Calibration

5.30

Instruments critical for IM and/or API quality are calibrated?

How is critical defined?

Written procedure in place?

Schedule followed?

               

5.31

Calibration done with standards that are traceable to certified standards?

               

5.32

Records of calibration maintained?

               

5.33

Calibration status of instruments known?

How (label, electronic)?

               

5.34

How is ensured that instruments out of calibration are not used?

               

5.35

If instruments have been shown out of calibration, are investigations performed to determine if this fact has an influence on the release of the IM/API?

               

5.4

Computerised Systems

5.40

Are GMP related computer systems validated?

               

5.41

IQ, OQ for Hard- and Software available?

               

5.42

Retrospective Validation for existing systems if not validated at time of installation

               

5.43

What controls are in place to prevent unauthorized access?

What controls are in place to prevent changes to data?

What controls are in place to prevent omissions in data?

Is there a document where changes to data are recorded, who made the change, when the change was made and of the previous entry?

               

5.44

Written procedures for the operation and maintenance of computerized systems available?

               

5.45

Is the entry of critical data checked by additional means (second operator or system itself)?

               

5.46

Incidents of computerized systems recorded and investigated?

               

5.47

Changes to the computerized system are made according to a defined procedure?

               

5.48

How are data protected in cases of system breakdowns?

Back-up system provided?

               

6.

Documentation and Records

6.1

Documentation System and Specifications

6.10

Written procedure in place describing preparation, review, approval and distribution of documents related to the manufacture?

               

6.11

How is revision, superseding and withdrawal of documents controlled?

Is a revision history maintained?

               

6.12

Procedure in place for retaining all appropriate documents?

Retention period specified?

               

6.13

Retention period for APIs with expiry date: 1 year after expiry (min.)

Retention period for APIs with retest date: 3 years after complete distribution (min.)

               

6.14

Are corrected entries in documents dated and signed?

Original entry still readable?

               

6.15

Are documents promptly retrievable (copies or electronic means acceptable)?

               

6.17

Are specifications for all materials, IM and APIs established?

               

6.18

Are electronic signatures authenticated and secure?

               

6.2

Equipment Cleaning and Use Records

6.20

Are there records for the major equipment used , cleaning and maintenance showing the following

  • date
  • time
  • product and batch number of each batch
  • person who performed cleaning
  • person who performed maintenance
               

6.3

Records of Raw Materials, IM, API Labeling and Packaging Materials

6.30

Records of each delivery should contain:

  • name of manufacturer/supplier
  • identity and quantity
  • supplier control or identification number
  • number allocated on receipt
  • date of receipt
  • result of tests and conclusion derived from this
  • trace of use
  • review of labels and packaging materials showing conformity with specifications
  • final decision release or reject
               

6.31

Are master labels maintained?

               

6.4

Master Production Instructions

6.40

Are Master Production Instructions for each IM/API

  • prepared
  • sated
  • signed
  • independently checked by QU
               

6.41

Do Master Production Instructions contain the following:

  • name of product including document reference code
  • complete list of raw materials
  • accurate statement of quantities needed or calculation of quantity
  • production location and major equipment to be used
  • detailed production instructions including sequences, ranges of parameters, sampling instructions, IPC, time limits, expected yield
  • instructions for storage
               

6.5

Batch Production Records

6.50

Are Batch Production Records checked before issuance for correct version?

               

6.51

Are the records showing an unique batch number (not for continuous production)?

               

6.52

The batch record should contain the following:

  • date(s) and times (if appropriate)
  • identity of major equipment
  • identification of materials used
  • actual results
  • sampling performed
  • signatures of the person(s) performing the operation
  • IPC / laboratory test results
  • Actual yield, if appropriate
  • Description of packaging and labels used
               
 
  • Deviation/investigation
  • Results of release testing
               

6.6

Laboratory Control Records

6.60

Laboratory records should contain the following:

  • description of sample including name, batch number or code, date when sample was taken, quantity
  • reference to test method
  • cross reference to preparation of reference standards, reagents and/or standard solutions
  • complete record of all raw data
  • record of all calculations
  • statement of test result if they comply with specifications
  • signature and date of person(s) performing the testing
  • signature of second person demonstrating review for accuracy, completeness
               

6.61

Other records to be maintained:

  • modification to test method
  • calibration of laboratory instruments
  • stability testing performed
  • OOS investigations
               

6.7

Batch Production Record Review

6.70

Is a written procedure for the handling of batch (laboratory) record review available?

               

6.71

Are Batch (laboratory) records of critical steps reviewed by the QU?

Are they reviewed before the release of the API?

               

6.72

Are all deviations, investigations and OOS reviewed as part of the batch record review?

               

6.73

Is the QU releasing all IM that are shipped outside the control of the company?

