42
Retrospective Validation
Kevin Jenkins
Pfizer Inc., Terre Haute, Indiana, U.S.A.
INTRODUCTION
Retrospective validation is the validation of older/legacy
products, processes, or equipments. Retrospective vali-
dation establishes documented evidence that a system
does what it is supposed to do based on a review and
analysis of historic information. It is normally conducted
on a product already being commercially distributed and
is based on accumulated production, testing, and control
data. Often these products or systems have not been
validated to contemporary standards due to their age. It
should be realized that there is a diminishing point of
return at which retrospective validation is no longer
justified. Current processes, products and equipment
are expected to meet contemporary regulatory standards
by the relevant regulatory agencies. However, all is
not lost—there is a rational approach to determine if
retrospective validation is appropriate. In these cases,
the approach needs to be evaluated and completed in
a timely manner with significant data to support the
product/process/system.
A key consideration in contemplating the use of
retrospective validation is the regulatory agency point of
view. It may be useful to discuss with your district, local
or market region regulatory agency any concerns with the
use of a retrospective approach. As always, an approach
to retrospective validation should be documented in
advance in the form of a validation plan. This chapter
serves as a guide to develop a supportable retrospective
validation approach in terms of prerequisites, regulatory
guidance, an overall approach, and examples. Finally, this
chapter will explore retrospective validation in a PAT
environment where the traditional three-lot validation is
replaced by a continuous stream of data.
The Foundation for Retrospective Validation
Any retrospective validation project should start with a
strong foundation with regard to the overall systems
which support operations. As shown in Figure 1, there
are five layers of systems leading up to retrospective
product validation that need to be in place for success.
These five systems are as follows:
Abbreviations used in this chapter: APIs, active pharmaceutical ingre-
dients; CA-HCl, Cure-all hydrochloride; CFR, Code of Federal
Regulations; CPK, capability index for process average; EMEA,
European Medicines Evaluation Agency; EP, European Pharmaco-
poeia; FDA, Food and Drug Administration; GC, gas
chromatography; HPLC, high-performance liquid chromatography;
IQ, installation qualification; JP, Japanese Pharmacopoeia; LOD, loss on
drying; NIR, near infrared; OQ, operational qualification; PAT,
process analytical technology; PQ, performance qualification; R/S,
requirements and specifications; USP, United States Pharmacopeia.
& Site culture/commitment. The first layer is the overall
culture of the site or operation. This includes the
change control culture—are all changes captured
and handled adequately in a system? Part of this
culture includes the support of leadership for
change control, quality and validation. These key
quality systems need to be at the foundation. Edu-
cation of the overall workforce is also critical at
this level.
& Life cycle and change control. The next level includes
functions such as project management, procurement,
and life-cycle review. Are these well-controlled
processes? Can it be assured that through these
areas the correct components, replacement parts and
processes are maintained?
& Equipment/instrument history, maintenance and
calibration. The third level includes equipment
history, drawings, calibration and preventive
maintenance. These are crucial to maintain equipment
and processes in the correct working order. Included
as well in this level are laboratory methods and
equipment—are they validated and maintained?
This is critical to the foundation of a working
quality system in the laboratory where the data
is generated.
& Equipment R/S. The next level is the equipment R/S—
do they exist? Are they maintained through a life
cycle approach? These R/S are critical since they are
the foundation for the next level—qualification of
equipment. They also contribute to the overall vali-
dation plan that describes the system as a whole, how
it functions together and the approach to validation.
& Installation and OQ. The final level in advance of
product validation is equipment installation and
operational and process qualification. It is critical to
have these in place to assure control of the process and
the products produced as part of that process.
Each layer builds on the previous one. If elements
are missing then there needs to be some form of remedia-
tion at each stage to assure a solid foundation before
undertaking any product or process retrospective vali-
dation. These elements are summarized in Table 1 with the
relevant considerations for each item listed. This table
should be consulted before undertaking a retrospective
validation project or approach. Missing elements erode
the foundation on which a case could be built for retro-
spective validation.
RETROSPECTIVE PRODUCT VALIDATION APIs
The first approach to retrospective validation explored is
for APIs. The elements discussed previously must be in
556 VII: MANUFACTURING RELATED ACTIVITIES

Re-validation Project Includes:

-Master Document Controls
-Revalidation Equipment and Products
-Training and Education
-Maintenance Systems for Sustainable Change

