A written protocol that describes what is to be accomplished should be prepared
[5]. It should specify the data to be collected, the number of batches to be
included in the study, and how the data, once assembled, will be treated for
relevance. The criteria for acceptable results should be described. The date of
approval of the protocol by the validation organization should also be noted.
The value of a protocol is to control the direction of the study, as well as provide
a baseline in the event unanticipated developments necessitate a change in strategy.
A written protocol is also an FDA recommendation
Sunday, January 31, 2010
Critical Process Steps and Control Tests
Critical process steps are operations performed during dosage-form manufacture
that can contribute to variability of the end product if not controlled. Since each
type of dosage form requires different machinery and unit operations to produce
the end product, the critical process steps will also differ. For each product
considered suitable for retrospective validation, a list of these steps must be
compiled following careful analysis of the process by technically competent
persons. In a similar manner, in-process and finished-product tests should be
screened to identify those that may be of some value. As a rule, tests in that the
outcome is quantitative will be of greatest interest.
A flow diagram of the entire operation, but particularly of the manufacturing
process, may be helpful in identifying critical steps, especially where the
process involves many steps. Such a diagram is also a useful addition to the
validation report prepared at the conclusion of the study.
that can contribute to variability of the end product if not controlled. Since each
type of dosage form requires different machinery and unit operations to produce
the end product, the critical process steps will also differ. For each product
considered suitable for retrospective validation, a list of these steps must be
compiled following careful analysis of the process by technically competent
persons. In a similar manner, in-process and finished-product tests should be
screened to identify those that may be of some value. As a rule, tests in that the
outcome is quantitative will be of greatest interest.
A flow diagram of the entire operation, but particularly of the manufacturing
process, may be helpful in identifying critical steps, especially where the
process involves many steps. Such a diagram is also a useful addition to the
validation report prepared at the conclusion of the study.
Written Operating Procedures
The various activities and responsibilities associated with retrospectively validating
a product must be put in writing. All too often this simple but crucial
step is omitted for the sake of expediency only to find at a later date that the
Copyright © 2003 Marcel Dekker, Inc.
initial assumptions cannot be recalled. Aside from maintaining consistency, a
written procedure to describe the work being performed satisfies the intent of
the current good manufacturing practice (CGMP) regulations.
In general, the written operating procedure should delineate in reasonable
detail how the validation organization will function. Not every situation can be
anticipated, and this should not be the goal. There should be sufficient detail,
however, to ensure consistency of performance in an undertaking that may continue
for several months. In the preparation of such a document, the following
questions should be answered:
1. Which organizational functions will be represented on the validation
committee?
2. What mechanism exists for validation protocol preparation and approval?
3. What criteria are used to select critical process steps and quality control
tests for which data will be collected?
4. How often will the committee meet to ensure prompt evaluation of
study data?
5. Who has responsibility for documenting committee decisions? For
report preparation?
6. Is there a provision for follow-up in the event of unexpected findings?
7. Where will the original study data and reports be archived?
In the preceding discussion of areas of interest to the validation organization,
two concepts were introduced that deserve further clarification: (1) critical
process steps and quality control tests that characterize the operation, and (2)
validation protocol.
a product must be put in writing. All too often this simple but crucial
step is omitted for the sake of expediency only to find at a later date that the
Copyright © 2003 Marcel Dekker, Inc.
initial assumptions cannot be recalled. Aside from maintaining consistency, a
written procedure to describe the work being performed satisfies the intent of
the current good manufacturing practice (CGMP) regulations.
In general, the written operating procedure should delineate in reasonable
detail how the validation organization will function. Not every situation can be
anticipated, and this should not be the goal. There should be sufficient detail,
however, to ensure consistency of performance in an undertaking that may continue
for several months. In the preparation of such a document, the following
questions should be answered:
1. Which organizational functions will be represented on the validation
committee?
2. What mechanism exists for validation protocol preparation and approval?
3. What criteria are used to select critical process steps and quality control
tests for which data will be collected?
4. How often will the committee meet to ensure prompt evaluation of
study data?