               

7

Materials Management

7.1

General Controls

7.10

Are written procedures available for handling of receipt, identification, quarantine, storage, sampling, testing, approval or rejection of materials?

               

7.11

System to evaluate suppliers of critical materials in place?

Evaluation must show that supplier can consistently provide material meeting specifications (7.31)

               

7.12

Materials purchased against agreed specifications?

Purchased from an approved (by QU) supplier?

               

7.13

If supplier is not the manufacturer, is the original manufacturer known?

               

7.14

Change of source/supplier handled according to Change Control procedures (chap. 13)?

               

7.2

Receipt and Quarantine

7.20

Upon receipt materials visually examined for

  • correct labeling
  • container damage
  • broken seals
  • tampering or contamination

Are materials held under quarantine until released for use?

How is this done?

               

7.21

Incoming materials are released before mixed with existing stocks?

Are procedures in place to prevent discharging materials wrongly?

               

7.22

If deliveries are made in non-dedicated tankers which assurance is provided to demonstrate no contamination (one or more of the following):

  • certificate of cleaning
  • testing for trace impurities
  • audit of the supplier
               

7.24

Is each delivery of materials identified (code or batch number)?

Is there a system in place to identify the status of each batch?

               

7.3

Sampling and Testing of Incoming Production Materials

7.30

Is at least one test conducted to verify the identity of incoming materials?

If suppliers certificate of Analysis is used instead of testing a system for evaluation must be in place.

               

7.31

(see also 7.11)

Are 3 full analyses conducted before reducing testing?

Is a full analyses performed at appropriate intervals and compared with the suppliers certificate of analysis?

               

7.33

How is demonstrated that samples taken from the material are representative?

Are sampling methods described with at least

  • number of containers to be sampled
  • which part of the container
  • amount of sample to be taken
               

7.34

Is sampling done at defined locations preventing contamination?

               

7.35

Are containers from which samples are taken marked?

               

7.4

Storage

7.40

Is material stored in a manner to prevent degradation and contamination?

               

7.41

Are fiber drums, bags and boxes stored off the floor?

Is stored material suitably spaced to permit cleaning and inspection?

               

7.42

Do materials met their respective storage conditions?

Is the FIFO principle followed?

               

7.43

In case materials is stored outdoors:

  • do labels remain legible
  • are the containers cleaned before opening
  • is it described in a procedure
               

7.44

How are rejected materials held under a quarantine system?

               

8

Production and In Process Controls

8.1

Production Operations

8.10

Are weighing and measuring devices of suitable accuracy for the intended use?

               

8.11

Do containers with subdivided material contain the following information:

  • name of material
  • code or control number
  • weight, if applicable
  • retest date, if applicable
               

8.12

How are critical weighing, measuring or subdividing operation witnessed?

Is an equivalent control used? If so which?

               

8.13

Are all other critical operations witnessed or subjected to equivalent control?

               

8.14

Are actual yields compared with expected yields at designated steps in production?

               

8.16

How is the processing status of major units of equipment indicated?

               

8.2

Time Limits

8.20

Are all specified time limits of the operating instructions met?

               

8.21

How are storage conditions for IM held for further processing determined?

               

8.3

In-process Sampling and Controls

8.30

Are IPC established to monitor the progress and control the performance of the processing steps?

               

8.32

Are critical IPC approved by the QU?

               

8.33

How is the qualification (training) of the production personnel documented, if they perform the IPC?

               

8.34

Are sampling methods for IPC described in writing?

               

8.35

Does in-process sampling not cause the contamination of sample and/or product?

               

8.4

Blending of Batches of IM or APIs

8.41

Are OOS batches blended with other batches meeting the specifications?

Are all batches individually tested prior to blending? And do they all have met the specifications?

               

8.43

Is the blending process adequately documented and the blended batch tested for conformance to specifications?

               

8.44

Does the batch record of the blended batch allow traceability back to the individual batches?

               

8.45

Are blending operations validated if physical attributes of the API resulting from this step are known to be critical?

               

8.46

How is demonstrated that the blended batch does not affect stability?

               

8.47

Is the expiry/retest date based on the oldest batch in the blend?

               

8.5

Contamination Control

8.50

How is ensured that carryovers (e.g. degradents) into successive batches of the same IM/API do not affect the impurity profile of the API?

               

8.51

What measures are taken in production to prevent contamination of IM/API?

               

8.52

What specific precautions are taken to avoid contamination of the API after purification?

               

9

Packaging and Identification Labelling of APIs and IM

9.1

General

9.10

Are written procedures available describing

  • receipt
  • identification
  • quarantine
  • sampling
  • examination/testing
  • release

of packaging materials and labels ?

               

9.11

Are specifications for all packaging materials and labels established?

               

9.12

Are records of each delivery of packaging materials and labels kept?

