T ECHNICAL G UIDE

EXPANDING THE GLOBAL KNOWLEDGE BASE

FOR COMPLIANCE PROFESSIONALS IN
FDA-REGULATED INDUSTRIES.
Technical Guide 1
A Practical Guide to
Change Control
Systems Management
C
hange is accepted as
. . . FDA has cited part of everyday manu-
facturing operations by
a number of current good manufacturing
manufacturers practice (cGMPs) and FDA.
Pharmaceutical manufacturers
for lack of have developed excellent qual-
ity/compliance systems to mini-
comprehensive mize unplanned changes in the
manufacturing/packaging opera-
change control tions. However, planned changes
also require a stringent set of
systems. controls to attain desired results.
In recent years, FDA has cited a
number of manufacturers for lack
of comprehensive change con-
trol systems. The Agency
expects industry to have qual-
ity/compliance systems in place,
which should trigger a chain of
events whenever there is change
involving a drug product or medi-
cal device intended for con-
sumer use. The ultimate goal is
to build quality into a drug prod-
uct instead of testing a sample
for conformance at the end,
thereby rigidly controlling any
changes and deviant behavior of
the systems involved.
by This paper will provide qual-
Shahid T. Dara ity/validation professionals with
President basic concepts about change
Compliance Consulting Inc. control systems, different types
2 Journal of GXP Compliance
of changes that might be
encountered in a pharmaceutical
operation, and the means to
control them.
cGMP REGULATIONS
AND CHANGE CONTROL
Since the end of World War II,
the pharmaceutical industry has
experienced tremendous growth
and expansion in more than just
economic terms. Starting with
antibiotics, the drug discovery
process has introduced hun-
dreds of new remedies along
with new and novel drug delivery
systems, transforming the art of
formulation into a pure science.
Technological advances in man-
ufacturing equipment enabled
industry to not only increase the
speed of manufacturing, but
improve the quality of the end
product as well. All these
changes in pharmaceutical man-
ufacturing happened in a little
over 50 years, and the process
is continuing. The new global
economic realities and market
pressures of the 1990s have
forced the entire industry to
adopt cost-effective ways of
managing every aspect of the

business. There are fewer qualified individuals
managing multitudes of critical responsibilities
within each organization, thereby making it impera-
tive that new techniques of managing quality and
compliance be adopted.
This constant cycle of change demands effec-
tive tools to control all such changes related to
drug products. FDA and other regulatory agencies
in the world accept the fact that change is part of
the pharmaceutical business, but expect industry
to have effective change control systems in place
to assure that the quality, strength, and efficacy of
drug products are not compromised.
Evolution of cGMPs
On the legal front, the regulatory and
quality/compliance expectations for the pharma-
ceutical industry have steadily increased over the
past 90 plus years, since the enactment of the
Food and Drug Act of 1906, to the point where it is
one of the most regulated industries in the world
today. Drug regulations continued to evolve over
the first half of the 20th century and culminated in
1962 with the introduction of Current Good
Manufacturing Practices (cGMPs) regulations.
Section 501(a) (2)(B) of the Food, Drug and
Cosmetic Act deems a drug to be adulterated if:
“…the methods used in, or the facilities or
controls used for, its manufacture, processing,
packing, or holding do not conform to or are not
operated or administered in conformity with cur-
rent good manufacturing practices to assure that
such drug meets the requirements of this Act as
to safety and has the identity and strength, and
meets the quality and purity characteristics,
which it purports or is represented to possess.”
The cGMP regulations were developed by the
Pharmaceutical Manufacturers Association as
guidelines for its member companies in the early
1960s and were later adopted by the FDA as part
of the Food, Drug and Cosmetic Act of 1962. From
FDA’s perspective, these regulations were meant
to provide a precise, easily understood set of stan-
dards that would help both compliance and
enforcement, while encouraging the new innova-
tions to improve the manufacturing and control
practices. Therefore, the word “current” in these
regulations takes on a critical meaning, as it
implies that the manufacturers will change their
Shahid T. Dara
practices as technological innovations are made in
components, machines, or manufacturing prac-
tices. Thus cGMPs indirectly ask for a change con-
trol system to manage any new developments
regarding manufacture of a drug product or medi-
cal device.
The cGMP regulations have been criticized as
being too vague by industry, but are based on
these fundamental principles of quality assurance:
“Quality, safety and effectiveness must be
designed and built into a finished drug product;
Quality cannot be inspected or tested into a
finished drug product; Each step of the manu-
facturing process must be controlled to assure
that the finished drug product will meet its
specifications.”
