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19 Tools for Quality Assurance

19.A Project management


19.A.1 Definition of project and project management

19.A.2 Project sequence


19.A.2.1 Project planning

19.A.2.2 Project controlling

19.A.2.3 Project conclusion

19.A.3 Project organisational structure


19.A.3.1 Project manager

19.A.3.2 Project team

19.A.3.3 Steering team

19.A.4 Project phases


19.A.4.1 Project start

19.A.4.2 Project implementation

19.A.4.3 Project conclusion

19.A.5 Aids

19.A.6 Multi-project organisation


19.A.6.1 Project classes

19.A.6.2 Project priorities

19.A.6.3 Management information

19.A.7 Frequently occurring problems in the context


of project management

19.B Risk analysis


19.B.1 Development of the risk analysis

19.B.2 FMEA - Failure Mode and Effects Analysis


19.B.2.1 Development
19.B.2.2 Procedure during FMEA

19.B.2.3 Failure finding

19.B.2.4 Failure evaluation

19.B.2.5 Measures to eliminate failures

19.B.3 Introduction of a GMP risk analysis according


to FMEA method
19.B.3.1 Advantages

19.B.3.2 Disadvantages

19.B.4 Company-specific risk analysis


19.B.4.1 Advantages

19.B.4.2 Disadvantages

19.B.4.3 Procedure

19.B.4.4 Example

19.B.5 Hazard Analysis of Critical Control Points


19.B.5.1 Failure finding

19.B.5.2 Evaluation of problem points

19.B.5.3 Definition of measures

19.B.5.4 Documentation

19.B.5.5 HACCP summary

19.C Change control


19.C.1 Principles of change control

19.C.2 Introduction and operation of change control programs

19.C.3 Documentation

19.A Project management


Here you will find answers to the following questions:
What are the forms of project organisation?
How are projects executed?
What aids are available?
What is the project manager's role?

There is no directive that demands that GMP projects be processed in accordance with a particular
organisational system. However, practice shows that the project management methods described below
contribute to the successful execution of even extensive projects.

19.A.1 Definition of project and project management


According to DIN standard 69 901, a project is a plan which is essentially characterised by the uniqueness of its
conditions as a whole, such as:

Objectives
Time, financial or personell constraints of the resources or other constraints
Delimitation vis--vis other plans
Project-specific organisation

Project management, then, according to DIN standard 69 901, is all the management tasks, organisations,
techniques and means used both for the processing of all projects and for the processing of an individual project.

Project management only works in the company if the following requirements are fulfilled:

The project is actually a unique plan (in accordance with DIN)


Processing of projects in the company is defined in guidelines or instruction manuals
(organisational design, procedural framework, authority to make decisions and authority to instruct,
interfaces between the line and the project)
Aids, tools and methods are available
All persons involved both in the project and in the line are trained or informed.

19.A.2 Project sequence


19.A.2.1 Project planning
The uniqueness of the project task requires that the processing at the start of the project be planned very
accurately, as no reference can be made to any routine processes, and a large number of people have to
achieve a collective target.

Therefore, the first step is to compile a rough description of the project:

Description of the objective in terms of content


Time frame
Budget and
Resource scheduling

Secondly, the interim results are defined, which are to be achieved in the course of the project (usually
designated as milestones). Work packages are derived from this (in man days (MD)).

Through this more detailed planning, the necessary resource scheduling (money, staff, equipment) can also be
planned in more detail.

In the third step, the work packages to the next milestone are planned in detail (work packages in hours). The
period to the next milestone is manageable and detailed planning of the project sequence is advisable. Planning
also always includes the question of which problems (e.g. resource conflicts) could occur and if they can be
prevented in this early project phase?

19.A.2.2 Project controlling


In the course of the project, the planning data are reviewed during execution of the project and, above all, at the
milestone deadlines. In this way, deviations can be determined in good time. Based on these, it is possible to
make controlling interventions and to establish consequences for the further project processing. Without this
review of the actual status during the project, deviations, e.g. in costs, are only ascertained if the objective in
terms of content is achieved or not achieved.

In sports competitions it goes without saying that interim results and half time results are taken into account in
order to figure out the consequences for the rest of the match or the competition.

19.A.2.3 Project conclusion


When the project is concluded, the project result is summarised and evaluated. This task is often neglected in
practice, as new tasks are already at hand. However, this means a missed opportunity to learn lessons from a
previous project and apply them to new projects.

19.A.3 Project organisational structure


A distinction is made between three types of project organisational structure for implementing project
management in the company:

Pure project management


For very large, extensive projects, a project organisation that is independent of the company workflows is
established. All project employees apply 100% of their capacity to work on this project. As back-up, experts from
the company can be called in from time to time. A typical example for such a project is the planning of a new site
or the new building of a manufacturing plant with high investment volumes. For the persons involved in the
project, reintegration in the company after conclusion of the project is often problematic. In sport, this would be a
professional football team whose main task is to play football.

Matrix project management


Matrix project management is the most frequently used organisational form. In an existing line management
organisation, project organisation is established at right angles to this, intersecting each line:

Figure 19.A-1 Matrix project organisation


The project manager collaborates with staff from different specialist departments, who work on the project for a
defined proportion of their working time (sometimes up to 100%). With this type of organisational structure, it is
important to define the responsibilities and authorities of project managers and line executives, as competence
problems often occur at this interface. In such a dispute, it is convenient if a "project mentor" (a higher ranking
executive) is available to act as arbitrator.

In contrast to the professional team, these are amateurs whose sports activity is always in competition with their
work commitments.

Influence project management


In this type of organisation, a project manager is appointed who ensures that a defined task is processed in
certain specialist departments and that the work between the departments is coordinated without the employees
concerned being released from the line.

The project manager in this case corresponds to the coach of an amateur team, although in many companies, as
in sport, he usually plays in the team too due to capacity issues.

19.A.3.1 Project manager


As in the classical organisational structure where the line manager is given the most important role, so too is the
project manager given the most important role in the project organisation. For this task, the project manager
usually also requires different skills than an executive at the same level, for:

As a project, by definition, is unique, the project manager must find and take a "new path" to fulfil
the task each time.
For each project, the "team" is newly established. Often external employees are also involved.
With these employees in particular, it is necessary to ensure that the performance they are being paid
for is also delivered.
In addition to the specialist tasks, the resource conflicts with the line must also be solved In the
matrix organisation.

Figure 19.A-2 Requirements of the project manager


Requirements of the project manager
Management and negotiation skills
Knowledge of the company workflows
Ability to take the initiative
Specialist knowledge of the main focus of the project
Ability to lead and motivate a team

In addition to a good technical basis (the project manager need not necessarily be a technical expert, as often
other employees are responsible for this), the most important thing is the social competence to be able to solve
conflicts through discussion and new procedures and to be able to bring about decisions.

19.A.3.2 Project team


Ideally, the project team is set up by the project manager in collaboration with the specialist departments. In
practice, however, the team members are usually determined by the specialist departments and sent to the
project team with a certain capacity and the responsibility of representing the specialist department. In this case
project work is efficient if project members are able to make decisions largely independently of the specialist
departments, even for decisions that have an influence on the specialist department.

As a new project team is set up for the project task, those involved must first learn to work together. There are
four phases of team building:

Familiarisation phase (expectant observation)


Conflict phase (definition of the social order in the group, important role of the project manager)
Organisation phase (sense of belonging to the group develops)
Work phase (recognition: objective can only be achieved together)

19.A.3.3 Steering team


Above all with larger, strategically important projects, a steering team is often still set up, which consists of
executives from the line. This team only meets every two months. The project manager reports to this team on
the progress of the project and the deviations from plan. Any problems that occur are discussed and the further
"direction" is established.

19.A.4 Project phases


19.A.4.1 Project start
The start phase of a project is often a protracted process. The project task is identified and roughly defined in the
line organisation, a project manager is sought, a project team is set up and the project objective specified, at
which point the starting signal can be given.

The first task in the team is to clarify technical questions and check the planning documents for completeness
and give full particulars in relation to the team:

Check schedule, budget and resource plan, revise if necessary


Define work packages for the individual team members,
Define organisation of the teamwork (project meetings with minutes)
Project documentation and reporting (information from the line manager)

19.A.4.2 Project implementation


Depending on the type of project, different milestones are defined so that deviations from the plan can be
counteracted in good time: e.g. for a production facility:

Project start
User requirements
Technical specification
Design qualification (DQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
Process validation
Production

At the end of each phase, a specific interim result should be achieved in terms of content. The costs and
resources consumed are compiled. The objectives and estimates for the individual milestones and to the end of
the project are redefined. Controlling measures are derived from this, e.g.

Request increase in project budget


Request more resources or make recourse to external resources
Adjust the project deadlines, e.g. the market launch deadline

All these controlling measures are usually difficult to implement. However, it makes no sense to bury your head
in the sand and hope for a miracle. If you do this, there will be even greater damage at the end of the project
than if you ask for support in the early stages and clarify any problems that occur. The sooner problems are
identified in the course of the project, the greater the chance of solving them by the end of the project.

Here's another example from the world of sport: With a score of 5:7 in the first set in tennis, the game is not yet
lost and it still makes sense to change tactics. With a score of 5:7, 4:6 and 4:5, this is of course still possible, but
the prospects of success are much lower.

19.A.4.3 Project conclusion


Project conclusion analysis is recommended for all those involved for the purpose of continuous improvement.
Here, a last target/actual comparison of the "hard" data is carried out in a project conclusion meeting and the
"soft" data, the assessment of the project by the employees, is compiled. The following questions are key here:
What went well? What could be improved on in the next project? Based on the results of the analyses of many
projects, the project organisation can be adapted, aids can be improved and workflows can be optimised.
19.A.5 Aids
Project controlling, i.e. early intervention if project parameters do not reach required values, is only possible if
these required values have been defined and if actual values are recorded, so that deviations can be
ascertained.