Product
Validation

I/O/ Process Qualification

Equip Req. & Specs

Improvements/Remediation
Validation Plans

Equipment History Files Engineering Drawings

Calibration Preventative Maintenance
Equipment Access Lab Methods and Equip.Validation

Documentation Management and Control

Project Management Procurement Process Improvements
Periodic Lifecycle Review New Equip./Processes/Products

Education Culture Change Change Control Processes

Leadership Support and Financial Commitment

Figure 1 Support systems for restrospective validation.

place from a system perspective—now the discussion will
be from a product standpoint. The first requirement for
retrospective validation applied to a particular API is that
“it must be a well understood product/process with few
deviations” (1). If this initial requirement cannot be met,
then a concurrent validation approach may have to be
considered. If this initial criterion can be met, then there
are a series of prerequisites that must be further
considered as follows:
& The process is well understood and documented
throughout the full-scale manufacturing process.
& Critical process parameters and critical attributes are
identified, justified and understood.
& Reliable test data were/or will be generated using a
pharmacopoeia (USP/EP/JP) method or internally
validated test methods.
& There are no significant process or product failures
and any failure must be attributed to operator error or
equipment failure or a “one-off” well-understood
deviation.
& Impurity profiles are well established for the API.
Exploring each of these prerequisites in more detail:
1. The process is well understood and documented throughout
the full-scale manufacturing process. Processes that are
not well understood are not acceptable candidates for
retrospective validation. The execution of retrospec-
tive validation is not an acceptable time to gain
knowledge and understanding of the process.
There must also be sufficient documentation of the
process to qualify for retrospective validation. The
firm must be able to produce all relevant documen-
tation to demonstrate the conditions under which all
batches included in the retrospective validation were
produced. This task may be complicated by the low
volume production over time and changes during
this time period. As discussed previously, part of the
foundation is the data, documentation and change
history.
2. Critical process parameters and critical attributes
are identified and understood. Critical process
parameters contribute to critical attributes. For
instance, the critical process parameter of drying
time has a direct impact on the attribute of moisture
content through physical measurement via LOD
testing. This attribute is thereby the measure of
the process parameter. These process parameters
need to be identified and the attributes measured
and demonstrated to be in control. Any attribute not
in control needs to be critically evaluated to determine
if the batches under retrospective validation allow this
approach to be utilized.
3. Reliable test data generated using a pharmacopoeia
(USP/EP/JP) method or internally validated test methods.
The data utilized as part of retrospective validation are
critical to proving whether the process is well defined
and controlled. Data integrity is therefore crucial to the
retrospective validation the platform being built. All
data utilized must be either from pharmacopoeia or an
internally validated method. If it is a pharmacopeial
method, assure that the current version of the method
was used at the time these data were generated. In the
case of an internally validated method, assure that it
meets contemporary validation standards at the time
generated. Failure to meet these requirements puts
these data, and thereby the retrospective validation,
in jeopardy.
 42: RETROSPECTIVE VALIDATION 557

Table 1 Foundation Elements and Considerations for Retrospective Validation

Element
Product validation
IQ/OQ and process qualification
Equipment requirements and
specifications
Improvements and remediation
Validation plan
Equipment history files
Engineering drawings
Calibration
Preventative maintenance
Lab method and equipment
validation
Documentation management
Project management
Procurrement
Process improvements
Periodic life cycle review
New equipment, processes and
products
Education
Culture change
Change control processes
Leadership support and financial
commitment
Considerations
Need a strong product validation approach for prospective validation before approaching a
retrospective project
The underlying IQ and OQ need to be robust for the related equipment/facility. In addition, any PQ for
processes such as sterilization or aseptic processes must be in place
Need to be in place and act as foundation for the related IQ and OQ. Should be current and under
revision control
Any improvements or remediation to equipment, facility and processes should be captured in updated
requirements, specifications and related IQ, OQ and PQ
An overall comprehensive validation plan should be in place. Retrospective validation, where applied,
should be included and justified in this plan
Equipment history files should exist which capture changes, updates and overall maintenance of the
equipment
Engineering drawings for the equipment should be up to date and linked to change management
system
Calibration for the equipment and related instruments should be maintained and current
Preventative maintenance should be documented and current
The lab methods that will be used to support retrospective validation need to validated to contemporary
standards. All relevant instruments should have contemporary qualification
Documentation should be current for site and under the change management system control
There should be a strong project management group that assures systems are maintained
Procurement should control purchase of new equipment, spare parts and materials. Changes should
be under the change management system
Process improvements should be captured in the change management system in regards to drawing
updates, revalidation and instructions
A program should be in place to periodically review the status of all systems and recommend actions
such as revalidation. This should occur on at least a three year cycle
Should be evaluated against current systems and included in validation plan and life cycle
Assure colleagues in operation are educated on requirements for validation, change control and
validation planning at a minimum
Assure there is a culture shift if change control and validation were not robust in the past
Assure robust change control process is in place for facilities, utilities, equipment, lab methods,
processes and products
All of the items listed above require leadership support and financial commitment or they will not be
sustainable and erode the overall foundation of a robust system