               

9.2

Packaging Materials

9.20

Can containers/packaging material used provide adequate protection against deterioration or contamination during transportation?

               

9.21

Are containers cleaned so that they are suitable for their intended use?

               

9.22

Are written procedures for cleaning in place for re-used containers?

Are all previous labels removed or defaced?

               

9.3

Label Issuance and Control

9.30

Is access to label storage area limited to authorized personnel?

               

9.31

Are procedures in place to reconcile the quantities of labels issued and used?

Are discrepancies investigated and approved by the QU?

               

9.32

Are all not used labels bearing batch numbers and not used being destroyed?

How is it documented?

               

9.33

Are all out-dated and obsolete labels destroyed?

               

9.34

Are printing devices checked that the imprint conforms to the print specified in batch record?

Is an examination done to check if the correct label is on the packed IM/API? (9.45)

               

9.36

Is a representative label included in the batch record?

               

9.4

Packaging and Labelling Operations

9.40

Are written procedures in place ensuring that correct packaging materials and labels are used?

               

9.41

Is physical or spatial separation of labels done when multiple labeling operations are done at the same time?

               

9.42

Labels should indicate the following information (at least):

  • name of product
  • identifying code or batch number
  • storage conditions, when such information is critical to assure quality
               

9.43

If the IM/API is transferred outside of the control of the manufacturer the label should contain:

  • name and address of manufacturer
  • quantity
  • special transport conditions, if applicable
  • special storage conditions, if applicable (10.22)
  • legal requirements, if applicable

For APIs with expiry date: date to be included on label and certificate of analysis

For APIs with retest date: date to be included on label and/or certificate of analysis

               

9.44

Are packaging and labeling facilities inspected before use to ensure that all materials not needed are removed?

Is this inspection documented?

               

9.46

Are seals used that will alert the recipient that the material may have been altered?

               

10

Storage and Distribution

10.1

Warehousing Procedures

10.10

Are facilities for the storage of materials available supporting the claimed storage conditions (e,g, temperature, humidity)?

Are records of the storage conditions kept?

               

10.11

Are separate storage areas provided for quarantined, rejected, returned or recalled products?

Or is an alternative system used? If so, how is it designed?

               

10.2

Distribution Procedures

10.20

How is ensured that APIs/IM are not distributed outside of the company before the release of the QU?

               

10.21

How are transportation conditions ensured so that the quality of the product will not adversely being affected?

               

10.23

How does the manufacturer ensure that the transporter knows and follows the appropriate transport and storage conditions?

               

10.24

Which system is in place to easily permit an recall?

               

11

Laboratory Controls

11.1

General Controls

11.10

Are adequate laboratory facilities available?

               

11.12

Are all sampling plans and testing procedures reviewed and approved by the QU?

               

11.13

Do the specifications set for the APIs include a control of the impurities?

If the API has a specification for microbiological purity and/or endotoxins what appropriate action limits have been established?

               

11.15

Are all OOS results investigated?

Is resampling after OOS described in a procedure?

               

11.16

Are written procedures in place for preparation of reagents and standard solutions?

               

11.17

Are primary reference standards stored under appropriate conditions?

Is the source of the primary standard documented?

               

11.18

If the primary standard is not obtained from an officially recognized source, is appropriate testing conducted to fully establish the identity and purity of the primary standard?

               

11.19

Are procedures in place to prepare, identify, test store and approve secondary reference standards?

Is the suitability of the secondary standard determined prior to use by comparing it against the primary standard?

Are secondary reference standards periodically re-qualified?

               

11.2

Testing of Intermediates and APIs

11.21

Is there an impurity profile established for every API?

               

11.22

Is the impurity profile compared at appropriate intervals against the impurity profile in the regulatory submission or against historical data?

               

11.3

Validation of Analytical Procedures

 

See section 12.8

               

11.4

Certificates of Analysis

11.40

Are authentic Certificates of Analysis issued for each batch of IM/API?

               

11.41

Information on the Certificate of Analysis:

  • name of IM/API
  • batch number
  • date of release
  • expiry date, if applicable
  • retest date, if desired
               

11.42

On the Certificate of Analysis, are all tests performed listed, together with acceptance limits and numerical results obtained?

               

11.43

Certificates of Analysis should be

  • dated
  • signed by authorized personnel of the QU
  • show name, address and telephone number of manufacturer

If Certificate of Analysis is issued by agents (chap. 18) the name, address and telephone number of the agents must be shown.

               

11.44

If Certificate of Analysis is issued by agents the name, address and telephone number of the laboratory that performed the tests must be shown.

It also should contain a reference to the original manufacturer and to the original Certificate of Analysis.

               

11.5

Stability Monitoring of APIs

11.50

Is an on-going stability testing programme conducted?

Do the results of the stability programme justify storage conditions and expiry/retest dates (see also 11.61)?