The following aids are available for planning and control:

Project structure plan


The content of a project is divided up in the project structure plan so that all aspects are covered during
processing:

e.g. for a new-build project, the starting structure could be as follows: building shell, infrastructure, facilities,
computer systems.

Then the building shell is further subdivided into the individual rooms, etc.

This systematic procedure prevents important aspects of the project plan from being disregarded.

Schedule
This plan is based on the project structure plan. Rough planning takes place for the entire project, the times of
milestones are defined and important, time-critical deadlines, such as a trade fair, are recorded. Depending on
the scope of the project, the schedule can be compiled in the form of a bar chart using a computer-assisted
project management system or manually (e.g. with Excel).

It is important that the dependencies between the operations are also taken into account (a truss can only be
built if the external walls of a building shell are already standing) and the processes are assigned to responsible
persons. If nobody is responsible for compliance with a deadline and it is not clear to those involved that certain
tasks are to be completed before others can be started, then the schedule is not worth the time taken to compile
it.

Resource plan
This plan is closely related to the schedule. For planned activities, certain resources are required in a certain
timeframe in order to be able to meet the deadlines. As unlimited resources are not generally available - above
all from the experts - the project manager must ensure a continuous optimisation process to comply with the
deadlines using the available resources, even if there are changes in the course of the project.

Budget
The budget includes the project costs and the investments that are made as part of the project, and possibly also
the manufacturing costs of a product, which are regularly determined during a development project.

The project costs consist of the personnel and materials costs.

Project report and documentation


As many departments are directly involved in the project, especially in the matrix organisation, regular reports on
the status of the project are necessary and changes that are required in the course of the project must be
communicated. The management also expects information on the status of a project. Thus, it is usual that a
written project report is compiled by the project manager at least at the time of the milestones (figure 19.A-3).

Figure 19.A-3 Project status report at milestone


Project status report at milestone (MS) "Number"
Have the technical objectives been achieved?
Yes Partly No
If partly or no:
Why not, what are the critical points, what problems occurred?
Can these problems be controlled or solved?
Have the deadline targets been achieved?
Yes Partly No
If partly or no:
Why not, can the final deadline still be achieved, is "rescheduling" necessary?
Have the cost targets (planning costs, tool costs, etc.) been achieved?
Yes Partly No
If partly or no:
Why not, can a long-term trend be anticipated? Is re-budgeting necessary?
Target-Actual data comparison
Target at MS Actual at MS
Resources
Costs (planning costs, etc.)
Deadlines
What changes to the planning data are necessary?
Technical targets Agreement of the customer necessary?
Deadline targets Deviation in %
Cost targets Deviation in %
What still has to be changed? Are there any other problems?

Project instruction manual


All the above-mentioned aids are available in theory, but often cannot be used by the project manager in
practice. It is therefore advisable to compile a project instruction manual in which important aspects of project
management are regulated across the company and the above-mentioned aids are implemented as forms for
the everyday project work.

Definition of the competencies between the project manager and the line (table of who does
what)
Forms for project definition
Forms for expenditure planning, scheduling, budgeting
Forms for milestone reports
Form for project conclusion report
Structure for project documentation (user requirements, technical specification, etc.)

19.A.6 Multi-project organisation


In most companies, several projects run at the same time and it is necessary to create structures for this
scenario too.

19.A.6.1 Project classes


For very large, ongoing projects, it is advisable to create more sophisticated structures than for medium-sized
and small projects.

The type of project is another classification. Production projects are processed according to a different structure
than development projects.

19.A.6.2 Project priorities


As resource bottlenecks occur in every company, it is necessary to prioritise the projects. All decision-makers
and project employees must know which work packages have to be processed first. The project priorities usually
lead to projects with a lower priority being left alone until they are either no longer needed or are given a higher
priority.

19.A.6.3 Management information


The work of the project employees and the management is much easier if, for the project reports that have to be
compiled, there are forms available in which, or according to the structure of which, the project reports are
compiled at the milestones. For the management, the great advantage here is that specific data on a project can
be found at the same place in each report and thus a certain comparability between similar projects is possible.

19.A.7 Frequently occurring problems in the context


of project management
Project management only works in practice if the management supports this form of work organisation and if
certain rules are complied with. Below are some examples that cause projects to fail:

The project definition is not clearly and uniquely formulated The task is "gradually" changed or
changes in the course of the project, so that no target/actual comparison is possible any more during
controlling, as the planning data was compiled under different requirements than in the actual data
record. exact target definition required
The project manager is "the" expert and therefore also mostly undertakes specialist processing
The project manager's activity, such as coordination of tasks, project planning and controlling
cannot/is not undertaken correctly. Limitation of the project manager's specialist tasks
The project employees are formally assigned to the project, but have no resources available
The conflict with the line can only be solved via corresponding management decisions
The course of the project is not correctly documented, therefore no project changes can be
traced and deviations from the plan cannot be explained Define a reporting and documentation
structure
Specialist departments guarantee punctual completion of a work package shortly before the
submission deadline, but then cannot meet the deadline The specialist department must be shown
the impact of this for the entire project. Management should intervene if this occurs frequently.

Finally, it can be said that project management is a very good form of organisation for processing complex "one-
off" interdepartmental tasks, as all those concerned are involved from an early stage and risks can be covered
that much earlier.

Summary
Project management is a good form of organisation for "one-off, interdepartmental" tasks, which only works if it is
desired by the management and if the employees are provided with the necessary structures and resources.

19.B Risk analysis


Here you will find answers to the following questions:
When is risk analysis recommended?
What are the methods of risk analysis?
How is the FMEA method applied?
How is the HACCP method applied?
How can risk analysis be carried out?
What are the advantages and disadvantages of different risk analyses?

19.B.1 Development of the risk analysis


For a long time, risk analyses have been being carried out in the chemical-pharmaceutical industry in the field of
safety engineering. They started in the early 60s when the aerospace industry developed risk analyses.
Ultimately, technical systems had to be realised which had to be 100% operational, far from any maintenance
unit. Breakdowns would have (and did, as history teaches us) brought unexpected consequences. In any case,
human lives were put at stake. So, already in the development phase of a product (Apollo rocket), every possible
type of malfunction had to be ruled out. To do this, methods with which the aggregates could be systematically
analysed for their failure rate, were developed. This was the hour of birth of Failure Mode and Effects Analysis
(FMEA).

For a long time, such analyses were only used in high-risk industries (aerospace, nuclear engineering, etc.). In
the context of the emerging quality instruments in the 80s, methods had to be found to help increase the quality
of industrially created products. These methods made a crucial breakthrough in the automotive and
semiconductor industry and for their suppliers in the 80s and 90s. The cost pressure on these industry branches
increased drastically and the industry was required to simultaneously increase quality and reduce costs. The use
of risk analyses was a question of survival and the ability to reach the target of high quality with low costs was of
crucial importance.

Figure 19.B-1 Result of risk analyses

to enlarge, click here!

In the pharmaceutical industry, the discussion of risk analyses often focuses on the costs. Yet risk analyses were
developed not to increase costs, but to save costs. These methods should therefore also be implemented in this
spirit.

Experience shows that early system analysis can lead to significant advantages for investment projects. The
form of risk analysis used is unimportant. What is crucial is an awareness of the GMP risks associated with the
selection of certain machines, apparatus and equipment. It should be a matter of course that, at the time of
ordering a technical system, the requirements of the future user should be present. These user requirement
specifications form an essential basis for the execution of a risk analysis.

Figure 19.B-2 Fields of use of risk analyses


Example Basis Methods
Definition of GMP requirements for Experience with other facilities, GMP Structured procedure,
a process facility guidelines, laws company-specific risk analysis
Construction review of process User requirements, technical specification, FMEA, company-specific risk
facility (fill line, blender, etc.) construction documents analysis
Definition of GMP requirements for Experience with the facility, facility FMEA, company-specific risk
old facilities documentation, GMP guidelines, laws analysis

Risk analyses can be applied in various task areas. It is always important to be in a position where the changes
can still be carried out cost-effectively, but where important basic conditions have already been established.
Some possible uses for risk analyses are listed in figure 19.B-3.

Figure 19.B-3 Possible uses for risk analyses


Examples of risk analyses
Area of
Time of the risk analysis Content of the risk analysis
application
Validation Rough plan available What technical facilities and systems are to be classified as
master plan GMP-critical, and which as uncritical? The influence of the
systems on the product quality is crucial.
Qualification Conclusion of engineer GMP-critical systems are inspected in detail for compliance with
planning; Design review; the GMP requirements and for whether or not GMP risks have
Construction review been take into account adequately in the design.
Computer Conclusion of the specification Review of the extent to which the specification contains GMP
system (functional and technical risks that must be tested (validated) in later project phases.
validation specification)
Process Conclusion of process What GMP risks are included in the sequence of operation? In
validation development what processing step of the industrial implementation are GMP
problems to be expected?
Cleaning After development of the What GMP risks are contained in the processing steps? Which
validation cleaning process are worst-case products for the established cleaning sequence?
and others

Official requirements for risk analyses


The monitoring by the authorities also places increasing value on the execution of risk analyses. Information on
this is given in particular in the ICH Q9 Guideline "Quality Risk Managment" and in Annex 15 of the EU GMP
Guideline.

The following methods are interesting for use in the pharmaceutical industry:

Failure Mode and Effects Analysis (FMEA)


Fault Tree Analysis (FTA)
Ishikawa method (Fishbone analysis)
HACCP
The ICH Q9 defines risk analysis as:
"The estimation of the risk associated with the identified hazards."
Annex 15 defines risk analysis as follows:
"Methods to assess and characterise the critical parameters in the functionality of an equipment or
process."

Both definitions show that risk analysis is a procedure with which critical parameters should be determined or
evaluated.

Annex 15 also goes into the increasing importance of risk analysis where changes have been made:

"All changes that may affect product quality or reproducibility of the process should be formally requested,
documented and accepted. The likely impact of the change of facilities, systems and equipment on the product
should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation
should be determined." (Annex 15, paragraph 44)

The ICH Q9 deals with the different forms of risk analysis in much more detail and also introduces these briefly.

