Self-Inspection

It is a important tool to challenge your Quality System. The US and the EU have different regulations regarding internal audit/self-inspection. If you destroy your internal audit reports after resolving the identified issue, you would be still compliant with US regulations, but not with EU regulations. To further elaborate, it’s important to realize that the US cGMP regulations (21 Code of Federal Regulations [CFR] Parts 210 and 211) do not describe specifically a requirement to conduct or keep records of an internal quality assurance audit which is not the case with EU GMP. So in this article we discuss about Self Inspection considering EU GMP.

Article 14 of the EU GMP Directive 91/356/EEC and Chapter 9: Packaging and Identification Labelling of APIs and Intermediates of the EU GMP Guideline indicate that self-inspection should be considered part of the quality assurance system. The manufacturer should monitor itself at regular intervals to check whether staff members are applying and adhering to the rules of good manufacturing practice. This applies to all practical conditions on-site and the corresponding documentation. The company should also make proposals for remedial actions if necessary. In the U.S., self-inspections or self-audits have been considered a part of a sound quality system.

Carrying Out the Self-Inspection

According to Chapter 9.1: General of the EU GMP Guideline, self-inspections should examine Personnel matters, premises, equipment, documentation, production, quality control, and distribution of the medicinal or drug 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 program. In preparation, the manufacturer should define the rough process in advance. This means that specific key aspects are detailed during self inspection. Ideally, manufacturers should compile checklists (questionnaires) so the inspectors can ask each question successively. The advantage of this format is that follow-up inspections carried out by other inspection teams will be more or less comparable.

Process for a Self-Inspection

Step1: 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

Step 2: Implementation Phase

 ? Inspection observations, talks

? Status protocols (form, checklist)

? First comments during talks

Step 3:Wrap-up Phase

? Compilation of a report containing evaluations and recommendations

? Comments from production management (and company management)

Step 4: Follow-up Phase

? Follow-up of actions relating to the deficiencies mentioned

? Specification of follow-up inspections

The EU GMP Guideline does not mention the frequency of self-inspections. Shorter inspection intervals are best initially (every three months). Later, when sufficient experience is available, companies can extend the interval (half yearly). Naturally, companies should inspect critical areas (that is, operations with the exposed product) and procedures (such as those with narrow acceptance criteria) more often than areas and procedures that are easily controlled. Counteract negative developments observed during trend analysis of monitoring, for example, by investigative measures in as early a phase as possible. The setting of priorities must also be transparent to the supervisory authorities

Detail the self-inspection procedure in an instruction and take into consideration the points outlined below. The reason for a self-inspection may be routine scheduling or there may be a precise cause, such as out-of-specification (OOS) results caused by manufacturing errors. In the event of a deviation, take this as the “reason” for analyzing procedures and processes. Self-inspections are often used to prepare for an upcoming inspection by the authorities. Assign designated competent people from the company to conduct the self-inspection (Cross Functional Team). These employees should be independent of the subject of the inspection. The EU GMP Guideline explicitly states that it is useful for external experts, such as staff from other facilities or consultants, to participate. Manufacturers will increase the likelihood of objectivity if inspectors are independent. It is, however, not compulsory to call on external experts. Generally, companies create inspection teams using representatives from different areas (such as manufacturing, quality control, engineering, development, microbiology and warehousing) 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 two to four people.

Consider including the following in instructions for a self-inspection procedure:

? 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; and

? Control of remedial action

Although it is not explicitly required, organizing 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. Smaller and medium-sized companies should form teams of inspectors recruited from quality assurance, production management, quality control management and individual departments.

Self-Inspection Documentation

Companies must document and store self-inspection records. 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. [...]” (EU GMP Guideline, Chapter 9.3: Label Issuance and Control). Company can use audit checklist for this purpose. Any observations noted during self-inspection should consider as an Error in System/ Process.

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 or drug product provisions. In each of these cases, there is a deficiency. Use a uniform evaluation basis for grading deficiencies. The evaluation of the qualitative rating of deficiencies is determined by the production-specific conditions and the in-house GMP standard. Graded error classification as mentioned below has the advantage, because a company can determine measures according to their type and extent, depending on the gravity of the error. A company can also record error statistics according to quality and quantity of errors.

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

It’s important to determine the causes of failure in order to specify practical remedial actions and to prevent future errors. In the case of product-related errors, this can be done according to an established OOS procedure. 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.

Error Classification of Self Inspection Observation and Action:

1)     Unacceptable

Criteria: Gross breaches with respect to prevention of cross-contamination (such as inadequate cleaning)

Measure: Take measures immediately (while the self-inspection is ongoing)

2)     Critical Deficiencies

Criteria: High level of risk (such as balances not calibrated)

 Measure: Take measures immediately after the inspection is concluded

3)     Gross Deficiencies

Criteria: Medium level of risk (such as labeling of containers incomplete but clear)

Measure: Take measures in the short and medium term

4)     Slight Deficiencies

Criteria: Low level of risk (such as SOP exists, but invalid and being revised)

Measure: Take measures in the medium or long term.

Follow-up Activities

Self-inspection only has any significance if the companies follow up on deficiencies identified by the team. The recommendations in the inspection report form the basis for production activities within a determined time limit. The company must determine whether implementation of the recommendations would be an improvement. Thus, a complete follow-up inspection may be carried out or it may be limited to certain sub-areas.

In order to provide an overview, summarize the inspection report with the corresponding activities and dates in tabular form. Then make it available to staff in the areas concerned. This document makes it easier to trace those activities, which are already completed or agreed on, and those activities that are not addressed