With advances in technology and scientific
knowledge, the understanding of critical mate-
rial, equipment, and process variables also
increases, thereby resulting in a better definition
of the variables that could impact the overall
quality of the drug product. Such variables
should be closely monitored and controlled to
assure end product homogeneity and confor-
mance to specifications.
21CFR – Parts 210 and 211 describe the cGMP
regulations for human and animal drug products.
Change control is specifically addressed in the fol-
lowing sections of cGMP Regulations and the
Quality System Regulation (QSR):
21CFR – Part 211 Subpart F –
Production and Process 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.
(b) Written production and process control pro-
cedures shall be followed in the execution of the
various production and process control functions
and shall be documented at the time of perfor-
mance. Any deviation from the written procedures
shall be recorded and justified.
Technical Guide 3
Shahid T. Dara
21CFR – Part 211 Subpart I –
Laboratory Control
211.160:
(a) The establishment of any specifications,
standards, sampling plans, test procedures, or
other laboratory control mechanisms required by
this subpart, including any changes, in such
specifications, standards, sampling plans, test
procedures, or other laboratory control mecha-
nisms, shall be drafted by the appropriate orga-
nizational unit and reviewed and approved by
the quality control unit. The requirements in this
subpart shall be followed and shall be docu-
mented at the time of performance. Any devia-
tion from the written specifications, standards,
sampling plans, test procedures, or other labora-
tory control mechanisms shall be recorded and
justified.
21CFR – Part 820, which became effective in
October 1996, details the Quality System Reg-
ulations, which governs the manufacture of medi-
cal devices, addresses the subject of change con-
trol in the following subparts:
■ 820.30 – Design Controls
(i) Design changes
■ 820.40 – Document Controls
(b) Document changes
■ 820.70 – Production and Process Controls
(c) Production and process changes
■ 820.75 – Process Validation
(d) Changes or process deviations
■ 820.90 – Nonconforming Product
As is evident from the above listing, the Agency
has put forth these requirements with a clear
objective, i.e., to build quality into a medical device
being manufactured by adhering to these regula-
tions while controlling every aspect of possible
changes.
FDA has amended the cGMP regulations
many times since their implementation in 1963.
Major revisions were made in 1971, 1978, and
1995. A new set of regulations was issued in
1997 to address the electronic signature and
related issues. In 1996, the Agency proposed
the latest revisions to these regulations to clarify
the subject of process validation, but also
addressed other issues, including change con-
trol.
4 Journal of GXP Compliance
21CFR – Part 211 Subpart B –
Organization and Personnel
211.22 Responsibilities of Quality Control Unit
(Proposed)
The quality control unit shall be responsible for
the review and approval of validation protocols and
the review of changes in product, process, equip-
ment, or other changes to determine if and when
revalidation is warranted.
By proposing this revision to the quality control
unit, the Agency has clearly stated its position on
the subject of change control and its compliance
expectations from the pharmaceutical industry.
Since the inception of the cGMP regulations in
1962, pharmaceutical manufacturers have variously
interpreted them to suit their particular organiza-
tional and operational needs. As a result, each com-
pany has a unique change control system in place,
attempting to assure the quality, strength, and purity
of the drug products being manufactured. As the
industry is consolidating via mergers and acquisi-
tions, the change control systems of both the indi-
vidual and the combined companies are stressed to
the limit with no relief in sight. Another aspect is the
increasing use of third party manufacturing/pack-
aging facilities by major manufacturers, which cre-
ates its own set of change control issues.
Nonetheless, an effective and comprehensive
change control system is essential for every phar-
maceutical and medical device manufacturer, with
built-in flexibility to deal with all kinds of scenarios.
CHANGE CONTROL MANAGEMENT
Whether it is a small pharmaceutical manufactur-
ing operation or a multinational drug house, it makes
perfect sense to define the quality/compliance goals
of the organization and have top management in-
volved in defining and designing such a policy. In
recent years, FDA has increasingly emphasized the
accountability of senior managers within a pharma-
ceutical company whenever the Agency encountered
quality/compliance issues; therefore, the responsibil-
ity for cGMP compliance is directly brought to the
boardrooms of huge corporations.
Corporate Quality Policy
The corporate quality policy is a sensitive sub-
ject that should be developed with the utmost care,
taking into consideration the organization’s

strengths and weaknesses from a quality/compli-
ance point of view. The policy is a general state-
ment which should spell out the quality mission of
the company along with broad guidelines on which
different quality systems will be part of the quality
program. Quality policy is usually part of the
Corporate Quality Manual, which delineates the
generic quality concepts and systems that all the
divisions of a company are supposed to develop,
depending on each unit’s individual requirements.