4. There are no significant process or product failures. Any
failure must be attributed to operator error or equipment
failure. Often the significance is difficult to judge.
Remember that any product failure should have
been thoroughly investigated via a deviation investi-
gation procedure. If the failure investigation
determines the root cause was due to operator error
or equipment failure and not the process itself then
this does not necessarily implicate the process. An
example would be equipment malfunction—such as a
centrifuge in the process that stopped mid-batch due
to a power failure and resulted in an aborted or failed
batch. If, however, the batch completed without attri-
buted operator or equipment error and was out
of specification, this would cast doubt on control of
the process. This must be critically evaluated through
a comprehensive deviation investigation for each
batch included in the retrospective validation.
5. Impurity profiles are well established for the API. Since the
firm will typically have experience with the API
considered for retrospective validation there should
be substantial data on the impurity profile of the API.
These data must be reviewed to assure there were no
adverse trends or issues with impurities. Once again,
the methods utilized for the impurities evaluation
should be validated.
RETROSPECTIVE PRODUCT VALIDATION
PLANNING FOR APIs
Current ICH Q7A (1) guidelines recommend between 10
and 30 consecutive batches be examined as part
of retrospective validation. Fewer batches may be used
to justify retrospective validation, providing a docu-
mented sound scientific rationale is provided. These
batches need to be statistically examined closely for any
trends, deviations, and/or out-of-specification results.
Such data may call into question the applicability of a
retrospective approach to validation unless there is sig-
nificant evidence to indicate these trends or results are not
indicative of the process.
The validation plan for retrospective validation
needs to define the number of batches to include with a
scientific rationale for the number. The frequency of
production and age of the process (years produced)
should be considered. For instance, an API that is
produced infrequently such as a once a year, but only
produced for the past five years, provides limited data
over a short time span. The production of 10 batches per
year over two years provides both a wealth of data and a
shorter time span (12). The time span is an issue since the
longer the time span the greater chance of significant
changes to the process, equipment, and methods. Once
558 VII: MANUFACTURING RELATED ACTIVITIES
again this should be evaluated and factored into the
rationale included in the plan.
The contents of validation plans and protocols were
discussed previously in chapter 1. The content of the plan
should include the consideration of the prerequisites,
number of batches to be included, critical process par-
ameters, critical attributes, acceptance criteria and data
analysis approach to be utilized.
Case Study A Retrospective Validation
Approach for API
This section explores retrospective validation for a
fictional API called CA-HCl. First, examine some back-
ground on the API. CA-HCl starts as a precursor, cure-all
salt, that processes through a reaction process with
hydrochloric acid to form the CA-HCl form. This is
accomplished by charging the cure-all salt into a 50 kg
reaction vessel V-1. The hydrochloric acid is transferred
from a holding tank into the reaction vessel V-1. Next, a
wash process with acetone is conducted to remove
impurities and then an aqueous wash to remove water
soluble impurities. This is accomplished by transfer of the
slurry into vessel centrifuge C-1 and charging the acetone
from a separate transfer tank T-1. After centrifugation
water is added. The next step is the drying process
through centrifugation to remove excess moisture to a
target of 3.0% in the centrifuge. The final product is then
packaged into polyethylene-lined drums.
The initial CA-HCl process was developed and
implemented 20 years ago. Each year about 10 batches
are produced. The equipment was not initially validated
at installation 20 years ago, but the centrifuge was
replaced 5 years ago and was completely validated
