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Organisation of inspections

 

Here you will find answers to the following questions:

  • According to which principles should inspections be planned?
  • What must be taken into consideration when preparing inspections?
  • How are inspections carried out?
  • How can complaints during inspections be classified?
  • How should inspections be documented?

1 Inspection planning

Supervisory authorities must propose yearly inspection plans to ensure that the companies subject to monitoring are inspected within the required time interval. Inspection planning is also advantageous in pharmaceutical companies; to cover the quota for the self-inspection and also to plan the inspection of contract manufacturers and suppliers.

The basis for inspection planning is a current list of all companies in accordance with figure -1.

Figure -1 List of companies to be inspected

Content of the list of companies to be inspected

  • Company name, address
  • Addresses of the plants to be inspected
  • Date of the last inspection
  • Risk classification for the plant
  • Degree of plant conformity with GMP requirements
  • Inspection priority

When establishing the inspection sequence, the significant factors are that the inspections follow a comprehensible pattern and have defined criteria. In the past, a calculation mode for determining the inspection sequence has been used in a regulatory inspectorate and has proven its worth in practice many times: Priority P of the inspection is determined from the total time T (time in years since the last inspection), risk R (classification of the plant according to type of activity), which agrees with factor 2 of the equation due to its significance, and compliance C (degree of conformity of the company with the requirements), cf. figure -2.

The time passed since the last inspection should not exceed 2 years for inspections by the authorities. Inspections of facilities which process blood and blood products must be carried out once a year. However, a longer frequency can be determined for designated companies, such as distributors without own drug product manufacturing, or wholesale dealers. The main decisive factor for determining the priority of the inspection is the type of products manufactured in the company and the activities involved, cf. figure -3. The inspector responsible then assigns a risk number to the company.

Figure -2 Calculating the inspection priority

Calculating the inspection priority

Link to 18D-1.jpg

P = priority; R = risk; T = time; C = compliance

Figure -3 Risk classification for a plant

Risk no.

Type of products

Type of activity

10

Blood products, serums, vaccines

Bulk manufacturing

Link to 18D-3.jpg

Large volume parenterals (LVP)

 

Small volume parenterals (SVP)

Primary packaging

Sterile powder, eye drops

 

Inhalants

Secondary packaging

Emulsions, creams

 

Suspensions

tablets, sugar coated tablets, capsules

Suppositories

Direct marketing

Wholesale dealers

Pharmacies

1

Solutions

OTC retail dealers

Figure -4 Compliance of a plant

Compliance no.

Degree of conformity with requirements

0

no deficiencies determined

company is uncooperative

deficiencies determined

considerable deficiencies determined

critical deficiencies determined

regulatory offence procedures determined

elements of an offence determined

Link to 18D-2.jpg

10

Experience from the previous inspection (willingness of the company to cooperate, established deficiencies, performed regulatory offence procedures) ultimately determine how soon the next inspection is necessary. Note that the company's high conformity (compliance C) with the legal requirements is showed with a low compliance number (cf. figure -4)

2 Inspection preparation

As part of the inspection preparations, the inspector compiles the information required for the company to be inspected. The company description (see chapter 15.E Site master file) is a suitable basis for learning about the company. The submitted company description is checked for accuracy (plausibility), completeness and up-to-dateness. The availability and readability of all important appendices, such as plans, flow charts, water processing and air conditioning systems is checked.

Figure -5 Preparations for an inspection

Preparation for an inspection

  • Check the company description (site master file)
  • Establish the persons responsible
  • Compare the specified manufacturing scope with the valid manufacturing authorisation
  • Determine the available production equipment, compare with the manufacturing procedure flow charts
  • Select one of several products manufactured or checked by the company for the purpose of comparing the manufacturing and test documentation with the submission file for marketing authorisation
  • Check reports from previous inspections including reports about remedying deficiencies
  • Check past complaints about drug products manufactured or distributed by the company
  • Check product recalls since the last inspection
  • Create a list of samples to be taken
  • Review GMP Guidelines and standards relevant for on-site manufacturing
  • Compile an inspection plan (inspectors, dates of inspection, work/topic apportionment)

Figure -5 gives an overview of further preparations necessary for the inspection. The measures shown can be adapted to the respective ratios and used by the companies for inspection preparations for contract manufacturers and/or suppliers.