With the help of a documented risk analysis, it is possible to show why certain facility functions or procedure
steps should be classified as critical or non-critical. This evaluation is then a traceable basis for qualification and
validation activities.

Type of risk consideration


The type of risk analysis that is suitable for the project must be decided within the project team. This decision
can only be reached within the project. For other parties, it is irrelevant if this is a formal procedure according to
existing methods or a newly developed approach. What is crucial is whether or not an outsider can trace how it
was applied and if it can be clearly explained. Possible risk analyses are, for example, Failure Mode and Effects
Analysis (FMEA), Fault Tree Analysis, Fishbone diagram (Ishikawa diagram), HACCP, free form of risk analysis.

19.B.2 FMEA - Failure Mode and Effects Analysis


19.B.2.1 Development
FMEA is a method that was developed by NASA during the Apollo program. Through various phases of further
development, it has experienced significant developments through application in the mass industry of automobile
and machine construction and in the semiconductor and microelectronics industry. The practical feasibility of the
method was proven by these applications. FMEA is allegedly the most used form of risk analysis.

FMEA is a quantitative risk analysis, the result of which is a list of risks with an assigned risk value.

To date, every industry has changed certain aspects of FMEA in implementation. The introduction of FMEA in the
operational sequence of pharmaceutical companies also requires adjustments. In recent years, especially in the
evaluation system, a certain "pharmaceutical standard" has been established which must be taken into account
in the procedure described below.

19.B.2.2 Procedure during FMEA


Figure 19.B-4 shows a flow chart of the sequence of a GMP-FMEA. Three important stages can be
distinguished:

Failure finding
Failure analysis
Measures to eliminate failures

Here, a failure is to be understood as a GMP risk. Thus, for example, a failure can be a leaky cable duct through
a wall in a clean room or a difficult to clean point in a coater or a ball valve in the distribution ring of a WFI
system.

Figure 19.B-4 FMEA flow chart


19.B.2.3 Failure finding
The first phase of FMEA is to find GMP deficits. Before GMP risks can be evaluated, they must first be identified
and described.

If the FMEA is only used for a rough evaluation of systems, then the team discusses the entire system and
describes general GMP deficits that could be caused by the system. At this level, it is usually not necessary to
deal with the cause of failure, as this can often be very multifaceted (e.g. see figure 19.B-5).

Figure 19.B-5 Finding GMP risks (rough analysis example)


System Failure Cause of failure Failure implications
Water for injection Microbial contamination of the various Microbial contamination of
(WFI) WFI products

If the FMEA is for subsystems, failure finding is carried out in significantly more detail. Individual subsystems are
examined and the causes of failure and failure implications are investigated, so that later evaluation is easier.

Figure 19.B-6 Finding GMP risks (detailed analysis example)


Cause of
System Failure Failure implications
failure
Water for injection (WFI), 3-D rule not complied with Faulty Microbial contamination of products
distribution system execution
Washing system for sterile Exhaust air air contains No sterile filter Microbial contamination of products
primary containers particles/organisms planned and high content of particles

The most time-consuming part of the FMEA is the failure finding. All systems or subsystems must be checked for
their possible failures. Even failures that may appear hypothetical must be taken into account, as practice shows
that every failure occurs at some time.

Failure finding, in particular in the initial phase of execution of FMEAs, is time-consuming. If several similar
systems have already been analysed, then there will be many similarities also in the occurrence of failures,
which reduces the effort for this phase. Generally, failures are found by the team members who work with the
corresponding facility in practice and through the application of creativity methods (e.g. brainstorming,
brainwriting, etc.), which are not dealt with in detail here.

At this time, it is important to take into account all GMP-relevant aspects and official requirements. Official
requirements which, if not complied with, can also be classified as failures, can be derived from the bodies of
rules (e.g. CFR, EU GMP Guideline, Guides, Guidelines, etc.). However, it is also important to take into account
the state-of-the-art, as one of the official requirements is to consider the state-of-the-art in the design of technical
systems. Determining the state-of-the-art is not always easy. The IPSE Baseline Series documents are helpful.
These documents show how today's technical systems should be designed by pharmaceutical production
companies. As these documents are compiled by engineers and are agreed with the FDA, they are good
guidelines for the state-of-the-art.

If all feasible failures have been documented with cause of failure and implications of failure, these must be put
into some order. Different causes of failure often lead to the same failures and the same failures have different
implications. This too is documented in a traceable manner using the form (see figure 19.B-7).

Figure 19.B-7 Example of a FMEA


19.B.2.4 Failure evaluation
In the failure evaluation phase, principly only one line in the FMEA form is evaluated at a time. If, for example,
there are several causes of failure which are linked with a failure in separate lines, these must be taken into
account separately. However, if the different causes of failure were grouped together in one line, the causes of
failure are evaluated together.

In general, the following aspects of failures are evaluated:

Probability of occurrence of the failure (O)


Severity of the failure (S)
Probability of detecting the failure (D)

These three defect characteristics are assigned numerical values from which the risk priority number is
determined by multiplying the three values with each other (see figure 19.B-8).

Figure 19.B-8 Calculating the risk priority number (RPN)


Calculating the risk priority number (RPN)
RPN = O x S x D
O = Probability of occurrence, S = Severity, D = Probability of detection

It is of fundamental importance that the three evaluations take place independently of each other. The probability
of occurrence or the probability of detection of a failure must not be included in the severity of the failure. For
example, if the implications of a failure lead to S = 5, then the number must not be reduced purely because this
failure only occurs once a year. This step is carried out in the concluding calculation of the risk priority number
RPN (see figure 19.B-8).

The scale for the numerical values can be defined by the company applying them. So, for example, to achieve a
rough classification of systems, it may be advisable to make an evaluation of 1 to 3 in each case. This way a
result can be reached more quickly and efficiently. The evaluation aids described in figure 19.B-9 to figure 19.B-
11 are a suggestion. Each company must develop evaluation aids when introducing FMEA.

Probability of occurrence (O)


For a GMP risk, the frequency with which a failure occurs or can occur is of great importance. The more
frequently a failure occurs, the higher the risk. Unlike in other industry branches, evaluation in the
pharmaceutical industry is usually carried out with number values between 1 and 5. O = 1 means rare
occurrence and O = 5 means frequent occurrence (see example in figure 19.B-9). Other industry branches use a
system of 1-10 and thus offer more detailed classification. This is not necessary for the current application in the
pharmaceutical industry and also saves valuable time in the FMEA meetings, as it is easier to reach an
agreement when the margin is narrower.

Figure 19.B-9 Example of an evaluation aid for the probability of occurrence


Example of an evaluation aid for the probability of occurrence
Probability of occurrence Evaluation
Improbable: 1
The failure occurs less than once a year.
or
It is improbable that a failure will occur.
Very low: 2
The failure occurs at most three times a year.
or
The construction generally corresponds to previous drafts in which few failures occurred (max. 3
times per year).
Low: 3
The failure occurs at most once per month.
or
The construction generally corresponds to previous drafts in which failures occurred occasionally
(max. once per month).
Moderate: 4
The failure occurs repeatedly.
or
No information is available
High: 5
The failure occurs frequently. There is an increasing trend.
or
It is almost certain that failures will occur to a large extent.

Failure severity (S)


The severity of a failure is fundamental for its assessment. The severity is usually determined by the implications
of the failure. If, for example, a patient is injured as a result of a failure, the severity must be classified as high.
On the other hand, if only a review of the technical system is required, the severity is to be classified as low. The
numerical values from 1 to 5 ascend with increasing severity (see figure 19.B-10).

Figure 19.B-10 Example of an evaluation aid for the failure severity


Example of an evaluation aid for the failure severity
Severity in terms of product quality Evaluation
No disadvantageous impacts on the product quality can be deduced. 1
The failure has an impact on the technical sequences, but there is no impact on the product quality 2
Slight deviations in the product specifications can occur which require moderate measures (e.g. 3
higher monitoring frequency in final testing, additional testing, etc.).
Significant deviations in the product quality can occur which require extensive measures (e.g. 4
rejection of a batch, recall of products, etc. ).
Deviations can occur that might cause injury to consumers. 5

Probability of detection (D)


To determine the GMP risk, it is important to know if a failure that has occurred will be detected or if it will only be
noticed once it has reached the customer. This also includes a failure that is detected in the pharmacy, as this
too is a customer.

The easier it is to detect the failure, the lower the risk. Therefore, the numerical value falls from 5 to 1 the higher
the probability of detection. D = 1 is thus a value that can only be achieved if a fully automatic 100%-control is
integrated in the production sequence. D = 5 means that a failure is not detected (see figure 19.B-11)

When evaluating the probability of detection, the test measures that are already planned or designed at the time
of executing the FMEA must be taken into account. This being the case, they must also be documented in the
FMEA form in connection with the evaluation.

Figure 19.B-11 Example of an evaluation aid for the probability of detection


Example of an evaluation aid for the probability of detection
Probability of detection Evaluation
High: 1
100 % automatic control, coupled with an alarm system.
or
Operating failure that is almost certainly noticed in the subsequent operations.
Average: 2
100% control, different analysis mechanisms, e.g. monitoring of process parameters with alarm.
or
Obvious failure that is very probably detected in the subsequent operations.
Low: 3
Frequent in-process control or continuous monitoring.
or
Easy to recognise failure, which is controlled.
Very low: 4
Established quality controls
or
Defect characteristic that is difficult to recognise
Improbable: 5
The failure cannot be detected or is not routinely checked.

Evaluation of the risk priority number (RPN)


The risk priority number (RPN) is determined by multiplying values O, S and D.

This results in an RPN of between 1 and 125 with the above-mentioned assessment values. In addition to the
RPN, the company's risk tolerance is of great importance. That is, where the limit is set by the company for the
determination of measures. It is necessary to clarify the RPN from which measures must be initiated in order to
reduce the risk. It must also be clarified whether this should be a single limit or if there should be two limits, for
example (see figure 19.B-12).