               

11.51

Are the test methods used in stability validated and stability indicating?

               

11.52

Are the stability samples stored in containers of the same material as the market containers?

               

11.53

Are the first three commercial production batches placed on stability?

               

11.54

Thereafter, is at least on batch per year added to the stability monitoring programme?

Are annually tests performed to confirm stability?

               

11.55

For APIs with less than 1 year stability:

Is testing performed monthly for the first three months and at three month intervals after that?

               

11.6

Expiry and Retest Dating

11.60

Is an expiry/retest date assigned when the APIs transferred outside of the control of the company?

               

11.7

Reserve/Retention Samples

11.71

Are reserve samples stored for 1 year after expiry date or 3 years after distribution (whatever is longer)?

For APIs are reserve samples stored for 3 years after completely distribution?

               

11.72

Are reserve samples stored in same packaging system or more protective than the marketed?

Is the amount of sample sufficient to conduct at least 2 full compendial analyses?

               

12

Validation

12.1

Validation Policy

12.10

Is the company's overall validation policy documented?

(Could be combined with 2.12)

               

12.11

Are all critical parameters defined during the development (or from historical data)?

Are the operating ranges defined?

               

12.12

Are all critical operation steps validated?

               

12.2

Validation Documentation

12.20

Is a validation protocol established?

Is it approved by the QU?

               

12.21

Is the following specified in the validation protocol:

  • critical process steps
  • acceptance criteria
  • type of validation
  • number of process runs?
               

12.22

Is a validation report prepared summarising the results obtained, including recommendating changes to correct deficiencies?

               

12.23

Are variations from the validation protocol documented and justified?

               

12.3

Qualification

12.30

Is appropriate qualification (DQ, IQ, OQ, PQ) conducted for critical equipment and ancillary systems?

Is qualification completed before process validation activities?

               

12.4

Approaches to Process Validation

12.40

Is the process validation (PV) conducted?

               

12.42

Prospective Validation should normally be performed. What is the justification of performing other types?

Is the validation completed before commercial distribution of the drug product?

               

12.44

If retrospective validation is conducted for well established processes, are the following requirements met:

  • critical process parameters have been identified
  • appropriate in-process criteria have been established
  • no significant process failures have been occurred
  • impurity profiles have been established for the existing API
               

12.45

Are batches selected for retrospective validation representative for all batches made during the review period?

               

12.5

Process Validation Programme

12.50

Are at least 3 consecutive successful production batches made for prospective and concurrent validation?

For retrospective validation are 10 to 30 consecutive batches be examined? If fewer batches are examined, what is the justification for it?

               

12.52

Has process validation confirmed that the impurity profile is within the specified limits?

               

12.6

Periodic Review of Validated Systems

12.60

Are systems and processes periodically evaluated to verify that they are still operating in a valid manner (e.g. through product quality review)?

               

12.7

Cleaning Validation

12.70

Are cleaning procedures validated?

If not, is there a justification?

Is cleaning validation directed to situations where contamination or carryover poses the greatest risk?

               

12.71

If various APIs/IM are produced in the same equipment and the same cleaning process is used, is a representative API/IM selected for cleaning validation (on the basis of solubility, difficulty to clean and calculation of residue limits based on potency, toxicity and stability)?

               

12.72

Does the cleaning validation protocol include

  • equipment to be cleaned
  • procedures
  • materials used
  • acceptable cleaning levels
  • parameters to be monitored
  • analytical methods
  • type of samples (swab, rinse)
  • how samples are collected and labeled
               

12.73

Does the type of sampling detect insoluble aqnd soluble residues?

Is the sampling method capable to quantitatively measure levels of remaining residues?

               

12.74

Are the analytical methods sensitive enough to detect residues or contaminates?

How are residue limits established (on minimum known pharmacological, toxicological or physiological activity or the most deleterious component)?

               

12.75

If claims on microbiological and/or endotoxin specifications are made, does the cleaning validation take this into account?

               

12.76

Are the cleaning procedures monitored at appropriate intervals to ensure their effectiveness?

               

12.8

Validation of Analytical Methods

12.80

Are the analytical methods validated?

               

12.81

How is the degree of analytical validation (e.g. for different steps of production) justified?

               

12.82

Is the analytical equipment qualified?

               

12.83

Are records of modified validated analytical methods maintained?

Is the reason for the modification documented?

               

13

Change Control

13.10

Is a formal change control system in place capable of evaluating all changes?

               

13.11

Written procedures should be provided for the identification, documentation, review and approval of changes.

               

13.12

Are all changes impacting the quality of the API/IM approved by the QU?

               

13.13

Are changes classified (e.g. major, minor)? If not, how is the impact on the quality of the API being evaluated? How is level of testing, validation, documentation determined (scientific judgement)?