In good time before the inspection, the company is informed of the planned chronological sequence, so that it can compile the necessary documentation and name the contact persons for the areas to be inspected.

3 Carrying out the inspections

An inspection is carried out depending greatly on the reason (e.g. routine, reinspection, pre-approval) and the type of inspection (system/product/area/procedure-oriented).

An inspection typically consists of:

  • Opening discussion
  • Site inspection, with samples being taken if necessary
  • Documentation check
  • Concluding discussion

3.1 Opening discussion

The group of inspectors (inspection team), the management (management board) as well as the company staff responsible under public law introduce themselves and discuss the organisational procedure of the inspection. The topics of the opening discussion are the points stated in figure -6. The general management should not use the opening discussion incorrectly, as a promotional event for the company. Inspectors are not generally interested in sales figures, market strategies, stock developments and similar, unless these account for particular changes to rooms and facilities. Slides are always suitable for the opening discussion if they can summarise what is said briefly and concisely and can be passed onto the inspectors as hard copies. These also aid the inspectors in writing their reports later. The presenters must be well prepared and appear well-informed and confident when introducing the company. The opening discussion of the presentation will make the first impression on the inspectors, so it might be a good idea to practise the presentation in advance in the form of a role play.

Figure -6 Topics of the opening discussion

Roles of the inspectors

Roles of the company

  • To introduce the inspectors and the apportionment of their tasks
  • To show the reason, purpose and scope of the inspection
  • To name the documents to be viewed
  • To make suggestions for the organisational procedure
  • To introduce the persons responsible at the company
  • To describe the QM/QA system
  • To demonstrate the essential changes since the last inspection
  • To report on the remedying of deficiencies from the last inspection
  • To provide escorts
  • To allocate rooms for the inspectors

3.2 Site inspection

During the site inspection, the inspector should follow the flow of components from receipt, through the corresponding manufacturing steps, the primary and secondary packaging, to storage and delivery. The quality control areas and all auxiliary areas (locks, washing rooms, changing rooms, preparation zones) and supply areas, e.g. water, steam and air, dust extraction systems and engineering services must also be taken into consideration. The scope of the site inspection is dependent on the objective and type of the inspection and can be adapted during the inspection at any time. Even the inspectors in charge of simply checking the documentation should take the time for a short company tour, as an overall impression of the company can also be important for understanding the documents.

The company should always provide an escort for accompanying the inspectors. The escort will either answer the inspector's questions himself or obtain the information required. He/she will also make note of the inspector's complaints and suggestions for improvement. As well as the escort, it has proved useful to make an additional person (runner) available to procure the information requested by the inspectors. This guarantees the smooth running of the inspection without long periods of waiting. If the requested documentation can be procured quickly, this makes a much better impression than laboriously searching for each document. There are companies that deliberately delay the procurement of documents in order to keep the number of checked documents and the potential related deficiencies to a minimum. Such behaviour is not recommended: experienced inspectors can quickly see through this tactic and will then carry out exceptionally thorough inspections. If questions are posed during the tour, these should be logged along with the answers for internal evaluation at a later stage. Each inspector usually has his/her own individual focal point, for which one can prepare in this way.

The list of questions can also be useful during company self-inspections and training measures. Internal training courses can deal with the behaviour for posed questions. You can differentiate between "closed" and "open" questions. "Closed" questions, such as "When was the last hygiene training course held by Ms. Meier?" or "According to which process instruction is this equipment maintained?" expect well formulated factual answers; there is no alternative answer. This style of question is particularly suitable for determining individual facts.

"Open" questions, such as "How is the sampling of starting materials performed at your company?" or "Describe the training received by new employees" give the respondent the option of giving a short, brief answer or a more detailed answer. Open questions should be asked where system functioning or complex procedures are concerned. The questioner must intervene and steer the respondent away if answering in too much detail or digressing from the topic. As for all communication, and especially for "open" questions, eye contact with the other party is vital: With a direct glance at the inspector, you can usually tell whether or not he is satisfied with the scope of the information provided.

