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Self-inspection

 

Here you will find answers to the following questions:

  • What is the purpose and objective of self-inspection?
  • What is the procedure for a self-inspection?
  • How can self-inspections be organised?
  • How should self-inspections be recorded?
  • How can deviations observed be classified and dealt with?
  • How is it advisable and effective to use self-inspections?

18.E.1 Purpose of self-inspection

Article 14 of the EU GMP Directive 91/356/EEC and chapter 9 of the EU GMP Guideline indicate that self-inspection should be considered as part of the quality assurance system. The manufacturer should monitor itself at regular intervals to check whether the rules of good manufacturing practice are being applied and adhered to. This applies to all practical conditions on-site and the corresponding documentation. It should also make proposals for remedial actions, in the event that they are required.

18.E.2 Carrying out the self-inspection

According to chapter 9.1 of the EU GMP Guideline, self-inspections should examine personnel matters, premises, equipment, documentation, production, quality control,distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self-inspection.

Self-inspections should be pre-arranged and laid down in the form of an inspection programme. In preparation, the rough process should be defined in advance. This means that specific key aspects are detailed. (see chapter 18.D Organisation of inspections) Ideally, checklists should be compiled (questionnaires) so the inspectors can ask each question successively. The advantage of this is that follow-up inspections carried out by other inspection teams will be more or less comparable.

Figure 18.E-1 Process for a self-inspection

Process for a self-inspection

Planning phase

  • Definition of the area to be inspected
  • Appointment of the inspection team
  • Definition of the topics or the key aspects of topics
  • Compilation of a checklist
  • Information on the department concerned

Implementation phase

  • Inspection Observations, talks
  • Status protocols (form, checklist)
  • First comments during talks

Wrap-up phase

  • Compilation of a report containing evaluations and recommendations
  • Comments from production management (and company management)

Follow-up phase

  • Follow up of actions relating to the deficiencies mentioned
  • Specification of follow-up inspections

  

Figure 18.E-2 Self-inspection procedure

Contents of the instruction on the procedure for self-inspection

  • Timing of inspections
  • Specification of inspection contents
  • Definition of responsibilities
  • Preparation for the inspection
  • Inspectors' qualifications
  • Formation of inspection teams
  • Recording the self-inspection (format and content)
  • Classification of deficiencies
  • Definition of remedial actions
  • Control of remedial action

The EU GMP Guideline does not mention the frequency of self-inspections. It is, however, advisable to chose shorter inspection intervals initially (every three months). Later, when sufficient experience is available, the interval can be extended. Naturally, critical areas (e.g. operations with the exposed product) and procedures (e.g. those with narrow acceptance criteria) should be inspected more often than areas and procedures that are easily controlled. Negative developments observed during trend analysis of monitoring, for example, should be counteracted by investigative measures in as early a phase as possible. The setting of priorities must also be transparent to the supervisory authorities. The self-inspection procedure should be detailed in an instruction and take into consideration the points outlined in figure 18.E-2.

The reason for a self-inspection may be routine scheduling or there may be a precise cause, e.g. OOS results caused by manufacturing errors. In the event of a deviation, it is advisable to take this as the "reason" for analysing procedures and processes. Self-inspections are often used to prepare for inspection by the authorities.

Designated competent person(s) from the company should be assigned to conduct the self-inspection. They should be independent of the subject of the inspection. The EU GMP Guideline explicitly states that it is useful for external experts, e.g. staff from other facilities or consultants, to participate. It is obvious that if the inspectors are independent, objectivity and the significance of inspections is increased. It is, however, not compulsory to call on external experts. Generally, companies create inspection teams using representatives from different areas (e.g. manufacturing, quality control, engineering, development, microbiology, warehouse) so that there is a broad base of knowledge and experience for carrying out the inspection. The WHO GMP Guideline talks about "self-inspection teams". From the point of view of the practical aspect of carrying out the inspection, it is advisable to form groups of 2-4 persons.

Although it is not explicitly required, organising and carrying out self-inspections can be considered as an important task for quality assurance. The extent to which these inspections are only carried out by staff from this area depends on the size and structure of the quality assurance division. In smaller and medium-sized companies it is advisable to form teams of inspectors recruited from quality assurance, production management, quality control management and individual departments.

18.E.3 Self-inspection documentation

Self-inspection records must be made and stored. The EU GMP Guideline requires that: "All self-inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. [...]" (9.3 EU GMP Guideline) figure 18.E-3 shows an example form for documenting a self-inspection. It is unimportant whether the company uses checklists or prefers a narrative form for the documentation.

Figure 18.E-3 Record of self-inspection  

Company logo

Document no.

Page no.

Record of self-inspection

Cross-reference to relevant procedure(s):

Inspection date/time: ##.##.####

Subject of the inspection:

e.g. system, product, procedure, area or cross reference to inspection programme

Reason for the inspection:

e.g. routine inspection, control of remedial action, preparation for inspection by the authorities or supplier audit

Last inspected on:

##.##.####

see record dated:

##.##.####

Inspection team:

Names of participating inspectors

Responsible persons participating from the inspected areas:

Foreman, etc.

Observations:

short description of the current status, significant changes in comparison to the last inspection, documents seen

Deficiencies observed including classification:

Exact description of the error and deficiency, stating the cause where possible. Continuous numbering to simplify processing.