Figure 19.B-12 Limits for initiation of measures

to enlarge, click here!

If the set limits are exceeded, the FMEA team must define measures that will reduce the RPN.

19.B.2.5 Measures to eliminate failures


The definition of measures to be implemented when the RPN is exceeded is a preventative failure prevention
program which is very cost/benefit efficient from a very early stage. Below are some examples of such
measures:

Introduction of IQ or OQ tests
Introduction of an additional quality check
Changes to the facility to completely prevent certain failures
Introduction of an additional point in the context of preventative maintenance

When defining measures, their impact on the RPN and the previous evaluation of the individual criteria, O, S and
D are crucial. It is therefore advisable to carry out a second evaluation after the measures have been
established.

If you consider the above-mentioned examples of measures, one of the results of a detailed FMEA could be a
complete list of all necessary IQ and OQ or PQ tests. This means that this information is available from a very
early stage and the course of the project or the necessary resources can be planned more accurately. In
addition, time-consuming agreements at a later time are no longer necessary which, according to experience,
weigh heavily on the project if the necessary tests have not been defined at such an early stage.

19.B.3 Introduction of a GMP risk analysis according


to FMEA method
The introduction of a GMP risk analysis according to the FMEA method must be very well planned. Figure 19.B-
13 shows a checklist of all the important points, listed in chronological order, which should be carried out during
introduction of FMEA. It is the task of the project planning for the implementation of a GMP-FMEA to decide the
timeframe in which the individual points are to be processed.

Figure 19.B-13 Checklist for the introduction of a GMP risk analysis using the
FMEA method
Checklist for the introduction of a GMP risk analysis using the FMEA method
Project start
Appointment of project manager The project manager must have the corresponding authorities
Establishment of the project team The project team must include employees representing production,
engineering and quality assurance. Further project members must be selected
according to the project demand.
Establishment of the fields of This is where the project scope is defined, i.e. which systems are to be
consideration investigated.
Establishment of the depth of Is it a rough analysis or a detailed analysis?
consideration
Establishment of the Will aspects O, S and D be assessed with values from 1 to 5 or is another
classification system being used?
Evaluation aids for determining; These aids should ensure that different teams can achieve equivalent results.
O, S and D must be compiled
Development of principles for the Efficient processing of the GMP risk analysis is facilitated through the
GMP risk assessment existence of operational and official requirements and the state-of-the-art.
Establishment of RPN limits Have one or two limits been established and how high are they? What
happens if the limits are exceeded?
Establishment of the FMEA These will not always agree with the project team, in particular if the projects
teams are extensive.
Training of moderators At least one FMEA team member should be trained as a moderator.
Training of the FMEA team The FMEA should be trained using examples.
members
Execution of GMP risk analysis in Experiences in the first teams should be particularly well documented.
first teams
Implementation of the decided The measures must be implemented, otherwise the risk assessment is
measures meaningless
Monitoring of the measures Likewise, the implementation of the measures must be monitored.

19.B.3.1 Advantages
As a method, FMEA has many advantages which, in other industry areas, have ultimately lead to FMEA
asserting itself significantly more strongly over other risk assessments (see figure 19.B-14.)

Figure 19.B-14 Advantages of FMEA


Advantages of FMEA
Quantitative evaluation of GMP risks
Possibility of ranking GMP risks
Qualification aspects are defined at an early stage
Different levels of consideration are possible
Team approach
Comprehensive method, can also be used for security, etc.

Quantitative evaluation of GMP risks


Quantitative evaluation of GMP risks is possible with FMEA. In the form shown below, this results in a risk value
(risk priority number) between 1 and 125. The risk increases as the value increases. The company or team can
decide for itself where the tolerable risk, and thus a limit, is set (see figure 19.B-12). Usually, this is a risk value
between 15 and 30. The risk priority number (RPN) means that it is possible to compare risks from different
technical systems. This is of particular significance for strictly cost-limited projects.

Ranking of GMP risks


By determining an RPN for each GMP risk, it is possible to compile ranking lists. This distinctly simplifies priority
determination. The decision regarding which aspects must be handled with priority is documented in a traceable
manner. For projects with a limited budget, an efficient instrument is available for implementing the available
resources efficiently for the critical GMP risks.

Qualification aspects are defined at an early stage


Since the detection of GMP failures (probability of detection) is an evaluation criterion within FMEA, the tests of
IQ, OQ and PQ can be established at a very early stage. This is very advantageous for resource planning for
qualification.

Different levels of consideration


Depending on the project progress, FMEA can be executed in more or less detail. This means that the critical
systems can be classified in a rough planning stage and, in a later step, the critical systems can be checked at
aggregate level for GMP-critical facility parts and functions. The results will be correspondingly rough or detailed.
Thus, every company can adapt FMEA to its requirements.

Team approach
The composition of the group that carries out the FMEA is crucial for the success of the FMEA. An optimal result
is achieved, as people with different levels of knowledge are collaborating in the group. In order to achieve this,
the group must work out the result together, with the later user and engineering always being represented in the
group.

Comprehensive method
In contrast to other risk analysis methods, FMEA can also be used to carry out other risk analyses, e.g. safety,
environmental protection, technical risk analysis. This would make it possible to investigate and consider all risks
with this method.

19.B.3.2 Disadvantages
The disadvantages of FMEA are essentially rooted in its initial implementation, but also in the continuity
generally required for carrying out a risk analysis.

Figure 19.B-15 Disadvantages of FMEA


Disadvantages of FMEA
Training effort before first execution
Implementation requires time
Availability of resources must be guaranteed
Risk is quasi-objective due to RPN
Training
Before carrying out a FMEA, the participants must be trained in its application. This is indispensable as the
participants in the group will otherwise be working with different perceptions and requirements. This leads to
endless discussions and dissatisfaction in the group members and during the FMEA meetings.

For this reason, a FMEA training course should be attended, in which the team members are familiarised with
the method and gain certainty in how to execute a FMEA. If all members of a FMEA know what they are dealing
with, FMEA meetings can be held efficiently. A training course of 0.5 - 1.5 days should be held, depending on the
level of knowledge of the employees.

In addition to the FMEA training, one member of each FMEA team should be trained as a moderator. The
moderator has the task of guiding the team to a result during the meetings. This does not mean that the
moderator develops the solution, but that he helps the team to reach the target. Therefore, the moderator must
know the method inside out and must also be able to explain it. He must always have the objective of the FMEA
in sight. Often, in cases of dispute within the team, the moderator provides a consensus.

Implementation
The initial implementation of FMEA in the company should not be rushed. The staff must first become
familiarised with the method and practice it for a long period of time before each individual can form an actual
image of the effectiveness of the method. This process takes time. Unfortunately time is rarely available in the
company.

If the implementation phase is too short, this often leads to dissatisfaction of the executives and staff. The former
are disappointed by the results and the latter are overtaxed with expectations. The implementation phase can be
shorter if the staff and teams are provided with corresponding aids, e.g. in the form of coaching or training.

Resource availability
In order to be able to hold FMEA meetings efficiently, all members must be able to participate in the discussion. If
this is not possible, it inevitably leads to losses of efficiency and the result suffers from the lack of resource
availability. Therefore, FMEA meetings must be prepared in good time and all team members must be aware of
the associated priority.

Quasi-objectivity of the RPN


As the RPN (risk priority number) is a numerical value, you could incorrectly assume that it is an objective
estimate of the facts. However, the RPN is only an indicator of the significance of a GMP risk. It does not matter
if the RPN is 15 or 16, but rather if a value is 15 or 30. You must always be aware that the RPN is the result of a
subjective estimate by the team. Just because the process for forming an opinion ends in a tangible numerical
value does not make it more objective, but rather it remains a subjective estimate.

This would mean that different teams could easily obtain different results. All those involved must be aware of
this fact in order to avoid misinterpretations.

An example operating procedure for carrying out risk analysis according to the FMEA method is shown in
figure 19.B-16.

Figure 19.B-16 Example SOP of a GMP risk analysis according to FMEA


19.B.4 Company-specific risk analysis
The fact that a GMP risk assessment was carried out according to a current method is not crucial for its
efficiency. Rather, what is crucial is whether or not the risk analysis is anchored in the project or in the company
and if it is suitable for showing the GMP risks transparently and for documenting them.

Therefore, the "company-specific risk analysis" is attributed a high level of importance. Different models of highly
simplified risk analyses are often practised, which supply less detailed results but can be processed in a shorter
period of time.

19.B.4.1 Advantages
The advantages of company-specific risk analysis are essentially its better adaptability and thus the higher level
of acceptance within the company. In addition, a resource-saving route is often chosen.

Figure 19.B-17 Advantages of company-specific risk

analysis over existing methods


Advantages over an existing method
Risk analysis is adapted to the company requirements
High level of acceptance
Resources saved

Risk analysis is adapted to the company requirements


Company-specific risk analysis is ideally adapted to the requirements of the company. Therefore, this form can
be the best instrument for the respective company. The requirements of different departments can be accounted
for to a greater extent or the human resources requirements can be more easily taken into account.

High level of acceptance


Since the method is developed in and with the company, a company-specific risk analysis usually has a higher
level of acceptance than an "external" method. This is of great importance for the introduction of a GMP risk
analysis, as it can decide on the success or failure of the implementation.

Resources saved
With company-specific risk analysis, methods can also be established that are adapted to the company's human
resources.

19.B.4.2 Disadvantages
Company-specific risk analysis also has disadvantages compared with existing methods (see figure 19.B-18)

Figure 19.B-18 Disadvantages of company-specific risk

analysis compared with existing methods


Disadvantages compared with an existing method
In-house development costs time and resources
Specialist knowledge and experience is necessary
Exchange throughout the company is difficult
In-house development costs time and resources
It is easily comprehensible that it is more costly to develop a GMP risk analysis in-house than to adopt a tried
and tested method. In any case, this applies to the development stage. This additional effort, however, can be
justified if corresponding resources can be saved in the subsequent application time. The importance of time
must not be underestimated. A method must be developed but also tested. If inadequacies come to light in the
testing stage, they can be eliminated in the appropriate manner. However, if a method has to prove itself
immediately in practice, e.g. because a new project is at hand, then there is the risk that there will be not time for
testing and deficiencies will first occur at a later stage when it is too late to make cost-effective corrections.

