WHO Basic Training Modules on Good Manufacturing Practices (GMP) - GMP

Inspection Process: Module 2 (Part 04): Types of GMP Inspection

World Health Organization

GMP Inspection Process

Types of GMP Inspection

This module deals with the different types of drug regulatory authority inspection. It is
a quarter-day session, split into activities as follows:

Presentation 30 minutes

Group 45-60
discussions minutes

Plenary 30-45
minutes
 Types of GMP Inspection

Objectives

1. To review the different types of inspection

2. To examine when each is appropriate

3. To discuss inspections in your country

There are three main objectives of this session:

Firstly we will review the different types of inspection that are carried out by
regulatory authorities.

Secondly, we will look at the situations when each of these types of inspection is
most appropriate.

Finally, we will discuss the drug regulatory authority inspections in your country
and review any specific issues relating to them.
 Types of GMP Inspection

Objective of the inspection

Routine inspection

Concise inspection

Follow-up inspection

Special inspection

Quality systems review

The objective of the inspection influences the inspectors planning, organization,

method of work, and the format of the report that will be written after the inspection.

Different types of inspections can be performed depending on the objective of the

inspection.

Types of inspections identified in the WHO text, include:

Routine inspection

Concise inspection

Follow-up inspection

Special inspection, and

Quality systems review.

Lets look at each of these types of inspections in more detail.

 Types of GMP Inspection

Routine Inspection

Full inspection of all components of GMP

Newly established manufacturer

Renewal of a license

Changes:

- new product or product lines

- modifications to manufacturing methods

- key personnel, premises or equipment

History of non-compliance with GMP

Not inspected in the last 3-5 years

A routine inspection is a full review of all aspects and components of GMP within a
facility. The inspector should also be aware of the licensing provision. Routine
inspections may be announced or unannounced, depending on the history of the
company, previous inspections and the policy of the country.

It is appropriate to perform a routine inspection under the following circumstances:

When there is an application for a new manufacturing license for a newly

established manufacturer

When a manufacturing license is due for renewal.

If there have been significant changes such as new products or new product
lines, modification to manufacturing methods or processes, or changes in key
personnel, premises, and or equipment.

If the company has an history of non-compliance with GMP.

If an inspection has not been carried out within the past 3-5 years.
 Types of GMP Inspection

Concise Inspection

Consistent record of compliance with GMP

Focus on limited number of GMP requirements

- selected as indicators

Identify significant changes

Indicate attitude towards GMP

Non-compliance

- should trigger comprehensive inspection

A concise inspection is the evaluation of limited aspects relating to GMP compliance

within a facility. (It is known as an abbreviated inspection in some countries.) A limited
number of GMP requirements are selected by the inspector to serve as indicators of
overall GMP compliance by the manufacturer. The inspector also has to identify and
evaluate any significant changes that could have been introduced by the manufacturer
since the last inspection.

Collectively, the selected indicators and identified changes indicate the manufacturers
attitude towards GMP.

Depending on national practice, a company would normally not be warned in advance

about a concise inspection.

A concise inspection is applicable under the following circumstances:

Where a manufacturer has a consistent record of GMP compliance through

routine inspections in the past.

Where a sample of aspects can be taken as a good indication of the overall level
of GMP compliance.

However, if the concise inspection uncovers evidence that the level of GMP compliance
has fallen, a more comprehensive or full GMP inspection should then be performed
soon after the concise inspection.
 Types of GMP Inspection

Follow-up Inspection

Reassessment or re-inspection

Monitor result of corrective actions

6 weeks to 6 months after initial inspection

- nature of defects

- work undertaken

Specific GMP requirements

- not observed

- not adequately implemented

A follow-up inspection is also referred to as a re-inspection or a re-assessment of the

manufacturer.

A follow-up inspection is performed specifically to monitor the result of corrective

actions of the manufacturer following a previous inspection. The manufacturer would
not necessarily know in advance about the follow-up inspection.

Depending on the nature of the defects and the work required, the follow-up inspection
could be carried out between 6 weeks and 6 months after the original inspection had
taken place.

The inspection is limited to specific GMP requirements that have not been observed or
that have been inadequately implemented by the manufacturer.
 Types of GMP Inspection

Special Inspection

Spot check focusing on

- one product, a group of related products

- specific operations, e.g. mixing, labelling

Complaints or recalls

Adverse drug reactions

Marketing approval or export certificate

Information or investigation

- specific information

- advice on regulatory requirements

There are a number of circumstances in which special visits or inspections may be

necessary. A special inspection is undertaken to do spot checks. Spot checks could
focus on one product, a group of related products, or specific operations e.g. mixing, or
labeling.

The manufacturer may or may not be aware in advance of the inspection, depending
on the reason for it.

If there have been complaints about a specific product that suggest there may be
defects, then a special inspection could be performed to investigate the quality defects
of the product. It is unlikely that the company would be warned in advance in this case.

If there has been a product recall, this can also trigger an inspection, as would adverse
drug reactions.

In the above cases, the inspection would focus on the specific product or aspect of
production that is suspect.

An application for a marketing authorization or an export certificate may also trigger

such an inspection.