Quality Culture
Corporate quality policies and quality manuals
can be useful only if the organization as a whole is
committed to its principles. Otherwise, these docu-
ments would collect dust on bookshelves, while
everyone in the company had their own interpreta-
tion of quality responsibility and accountability.
Therefore it is imperative that the organization strive
to develop a quality culture based on mutual under-
standing of each operational unit’s function within
the company, with due recognition for the expertise
of different departments and individuals. Such a
working environment creates mutual respect among
peers while developing a team with a common goal:
to produce quality drug product within the cGMPs.
This means quality assurance inspectors and audi-
tors are considered part of the team and not the
cops with a “got-you” attitude. Also, in such a quality
environment, efforts are directed at solving the
quality problems by addressing the systems
related issues instead of finger pointing to who did
it. In other words, the quality issues are freed from
the cult of personality conflicts.
Organizational Structure
One key aspect of the quality policy and manual
is that it should define the quality responsibility and
reporting structure of different operational units,
assuring that there is no bias when a critical quality
decision is to be made. FDA and cGMPs are vague
on the organizational and reporting structure within
a pharmaceutical manufacturing operation.
However, the Agency does expect an independent
quality function responsible for deciding all the qual-
ity-related issues which could impact a distributed
drug product or a clinical study material.
With the evolution of quality assurance practices
over the past 30 years or so, most pharmaceutical
companies now have a separate quality assurance
Shahid T. Dara
function, independent of the quality control laboratory,
recognizing the fact that even analytical operations
need to be monitored for quality and compliance prac-
tices. The reporting structure should be such that the
quality assurance function should not report to the
individual who heads up the manufacturing operations
in general. This leads to a conflict of interest, as some
quality decisions may not be very pleasant for the
operations folks. However, sound management prac-
tices and a genuine commitment to quality practices
can help the organization overcome such fears. The
corporate quality policy and manual can also estab-
lish the basic procedures on change control and
resolution of any issues that might arise because of
any of the critical changes involved.
Quality/Compliance Review Committee
As part of the organizational structure, there
should be a group of designated individuals from key
operational and quality/compliance functions with the
responsibility to evaluate all quality/compliance-
related changes/issues, assess their impact on the
drug product involved, define any corrective actions
needed, and the authority to make critical decisions
as to the disposition of the materials or drug products
involved. Such a group or committee can be named
the Material Review Board or Quality/Compliance
Committee and quality assurance should lead the
group. However, in some cases, such decisions
involve major capital investments or critical compli-
ance decisions. Under such circumstances, the group
should make recommendations to upper manage-
ment, defining the possible course of action to resolve
the situation at hand while addressing the long-term
solution to the problem as well and thereby forcing
the senior managers to get involved in the
quality/compliance decision making process.
Change Control Master System
and Subsystems
Fundamentals of a change control system
should be spelled out in the corporate quality man-
ual, if there is one. A typical change control system
usually has a master change control system and a
number of subsystems, depending on the types of
changes encountered.
A master change control SOP details the basics of
the master change control system, defining the over-
all responsibility and authority for reporting, investigat-
ing, and decision-making for a critical change. The
Technical Guide 5
Shahid T. Dara
master SOP also defines the general classes or
types of changes that might be encountered within a
given manufacturing operation and which changes
are considered critical, major, or minor, based on
general guidelines. The master change control sys-
tem oversees the functioning of subsystems, as each
one is established for a unique type of change, for
example deviations, nonconforming materials han-
dling, out-of-specifications data investigations, etc.
For the change control subsystems, each should
have an SOP defining a given change and how to
manage it, with its attendant corrective actions, etc.
One key element of any corrective action plan is
how it is to be implemented and whether it involves
additional training for employees. Finally, there
should be an effective audit trail to assure that the
desired changes are being implemented in a con-
trolled environment, with full documentation of each
critical step involved and employee training and
retraining whenever necessary.
Enforcement of Change Control Systems
Like any other quality practice, a change control
system can only be effective if it is implemented as
part of everyday operational activities, thereby mak-
ing everyone aware of the fact that every change has
to be documented and reported to appropriate orga-
nizational units. Many times machine operators and
front line supervisors have a tendency to consider a
given change as a minor one, forgetting the fact that
an accumulation of these minor changes could lead
to major deviations from approved practices. A key
factor in successful implementation of any change
control system is that it should be implemented con-
sistently, meaning all changes must be documented,
reviewed, justified, and approved or rejected by
Quality Assurance.