5. Who has responsibility for documenting committee decisions? For
report preparation?
6. Is there a provision for follow-up in the event of unexpected findings?
7. Where will the original study data and reports be archived?
In the preceding discussion of areas of interest to the validation organization,
two concepts were introduced that deserve further clarification: (1) critical
process steps and quality control tests that characterize the operation, and (2)
validation protocol.
Organizing for Retrospective Validation
To this point we have produced a list of products that may be validated retrospectively;
that is, their manufacturing processes are relatively stable, and so
adequate historical data exist on which to base an opinion. The next consideration
is the formal mechanism for validating the individual products. Appropriate
organizational structures for effectively validating processes have been
put forth, but mostly in conjunction with the validation of new product introductions.
Still, these recommendations can serve as models. Because the products
being studied are marketed products, the quality assurance and production departments
can be expected to make major contributions. In fact, as far as retrospective
validation is concerned, it may be more appropriate for one of these
departments to coordinate the project. The research and engineering departments,
of course, will be needed, especially where recent process changes have
been encountered or equipment design is at issue.
Operating as a team, the previously discussed disciplines will determine
which data should be collected for each product and from how many batches;
subsequently, they will evaluate the information and report their findings. Personnel
resources beyond this committee are necessary to accomplish the tasks of data collection and analysis. The time requirements dictate that such work be
assigned to a function with discretionary time, possibly a technical services
group or a quality engineer. Management commitment is especially crucial if
disruptive influences are to be minimized. The loss of a committee member to
another project is such an example.
that is, their manufacturing processes are relatively stable, and so
adequate historical data exist on which to base an opinion. The next consideration
is the formal mechanism for validating the individual products. Appropriate
organizational structures for effectively validating processes have been
put forth, but mostly in conjunction with the validation of new product introductions.
Still, these recommendations can serve as models. Because the products
being studied are marketed products, the quality assurance and production departments
can be expected to make major contributions. In fact, as far as retrospective
validation is concerned, it may be more appropriate for one of these
departments to coordinate the project. The research and engineering departments,
of course, will be needed, especially where recent process changes have
been encountered or equipment design is at issue.
Operating as a team, the previously discussed disciplines will determine
which data should be collected for each product and from how many batches;
subsequently, they will evaluate the information and report their findings. Personnel
resources beyond this committee are necessary to accomplish the tasks of data collection and analysis. The time requirements dictate that such work be
assigned to a function with discretionary time, possibly a technical services
group or a quality engineer. Management commitment is especially crucial if
disruptive influences are to be minimized. The loss of a committee member to
another project is such an example.
PROCESS VALIDATION STRATEGIES
For a product to be considered for retrospective validation, it must have a stable
process; that is, one in which the method of manufacture has remained essentially
unchanged for a period of time.
The first step in the product selection process is therefore to obtain a
summary of changes in the method of manufacture. In most companies such
information is part of the master batch record file. Then a time interval is selected
that represents the last 20 to 30 batches. Products for which there is no
record of a change in the method of manufacture or control during this period
can be regarded as candidates for validation. The 20-to-30-batch rule originates
from control chart principals, which consider 20 to 30 points that plot within
the limits as evidence of a stable process [4]. Once this criterion is met, the
number selected is actually somewhat arbitrary, as there is no one number that
is correct for every product. The ideal number of batches required to study a
product is theoretically the number that permits all process variables to come
into play. By process variables, we mean raw materials from different but approved
vendors, introduction of similar but different pieces of equipment, personnel
and seasonal changes, and the like. This academic approach may present
a rather unwieldy situation, especially for a high-volume product, for which
change in process variables occurs infrequently. The influence of seasonal
changes is such an example. In such instances, compromise will need to be
reached between process variables included for study and the number of batches
that can be examined for data. This decision making is best handled by a validation
committee, the organization and makeup of which is covered in detail later
in this chapter.