Measures for remedying deficiencies:

Person responsible for remedying deficiencies:

Deadlines for remedying deficiencies and report:

##.##.####

Date of possible follow-up inspection:

##.##.####

Data on the type and extent of successful remedial action:

Confirmation by responsible person(s) from the inspected areas:

e.g. signature of the head of production

Record date:

Signature of the recording person:

If a checklist is being used, simply attach the documentation about the observations to it. figure 18.E-4 shows how the documentation area in production can be recorded using a checklist.

Figure 18.E-4 Example of a checklist for self-inspection  

Link to 18.E-4.jpg

Link to 18.E-4afp.jpg

Link to 18.E-4afq.jpg

Link to 18.E-4afr.jpg

As well as recording the status of the production area, the final report should include evaluations and proposals for corrective measures in the event of deficiencies, where necessary. The report containing the analysis of the current status forms a basis for decisions made by production and company management regarding the elimination of deficiencies. The record history allows its development to be traced in conformity with GMP.

It is not usual for authorities to have access to the self-inspection records. The manufacturer notes the deficiencies observed during its inspection in the records. If the records were subject to control by the authorities, the result could be that the manufacturer no longer established and documented deficiencies with the same care. If the supervisory authorities inquire how the manufacturer fulfils its obligations regarding self-inspection, the process instruction according to figure 18.E-2 and the inspection programme should be produced.

18.E.4 Errors and remedial action

It is necessary to differentiate the treatment of errors revealed during self-inspection. The term error should be viewed as neutral and means non-fulfilment of a requirement according to DIN 55350. However, this non-fulfilment of a requirement does not always have to have an effect on product quality or process reliability in all cases. Such instances include slight deviations from the norm of vial glass thickness or differences in the shade of labels.

An error is problematic if it affects the safety of a product, or if it increases or reduces the value or fitness of the product for use. Errors can also represent a breach of GMP principles or legal medicinal product provisions. In each of these cases, there is a deficiency.

It is advisable to use a uniform evaluation basis for grading. The evaluation of the qualitative rating of deficiencies is determined by the production-specific conditions and the in-house GMP standard. Graded error classification (cf. examples in figure 18.E-5 and figure 18.E-6) has the advantage that measures can be determined according to their type and extent, depending on the gravity of the error. Error statistics can also be recorded according to quality and quantity of errors.

Figure 18.E-5 Example 1 for an error classification  

Error class

Example

Critical error: critical

  • Affects product quality, efficacy or safety

or

  • Serious breach of GMP principles

or

  • Regulatory offences, elements of an offence
  • A rejected starting material has entered the production process
  • A batch has been released although quality control had not been completed
  • A manufacturing procedure was changed without revalidation and authorisation
  • Mix up of porosity during sterile filtration
  • Manufacture of a product without a manufacturing authorisation

Major errors: major

  • Major breach of GMP principles

or

  • Other breach of legal drug product provisions
  • A floor balance is outside the calibration interval
  • There is no sanitation programme for an instrument washing room
  • The cleaning personnel have not been adequately trained
  • Staff enter the production area without working clothing

Minor error: minor

  • Other breach of GMP principles

or

  • Formal deviations from on the process instructions form
  • Correction of a written error without date and initials
  • Floor drains were not cleaned at the specified intervals
  • Staff use incorrect forms

Figure 18.E-6 Example 2 for an error classification

Evaluation

Criteria

Measures

Unacceptable

gross breaches with respect to prevention of cross-contamination (e.g. inadequate cleaning)

take measures immediately (while the self-inspection is ongoing)

Critical deficiencies

high level of risk (e.g. balances not calibrated)

take measures immediately after the inspection is concluded

Gross deficiencies

medium level of risk (e.g. labelling of containers incomplete but clear)

take measures in the short and medium term

Slight deficiencies

low level of risk (e.g. SOP exists, but invalid and being revised)

take measures in the medium and long term

It is sometimes logical to set time limits for the deficiencies to be removed. However, this depends on the competencies and position of quality assurance within the company. Here it is the duty of the management board to ensure adequate support in line with the quality assurance policy.

The causes of failure must be determined to enable practical remedial actions to be specified and to prevent future errors. In the case of product-related errors, this can be done according to an established OOS procedure (see chapter chapter 14.H Out-of-specification results). For other sources of error, there should also be a systematic process if possible, for instance fault tree analysis, which is used to identify the causes.

18.E.5 Follow-up activities

The self-inspection carried out only has any significance if the observations made and the deficiencies are followed-up. The recommendations in the inspection report and comments on them by production management form the basis for activities on the part of production within a determined time limit. It must be reviewed whether implementation would be an improvement . Thus, a complete follow-up inspection may be carried out or it may be limited to certain subareas (see figure 18.E-7).

In order to provide an overview, it has proved useful to summarise the inspection report with the corresponding activities and dates in tabular form. This is then made available to the areas concerned. This makes it easier to trace those activities which are already completed or agreed on, and those which are still unsettled.

Figure 18.E-7 Follow-up activities

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Summary

Every pharmaceutical manufacturer has an obligation to carry out self-inspection. He should plan, carry out and document self-inspections according to established written procedures. Deficiencies observed should be evaluated and remedied according to a uniform procedure.

With careful planning and the aid of checklists, self-inspections can be used logically and effectively to check GMP status.



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