Training
Employee training in change control systems and
related procedures is essential in enforcing such a
system. The training program should be interactive,
detailing the impact of changes on the overall quality
of the drug product being manufactured and the con-
sequences if these changes are not controlled. For
example, little deviations from an approved NDA pro-
cedure or SOP, at the time of occurrence, might
seem of no consequence, but an accumulation of
these changes can result in an adulterated drug
product, since the NDA procedure or SOP is no
6 Journal of GXP Compliance
longer being followed. Thus, the SOPs detailing
change control systems should be very clear as to
their contents, as ambiguous SOPs lead to ineffec-
tive training and, therefore, could cause failure of the
change control system itself. The importance of utiliz-
ing effective change control systems is evident when
employees are trained on revised SOPs. Here is an
opportunity to explain why a change was made and
how it would impact the quality of the product.
Empowerment and Shared
Quality Responsibility
Individual employees within the operations group
should not only be trained in detecting any changes
from approved practices, but they should also be
empowered to bring such a situation to the attention of
their immediate supervisors and the quality assurance
function, without fear of reprisals. This approach can
work miracles for the organization as it makes each
individual at every level responsible for the quality of the
product and, therefore, forces everyone to watch for
deviations from approved practices. One way to imple-
ment such a system (which can be termed as Shared
Quality Responsibility) is to ask the frontline operators
to write their own SOPs, thereby minimizing the poten-
tial for a conflict between an approved SOP and actual
practice on the floor. Also, this approach helps to iden-
tify any changes in approved practices/SOPs in a much
more organized and timely fashion.
Routine audits of batch records indicate if there
are any unreported changes in any process. If there
are no changes documented in the records, then
one has to be concerned about the effectiveness of
the change control system. There is a possibility
that many changes are considered minor by the
operators and therefore are neither documented
nor reported to the appropriate authorities, and
eventually such minor changes could lead to a total
loss of control over a period of time.
Regulatory Means for Change
Control Management
For approved application drug products (New Drug
Applications [NDA]/Abbreviated New Drug Applica-
tions [ANDA]), all changes have to be reported to the
FDA. Depending on the nature of the change, these
could fall into one of the following categories:
Pre-Approval Supplements
A major change to manufacturing/packaging pro-

cess, materials, product, or procedures require
prior approval by the FDA before it can be imple-
mented. Such a submission to FDA is referred to as
a Pre-Approval Supplement. However, there is a
minor distinction here that the change under review
can be implemented prior to FDA approval, but the
drug product so manufactured/packaged cannot be
marketed until FDA’s approval of the supplement.
Change Being Effective (CBE)
Improvements to manufacturing/packaging pro-
cess, materials, product, or procedures do not require
prior approval by the FDA before they can be imple-
mented. The Agency wants to review these, but there
is no need to wait as it is classified as an improve-
ment. Such a submission to FDA is referred to as a
Changes Being Effective (CBE) supplement.
Annual Drug Product Reports
Routine or minor changes in manufacturing/-
packaging process, materials, product, or proce-
dures do not require submission to FDA at the time
that the change is made. Such changes are
reported as part of the NDA/ANDA annual reports
and are usually of little consequence to the quality,
safety, or efficacy of the drug product. However,
such changes must be reviewed and approved by
quality assurance prior to their implementation.
Quality Failure Investigation Procedure
A quality failure incident is usually caused by an
unplanned change in materials or practices, with
the possible rejection of the raw material or drug
product involved. A thorough investigation of such
incidents can be of tremendous value in determin-
ing whether the change control systems in place
work effectively. If there are a number of rejects
because of quality failure, that is a sure sign that
the materials or process or both has definitely
changed without triggering the change control pro-
cess to avoid the quality failure. Therefore, it is
important that a comprehensive quality failure
investigation procedure be in place and strictly fol-
lowed whenever a quality situation arises.
Drug Product Annual Quality Review Reports
21CFR 211.180 (e) requires that an annual
quality review report be prepared for each mar-
keted drug product to evaluate all the changes
made during the review period and their impact on
the overall quality. Such a report can be a useful
tool for the quality assurance function to detect
Shahid T. Dara
minor changes in manufacturing/packaging pro-
cesses that might have gone unreported.
Internal Audits
An effective internal audit program is another
practical approach to managing change control, as
it enables the entire organization to be proactive
for planned changes while ensuring the resolution
of unplanned changes, which might have gone
unnoticed. Also, the internal audit program can be
designed to help promote a team approach to
resolving quality/compliance issues; however, it is
a huge subject in itself and, therefore, cannot be
discussed in any detail here.
Product Complaints
Product complaints should be thoroughly inves-
tigated and quantified where needed. A rash of
related complaints could be an indication of a
major change in the product, involving the compo-
nents, the process, or both. Such a situation
should be handled as an emergency, and a full-
scale investigation should be initiated to pin down
the change causing the quality complaints.
How to Avoid Surprises?