In each case, the respondent should only respond with facts about the material. Assumptions or assertions such as "something might/could be like this or this" should be avoided altogether. If the respondent cannot answer a question, he/she should say this and endeavour to find someone more competent in this regard. The unanswered questions in particular should be documented and must be clarified before the end of the inspection. Discussions or even a dispute with the inspector about specialist questions are generally not recommended. They spoil the atmosphere and interrupt the inspection progression. The inspector should also refrain from giving answers in too much detail so that he/she does not unwittingly take over the role of a consultant. Complaints should be made objectively and factually without arguments.

From the company's point of view, excuses for deficiencies determined ("The head of production was ill for a long time", "We had a high turnover of personnel", "That was a year ago, we deal with everything differently now") do not generally change the fact that there is a deficiency and will rarely prevent the inspector from documenting it. Excuses could, however, be interpreted to hide malpractice or weak points or be an attempt to minimise a deficiency.

3.3 Documentation check

The documentation check is the most important part of an inspection along with the company tour. In the documentation, a company describes the target tasks (directions) and how it has implemented them (records). If something is not documented, it has not taken place; chapter 15 Documentation covers in detail the aspects in form and content of good documentation. The inspected company should, as long as it has the inspection procedure with the relevant inspection contents, compile the relevant documentation about the topics to be expected. The presented documentation must be valid and in effect. Plans, old versions or samples should only be presented if expressly desired by the inspector. If originals are presented, the inspector should be informed so that he/she does not write comments in the documentation by mistake. All official inspectors are sworn to secrecy. This also refers to all the documents involved. The official inspectors are authorised to make duplications or copies of originals and take them for further processing back to their offices. The company and the inspectors should make a list of all documents viewed and handed out, containing at least the title, document number and version. The handling of the documentation is considerably facilitated for the inspector if internally-used terms are defined in a list of synonyms. The documentation structure should be apparent from a table of contents (directory structure) and give the number keys of the documents. When presenting the documents, note that there may be cross references within the documents. The relevant papers should be provided without having to be requested. Figure -7 shows a selection of documents that can be reviewed as part of an inspection.

Figure 7 Reviewing the documentation  

Reviewing documentation validation as part of the inspection

  • Organisation chart and job descriptions
  • Change control procedures
  • Evidence of personnel medical examination
  • Evidence of training planning and execution
  • Marketing authorisation files
  • Manufacturing instructions and records
  • Test procedures and records
  • Procedural directions
  • Evidence of calibration, qualification and validation
  • Records of maintenance and repair
  • Hygiene programs and plans
  • Records of environmental monitoring
  • Batch release documentation
  • Evidence of proper storage
  • Distrubution documentation
  • Evidence for procurement of starting materials and packaging materials including their specifications
  • Procedure for deviations from specifications
  • Processing of batches that are non-compliant with the specifications (reprocessing, reworking)
  • Handling complaints
  • Records about drug product risks
  • Records about recalls
  • Contracts between the contract giver and the contract acceptor as part of contract manufacturing and testing, and contracts with other service provider companies (e.g. maintenance, software)
  • Planning and general procedure of self-inspection

3.4 Concluding discussion

The inspectors involved in the inspection generally meet before the concluding discussion to coordinate results. The leading inspector then summarises the observations and deviations determined in a meeting with the company management personnel and all inspectors. As well as demonstrating the deficiencies, they should be graded according to their severity. If an inspector has made factually incorrect assumptions when determining the deficiencies, these can be corrected by the company during the concluding discussion. It is vital in all cases that the company has understood all conclusions and deficiencies submitted. If this is not the case, any queries regarding understanding must be answered on the spot. The inspector will then establish deadlines for remedying the deficiencies determined. Where possible, the company can discuss the first suggestions for remedies with the inspectors. The inspector can arrange immediate measures in the case of severe deficiencies.