The second step in the product selection process addresses the situation in
which a change in the method of manufacture or control was implemented during
the last 20 or so production batches. The fact that a change has occurred
does not automatically disqualify the product for retrospective validation. One
must first know whether the particular modification has caused an expected
result to be different to the extent that it is no longer comparable to previous
batches. An example may be helpful. Suppose the method of granulating was
changed midway through the series of 20 batches selected for the validation
study. The number of batches representing the new process would be significantly
reduced and could be insufficient to capture some of the interactions that
can affect process reproducibility. In general, a history of any one of the follow-
Copyright © 2003 Marcel Dekker, Inc.
ing changes to the method of manufacture and control should be fully investigated
before any decision is made to validate retrospectively:
1. Formulation changes involving one or more of the active ingredients
or key excipients
2. Introduction of new equipment not equivalent in every respect to that
previously in use
3. Changes in the method of manufacture that may affect the product’s
characteristics
4. Changes to the manufacturing facility
A product found to be unsuitable for retrospective validation because of a
revised manufacturing process is a likely candidate for prospective validation,
which is beyond the scope of this chapter [1]. Such a discovery, however, should
be brought to the attention of the appropriate authority. In today’s regulatory
environment ignoring the matter would be imprudent.
The third and last step in our selection process is to identify which products
are likely to be discontinued because of a lack of marketing interest or
regulatory consideration, to be sold, or to be reformulated. The timing of these
events will dictate whether the product in question remains a viable candidate
for retrospective validation.
process; that is, one in which the method of manufacture has remained essentially
unchanged for a period of time.
The first step in the product selection process is therefore to obtain a
summary of changes in the method of manufacture. In most companies such
information is part of the master batch record file. Then a time interval is selected
that represents the last 20 to 30 batches. Products for which there is no
record of a change in the method of manufacture or control during this period
can be regarded as candidates for validation. The 20-to-30-batch rule originates
from control chart principals, which consider 20 to 30 points that plot within
the limits as evidence of a stable process [4]. Once this criterion is met, the
number selected is actually somewhat arbitrary, as there is no one number that
is correct for every product. The ideal number of batches required to study a
product is theoretically the number that permits all process variables to come
into play. By process variables, we mean raw materials from different but approved
vendors, introduction of similar but different pieces of equipment, personnel
and seasonal changes, and the like. This academic approach may present
a rather unwieldy situation, especially for a high-volume product, for which
change in process variables occurs infrequently. The influence of seasonal
changes is such an example. In such instances, compromise will need to be
reached between process variables included for study and the number of batches
that can be examined for data. This decision making is best handled by a validation
committee, the organization and makeup of which is covered in detail later
in this chapter.
The second step in the product selection process addresses the situation in
which a change in the method of manufacture or control was implemented during
the last 20 or so production batches. The fact that a change has occurred
does not automatically disqualify the product for retrospective validation. One
must first know whether the particular modification has caused an expected
result to be different to the extent that it is no longer comparable to previous
batches. An example may be helpful. Suppose the method of granulating was
changed midway through the series of 20 batches selected for the validation
study. The number of batches representing the new process would be significantly
reduced and could be insufficient to capture some of the interactions that
can affect process reproducibility. In general, a history of any one of the follow-
Copyright © 2003 Marcel Dekker, Inc.
ing changes to the method of manufacture and control should be fully investigated
before any decision is made to validate retrospectively:
1. Formulation changes involving one or more of the active ingredients
or key excipients
2. Introduction of new equipment not equivalent in every respect to that
previously in use
3. Changes in the method of manufacture that may affect the product’s
characteristics
4. Changes to the manufacturing facility
A product found to be unsuitable for retrospective validation because of a
revised manufacturing process is a likely candidate for prospective validation,
which is beyond the scope of this chapter [1]. Such a discovery, however, should
be brought to the attention of the appropriate authority. In today’s regulatory
environment ignoring the matter would be imprudent.
The third and last step in our selection process is to identify which products
are likely to be discontinued because of a lack of marketing interest or
regulatory consideration, to be sold, or to be reformulated. The timing of these
events will dictate whether the product in question remains a viable candidate
for retrospective validation.
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