No one likes surprises during an FDA visit,
especially it demonstrate that the company does
not have an effective change control system. And
that could have far reaching consequences. In
recent years, FDA has cited a number of manufac-
turers for a lack of comprehensive change control
systems, especially in regard to incomplete failure
investigations. The best way to avoid any surprises
is to have a vibrant quality function within the orga-
nization with a quality culture that promotes self-
policing by all departments. The change control
system should trigger a chain of events that pro-
hibits the use or distribution of suspect quality
materials or drug products until the resolution of
change. Communication is the key to the success
of such a system, as sharing information helps
everyone understand the situation in a better way
while training individuals for future incidents.
POSSIBLE CHANGES ENCOUNTERED
IN PHARMACEUTICAL
MANUFACTURING
FDA compliance enforcement policies have
evolved over the past 30 plus years, as the Agency’s
understanding of its own regulations and their impact
Technical Guide 7
Shahid T. Dara
on industry practices grew with time. In recent years,
the change control issue has been cited as a major
cGMP deficiency by the FDA, while inspecting manu-
facturing facilities, both for dosage forms and active
pharmaceutical ingredients (API), but this discussion
is limited to dosage form manufacturers only. A com-
prehensive change control system should be able to
control the impact of any changes encountered
within a pharmaceutical company that might have a
bearing on product quality/compliance status. Also,
the master change control system should have sup-
porting subsystems, which can adequately handle
any of the situations possible.
The following is an overview of different phases
and components involved in drug product develop-
ment, the manufacturing process, and what
changes can occur in different scenarios. This
review is meant to address the possible quality
impact of the potential changes as well as how to
control them without compromising the quality of
the drug product and outlining what the procedural
considerations should be.
Product Development Phase
All drug products involve some level of research
and development effort, be it a new chemical entity or
generic version of a monograph product. Over the
past few years the research and development activi-
ties have come under increased scrutiny by the
Agency, especially as part of Pre-Approval Inspections
for NDA/ANDA drug products and as a result of the
generic drug scandal of the late 1980s. The Agency
expects the company to have a complete develop-
ment report that summarizes the entire process of
development of a given drug product. This subject is
discussed in detail toward the end of this section.
With the introduction of the proposed cGMPs for
APIs, the change control net has widened its range
beyond traditional dosage form manufacturing pro-
cesses, and the critical decision is determining
when the process fall under cGMP regulations.
Here, the change control decisions should be made
by the development scientists at an earlier stage of
development. As the drug product enters the clinical
testing phase, the cGMP-based change control sys-
tems should take over, with due review and approval
of all critical changes by quality assurance.
When to Initiate Change Control Practices?
When do the cGMP regulations apply during the
development process? The industry standard has
8 Journal of GXP Compliance
been that with the manufacture of the first bio-
batch, the entire manufacturing process should be
performed in compliance with cGMP regulations.
Bio-batch is the term used to describe that lot of
drug product used for the first clinical studies. That
is the reason that companies have a cGMP devel-
opment area and a non-cGMP development area.
This practice has some benefits, but in today’s
cost-conscious environment, it is much more bene-
ficial to have one set of rules for the entire com-
pany to follow, with far less potential for any major
mishaps. If research and development and manu-
facturing departments are following the same basic
procedures as far as documentation practices,
change control, and employee training are con-
cerned, then the transition from R&D to manufac-
turing can be much smoother. Another advantage
is that all changes and improvements made during
the development phase are properly documented
and can be a tremendous source of information for
future references.
Potential Changes During Development
Following are some of the changes that can
happen during the research and development
phase and should be controlled and documented
according to company procedures.
Formulation
Formulation development is a very controlled
process, and initial assessment of a new formula-
tion has a number of variables involved; however,
once the basic formulation of a dosage form is
finalized, all changes should be carefully con-
trolled, documented, and evaluated. Some of the
possible changes are:
Composition
Percentages of active and inactive ingredients
per unit dosage define the composition of a given
drug product. Once the pharmacological dose of a
drug substance is established, its quantity per unit
dose is easy to calculate based on the dosage regi-
men. It is only changed if the stability profile of the
drug product indicates a need for an overage, or
there is a substantial loss of active pharmaceutical
ingredient during the manufacturing process. In the
first case, the overage issue will surface at an early
stage of development, while production loss may
not be detected until the final scale-up batches are
manufactured. In either case, the excess must be
justified and require pre-approval by FDA prior to its

implementation and will be submitted to the Agency
as a supplement to an NDA/ANDA drug product
with pertinent stability and process data.