               

13.14

How is ensured that after a change all affected documents are revised?

               

13.15

Are the first batches after the change has been implemented evaluated?

               

13.16

If critical changes have been made, has the impact on expiry/retest dates been evaluated?

               

13.17

Are medicinal product manufacturers notified about changes that could impact the API quality (especially physical attributes)?

               

14

Rejection and Re-Use of Materials

14.1

Rejection

14.10

Are IM/APIs failing to met specifications identified? How?

               

14.2

Reprocessing

 

Are all steps where reprocessing is conducted part of the filing documents?

               

14.3

Reworking

14.30

Is an investigation performed before a decision is taken for rework a batch?

               

14.31

Have reworked batches been subjected

  • to appropriate evaluation
  • stability testing
  • to show equivalency to original process?

Is concurrent validation performed if more than one batch is affected?

Is a report issued if only one batch is affected?

               

14.32

Is the impurity profile of the reworked batch compared with the one of the established process?

If routine analytical methods are inadequate, are additional methods used?

               

14.4

Recovery of Materials and Solvents

14.40

Do procedures exist for the recovery of materials?

Do the recovered materials meet specifications for their intended use?

               

14.41

Do recovered solvents used in different processes meet appropriate standards?

               

14.42

Are recovered solvents been tested for suitability before combined with fresh solvents?

               

14.5

Returns

14.50

Are returned APIs/IM identified and quarantined?

               

14.51

Is evaluated that returned materials casts no doubt on their quality before re-use?

               

14.52

Are records of returned goods available containing

  • name and address of the consignee
  • API/IM, batch number and quantity
  • reason of return
  • use or disposal of API/IM
               

15

Complaints and Recalls

15.10

Is a written procedure available describing the handling of complaints?

               

15.11

Do the complaint records include the following:

  • name and address of complaint
  • name and phone number of person submitting the complaint
  • complaint nature (including name and batch number of API)
  • date complaint is received
  • action taken (including person taking the action)
  • any follow-up, if applicable
  • response provided to the originator of complaint including date of response
  • final decision on API
               

15.12

Are the records of complaints retained?

For how long? Can trends be evaluated?

               

15.13

Is there a recall procedure in place?

               

15.14

Does the recall procedure specify

  • who should be involved
  • how the recall is initiated
  • who should be informed
  • how recalled material is treated
               

16

Contract Manufacturers (including Laboratories)

16.10

Is ensured that all contract manufacturers engaged comply with the GMP requirements of Q7a?

               

16.11

How is the contract manufacturer evaluated for GMP compliance?

               

16.12

Is there a written contract (agreement) with the contract manufacturer?

Are the GMP responsibilities defined in detail?

               

16.13

Does the contract permit to audit the contract manufacturer?

               

16.14

Is subcontracting by the contract manufacturer excluded?

If not, how is ensured that the contract giver is involved in prior evaluation of the subcontractor?

               

16.15

Are all records kept at the contract manufacturers site?

How is ensured that these are readily available?

               

16.16

Does the contract manufacturer has a change control system?

How is ensured that the contract giver is informed about all intended changes of the contract manufacturer to the process?

Does the contract giver approve all changes?

               

17

Agents, Brokers, Traders, Distributors, Repackers, and Relabellers (Agent)

17.1

Applicability

17.10

Is this not the original manufacturer of the API?

(Then this section applies.)

               

17.11

Does the Agent comply with the GMP requirements as defined in Q7a?

               

17.2

Traceability of Distributed APIs and IM

17.20

Is the following information retained:

  • identity of original manufacturer
  • address of original manufacturer
  • purchase orders
  • transportation documentation
  • receipt documents
  • name or designation of API
  • manufacturers batch number
  • distribution records
  • authentic certificate of analysis, including those of the original manufacturer
  • expiry/retest date
               

17.3

Quality Management

17.30

Has the Agent established a system of managing the quality as defined in section 2?

               

17.4

Repackaging, Relabeling and Holding of APIs and IM

17.40

How does the Agent ensure that during repackaging, relabeling and holding of APIs/IM no mix-ups and loss of identity and purity of the API/IM occurs?

Are these operations conducted under conditions described in Q7a?

               

17.41

Is repackaging done under conditions to avoid contamination?

               

17.5

Stability

17.50

Are stability studies conducted if the API is repacked in a different type of container?

               

17.6

Transfer of Documentation

17.60

Does the Agent transfer all quality and regulatory information from the original manufacturer to the customer?

               

17.61

Does the agent provide the name of the original manufacturer and the batch number to the customer?

               

17.63

Is the specific guidance for Certificates of Analysis described in section 11.4 followed?

               

17.7

Handling of Complaints and Recalls

17.70

Does the Agent maintain records of all complaints and recalls that where brought to their attention?