(IQ/OQ) to contemporary standards. In addition a new
control system for the vessels V-1, transfer tank T-1 and
centrifuge C-1 was installed three years ago and full
computer validation completed. The test methods for
CA-HCl consist of the following assays:
& Potency by HPLC
& Impurities by HPLC
& Moisture by LOD
& pH measurement
& Residual solvents by GC
All methods were validated to contemporary stan-
dards five years ago. In addition, a retrospective
validation project was conducted at the same time to
qualify all instruments in the lab.
Before starting determine if the API is appropriate
for retrospective validation. Using criteria previously
established by Trubinski, it is determined from Figure 2
that there are over 20 batches in the product history and it
is a product which the company intends to continue
manufacturing (2).
Examination of the systems in place as described
previously in Table 1 and Figure 1 is conducted.
All identified systems are robust and therefore it
appears to be a candidate for retrospective validation.
At this point, a protocol to examine the 20 batches against
predetermined criteria should be written. This approach
will utilize each of the previously mentioned test
methods and assure all data meet defined specifications.
In addition, statistical analysis of the data will be
performed to assure no values are out of trend over
time. In this instance there was one out-of-specification
result for batch number 17. An investigation determined
that this was due to adding a low volume of acetone,
which resulted from a deviation to procedure. The batch
deviation was determined post completion and analysis.
The batch was rejected since it was outside the registered
specification for acetone addition quantity. Therefore, it is
not considered to have an impact on the retrospective
validation. The investigation is included as part of the
validation package. The conclusion will need to defend
the use of the 19 remaining batches for retrospective
validation.
DRUG PRODUCT
Retrospective validation for drug products has some
different considerations than APIs. Routinely, the FDA
expects prospective validation for any new product
coming to market. Even for existing products the
window for retrospective validation “is closing if not
already closed” (3). The guidelines for prospective
validation have been around since 1983 and inves-
tigators tend to view retrospective validation in a
negative framework since it is expected that all
products on the market at this point comply with
those guidelines. As a result, retrospective validation
is not as commonly used in drug product validation
as it once was. Retrospective validation was applied
when validation requirements were first put in place.
Today it is an expectation that firms have con-
temporary validation data (4). Once again, as stated
previously, retrospective validation applicability is
dictated by the change history for the process.
Therefore one needs to define upfront what will be
evaluated as part of retrospective validation for
drug products. This section will explore a number of
considerations.
Just as was the case for APIs, in the case of drug
products, the product must be a well-understood
product/process with few deviations. If this is not true,
then retrospective validation for the particular product
may not be the best choice and a prospective approach
should be considered. If a retrospective approach is
followed, the validation requirements may need to be
tightened, added further batches and provided a strong
rationale for why this approach is still valid. As always,
consultation in advance with regulatory agency or
industry consultants should be considered as a
logical choice.
Just as with retrospective validation for APIs if this
initial criterion is met then there are a series of prerequisites
that must be further considered as follows:
& The process is well understood and documented
throughout the full-scale manufacturing process.
& Critical process parameters and critical attributes are
identified and well understood.
& Reliable test data can be generated using pharmaco-
peias (USP/EP/JP) methods or internally validated
test methods.
& In-process controls and acceptance criteria are estab-
lished and in use throughout the critical portion of
the process.
 42: RETROSPECTIVE VALIDATION 559