4 Evaluation and documentation

The basis of every inspection evaluation and reporting is a thorough review of the current status of the company during the inspection. Observations and conclusions should depend on facts and not on assumptions or analogies. All conclusions should therefore state the relevant concrete facts (document numbers, equipment identification numbers and similar). This requirement demands a lot from the inspector, as he/she has to lead the inspection, ask the correct questions and record the answers correctly, be able to recognise weak points and demand for further enquiry and at the same time document all results thoroughly and comprehensively.

Figure -8 shows the example of an inspection record.

Figure -8 Extract from a record made during the inspection (raw documentation)  

Inspection of the example company on 02.- 04.02.2000 Page 8

Inspector:
Escort:

Company tour on 00.00.00

Area

Observation

Evaluation

Cream manufacture Room 301

(1) Stirring vessels 1 and 2 are maintained in an established rhythm (log books 12+13).

NAD

(2) Pipes and extraction plug valves in room 14 are not indicated.

Violation of 3.42*
major
Violation of 4.7*
minor

(3) In the manufacturing record for cream XY, Ch.B. 23455, on 04.02.00, there are many changes without initials and date.

SOP 4567 suitable, NAD

(4) Personnel wearing the working clothing in accordance with SOP 4567.

 

Cream manufacture Room 301

(5) An approval sticker on container WE 456789 has been heavily soiled and is not legible.

Violation of 5.13*
minor

(6) The maximum storage time (standing time) for the bulk has not been determined.

Violation of A9.9*
major

Instrument washing room
Room 309

(1) Equipment and tools are cleaned with purified water.

NAD

(2) The containers used contain numerous blind angles and are therefore difficult to clean.

Violation of A9.2*
major

(3) The cleaning process for the containers used in penicillin production, and also used for other products, is not validated.

Violation of 5.19e*
critical

* Refer to chapter or appendix of the EU GMP Guideline

The deviations established during the inspection should be graded using the error classification system described in figure -9.

Figure 9 Classification of errors and deficiencies during inspections

Link to 18.D-9.jpg

A prerequisite for dealing with errors effectively is that the source of error (e.g. incorrectly-set equipment, deviations in procedure or errors inherent to the product) has been clearly localised. As well as the classification of the level of danger, the type of occurrence, the error causality, potential error sequences and the possibility of removing the cause of failure are also relevant for dealing with errors.

Once the inspection has been evaluated, an inspection report must be created, highlighting the scope of the inspection and all observations, errors and deficiencies. The report should include general information about the company, a description of the inspection procedure and the inspector's determinations and conclusions. It must also include a clear statement about whether the company has complied with GMP principles. If the inspector imposed conditions or deadlines, these should also be mentioned in the inspection report.

Figure -10 shows the content of an inspection report.

Figure -10 Content of an inspection report  

Content of an inspection report

1 General details

1.1 Name and address of the inspected company

1.2 Scope of manufacturing authorisation

1.3 Persons responsible

1.4 Currrent verison of site-master-file

1.5 Date of the last inspection

1.6 Essential changes since the last inspection

2 Carrying out the inspection

2.1 Cause for inspection

2.2 Inspection time period

2.3 Inspectors involved and task assignment

2.4 Company contact person

2.5 Inspection procedure, areas visited

3 Determinations and observations

3.1 Quality assurance

3.2 Personnel

3.3 Rooms and facilities

3.4 Documentation

3.5 Production

3.6 Quality control

3.7 Contract manufacture and analysis

3.8 Complaints and recalls

3.9 Self-inspections

4 Miscellaneous

4.1 Sampling data

4.2 Comments about the site-master-file

4.3 Distribution of inspection report

5 Enclosures

5.1 Plans

5.2 Copies of company documentation

6 List of errors and deficiencies

6.1 critical

6.2 major

6.3 minor

7 Recommendations and notes

7.1 Information for third parties

7.2 Details of conditions and deadlines

8 Summary and conclusions

9 Date and signature of inspectors

Summary

Inspections can be planned subject to these factors; risk, compliance and time (inspection program).

Inspections must be carried out in accordance with the written process procedures.

The company tour and documentation check are essential parts of an inspection.

Deviations should be classified and dealt with according to an error classification system.

Inspections should be recorded in the form of inspection reports.



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