Inactive ingredients or excipients however, are
changed more frequently as the dosage form for-
mulation is optimized. Depending on the drug sub-
stance and dosage form involved, there are always
a couple of excipients in each drug product that
are critical for its success, both for drug delivery as
well as stability of the dosage. Their percentages in
a formulation are finalized based on both scientific
knowledge and experimental data. However, any
quantitative change in a critical excipient could
have a devastating effect on the quality of the drug
product, as it can be the bulking agent in tablet, a
carrier for a lyophilized injectable, or a key preser-
vative in a liquid. If the change in excipients is con-
sidered critical, it requires FDA pre-approval.
Active Pharmaceutical Ingredient (API) Changes
Active pharmaceutical ingredient/s (API) are well-
defined molecular entities with a known impurity
profile and should not be changed. However, some
of the changes that could occur with an API include:
New Manufacturer: Alternate manufacturers
are essential to maintaining the reliable supply of a
drug product. It is highly unlikely that API from mul-
tiple sources will be available for evaluation during
the formulation development phase. But whenever
this change is made, the formulation has to be
reevaluated, and the drug product has to undergo
stability testing to assure that the new API has no
impact on the purity, safety, efficacy, and quality of
the drug product. Also, the impurity profile of the
new API and its stability must be established to
make it a viable source. Such a change would
require pre-approval by FDA prior to its implemen-
tation and will be submitted to the Agency as a
pre-approval supplement to an NDA/ANDA drug
product with pertinent stability and process data.
A new manufacturing process or major change in
the manufacturing process of an API can have simi-
lar consequences. Such a change again requires
pre-approval by FDA prior to its implementation and
will be submitted to the Agency as a pre-approval
supplement to an NDA/ANDA drug product with per-
tinent stability and process data. However, in some
cases, this can be a changes-being-effective (CBE)
supplement, if the change in manufacturing process
is an improvement in the overall quality of the API.
Nonetheless, the drug product manufactured with
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new API has to be evaluated for stability.
A change in physical characteristics of an API
can also have a critical effect on the drug product,
for example, particle size, crystal form, isomeric res-
olution, etc. These can impact the manufacturing
process, like mixing times for powders, dissolution
rates, drug delivery, and invivo bioavailability. Such
potential changes should be carefully monitored and
controlled via routine sampling and testing of API. If
there is a sudden change in physical characteristics,
that is a clear sign of a change or deviation in the
manufacturing and purification process of the API.
For dosage form manufacturers, such changes can
be reported to FDA as part of the Annual Report, if
the data shows no adverse effects on the drug prod-
uct quality, safety, and efficacy.
A change in the impurity profile of the API poses
an equally serious challenge and could go unde-
tected if the incoming API samples are not routinely
checked for impurities. Potentially, this could have
fatal consequences for the end user and be a major
regulatory nightmare for the drug product manufac-
turer. To avoid this situation, each shipment of an API
should be tested for known impurities of conse-
quence, and if the API fails its specifications for
impurities it should be considered for rejection. It
gets interesting when unknown impurities are found
during testing of the finished drug product while
assaying for the API, putting the drug product
release in jeopardy. To trace the source of such an
impurity is a monumental task, and the culprit could
be the API itself or the manufacturing process, like a
cleaning agent residue. Such instances should be
duly investigated and the drug product disposition
decision made after considering all the relevant facts,
analytical data, regulatory consequences, and,
above all, the consumer’s health and well-being.
Excipients
Most excipients used in drug product formulation
are United States Pharmacopoeia (USP) or National
Formulary (NF) grade and therefore are well charac-
terized chemical entities. It is common practice to
use more than one manufacturer of an excipient as
long as the raw material meets its compendial spec-
ifications. Of course, formulations using different
sources of excipients have to be evaluated for stabil-
ity and overall quality of the drug product. However,
there is a potential that an unapproved source of an
excipient might find its way into a formulation, con-
tending that it is the same official grade material.
Chemical distributors have earned a reputation for
Technical Guide 9
Shahid T. Dara
switching raw materials manufacturers without
notice. In most cases, such a change should be
caught at the time of receiving the material, not dur-
ing the sampling/inspection process. The material
should then be put on hold for latter disposition.
Sometimes a source change is inevitable due to
natural disaster or other reasons, and that is where
the change control system should trigger the mech-
anisms to protect the safety, efficacy, and purity of
the dosage form. Such a change might necessitate
a reevaluation of the formulation and could even
affect the manufacturing process. In most cases, this
leads to additional stability testing of the finished
drug product, concurrent at controlled room temper-
ature (CRT) and ambient humidity.
Equipment
The manufacturing process development starts
with lab-scale equipment and moves through mid-
size equipment in the pilot plant, leading to a bio-
batch size, which is the base for future scale-up.