               

17.71

Does the Agent review the complaint together with the original manufacturer for determining further action?

               

17.72

Do the records of the Agents include responses from the original manufacturer to a complaint?

               

17.8

Handling of Returns

17.80

Are returns to the Agent handled in the way described in section 14.52?

Is documentation maintained of returned APIs/IM?

               

18

Specific Guidance for APIs Manufactured by Cell Culture / Fermentation

18.1

General

18.10

Are the GMP principles of the other sections applied to?

               

18.13

What measures are taken for Biotech processes to ensure that raw materials (media, buffer components) are no source of microbiological contamination?

If applicable, is the bioburden, viral contamination and/or endotoxins controlled at appropriate stages of production?

               

18.14

Which controls are performed for steps prior to this guide, e.g. cell banking?

               

18.15

Which equipment and environmental controls are used to minimize contamination?

Are adequate acceptance criteria for quality and frequency's for monitoring set at the various steps of production?

               

18.16

Are the following controls taken into account:

  • maintenance of WCB
  • proper inoculation and expansion of the culture
  • control of critical operating parameters
  • monitoring the process for cell growth, viability and productivity
  • harvesting and purification procedures
  • monitoring of bioburden
  • viral safety concerns (ICH Q5a)
               

18.17

Is removal of media components, host cell proteins process and product related impurities and contamination demonstrated?

               

18.2

Cell Bank Maintenance and Record Keeping

18.20

Is the access to the cell banks limited to authorized personnel?

               

18.21

Do the storage conditions of the cell banks ensure that viability is maintained and contamination prevented?

               

18.22

Are records of the use of vials from the cell banks and storage conditions maintained?

               

18.23

Are cell banks monitored periodically for suitability for use?

               

18.24

For handling of cell banks check ICH Q5a

               

18.3

Cell Culture / Fermentation

18.30

Are closed and contained systems used when aseptic additions are needed?

If open vessels are used which measures and controls are used to minimise risk of contamination?

               

18.31

If use of open equipment can cause microbial contamination which environmental controls are done?

               

18.32

Is personnel handling the cultures appropriately gowned?

               

18.33

Are critical operating parameters including cell growth, viability and productivity monitored?

               

18.34

Is cell culture equipment cleaned after use?

               

18.35

Is culture media sterilized before use?

               

18.36

Are procedures in place to detect contamination and to determine necessary action?

Is the impact of the contamination evaluated?

               

18.37

Are records of contamination maintained?

               

18.38

Is multi-purpose equipment sufficiently tested to minimize contamination?

               

18.4

Harvesting, Isolation and Purification

18.40

Are harvesting steps performed in equipment and areas designed to minimize risk of contamination?

               

18.41

Can the harvesting and purification procedures remove or inactivate organisms in a way that the API is recovered with consistent quality?

               

18.42

Is all equipment cleaned properly after use?

               

18.43

Is purification performed under controlled environmental conditions if open systems are used?

               

18.44

If equipment is used for multiple products additional controls and testing is to be conducted.

               

18.5

Viral Removal / Inactivation steps

18.50

See ICH Q5a

               

18.51

Are viral removal and inactivation steps performed within their validated parameters?

               

18.52

Are appropriate precautions been taken to prevent viral contamination from pre-viral to post-viral removal/inactivation?

Do open processing take place in areas that are separate from other processing activities and have separate air handling units?

               

18.53

If equipment is used for different purification steps is it appropriately cleaned?

               

19

APIs for Use in Clinical Trials

19.1

General

19.11

Are the controls used consistent with the stage of development?

Are procedures flexible enough to provide changes as knowledge of the process increases?

If APIs are intended to be used for clinical trials, is the API produced in suitable facilities with appropriate controls to ensure the quality?

               

19.2

Quality

19.20

Is there an appropriate GMP concept in place?

Is a procedure for approval of batches in place?

               

19.21

Is there an independent QU in place?

               

19.23

Are raw materials, packaging materials IM and APIs tested?

               

19.24

Are process and quality problems evaluated?

               

19.25

Does the labeling of APIs for use in clinical trials indicate the material as being for investigational use?

               

19.3

Equipment and Facilities

19.30

Is ensured that during all phases of clinical development the equipment is qualified, instruments calibrated, clean and suitable for it intended use?

               

19.31

Are materials handled in a way to minimize contamination?

               

19.4

Control of Raw Materials

19.40

Are raw materials evaluated or tested?

               

19.5

Production

19.50

Is the production of APIs for use in clinical trials documented appropriately according to the stage of production?

Do these documents include information about materials used, equipment, processing and scientific observations?

               

19.6

Validation

19.60

Is the equipment used qualified and the instruments calibrated?

(Validation is not expected!)

               

19.61

If batches are produced for commercial use, then section 12 is to be applied.