Specialist knowledge and experience


If nobody within the company has operational experience of risk analyses, it is advisable to involve a specialist in
the project team, or someone with corresponding experience. Many possibilities that appear plausible in theory
are much less suitable in practice. Only if the design of risk analyses is derived from practical experience (this
implies corresponding loops), does the project have the prospect of success. If this point is neglected, methods
are often developed which come up against reservations, criticism or opposition from the employees who are
supposed to implement the methods. The damage that can result from the employees not adequately identifying
with procedures or rejecting them out and out, can barely be quantified, but is significant in any case. Specialist
knowledge and experience in dealing with risk analyses need not be taken into account to such a great extent for
the use of standardised risk analyses, but also in this case the acceptance of the method is crucial.

Exchange throughout the company is difficult


For the design, improvement and further development of company-specific risk analyses, a smaller public is
available, in contrast to the tried and tested methods. This means that most suggestions have to come from
within the company. Known methods, such as FMEA, on the other hand, are often publicly discussed and
opinions and experiences are exchanged. Thus, more widespread methods can be optimised more quickly and
practice oriented.

19.B.4.3 Procedure
On the basis of the above-mentioned points, the existing risk analyses should first be intensively investigated in
the company. If no risk analysis is found that meets the internal requirements, then the development of a
company-specific risk analysis is on the cards.

However, the last resort should be doing this entirely independently. Many companies will be more than happy to
provide you with experiences they have made. Therefore, the best path to take is to first ask other companies
about their experiences and the methods they use. If this too brings you no further, the last resort is to develop a
method alone or in collaboration with another company.

An in-house development has a greater chance of acceptance if it is based on an existing method. So, for
example, FMEA can be used as a basis and converted accordingly, as shown in the following example.

19.B.4.4 Example
FMEA should be used as a basis for this example. After investigating FMEA, the following procedures should be
simplified:

Evaluation of the risk not to be carried out with numbers


Only two evaluation aspects are to be evaluated (three was too many)
A simple assessment grid should give clearer requirements for the final assessment.
The method should be more simple and transparent than FMEA

Modifications compared with FMEA


The evaluation of the risk should not be carried out with numbers, but with a descriptive grading. This will make it
clearer that the value is not objective. There should be evaluation aids for these gradings, as in the FMEA, which
facilitate the evaluation of risks.
The three evaluation aspects should be reduced to two. The evaluation should focus on the probability of
occurrence and the severity of a failure (see figure 19.B-19). The basic consideration is that the probability of
detection is also derived from the measures that are to be decided on for certain risks.

The probability of occurrence is graded as follows:

Improbable
Low
Average
High

The severity is graded as follows:

Low
Average
High
Legal and quasi-legal requirement

Due to the fact that no numerical values are determined, no risk priority number can be formed. However, there
is a clear matrix, with the help of which a risk value can be determined and the necessary measures can quickly
be deduced.

Figure 19.B-19 Assessment matrix


Severity
Low Average High Legal Req.
Occurrence High 1 2 3 3
Average 1 1 2/3 3
Low 0 0 2 2
Improbable 0 0 0 1/2
Legend
0: These fields do not require any GMP measures
1: These aspects must be reviewed during qualification
2: These aspects must be reviewed during qualification, where possible also with function tests, and measures
may have to be taken to reduce the probability of occurrence (change of facilities). The process may have to be
supplemented with quality checks to increase the detection of failures.
3: These aspects must be reviewed during qualification, corresponding measures for reducing the probability of
occurrence must be initiated or the detection of failures must be guaranteed through adequate checks.

If, for example, a moderate failure is found, the function must be checked during qualification, depending on the
severity of the failure. It may even be necessary to change the design of the facilities or to incorporate additional
quality checks in the production process.

With this modification of the FMEA method, the procedure before evaluation remains the same. This means that
the potential failures and risks must first be found. The changes result in the procedure shown in figure 19.B-20.

Figure 19.B-20 Risk analysis procedure example


There is also a significant difference in the fact that the loops now only relate to the reduction of the probability of
occurrence. Other facility and process changes (such as additional quality controls) can no longer be included in
the assessment matrix due to the change of method (see figure 19.B-20).

The form for this type of risk analysis can be seen in figure 19.B-21.

Figure 19.B-21 Risk analysis form example


An example operating procedure for carrying out company-specific risk analysis is shown in figure 19.B-22.

Figure 19.B-22 Example SOP for company-specific GMP risk analysis


to enlarge, click here!
19.B.5 Hazard Analysis of Critical Control Points
HACCP (Hazard Analysis of Critical Control Points) was developed in the early 60s as part of the NASA
program, so that food, which was 100% safe against contamination by bacteria, pathogenic viruses, toxins or
chemical and physical hazards, could be produced for the space program. HACCP replaced the end-product
testing and at the same time guaranteed the safety of food. In the meantime, HACCP has now gained
recognition world-wide as an efficient tool for quality assurance in the production of foodstuffs.

HACCP focuses on hygiene, which is of crucial interest for any plant that processes food. The legislator too has
acknowledged the significance of hygiene for this area. An important milestone for this method was the legal
obligation of food processing plants to execute this method (EC Directive 93/43, Hygiene of Foodstuff). Through
the requirements of 3 of the Hygiene Regulation, this form of risk analysis became standard in the industry.

In accordance with article 3(2) of the EC Directive 93/43 Hygiene of Foodstuff, the concept of HACCP should
satisfy the following principles:

Analysis of the potential risks for food in the processes of a food company;
Identification of the points in these processes at which risks could occur for food;
Definition of which of these points are critical for food safety - the "critical points";
Establishment and execution of effective test and monitoring processes for these critical points,
and
Review of the risk analysis for food, the critical control points and the test and monitoring
processes in regular intervals and each time the processes are changed in the food company.

The pharmaceutical industry also became aware of this form of risk analysis as it became more widespread. As
the authority also responsible for food, the FDA had already taken a leading role in introducing HACCP for food
processing. However, as hygiene also plays an important role in pharmaceutical production, it is worth
considering this form of risk analysis here too.

Procedure of HACCP
In HACCP, the team approach has also proven its worth and prevailed. This means that as many task areas as
possible should be represented in the team, e.g. quality assurance, engineering, laboratory and production. A
clear and uniform definition of terms is also important. The following key terms are of importance for HACCP
(source: HACCP Guidelines, FDA):

Hazard:
"Hazard [...] means a biological, chemical, or physical property that may cause an unacceptable consumer
health risk." (HACCP Guideline, FDA, 1997)

Hazard is an event or circumstance that can influence a product in such a way that may cause a direct consumer
health risk. The hazard can be of a biological, physical or chemical nature.

Figure 19.B-23 Examples of hazards

to
enlarge,
click
here!

Risk:
"Risk means an estimate of the likely occurrence of a hazard." (HACCP Guideline, FDA, 1997).

Critical control point (CCP):


"Critical control point [...] means a point at which loss of control may result in an unacceptable health risk."
(HACCP Guideline, FDA, 1997)

A critical point is therefore a stage, step or phase, at which a detected hazard is to be eliminated through
targeted and controlled measures or reduced to an acceptable level with the clear aim of controlling the hazard.

The general procedure for HACCP is the same as for all risk analyses:

Search for possible failures/problem points


Evaluation of these problem points
Definition of measures for problem elimination

The implications for the product quality must be the main focus. The search for problem points must concentrate
on this aspect. The points in the production process at which the product quality can be negatively influenced
must be found.

Figure 19.B-24 Sequence of an HACCP study

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19.B.5.1 Failure finding


Before failure finding is started, the production process (or the scope of the HACCP) should be described in
sufficient detail. The description can be omitted if all those involved in the HACCP are very familiar with the
system or the process. In any case, the system limits must be described.

Aspects for the description of a process or system:

Composition (raw materials, additives, excipients, APIs)


Nature and physico-chemical features (solid, liquid, pasty, emulsion, pH value, etc.)
Processing steps
Packaging (primary and secondary packaging)
Storage conditions (temperature, humidity, light)
Expiration dates
Application

If the system is adequately described, careful and extensive failure finding of potential failures can be carried
out. This is the first necessary condition for the success of a risk analysis, and for HACCP. With HACCP, all
individual operations throughout the production process are to be checked to see if they can exert a negative
influence on the product quality. Likewise, however, creative processes (brainstorming, brainwriting, etc.) can
also be combined with HACCP to achieve the desired result.

For failure finding, it is crucial that all negative influences on the product quality are found. These can result both
from the malfunctioning of machines, facilities or infrastructure or from human error. But the procedural
instructions and operating procedures can also provoke mistakes. Every aspect of the process under
investigation must withstand the questioning. There is no standardised catalogue of questions on which HACCP
is based. Rather, each company must find its own way or approach to find the potential failures. The FDA has
implemented a short catalogue of questions in the HACCP guideline in the food area, but unfortunately this does
not help in the pharmaceutical industry as the requirements are too rudimentary. There is therefore currently no
standardised catalogue of questions that accounts for the needs of the pharmaceutical industry.

In the established area of food processing, HACCP concentrates almost exclusively on hygiene. In the
pharmaceutical area, this narrow constraint must be expanded, as there are significantly more risks in this area
than just hygiene. For example, process management (temperatures, times, etc.), the initial weight of
substances, the functionality of control systems and aspects such as preventative maintenance exert a great
influence on product quality.

19.B.5.2 Evaluation of problem points


As shown in figure 19.B-24, the failure finding process (determination of feasible hazards) is followed by an
evaluation of the problem points.

The aspects are evaluated using a two-tier classification

Control point
Critical control point

The following definitions are used for the control point and critical control point (source: HACCP Guidelines,
FDA):

Control point (CP):


"Any point in a specific food system at which loss of control does not lead to an unacceptable health risk."