Throughout this process the equipment changes
occur. Sometimes it is not just a bigger piece of
equipment, but could be of different mechanical con-
figuration, if so dictated by the process needs. All
such changes should be documented and evaluated
for future references. During the development pro-
cess, the equipment needs to evolve as the formula-
tion characteristics are better understood. Also, batch
size and the economics of manufacturing efficiencies
also impact the selection process. Equipment
changes will be discussed in more detail later.
Process
As the manufacturing process evolves from the
development lab through the pilot plant, the pro-
cess parameters begin to take shape as well.
Some of these are as follows:
Critical Process Conditions
Process conditions include mixing times, machine
speed set-ups, processing temperatures, and pro-
cess time limits. Changes in these conditions should
be documented and evaluated for their impact on the
drug product. At this stage, change is part of the
development process, and it must happen. However,
even at this stage, all changes should be docu-
mented, evaluated, and kept under control.
Scale-Up Factors
Change from bio-batch to commercial-size batch
is termed scale-up, and the Agency allows a 10
10 Journal of GXP Compliance
times scale-up without additional testing. However,
the manufacturing process should be well qualified
before the scale-up factor is applied, as it will help
avoid unpleasant surprises. Also, one should con-
sider the capacity of the equipment and the
physico-chemical properties of the formulation
when deciding on scale-up of batch size. Recent
FDA guidelines on scale-up and post-approval
changes (SUPAC) are of great help in deciding
these issues. Commercially manufactured drug
product should be equivalent to the bio-batch prod-
uct for bio-availability of drug substance as well as
dosage form specifications.
Controlled Environment
Since most drug products are temperature or
humidity sensitive, the environmental conditions
should be defined as the process is being devel-
oped, based on chemical and microbial stability of
the formulation in general and end product in par-
ticular. Again this information evolves as the pro-
cess is developed, but any deviant behavior of the
manufacturing process should be documented
under adverse environmental conditions.
In-Process Controls
In-process controls and sampling/test points are
identified as the manufacturing process is evalu-
ated in detail. For each dosage form there are
some standard in-process tests, and then there are
others which are formulation specific. These latter
tests represent the critical stages during the manu-
facturing process, which can potentially compro-
mise the integrity of the drug product. The in-pro-
cess specification evolution should be documented
and justified so that any future changes can be
correlated without jeopardizing the drug product.
Finished Drug Product Specifications
Finished drug product specifications are, again,
those which are dosage-form specific and then others
are formulation specific. Their development history is a
reflection of the chemical and microbiological nature of
the API(s) and their interaction with excipients during
the manufacturing process. The finished drug product
specifications include physical characteristics, chemi-
cal purity, and acceptable bio-burden for a given
dosage form. These specifications do change as the
development process progresses and more informa-
tion becomes available from process evaluation and
stability studies. All such changes should be docu-
mented and explained for future reference.

Analytical Method Development
Whether it is a compendial method or not, each
analytical method has to be qualified for a given
testing laboratory. Depending on the nature of the
formulation, the methodology always undergo
changes, which should be fully documented and
justified according to method qualification protocols.
Stability Testing
Stability testing starts at an early stage in the devel-
opment process, and the only major change is usually
in the container/closure system, depending on the sta-
bility profile of the drug product. Another change can
be the storage conditions for the stability samples,
again depending on the temperature, humidity, and
sensitivity of the drug product. All changes in the con-
tainer/closure system and storage conditions should be
documented, explaining the reason for every change
and its impact on the drug product involved.
Product Development Report
As the initial development process comes to a
close for a drug product, a complete development
report should be prepared, detailing the following:
■ Formulation: List of ingredients with quantities
per dosage unit and their quality reference,
i.e., USP, NF, etc.
■ List of manufacturing equipment:
■ Manufacturing process: Development and
scale up process with special emphasis on
bio-equivalence of bio-batch versus the com-
mercial drug product
■ Packaging process: Container/closure system
and packaging conditions
■ Analytical methods
■ In-process and finished-product specifications
■ Stability studies protocols and data summary
■ Detailed discussion of process deviations and
excursions during the development and scale-
up process and consequent corrective actions
■ Conclusion and summary
Such a report can be a ready reference for a
given product for future trouble-shooting. Also, it
can be presented to the FDA if needed instead of
bringing in stacks of paper for their review.
Facilities Changes
Facilities are usually not considered critical
when a change control system is devised.
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However, the physical condition of manufacturing,
packaging, and warehousing facilities has a direct
impact on the drug product quality, and unautho-
rized changes should not be made. Facilities
should be monitored in the following areas from a
change control perspective:
Repair and Maintenance
Routine repair and maintenance activities should
be monitored within the facility, especially if contrac-
tors are employed for a given repair job. If there is a
structural modification made to an existing facility, the
proposed change must be reviewed and evaluated
according to company change control procedures.