A special inspection could also be performed to gather specific information, or to

investigate specific operations of the manufacturer. In some cases, this opportunity is
used to advise the manufacturer on specific regulatory requirements.
(The trainer should provide specific examples of special inspections e.g. after
receiving a complaint, etc)
 Types of GMP Inspection

Quality Systems Review

Assess the quality assurance (QA) system

Description of the QA system (e.g. manual)

Policy and standards to be observed

Management structure

- implementation

Procedures

- quality standards set for products

- correctly defined manufacturing processes

- records kept

- QC and QA functions are performed

The purpose of a quality systems review is to review the manufacturers quality system
and to describe whether that has been shown to operate satisfactorily.

The quality systems manual is a document describing the quality systems and the
standards to be observed. It also includes the entire operational process, and the
quality management policy and quality assurance approach of the manufacturer.

The manual reflects the process of implementation of the quality policy, keeping of
records, quality control and other quality assurance activities.

This type of review is similar to that which is carried out when a manufacturer is
applying for accreditation, e.g. international standards (ISO 9000).
 Types of GMP Inspection

Frequency of Inspections

Depends on type of inspection

Inspectorate resources (e.g. workload, number of inspectors)

New facilities - before licensed

All companies - regular schedule ideally annual

Large companies

- several visits over a period, e.g. 5 years

- validity of manufacturing license or GMP certificate

Although there are ideal timetables that should be achieved for inspections, in practice
there are a number of factors that influence the frequency of inspections. These are:

- The type of inspection being undertaken.

- The number of inspectors available and their workload.

- The number of companies to be inspected.

An ideal timetable would be an annual inspection of each manufacturer.

The size of the manufacturing site will also influence the frequency of inspection. A
large company with a wide range of products and several major departments may be
inspected in a number of stages over a time period taking cognisance of the period of
validity of the manufacturing license or GMP certificate.
 Types of GMP Inspection

Duration of Inspections

Depends on type of inspection

Inspectorate resources (e.g. workload, number of inspectors)

Size of the company

Purpose of the visit

Days to weeks

Number of inspectors

- including specialist support

The length of an inspection is determined by a number of factors, including the type of

inspection to be performed, the number of inspectors, the size of the company and the
purpose of the inspection or visit.

An inspection can be performed over a period of a few days to several weeks.

The time taken will also depend on the size of the inspection team. One or more
inspectors can perform the inspection and the inspector(s) may request a specialist to
accompany them during the inspection. Depending upon the area or specific aspects to
be inspected, a specialist could provide specialist support to the inspection team. This
can be very helpful in certain cases, e.g. the manufacture of biologicals.
 Types of GMP Inspection

Announced and unannounced inspections

Depends on type of inspection

Announced

- comprehensive inspection

Unannounced

- routine inspection (depending on country policy)

- concise inspection

- follow-up inspection

- special inspection

Inspectors have to decide whether the inspection to be performed, will be announced

or unannounced.

This is dependent on the type of inspection, and the policy of the regulatory authority.

A comprehensive inspection can be announced or unannounced.

Concise inspections, follow-up inspections and special inspections are normally

unannounced.
 Types of GMP Inspection

Regulatory Actions

Based on national regulations

Correction of unsatisfactory situations

Closing down of a factory

Withholding of authorizations

Product recall

The inspectorate of a regulatory authority normally has certain powers to allow for
regulatory actions. The regulatory actions are based on and controlled by national
legislation

The purpose of the regulatory action is to ensure that unsatisfactory situations in

manufacturing sites are corrected in the interest of the public by ensuring that safe,
effective, quality pharmaceutical products are manufactured.

These powers or regulatory actions often include:

- Closure of a facility (only used in an extreme case where a health hazard is perceived)

- Suspension or revoking of the marketing authorisation.

- Delay in approval of licenses or marketing authorisations.

- Delay in issue of a GMP certificate.

- Initiation of a product recall.

 Types of GMP Inspection

Group Session

The inspectorate received a complaint that an injectable product (water for

injection (WFI), 10ml ampoule) is possibly contaminated with microorganisms. You have
to organize an inspection of the company in question

What type of inspection would be performed?

Will the inspection be announced or unannounced?

Who will be part of the inspection team?

What will you consider in preparation for the inspection?

We will now move into syndicate discussion.

In your groups, discuss the situation in which 5 deaths are known to have occurred due
to pseudomonas-contaminated WFI.

Who would you take with you?

What objectives would you have?

Would you announce your visit?

What actions would you take?

 Types of GMP Inspection

Possible Issues

Purpose of the inspection

Notification (or not) of the company in advance

Make-up of the team

Programme for the inspection

Sterility test, leak test and visual inspection

Validation and qualification

Documentation review

The organization of the inspection will depend on the purpose - initial, routine, follow-
up, concise etc.

Whether the company is informed of the intention to inspect will depend on the
purpose of the inspection and also on common practice within the country.

Depending on the nature of the inspection, there will be times when the inspection
team will not have all the necessary expertise and will need to bring in a specialist. For
example, in the pseudomonas question, it might be necessary to involve a
microbiologist to review sterile procedure or an engineer to review the design of the
facility.

Although there will be a programme developed before the inspection begins, it will
often be necessary to revise that programme in the light of initial findings. Inspectors
should be flexible enough to adapt the programme if necessary, but should also ensure
that they are not deflected from their objectives by the company being inspected.