Critical control point (CCP):


"A point at which loss of control may result in an unacceptable risk."

In order to reach the evaluation of a control point or a critical control point, the following decision tree in figure
19.B-25 can be used.

Figure 19.B-25 HACCP decision tree (source: FDA)


With this grading, it is crucial that all processing steps be investigated systematically and consistently.

19.B.5.3 Definition of measures


If the decision has been made regarding which control points are present, then the measures to be initiated if
control is lost must also be defined. This must usually be put into writing in operating procedures, so that if a loss
of control does occur, it is clear what should be done. A loss of control occurs if the limits of a CCP are
exceeded.

However, not only the measures, but also the verification procedure must be defined, in the form of test
procedures, testing schedules or operating procedures (see figure 19.B-24). This step is crucial to be able to
keep a process in the safe range during production. Here, it is important that the parameters with which a
process can be brought back to the range that complies with the acceptance criteria, are known. Only if these
control aspects are documented and communicated can the process be controlled, even if a critical process
deviation occurs.

19.B.5.4 Documentation
As for every other risk analysis, HACCP too should be documented so that the results of the analysis are
available at a later time. The following simple table (see figure 19.B-26) has proven useful for documentation
purposes.

Figure 19.B-26 HACCP form (example)


There are also more simple forms which only take into account the first three columns, for example, but this is
less advisable as any further steps are not taken into account for CCPs and CPs and would have to be
processed in a different form.

For documentation, the records of the discussions and above all of the decision must be as complete as
possible. This is in the interest of anyone who has to represent the results at a later time (self-inspection,
external inspection).

19.B.5.5 HACCP summary


CCPs are control points with which a process can be optimised. Whether or not sufficient control points have
been defined is crucial for a process. If all significant control points are known and limits have been defined, the
process is usually a controlled process. Process control is also an essential objective of HACCP. In order to
achieve this objective, the process must be considered as a whole. HACCP offers a tool for localising CCPs and
CPs through an established procedure in the field of hygiene.

Summary
GMP risk analysis is a good instrument for establishing the GMP requirements in qualification and validation
projects and for monitoring their realisation. With the consistent application of FMEA, HACCP or other forms of
risk analysis, and the use of the results, the effort required for qualification/validation can be kept to the
necessary level.
The FMEA method, a company-specific risk analysis and the HACCP method are illustrated using examples, and
their advantages and disadvantages are explained.
It is especially important at the start of the project (procurement stage), to include a GMP risk analysis in the
project sequence.

19.C Change control


Here you will find answers to the following questions:
What is the purpose of change control?
What must be taken into consideration when introducing change control programs?
How can changes be graded?
What should be regulated in a "change control" operating instruction?
What is the function of the change control committee?
How shall the implementation of changes be recorded?
Example: operating instruction for change control with a change request form

19.C.1 Principles of change control


As a rule, before a medicinal product can be manufactured, the theoretical model of the medicinal product must
be specified in the form of an approval. Requirements regarding quality, efficacy and safety are thereby defined.

Reproducing the model in practice (GMP-conform manufacture/testing) also requires the specification of
numerous requirements. The manufacture and quality control procedure should be documented in the form of
instructions. The materials to be used here must be specified. The basic conditions required for a reproducible
quality, such as suitable rooms, qualified facilities, trained personnel and the type of documentation, must be
defined (cf. figure 19.C-1).

Figure 19.C-1 Change control area of consideration

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Before the requirements mentioned above can be implemented in practice, their suitability for the intended
purpose must be reviewed. In the theoretical approval model, this review is carried out by the regulatory
authorities as part of the authorisation procedure. The suitability and authorisation for use in practice is
confirmed by a notice of approval to the applicant. In the pharmaceutical manufacturing company, the suitability
of apparatus/facilities and procedures must be proven with qualification/validation. In these cases, suitability and
authorisation for use in practice is confirmed with a signature on the qualification/validation report of the person
responsible.

The principle that suitable requirements are available and must be adhered to, is not only valid the first time a
medicinal product is manufactured or the first time a facility is used/a procedure comes into effect. This applies to
the whole history of a medicinal product, a procedure or a facility and is to be guaranteed in every respect
throughout.

Just like the entire batch history must be documented, requirements must also be stipulated in documents.
These may be, for example, written specifications for materials or directions for procedures.

As each requirement is expressed in a corresponding document, it is clear that each change control for the
requirements must also always involve a documentation control.

As a result of scientific/technical development, changes to the legal basic conditions or business restraints,
requirements must be redefined, modified, enhanced or cancelled again and again in practice. In turn, this
change to previously approved requirements requires a review and authorisation procedure to keep the system
in its original state of proven suitability. This is the task of the change control.

Change control programs have become recognised as essential elements of the pharmaceutical quality
assurance systems. In the glossary to Annex 15 of the EU GMP Guideline, there is a definition of the term
"change control":

"A formal system by which qualified representatives of appropriate disciplines reviewproposed or actual changes
that might affect the validated status of facilities, systems,equipment or processes. The intent is to determine the
need for action that would en-sure and document that the system is maintained in a validated state."

However, the EU GMP Guideline basically contains only a few notes about the handling of changes. Chapter
5.23 claims:

"5.23 Significant amendments to the manufacturing process, including any change in equipment or materials,
which may affect product quality and/or the reproducibility of the process should be validated."

There are also only two brief items of information in the American Code of Federal Regulations (CFR) on the
topic of "change control":

211.100 Written procedures; deviations.


(a) "There shall be written procedures for production and process control designed to assure that the drug
products have the identity, strength, quality, and purity they purport or are represented to possess. Such
procedures shall include all requirements in this subpart. These written procedures, including any changes, shall
be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the
quality control unit."
211.160 General requirements.
(a) "The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory
control mechanisms required by this subpart, including any change in such specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational
unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed
and shall be documented at the time of performance. Any deviation from the written specifications, standards,
sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified."

While in the USA the responsibility for the verification and authorisation of changes is the task of the quality
control unit, in the relevant EU regulations, the responsibility is not assigned. However, as the change control is
considered an essential element of the pharmaceutical quality assurance system, it is only logical to transfer the
responsibility for the functioning of the change control program to the person responsible for quality assurance
(QA representative, QA head).

Change control is not department-specific, rather the task of the whole company. This is due to the wide area of
application of change control, as described in both Annex 15 and in the PIC/S document PI 006-2.

Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting
material, product component, process equipment, process environment (or site), method of production or testing
or any other change that may affect product quality or reproducibility of the process. Change control procedures
should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in
a product of the desired quality, consistent with the approved specifications." (Annex 15, no. 43)
"Change control is an important element in any Quality Assurance system. Written procedures should be in place
to describe the actions to be taken if a change is proposed to a product component, process equipment, process
environment (or site), method of production or testing or any other change that may affect product quality or
support system operation." (PIC/S document PI 006, section 6.7.1)

In this way, the change control monitors all types of changes which can influence the process reliability or
product quality, evaluates them in reference to the relevant established requirements and determines the
measures necessary for implementing the change or decides that a change should not be implemented. The
change control therefore ensures that a system remains in its suitable state.

19.C.2 Introduction and operation of change control programs


"Commitment of the company to control change to premises, supporting utilities, materials, equipment and
processes used in the manufacture of medicinal products is essential to ensure a continued validation status of
the systems concerned. This commitment should be stated in the relevant company documentation. For
example, the Quality Manual, Quality Policy Documents or the Validation Master Plan. As part of its Quality
Management System the company should have a defined and formalised Change Control Procedure. " (PIC/S
document PI 006, section 2.6)

The introduction of a change control program is a managerial task which must be supported by top management
levels of a company. A corresponding statement for quality management can therefore be expected (cf. figure
19.C-2).

Figure 19.C-2 Structure of change control

Many types of changes affect several regulation areas simultaneously (e.g. GMP requirements, authorisation
requirements, employment protection requirements). Because quality-relevant changes can affect several areas
of a company (e.g. research/development, regulatory affairs, manufacture, quality control, engineering,
marketing), the control must be a task for the whole company (cf. figure 19.C-3).

Figure 19.C-3 Areas of change

As a rule, it is therefore not useful to operate different parallel and independently-working inter-department
change control programs. In the past, the local processing of changes was carried out as the change control was
not then yet recognised to be a quality assurance task for the company as a whole. Some companies are still
making the mistake and work with parallel change control programs: a change control program for the EDP area,
a change control program for the regulatory affairs department and a change control program for the engineering
department. The collaboration of different departments in terms of change control is for this reason not always
guaranteed. It has therefore been the case in practice that control software was changed in the manufacturing
area, without the head of production being aware of this because he was not a member of the change control
committee for the EDP department which implemented this change autonomously.
Independent change control programs cause an unwanted attitude in the department, expressed as delimitations
of responsibility, ineffective inter-department communication and unfavourable procedure- and target-oriented
attitudes. In addition to this, it is often the case that decision procedures and documentation formats/contents are
not consistent and not well suited. This must be observed during the introduction of a change control program.

The central processing of change procedures, coordinated by the quality assurance department, has several
advantages compared with local procedures:

There is a common understanding of what a change represents.


The classification schemes used by the persons involved to grade changes are congruent.
The risks connected with the change can be evaluated in a multi-disciplinary manner.
There is a uniform documentation and authorisation procedure.

The main requirement for the introduction of a change control program is a high quality awareness and an
understanding for the functionality of quality assurance systems among the staff. Change control can therefore
not be assigned "from above", the significance and benefits must be communicated as part of an intensive
training. Changes which require control must be first recognised as such "on site" so that the necessary
procedures can be initiated. Only when the staff are motivated to continuously improve the quality of the product
they manufacture will they accept the change control as a suitable tool and not reject it as bureaucratic formality.