No Previous
Validation

Manufacturing
History of 20
Batches
Yes No

Yes No Are there

Product to be
Significant
Sold/Discontinued
Changes?

No Yes

Is Timing a No Accumulate 20
Consideration? Batches

Yes

Low Priority Candidate for

Validation Retrospec Valid

END

Figure 2 Selection of candidates for

restrospective validation.

& There are no significant process or product failures.
Any failure must be attributed to operator error or
equipment failure and not the process itself.
& Impurity profiles are well established for the API used
in the drug product.
& Change control is in place and followed for the process.
It should be noted that generally these prerequisites
are the same as they were for APIs—except in three cases.
The three cases are highlighted above and will be explored
in further detail.
1. In-process controls and acceptance criteria are established
and in use. Generally, a drug product process involves a
number of defined stages. In tablet production
processes, for example, there are blending, drying,
compression, and coating stages to mention a few. At
each stage, there are critical in-process controls which
assure the product is acceptable to progress to the next
stage. As part of retrospective validation, these in-pro-
cess controls and the relevant data should be
examined as part of the validation. There should be
acceptance criteria in place from a production
standpoint and retrospective validation criteria
which are wider than the operating range, but tighter
than development ranges must be applied. Any
deviation needs to be investigated and explained as
part of the validation.
2. Impurity profiles are well established for the API used in the
drug product. In the previous section on APIs this was
discussed in relation to the API itself. Now it needs to
be assured that the API or APIs used in the drug
product have a well-defined profile such that there are
analytical, impurity and stability data that characterize
the API. The data must be further reviewed to assure
no adverse trends or issues with degradation, by-pro-
ducts or impurities that would place the final drug
product at risk.
3. Change control is in place and followed for the process. In
the drug product/process change control is a critical
consideration. If the intention is to retrospectively
validate a product for which there was an underlying
560 VII: MANUFACTURING RELATED ACTIVITIES
lack of change control, how can the firm assure the
process/product is consistent? Remember the key
definition of validation is a proven evidence that
the product/process has been consistent over the
retrospective validation evaluation period. Change
control assures that the process is consistent with
processes which are in control. Adequate change
control is a premise to validation. Lack of adequate
change control requires a detailed review of the
process and some retrospective review of the
change history. If the change control is inadequate,
retrospective product validation may not be appro-
priate and a prospective or concurrent product
validation approach should be strongly considered.
This review should be documented as part of the
validation. It is important that this review be compre-
hensive such that changes to product/processes,
equipment, excipients, procedures, and systems are
reviewed.
RETROSPECTIVE PRODUCT VALIDATION PLANNING
FOR DRUG PRODUCTS
The FDA’s CFR does not specifically identify retrospective
validation. It only states that process validation is a
requirement for the manufacture of pharmaceuticals and
medical devices (5). There is, however, a section on retro-
spective validation in the FDA guidelines on validation.
These guidelines state that “in some cases a product may
have been on the market without sufficient pre-market
process validation. In these cases it may be possible to
validate, in some measure, the adequacy of the process by
examination of accumulated test data on the product and
records of the manufacturing procedures used” (6). The
question to ask is how much data is required for retro-
spective product validation? This chapter will explore
some examples as part of case studies later. For now it is
sufficient to say that this depends on the process and its
history. There is one other critical statement in the above
test from the guideline: “records of the manufacturing
process used.” It was stated in the opening of this
section that for the process to be a candidate for retro-
spective validation it must be well documented,
understood, and under change control. These are critical
to allow this retrospective validation approach.
The second paragraph of the guideline specific
to retrospective validation suggests that “retrospective
validation can also be useful to augment initial pre-market
prospective validation for new products or changed
processes.” Typically these are prequalification batches
that can be examined as part of developing a final
prospective validation approach. However, in many
cases these prequalification batches have inherent
differences from the final batch process to be qualified.
This must be taken into account as part of the approach.
Statistical analysis of the prequalification batches as
compared with retrospective data is a useful tool which
will be discussed later as one strategy.
The last paragraph of the guideline states in regards
to retrospective validation that “Test data may be useful
only if the methods and results are adequately specific.”
The section goes on to state that “Specific results, on the
other hand, can be statistically analyzed and a
determination can be made of what variance in data can
be expected.” This statement suggests that statistical
evaluation be performed on the method itself using tools
such as Gauge R&R or CPK calculations to determine
variation of the methods. If the variation is too extreme,
it may not be possible to use the method to justify the
previous set of acceptance criteria in the retrospection
validation plan. In those cases, other methods may be
necessary or tightening of the method variance required.
That is an acceptable approach in a prospective validation
plan where such adjustments can be made. In a retro-
spective validation approach these data have already been
generated. It may, however, allow a change to the
approach or target-specific methods as key to validation
based upon the statistical analysis of the data. For instance,
this analysis may determine one method is more critical
than another and narrow the scope of data required for the
retrospective validation.
The last sentence of the guideline section states that
“Whenever test data are used to demonstrate conformance
to specifications, it is important that the test methodology
be qualified to assure that test results are objective and
accurate.” This was also one of the principles required for
retrospective validation— that reliable test data are gener-
ated using a pharmacopeias (USP/EP/JP) method or
internally validated test methods.
EMEA View
The EMEA guidance for manufacturers has a section on
retrospective validation in annex 15.31–15.35 (7). There are
five major points (31–35) which support what has already
been stated as requirements and prerequisites. The first
point “retrospective validation is only acceptable for well-
established processes and will be inappropriate where
there have been recent changes in the composition of the
product, operating procedures or equipment.” This
supports the initial criteria that the process/product
must be well understood. This guidance also points out
the issue of change control as noted in the previous dis-
cussion on prerequisites. It brings up another point about
consistency of the process, that changes to the proces-
s/product over time have not included major changes
which may require significant revalidation. If that was
the case, then concurrent validation should have been
performed at that point, not retrospective validation at a
later point.
The next point in the EU guide is that “validation
of.processes should be based on historical data. The steps
involved require the preparation of a specific protocol.-
leading to a conclusion and recommendation.” It was
indicated planning for retrospective validation that a
predetermined validation plan or protocol must document
the approach and acceptance criteria. This guidance
further reenforces the point and highlights the importance
of the final conclusion and recommendation. Data are
another key aspects of the retrospective validation. There
is further guidance on the source of data. “The source of
data.should include.batch processing and packaging
records, process control charts, maintenance log books,
records of personnel changes, process capability studies,
finished product data, including trend cards and storage
stability results.” The point here is that there should be a