               

19.7

Changes

19.70

Are all changes adequately recorded?

               

19.8

Laboratory Controls

19.80

Are analytical methods used scientifically sound? (No analytical validation required)

               

19.81

Is a system to retain reserve samples in place?

               

19.9

Documentation

19.90

Is a system in place to document the information gained during the development?

               

19.91

Is the development of analytical methods appropriately documented?

               

19.92

Is ensured that all information is retained for an appropriate length of time?

               

20

Quality Management System

The following chapter is not part of ICH Q7a and thus the numbering cannot be referenced to ICH Q7a. The Quality Managment System section at this questionnaire refelcts ICH Q10 on the basis of ISO 9000: 2000.

20.1

Quality Issues

20.10

Has the organization established, documented, implemented and maintained a quality management system in accordance with the requirements of ISO 9000:2000?

               

20.11

Is the effectiveness of the quality management system continually improved?

               

20.12

Does the organisation manage these processes in accordance with the requirements of ISO 9000:2000?

               

20.13

Does the quality management system documentation include:

  • Documented statement of a quality policy and quality objectives
  • Quality Manual
  • Documented procedures required by ISO 9000:2000
  • Documents needed by the organization to ensure the effective planning, operation and control of its processes
  • Records required by ISO 9000:2000
               

20.14

Are documents required for the quality management system controlled?

               

20.15

Has a documented procedure been established identifying the following controls needed:

  • Approval of documents for adequacy prior to issue
  • Review, update as necessary and re-approval of documents
  • Ensure that changes and the current revision status of documents are identified
  • Ensure that relevant versions of applicable documents are available at points of use
  • Ensure that documents remain legible and readily identifiable
  • Ensure that documents of external origin are identified and their distribution controlled
  • Preventing the unintended use of obsolete documents, and to apply suitable identification to them if they are retained
               

20.16

Have records been established and maintained to provide evidence of conformity to requirements and of the effective operation of the quality management system?

               

20.17

Has a documented procedure been established to define the following controls needed

  • Identification
  • Storage
  • Retrieval
  • Protection
  • Retention time
  • Disposition
               

20.2

Management Responsibility

20.20

Has top management provided evidence of its commitment to the development and implementation of the quality management system and for the continual improvement of its effectiveness?

               

20.21

Has top management ensured that customer requirements are determined and met with the aim of enhancing customer satisfaction?

               

20.22

Has top management established a quality policy?

               

20.23

Has top management ensured that quality objectives are established at relevant functions and levels within the organization?

               

20.24

Has top management ensured that responsibilities, authorities are defined and communicated within the organization?

               

20.25

Has top management appointed member(s) of management who have responsibility and authority for quality management?

               

20.26

Has top management ensured that appropriate communication processes have been established within the organization?

               

20.27

Does the top management review the quality management system, at planned intervals, to ensure its continuing suitability, adequacy and effectiveness?

               

20.28

Do the outputs from the management review include the decisions and actions?

               

20.3

Resource Management

20.30

Have the resources for quality management been determined and provided?

               

20.31

Is competency for personnel who perform work affecting product quality based on appropriate education, training, skills, and experience?

               

20.32

Has the organization determined the necessary competency for personnel performing work affecting product quality?

               

20.33

Does the organization identify, provide, and maintain the facilities including: Buildings, Workspace and associated utilities, Process Equipment, hardware and software, Supporting services?

               

20.34

Has the environment needed to achieve conformity of product requirements been determined and managed?

               

20.4

Product Realisation

20.400

Is planning of the organization's product realization consistent with the requirements of the other processes of the quality management system?

               

20.401

Has the organization determined requirements specified by the customer, including the requirements for delivery and post-delivery activities?

               

20.402

Prior to the commitment to the customer (e.g. submission of tenders, acceptance of contracts or orders or acceptance of change orders) are requirements adequately reviewed?

               

20.403

Has the organization determined and implemented effective arrangements for communicating with customers?

               

20.404

Are inputs relating to product requirements defined, documented and maintained as a record?

               

20.405

Are outputs of the design and development provided in a form that enables verification against the design and development inputs?

               

20.406

Are systematic reviews performed in accordance with planned arrangements at suitable stages of the design and development?

               

20.407

Is design and development verification performed in accordance with planned arrangements to ensure that the design outputs have met the design and development input requirements?

               

20.408

Is design and development validation performed in accordance with planned arrangements?

               

20.409

Are design and/or development changes identified and recorded?

               

20.410

Are the purchasing processes controlled to ensure purchased product (or service) conforms to requirements?

               

20.411

Does purchasing information describe the product to be purchased?

               

20.412

Have the inspection or other activities necessary for ensuring that purchased product meets specified purchase requirements been established and implemented?

               

20.413

Are the production and service provision planned and carried out under controlled conditions?