The type and scope of a change control program must comply with the individual company requirements:

In classical GMP-relevant areas, the change control serves to maintain the validated and
specified status. Validated processes and qualified facilities can be influenced in their state by changes
so that the medicinal products manufactured no longer certainly comply with specifications. The same
applies for changes to material specifications. A complete revalidation/requalification can then be
necessary. In these cases, a formalised procedure is required to evaluate the risks associated with the
change, determine the measures necessary to maintain the validation status and authorise the change
after successful revalidation.
Holders of marketing authorisations must guarantee that for changes requiring reporting or
agreement, the necessary regulatory prerequisites are first met. Contract manufacturers that do not
have their own authorisations and resulting obligations for reporting must guarantee that the contract
giver is informed of the company-internal changes that could have an influence on their application
documentation. This requires that the contract giver is included in the change control program of the
contract manufacturer. Conversely, it is frequently the holder of the authorisation that causes the
corresponding subsequent changes with the contract manufacturer because he changed his
authorisation. Change control is in this case not only a task that applies within the company, rather a
task that applies across companies. This is valid in particular for multi-national companies: changes can
affect the approval status in different countries or affect the utilities at different manufacturing sites.
In areas where medicinal products are developed, processes are optimised or clinical research
takes place, the strict obligations to report that are linked with the approval do not have to be fulfilled.
However, persons working in this area expect their work to be comprehensible. Changes in these areas
should also be evaluated and documented in accordance with a described procedure. During the
approval procedure at the latest or during inspections before the approval (pre-approval-inspection), the
development of a medicinal product or process must be consistently proved.

According to the area of consideration (e.g. approval conformity or validation status), it may be necessary to use
different change procedures as a base. This is the way many companies deal with changes to printed packaging
material (information for use, folding cartons, labels) in accordance with a special change control procedure,
because these changes occur relatively frequently in practice and the process sequences can be standardised
easily. In these cases, it should be observed that the sequences and the criteria used are not independent, but
are carefully matched to suit and coordinate with each other.

The examples (lists, flow charts) for grading the changes, as used in many companies, can and should not
replace the individual evaluation of a change, in particular the linked consideration of risk. The example in figure
19.C-4 therefore only shows one way to grade changes. Some companies use different and extensive grading
categories. Others have extensive lists of possible changes and their grades. The display of change procedures
contains large flow charts which are often complicated and hard to understand. These companies have
previously tried to show all potential types of changes and define the required sequences in diagrams. Such a
procedure is not incorrect because it shows the scope of consideration of the change control and example help
in the introduction phase for evaluation and development of changes. This can however deceive one into
thinking everything is regulated. After the introduction phase, most companies find that changes do not always fit
into a prefabricated chart and instead experience and know-how for particular cases is required.
Figure 19.C-4 Grading of changes
Changes requiring control
Not requiring
Major Minor control
(major change) (minor change)
Significance Influences product quality or Influences a unit requiring No relevance to GMP or
of change process reliability. control. authorisation
Possible Official licence Amendment No relevance
measures New approval Review to GMP or
(selection) Revalidation Documentation authorisation
Examples Change of Replacement of Change to
manufacturer: other apparatus part of the working times
synthesis route of a same design Renovations in
starting material (other Change of administration area
impurities) cleansing agent for floors Installation of
Removal of Change of air conditioner in staff
processes to another laundry for work clothing room
site (non-sterile or antibiotics Introduction of
Change in the area) electronically-readable
product composition Introduction of plant ID cards
Change to the co-sales right
process parameters

Other classifications not included in figure 19.C-4 are possible. It is not decisive which and how many change
classes a company has determined, but how it is guaranteed that changes requiring control are recognised as
such and implemented according to a defined procedure.

See the PIC/S document PI 006 for notes on grading changes. In chapter 6.7.4. there is a list of changes that
may make a revalidation necessary (cf. figure 19.C-5).

Figure 19.C-5 Changes and revalidation


Changes which may require a revalidation
Physical characteristics of the raw material
Origin of the starting material (change of supplier)
Packaging material (e.g. replacement of plastic with glass)
Process changes (e.g. mixing times, drying temperatures)
Equipment (e.g. introduction of an automatic detection system)
Production area and supply systems (e.g. new water plant)
Moving manufacturing into a new building

The so called "trials" cause a problem area in change control. Trials are preliminary, temporary changes which
can be permanently established or revoked after a trial period. With trials, there is a risk that these intended
temporary changes gradually become permanent changes, without a formal change control procedure being
carried out. Regardless of how long a trial is retained and whether it is withdrawn after a trial phase or be
introduced permanently, trials should be dealt with according to the same procedure as all other changes. Before
the trial phase starts, an analogous change control procedure should therefore be carried out.

Deviations should not be treated as changes, not even when deviations become changes after the failure has
been clarified. A deviation is an unplanned and undesirable deviation from a requirement. It does not correspond
with the aim and procedure of change control and should be dealt with according to a special procedure about
handling deviations.

An important function as part of the change control program is fulfilled by the change control committee (also
known as: change control team, change control panel). This permanent committee generally consists of the head
of quality assurance, who frequently also chairs, and the heads of manufacturing, quality control, sales,
regulatory affairs and the information representative. If necessary, further departments (e.g.
research/development, EDP, engineering) also become involved. The task of the committee is to evaluate
changes, determine the measures required and coordinate measures for the departments affected by the
change and the final authorisation.
A major problem, especially during the introduction phase of the change control system, is the issue of which
changes the change control committee should deal with. It is obvious that this committee cannot deal with all
changes in a company due to capacity reasons. As a matter of fact, only changes requiring control should be
processed by this committee. Firstly, these are changes relevant for the regulatory status and involve reporting
or authorisation procedures. Secondly, they are changes which could have an influence on the attributes of a
GMP-relevant system, facility, apparatus, material/product or a procedure/process. This influence may be critical
as regards the product quality/process reliability and require a revalidation/requalification or simply require the
compilation/update of documentation. The change control committee is also involved in changes for which their
implementation is often extensive and coordinating measures are necessary. The committee should also deal
with all changes whose grade or implementation is unclear or questionable.

Figure 19.C-6 Data for the effectiveness of change control programs


Data for the effectiveness of change control programs
Number of completed change procedures/year
Number of prematurely terminated procedures of procedure deviations
Work expenditure/change type
Duration of procedure: from application to completion
Number of grading problems/total number of change procedures
Number of OOS results/year
Number of internal or external complaints/year
Stability problems/batch reviews/recalls

The question of how the committee members communicate with each other is significant. Not all change control
procedures urgently require the convening of a meeting, at which many important function heads must often be
present in person. In cases which are easy to make a decision about, it is also worth considering traditional
paper-based circulation procedures (serial or parallel), e-mail agreements or common access to Intranet-based
forms.

The committee can only deal with change applications if they are actually assigned. A high involvement is
transferred to the other staff in the company. If a critical change is not evaluated as such and no formalised
change control procedure is introduced, this can cause severe problems with quality.

When a change control program has been introduced, the effectiveness of the system can be reviewed using
data which is easy to determine (cf. figure 19.C-6). The functionality of the system can be measured by taking
into account the effort and speed of change procedures, for example, or the deviations can be examined. The
effectiveness of a change control program depends on the knowledge and experiences of the staff involved. The
regular training about change control procedures is therefore extremely important. Documentation procedures
and communication sequences should be structured as simply as possible to enable rapid implementation.

Deviations are unplanned and generally unwanted changes. They are expressed in the form of internal and
external complaints, stability problems or batch recalls. If they occur, this can be an indication that the change
control program has failed. It is possible that the change to a critical process parameter or material specification
has been overlooked or a negative trend in the development of process data has not been noticed in time.

19.C.3 Documentation

"All changes should be formally requested, documented and accepted by representatives of Production, QC/QA,
R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on
the product should be evaluated and the need for, and the extent of Re-validation discussed. The change control
system should ensure that all notified or requested changes are satisfactorily investigated, documented and
authorised." (PIC/S document PI 006, section 6.7.2)
"All changes that may affect product quality or reproducibility of the process should be formally requested,
documented and accepted. The likely impact of the change of facilities, systems and equipment on the product
should be evaluated, including risk analysis. The need for, and the extent of, re-qualification and re-validation
should be determined."
(Annex 15, no. 44)

Change control requires a written procedure (change control program) to regulate at least the points shown in
figure 19.C-7
Figure 19.C-7 Regulation content of a "change control" operating instruction
Necessary regulations of a "change control" operating instruction
What types of changes does change control take into account; for which areas does this
operating instruction apply?
Who can suggest/initiate changes?
How are changes requested (forms, methods of communication)?
How are changes graded, who is responsible for the grading?
How are the measures necessary for carrying out the change determined; who compiles the
directions required?
Who is responsible for the execution and monitoring of all necessary measures?
How is the change control committee assembled; what are the duties of the committee?
How is the change documented (format, content, storage)?
Who is responsible for authorising changes?
What are the special regulations for urgent changes?

If the change affects a manufacturing or testing process, then the qualified person must take this into
consideration when releasing the batch (cf. PIC/S document PI 006, chapter 6.7.3).

All quality-relevant changes should be documented in full and so that they are comprehensible. The records can
be archived in paper form or electronically. When storing documents, make sure that all facilities, raw data and
other documents relevant for the change are kept accessible.

Changes requiring control are generally documented in the form of a change request, in which the applicant for
the change proposes the type of grade/evaluation of the change, specifies the time frames and measures for
carrying out the change and the change is authorised or declined by the change control committee. The
documentation for the change procedure should prove that the change was evaluated (risk analysis) and the
subsequently defined measures were implemented as predetermined. When implementing the change, several
measures must often be coordinated as regards timing and contents. A clear display of the individual measures
for a project plan is useful for the coordination of complex changes.

The "change control" operating instruction in the appendix for this chapter describes the procedure of change
control and contains an application form for documenting the change procedure.

Summary:
Change control programs are an essential component of the quality assurance system.
They monitor all types of changes that influence the process reliability or product quality or may
be relevant for the marketing authorisation.
The influence of a change on a specified/validated system must be examined (risk
consideration).
For the implementation of critical changes, the change control committee coordinates all
essential measures.
Changes must generally be requested formally, implemented in accordance with a previously
defined procedure, documented and authorised by the responsible persons.