comprehensive data review from all of these documented
sources. Every “stone” must be overturned, so to speak, as
part of this review. This is a significant task in some cases
that requires a thorough approach to assure all data is
collected, analyzed, and included in the retrospective
validation package. These data must then be tested
against the pre-established acceptance criteria. In some
cases this is such a significant undertaking that a concur-
rent validation approach will require less investment.
The next section deals with the batches selected as
part of the validation. The EU guide states that “Batches
selected for retrospective validation should be representa-
tive of all batches made during the review period,
including any batches that failed to meet specifications.”
Previously, it was stated as a prerequisite that there may be
no significant process or product failures, and any failure
must be attributable to operator error or equipment failure.
This guidance appears to allow inclusion of failed batches
and notes that it must be a comprehensive set of batches
over the review period. A word of caution is appropriate
here—failed batches will have a great deal of scrutiny by a
regulatory agency. This means that the firm must exert an
even greater level of scrutiny and conclude if a consistent
and thereby validated process/product exists. The inves-
tigations of these failed batches need to have identified
root cause(s). That determined root cause(s) should not
indicate a process/product failure—if it does, concurrent
revalidation after the issue is resolved must be considered.
This may also require development work to understand
the source of the failure.
Another key point is made in the final sentence of
this reference: “Additional testing of retained samples
may be needed to obtain the necessary amount or type
of data to retrospectively validate the process.” During the
development of the validation plan and protocol, the firm
may find that the methods and data are not sufficient to
support the validation. This could be due to assay varia-
bility as mentioned previously or that the method was not
in place at the time the batch was initially analyzed. The
firm may also encounter during data review that there are
missing data. One additional word of caution: in the case
of failed batches do not use retained samples to try and
retest and eliminate failed results unless investigation(s)
can invalidate the initial result. If these issues do not apply,
then available retained samples may be useful to supple-
ment overall data and support the retrospective
validation.
The final point in the EU guide provides guidance
for the number of batches to include in the retrospective
validation. The recommendation is “ten to thirty consecu-
tive batches.but fewer may be examined if justified.”
This is consistent with previous ICH guidance for APIs.
One important note is the word “consecutive” batches—
the firm cannot pick and choose the batches it wants to use.
The number of batches must be defined in the preap-
proved validation plan and protocol. As stated clearly in
the guidance, any choice outside of 10–30 requires a
rationale for that choice. In the examples section this
chapter will explore how to arrive at this number.
It should be based on the specific attributes, history, and
characterization of the product.
Remember that a retrospective validation approach
is not generally accepted unless plenty of data are included
to make a case. The data are keys to justification of the
42: RETROSPECTIVE VALIDATION 561
retrospective validation and should utilize statistical
methods for evaluation.
STATISTICAL ANALYSIS OF BATCHES
In the case of measuring variation of the methods used to
generate retrospective data gauge, R&R and CPK values
are useful to assess each method. This evaluation should
be used to determine if the methods are suitable to provide
data for a retrospective validation strategy.
Once the data are generated there needs to be some
evaluation against either previous development data or
predetermined acceptance criteria. Significant testing,
where there is a null hypothesis of no difference between
the observed and the known or previous obtained values,
is useful (8). Useful analysis methods include but are not
limited to comparison of mean, paired t-tests, and F-tests
for comparison of standard deviation. The overall lesson is
that the use of statistics provides a scientific basis for
comparison to make a case that the process or product is
comparable to previous experience or data and that the
method is well under control.
An Approach to Retrospective Validation
for Drug Product
Case Study Examples
In this section a retrospective validation approach for
a fictional sterile product Steri-Cure will be provided. It
is an aseptically filled liquid composed of the
drug substance CA-HCl. Cure-All is dissolved in WFI
using a 500 L mixing tank, aseptically filtered, and trans-
ferred to a holding tank for aseptic filling. The following
table lists the critical quality attributes and parameters
which impact these attributes.
Critical process parameters
Critical quality attributes affecting quality attributes
Formulation
Temperature
Potency API dissolution mix speed
Degradation products API dissolution mix time
pH Final mix time
Color of solution Final mix speed
Appearance of solution Final mix pH
Hold times
Steri-Cure has been aseptically filled at this particu-
lar facility for 15 years. There is no contemporary
validation for this product. Previous validation was
performed on other aseptic products which utilize the
same filling equipment and filling suite. This validation
included all aseptic process validation, and media fills are
conducted on a semi-annual basis for this product and
aseptic process.
Retrospective validation is proposed to validate the
manufacturing process since Steri-Cure, an older product,
is only produced once every two years based on demand.
A validation plan was therefore written which considered
the change control history, development data, methods
validation and drug substance characterization.
562 VII: MANUFACTURING RELATED ACTIVITIES
In this case the change control on the tanks, pH
meter, and mixer used in the process are current since