               

20.414

Have processes where deficiencies may become apparent only after the product is in use or the service has been delivered been validated?

               

20.415

Is the product identified by suitable means throughout product realization?

               

20.416

Does the organization exercise care with customer property while it is under the organization's control or being used by the organization?

               

20.417

Is conformity of product preserved during internal processing and delivery to the intended destination?

               

20.418

Has the organization determined the monitoring and measurement to be undertaken and the monitoring and measurement devices needed to provide evidence of conformity of product to determined requirements?

               

20.5

Measurement, Analysis and Improvement

20.50

Have the monitoring, measurement, analysis and improvement processes been planned, and implemented?

               

20.51

Is information relating to customer perception monitored by the organization as to whether customer requirements have been met?

               

20.52

Are internal audits conducted at planned intervals to determine whether the quality management system:

  • Conforms to planned arrangements, requirements of ISO 9001 and the quality management system
  • Is effectively implemented and maintained
               

20.53

Are suitable methods applied for monitoring and where applicable, measurement of the quality management system processes necessary to meet customer requirements?

               

20.54

Are product characteristics monitored and measured to verify that product requirements are met?

               

20.55

Is nonconforming product identified and controlled to prevent unintended use or delivery?

               

20.56

Is appropriate data determined, collected and analysed to demonstrate the suitability and effectiveness of the quality management system and to evaluate where continual improvement of the effectiveness of the quality management system can be made?

               

20.57

Does the organization continually improve the effectiveness of the quality management system?

               

20.58

Are corrective actions taken to eliminate the cause of nonconformities and to prevent recurrence?

               

20.59

Has the organization determined actions to eliminate the causes of potential nonconformities in order to prevent occurrence?

               

SOP, Policy, Guideline, Operating Instruction, memo, notes (personal), Quality Manual, Description of
Procedure

tbi = to be implemented

18.I.3.6 Change of supplier

All the manufacturer specifications and definitions made in an application file for marketing authorisation and its subsequent labour-intensive formulation following the implementation of validation batches cannot prevent deviations suddenly emerging in practise.

This is inevitable if the supplier is suddenly unable to deliver (whether due to foreseen or unforeseen circumstances) or another manufacturer offers the same quality for more favourable prices.

The globalisation of the active pharmaceutical ingredient and excipient manufacturing markets reflects the situation for pharmaceutical businesses. If an amalgamation of manufacturers takes place, this often means that specific starting materials will no longer be manufactured and delivered. In practise, this is frequently communicated by a brief notice in writing from the manufacturer to the effect that the manufacture of a given starting material will be discontinued from a specific point in time. From this point onwards, a pharmaceutical manufacturer has no alternative but to take action.

As already explained in some depth, a change over to any desired manufacturer is not possible and compliance with the requirements of the application file still remains the number one priority.

The first three deliveries received from the new supplier must be subjected to a comprehensive analysis. As this is a new manufacturer, a revalidation must be carried out for the relevant preparation(s) which means that the first three batches must be designated as validation batches and evaluated. Once the validation results have been evaluated and analysis of the goods receipts is complete, the supplier can be approved. The supplier should then be audited once more as this means that a full analysis during routine manufacturing will no longer be required and the manufacturer's certificate of analysis can be accepted. Finally, the contract giver confirms the changeover to the new supplier in writing.

18.I.3.7 Suppliers of packaging materials

The procedure involved when changing manufacturers in the area of active pharmaceutical ingredients and excipients has been dealt with at some length in this chapter. It should however also be noted that the primary packaging material - in this case PCC/PCDC foils and aluminium foils - are also described in the application file for marketing authorisation in which the corresponding manufacturer is also specified. For this reason, procurement of primary packaging materials by purchasing departments from any desired source is not permitted and result in the product being recalled or a non-marketable product. If a substantiated change of manufacturer has taken place, a revalidation must be carried out in every case that must ensure subsequent linking to a stability programme. This stability programme must provide conclusive evidence that the stability of the dosage form in the new packaging can be guaranteed. 

Figure 18.I-6 Approval of a new manufacturer

Approval of a new manufacturer

  • Full analysis of the first three deliveries received
  • Three batches designated as validation batches
  • Supplier audit for acceptance of certificate of analysis

Summary

Starting materials can either be obtained directly from the manufacturer or from a trader. In each case, the manufacturer should be known as this aspect is the focus of supplier qualification activities.

If a specific manufacturer has been named in the application file for marketing authorisation, no other manufacturer may be used without changing the application file for marketing authorisation accordingly. However, the quality is not generally determined by specifying the manufacturer rather by referring to a pharmacopoeial monograph.

When changing supplier, a revalidation must be carried out for 3 production batches.

In the case of contract manufacture, a change of a supplier requires the written consent of the contract giver to ensure conformity with the application file for marketing authorisation.



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