Page/pages x of y
Company Change control procedures
Document number: Version: valid from: [Enter date]
[Enter document no.] [Enter version no.] valid to: [Enter date]
File name/path:
[Enter file name/path]
Area of application:
Changes to materials, products, facilities/apparatus, processes/procedures and systems in the areas of
purchasing, manufacture, quality control, engineering, research/development, marketing authorisation, sales,
EDP, contract manufacturing and external testing places, excluding changes to printed packaging materials
Key words:
Change, procedure
Replaces version: from:
[Enter version no.] [Enter date]
Changes made since last version:
[Enter main content of changes]
Cross references:
[Valid documents: Enter document no.]
References:
EU GMP Guideline, Annex 15, PIC/S document PI-006-2, Appendix I of the regulation (EC) no. 1084/2003
Distribution list:
[Enter recipients of document]
Compiled by: Checked by: Approved by:
[Name/signature of person who [Name/signature of person carrying [Name/signature of person giving
compiled it] out check] authorisation]
on: on: on:
[Date of compilation] [Date of check] [Date
of approval]
1. Purpose of the instruction:
Internal requirements are specified in order to comply with the legal drug product provisions and the GMP
Guideline, as well as to ensure that the quality of the medicinal product complies with the approval and is
reproducible. These requirements cover the entire manufacturing process and the quality control for a medicinal
product, including the materials and facilities/apparatus used. The purpose of this instruction is to ensure that the
quality of the medicinal product, the safety of facilities/apparatus, the safety of procedures/process and
conformity with the applicable application files for marketing authorisation are maintained in the event of changes
to these requirements.
2. Definitions/abbreviations:
Deviations: unplanned and undesirable deviation from a requirement
CCC: change control committee
Change: planned deviation (extension, replacement, removal, addition) as part of a requirement
Change control: system with which qualified representatives from corresponding departments evaluate current
or planned changes in terms of their effects with regard to a specific status. The aim is to establish precautions
that are necessary to prove and document compliance with the specific status.
Facility: total of all apparatus linked together with a common purpose.
Applicant: person who is initiating a change with a change request
Apparatus: object characterised by the technical processes carried out in it.
Minor change: change which fulfils the conditions of Appendix I of Regulation (EC) no. 1084/2003 or which
affects the attributes of a system, facility, apparatus, material/product or procedure/process. Impairment of the
product quality/process reliability is not likely. Minor changes may require notification to the regulatory or
supervisory authorities.
Major change: change which cannot be classified as a minor change or which may affect the critical attributes of
a system, facility, apparatus, material/product or procedure/process. Impairment of the product quality/process
reliability is likely. Major changes may require authorisation by the relevant regulatory or supervisory authorities
and/or prior revalidation or requalification.
Process: set of interrelated methods and activities which convert an input into results.
System: total of all facilities linked together with a common purpose.
Procedure: established way of carrying out an activity.
Trial: preliminary, temporary changes which are permanently established or revoked after a trial period
3. Responsibilities:
3.1. Responsibilities for the established procedures
3.1.1. The legal medicinal product responsibility for proper planning, implementation and authorisation of
changes is borne by the head of production, the head of quality control, the sales manager and the information
representatives for their relevant area. In particular, they must ensure that:
the qualification status of the rooms and facilities that are affected by a change is maintained or
that a requalification is implemented
the validation status of the processes/procedures that are affected by a change is maintained or
that a revalidation is implemented
changes to manufacturing, analysis and labelling of a medicinal product are based on a valid
approval/registration
the documentation required for the change is compiled or updated
3.1.2. The organisational processing and documentation of change control procedures is conferred to the change
control committee (CCC). The CCC comprises those in the roles mentioned above and the head of regulatory
affairs and the QA representative. Other heads of department or experts may be called in at the wish of one of
the members. The committee has the following tasks:
Risk evaluation of the change request
Authorisation or rejection of the application
Establishing and scheduling necessary measures
3.1.3. The chairman of the CCC is the QA representative. He has the following tasks:
Calling the CCC meetings and taking minutes
Coordination of circulation procedure
Maintenance of the database of change control procedures
Formal control of the change requests
Monitoring compliance with deadlines
Archiving the completed change requests
3.2. Responsibility for the revision of this instruction
The QA representative is responsible for checking this instruction regularly to make sure it is up to date and for
revising it if necessary. He must release a new version at least every two years.
4. Procedure
4.1. Basic principles
4.1.1. GMP or approval-relevant changes must only be implemented if they have been previously requested in
writing and authorised.
4.1.2. Trials are also subject to this procedure.
4.1.3. Deviations are not subject to this procedure, but to operating instruction [enter doc. no./version no.]
"Handling deviations".
4.1.4. Changes can be requested by any staff member using the form in Appendix 1.
4.1.5. Changes of which the grade is debatable or unclear must also be requested using this procedure.
4.2. Implementation of change control procedures
4.2.1. Forms for change control procedure are issued by the QA department. If a new form is issued, a change
number is automatically allocated to the change procedure by the change database and is entered on the form.
4.2.2. The applicant should specify the object of the change and the significant reasons and circumstances of the
change in no. 1 on the change request. He should then sign and date it.
4.2.3. The heads of area affected by the change should have the opportunity to give their opinion on the intended
change, to identify any risks and to suggest necessary measures and schedules. In any case, they should be
acquainted with the planned change. This is documented in no. 2 on the change request.
4.2.4. The QA representative transfers the data required to identify the procedure into the change control
database.
4.2.5. The members of the CCC jointly carry out a risk analysis of the change request under no. 3.1, classify the
change under no. 3.2 and give their decision to authorise or reject the change application under no. 3.3.
Authorisation may be associated with a time scale. The applicant and his head of area are informed of the
decision via a copy of the completed change request.
4.2.6. A decision by the change control committee in accordance with 4.2.5 may only be made if all the
information and documents relevant to the decision are submitted. If necessary, the request may be returned to
the applicant for completion.
4.2.7. If the change is authorised, the CCC can establish a measures plan in no. 3.4 of the change request
(tasks, responsibilities, schedule). This must be completed and authorised for the change procedure to be
completed.
4.2.8. Those responsible in accordance with the measures plan shall each receive a copy of section 3.4 and shall
inform the QA representative when the established measures have been completed.
4.2.9. The QA representative shall collect all the completed measures plans, check them for successful
completion of each task and include them with the original change request. The completed change request is
archived and the result and date of the completion is entered in the change database.
4.2.10. In simple cases, in which the applicant can implement the change himself without requiring any
scheduling, an electronic copy of the request may be distributed to the CCC via the internal e-mail system
instead of at a meeting (circulation procedure). Each CCC member then gives his written vote regarding the
change request via e-mail with electronic signature. The change request and electronic voting from the CCC
member are to be archived in accordance with chapter 4.3. If there is no unanimous decision, the QA
representative calls a meeting about the request.
4.3. Documentation
4.3.1. The procedure in accordance with chapter 4.2 must be documented on the "change request" form in
Appendix 1.
4.3.2. If necessary, documents relevant to the decision should be added to the change request.
4.3.3. The change request and documents relevant to the decision must be kept indefinitely in the "quality
assurance" area of the department.
4.3.4. If necessary for capacity reasons, the paper copy of the change request and its associated documents
may be replaced with an electronic archive file.
4.4. Deviation from the procedure
4.4.1. It is permissible to deviate from the regulations in chapter 4.2 only if:
an immediate change is urgently required for operational or staff safety or
an immediate change has considerable significance for the unit, the need for it was not
foreseeable and it was not possible to comply with the formal procedure in chapter 4.2 in the time
available.
4.4.2. In the cases in chapter 4.4.1, the consent of the responsible head of area or his representative should be
sought before the change is implemented.
4.4.3. Once the change has been implemented, the procedure in chapter 4.2 must be followed at the earliest
opportunity.
5. Appendices
Appendix 1: change request form

Change control procedure Page/pages x of


Company y
Appendix 1
Document number: Version: valid from: [Enter date]
[Enter document no.] [Enter version no.] valid to: [Enter date]
Change request
Page/pages
Company [Cross reference to the operating
[enter page no.]
instruction on which it is based]
Change no.: Change designation:
(to be entered by QA) (to be entered by QA)
1. Applicant
Name ... Department ...
1.1. Object of the change (mark with a cross)
Rooms Manufacturing procedure
Manufacturing facilities Test procedure
Quality control facilities Cleaning procedure
Media supply Other procedure
Computer-assisted system Starting materials
Organisation Packaging material
Contract acceptor/giver Semi-manufactured/bulk product
Supplier Finished medicinal product
Marketing authorisation Other material
Documentation ...
1.2. Description of change:
Cause, reason for the change Alternatives
Products, procedures, facilities affected Cross reference to
Necessary time frames appendices where necessary.
Suggestion for implementing the change Date and signature of the
Estimated costs applicant: .....................................
....
2. Area head
Response/risk assessment of the affected areas
Area:

Date and signature of the person responsible:


Area:

Date and signature of the person responsible:


Area:

Date and signature of the person responsible:


3. Change control committee:
3.1. Additional risk assessments:
3.2. Grade of change
Major change
Minor change
No major or minor change
3.3. Decision:
The change is authorised. Time limit for the implementation:
The measures list in no. 3.4 must be observed.
The change is not authorised. Rationale:
Date and signatures of the CCC members
Head of Production:
Head of Quality Control:
Sales manager:
Information representative:
Head of regulatory affairs:
QA representative:
Other members:
3.4. Measures list Responsible ... Time limit ... Signature ...
Directions for implementing and Completed on ...
documenting the measure
Cross references to affected
documents that require revision
Extensive directions or project
planning may be recorded in separate
documents
4. QA head
Completion of procedure
The procedure has been completed correctly.
The procedure has not been completed correctly. It should be abandoned and not continued. Rationale:

The procedure has not been completed correctly. Deviations occurred and measures required for procedure
completion:

Date and signature of the QA head ....................................................