they are shared with other products. There is cleaning
validation for this equipment as well. All analytical
methods for the product were validated two years ago as
part of an overall program in the laboratory. A review of
batch records indicated that dating back 10 years there
were 25 batches produced. The drug substance is well
characterized and method development data, while old, is
still available.
An evaluation of these data for a retrospective
approach indicates that while there are an adequate
number of batches for evaluation, only two batches were
manufactured since the analytical methods were fully
validated. This adds a degree of risk to a retrospective
validation approach. It is not necessary to include the
filling equipment or filling suite since adequate, contem-
porary validation exists for the filling of other comparable
liquid aseptic products in the same equipment and
line configuration. Although the same argument could
be applied for the manufacturing process, it is
not recommended.
The development data are older and at the time the
documentation did not cover all of the critical quality
attributes. It is discovered that the mixing time was
changed along with a pH step addition about five
years ago due to an incident where the drug substance
was not completely dissolved after the normal mixing time,
temperature, and drug substance addition. Investigation at
the time determined that mixing speed was not recorded in
the development, or in routine operation. It was
determined that due to changes in the operators who
previously performed this manufacturing process, a
change was made in mixing. A study was conducted at
that time to determine optimal mixing time, and a pH
adjustment step was added.
Due to these significant process changes and the lack
of previous batch data without adequate method vali-
dation retrospective validation is not recommended.
A concurrent validation approach is therefore rec-
ommended that will include three batches and also the
listed critical process parameters which will be measured
in the protocol through lab analysis of the critical attri-
butes. Given the normal low demand for the product, three
batches will be produced in succession with only one
going on to final filling. The critical attributes will be
measured against the existing specification for the
product in regards to the potency of solution, degradatio-
n/impurity limits, pH range, color of solution, and
appearance of solution.
In summary our review indicated that this product
was not a good candidate for retrospective validation.
Factors that contributed to this decision are the change
history, deviations in process, and analytical method
validation to contemporary standards. As mentioned pre-
viously, all of these must be critically evaluated to consider
retrospective validation. Often, age of the product/process
can work against a retrospective validation approach.
RETROSPECTIVE PROCESS VALIDATION
Retrospective process validation often has some of the
same concerns and considerations of prospective
validation as mentioned previously. Overall, there are
systems where it can be applied and those where it
cannot. For instance, a system which has routine in-process
data for evaluation and is controlled based on the data
could be a candidate. In the case of a water system,
perhaps there was some initial validation conducted long
ago, or the system was only qualified. Since it is a
requirement to continually monitor and control the
system, this previously generated data can be used to
retrospectively validate the system. The FDA guide to
inspection of water systems requires phase I, II and III
validation (9). In the final phase, the data for chemical and
microbiological analyses are required on a frequent basis
under protocol. Clearly there are USP criteria preestab-
lished for these tests. Therefore, if the data history is
available then these USP criteria can be utilized for
evaluation and retrospective validation of the system.
In other systems such as sterilization processes it is
clear that these must have not only prospective validation
but also an annual or a periodic requirement for revalida-
tion that is prospective as well (10). These sterilization
processes are part of a larger overall aseptic process and
often there is not the level of in-process data generated as
part of control for the water system example.
In summary, if the system has in-process controls
and preestablished criteria, these data could be used to
evaluate and validate the system.
RETROSPECTIVE EQUIPMENT
QUALIFICATION/VALIDATION
Retrospective equipment qualification/validation applies
in cases where contemporary IQ, OQ, and PQ do not exist
for equipment. In these cases, as mentioned previously,
retrospective product validation is not recommended since
the underlying foundation is not sound.
In the case of retrospective equipment qualifi-
cation/validation, many of the criteria mentioned
in Table 1 and Figure 1 still apply. Criteria such as
improvements and remediation to the equipment, equip-
ment history/use, calibration records, preventative
maintenance records, and change control should all be
evaluated. Leadership support and financial commitment
is important since retrospective qualification of some
equipment may be more costly and at greater risk than
to purchase and prospectively qualify new equipment.
If a retrospective approach can be justified, the first
activity is to develop an accurate set of combined R/S.
Since this equipment is already installed these combined
R/S should represent the “as-found” condition unless
there is a justification to change. For instance, if the
mixer is rotating in the opposite direction from initial
design it should be left that way and captured as such in
the R/S since all batches previously produced were under
these conditions. This assumes that all specifications
were met.
Once this combined as-found R/S is created, it can
be used for the foundation of the Retrospective IQ/OQ
and PQ, if applicable. Critical attributes and process
parameters should be defined. The IQ will be minimal
since the equipment is already in place, but will confirm
that installation was per original manufacturer recommen-
dations and that critical documentation, spare parts listed,

procedures, and operating instructions are in place. The
OQ will assure that the system operates as designed and
all critical parameters are met.
RETROSPECTIVE VALIDATION IN A PAT
ENVIRONMENT
PAT is a system for designing, analyzing, and controlling
manufacturing through timely measurements (i.e., during
processing) of critical quality and performance attributes
of raw materials and/or in-process materials and
processes with the goal of ensuring final product quality
(11). The specifics of PAT are covered in detail under
chapter 10. In this section we will only cover some
considerations in a PAT environment related to
retrospective validation.
In a process utilizing PAT, traditional validation
principles may not apply. Three batches are insignificant
where thousands of data points will be examined for the
critical parameter(s) measured. It is important to be aware
that PAT may show much more about the process than was
previously known or understood.
As an example, consider a batch API process where
moisture level after centrifugation and drying is critical.
The capability to measure moisture using PAT via an
in-line NIR is now available. Figure 3 is a set of data in
five-minute intervals for this process.
In order to make a change to the drying or centri-
fugation time to this process in the traditional validation
model it would be necessary to analyze three consecutive
batches. In a PAT environment continuous data are avail-
able that can be analyzed. The traditional three-batch
approach would not apply since continuous data are
present. Advantages of this approach include not only
the additional data, under real-time conditions, but also
the process understanding, quality of data, and reduced
validation time.
In fact, there is a preponderance of data—actually,
substantially more data than normally available, in
traditional validation. It is important to note when the
change occurred, set preestablished criteria for the
moisture level, and measure or trend data after the
change. If these data indicate a state of control within
predefined specification or limits then it may meet vali-
dation criteria. In essence, it is possible to concurrently
Process Moisture
0.7
0.6
% Moisture
0.5
0.4
0.3
0.2
0.1
0 Pharmaceutical cGMPs. Washington, DC: Food and Drug
0 50 100 150
Time (minutes)
Figure 3 In-process data for moisture.
42: RETROSPECTIVE VALIDATION 563
validate the process through use of on-line data generated
as part of a PAT measurement process.
If this PAT process measurement is new it would be
necessary to compare variability of PAT method to an
established, validated, analytical lab-based method as a
reference. The PAT Guidance from the FDA in
fact indicates that a test-to-test comparison may be
required when implementing a new on-line process
analyzer.
PAT opens up a new approach to validation—it
provides real-time data to examine and validate process
changes within the process itself.
CONCLUSION
This chapter has discussed retrospective validation
in relation to both drug substance and product. There are
a number of prerequisites which must be in place for a
process to be a candidate for retrospective validation. In
addition to these prerequisites, there is an underlying set
of elements that must be in place as a foundation to assure
a solid ground for retrospective validation.
It also includes examples of test cases for both drug
substance and product retrospective validation. These test
cases utilized the prerequisites and elements as criteria for
acceptance. Unless there are solid data sets, foundation and
rationale retrospective validation is not always justified as
an approach. In many cases, prospective or concurrent
validation is a better approach. All of these considerations
must be taken into account to pursue this avenue for
validation.
A brief examination of process and equipment
validation has been provided. The same considerations
apply in these instances. Finally, the chapter has explored
retrospective validation in regards to a PAT environment.
This area provides so much data that the traditional
approach does not apply.
Overall, retrospective validation has a number of
risks that must be carefully considered for the particular
product, history, and prerequisites described previously. If
a solid foundation does not exist it may not be the best
approach. This preevaluation will allow the risks to be
determined and made the validation approach decision
based on all the data.
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