Due consideration should be given to the material
and people flow if the facility is modified in any signifi-
cant fashion. The validation and quality assurance
departments should review all such changes to
assure that the facility’s qualified or validated status is
not compromised. Physical modifications can also
impact the functioning of certain utilities, like HVAC,
purified water system, dust collection system, etc.
Cross-Contamination Potential
Facilities should be constantly monitored for
cross-contamination potential, particularly when
there is a physical change in the facility itself or pro-
cedural changes which might impact the flow of
materials and personnel. Of particular concern is the
potential for inadequate cleaning by the repair crew
after the job is done. Company personnel should be
aware of such situations to assure that the areas
are properly cleaned and inspected before use. In
either case, the changes must be reviewed and
approved by the quality assurance function. If such
a change has affected any raw materials, packaging
components, or in-process/finished drug product,
the material involved should be carefully evaluated
for the potential impact on its quality and safety
before deciding its disposition. The quality failure
incident investigation procedure should be followed
for investigating all such incidents.
Pest Control
21CFR – Part 211, Subpart C –
Buildings and Facilities
211.56 Sanitation
This section clearly states that the manufacturer
should have written procedures in place to define the
responsibility and procedures for cleaning and sanita-
tion of facilities. It also requires that only those roden-
Technical Guide 11
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ticides, insecticides, and fungicides which are regis-
tered and used according to the provisions of the
Federal Insecticide, Fungicide, and Rodenticide Act
(7 U.S.C. 135) can be used in a pharmaceutical man-
ufacturing facility. Requirements of this section apply
to both contractors and company employees. Only
approved pest control agents should be used in the
facility, and this approval is granted by quality assur-
ance with due consultation with other departments.
Pest control is usually performed by outside con-
tractors. Each visit should be fully supervised to
ensure that components, container/closures, or drug
products are not exposed to any of these agents. If
there will be a change in any of the agents, it should
be pre-approved by the appropriate organizational
units according to the pest control SOP. The contrac-
tor should be periodically audited to ensure that only
approved chemicals are used and in the right con-
centration. An unauthorized change of pest control
agents could compromise the quality and safety of
the drug products involved.
Natural Disasters
Following a natural disaster, most organizations
experience the most profound changes possible, yet
companies strive to recover as quickly as humanly
possible. A tornado or a flood can devastate manu-
facturing facilities, destroying inventories of both com-
ponents and finished drug products. Even under such
circumstances, the change control activities should
be part of the Disaster Recovery Plan, as it will be
necessary to change the quality status of a number
of components, packaging/labeling materials, and fin-
ished drug products, from acceptable to rejected due
to natural cause. Though the investigation will be sim-
ple, the activities have to be performed to close out
inventory cards, batch records, etc.
Another aspect of the Disaster Recovery Plan
should address how to recover all the quality/com-
pliance information related to marketed drug prod-
ucts. Equipment could be replaced, but critical doc-
umentation recreation is a monumental task. In
brief, companies should have a comprehensive
Disaster Recovery Plan that addresses not only the
financial data, but also scientific, technical informa-
tion, and documentation, and this could be part of
the master change control system.
Utilities Changes
Although cGMPs refer only to lighting, the
HVAC system, and water supply under utilities,
12 Journal of GXP Compliance
today’s pharmaceutical manufacturing plant uses a
number of utilities to carry out everyday operations.
Utilities are the ancillary systems which provide
support to the manufacturing/packaging opera-
tions. These systems provide essential operational
accessories to manufacturing, like conditioned air,
purified water, clean steam, oil-free compressed
air, etc.
In most organizations, engineering and mainte-
nance department usually manage utilities indepen-
dently once these systems are installed and quali-
fied. Potentially, a number of changes could be
made to these systems without due review and
approval process, resulting in an out-of-control sys-
tem. To avoid such a situation, there should be a
Utilities Change Control SOP in place to assure
that all critical changes to a utility system are
reviewed and approved by appropriate organiza-
tional units, including quality assurance. One way to
keep abreast of changes made to a given utility
system is to have each repair and maintenance
activity performed reviewed and pre-approved by
the quality assurance function. Once the task is
completed, the system should be examined and
released for use. All activity should be fully docu-
mented.
An alternate system could be integrated into a
validation change control system, requiring review
of each critical change in a utility system for its
impact on the validation status of that particular
system to decide whether a revalidation is needed.
Critical Utilities
Define the critical utility systems for the opera-
tions, ones that could have an impact on drug
product quality and include:
■ HVAC system
■ Water purification system
■ Dust collection system
■ Compressed air system
■ Clean steam
Any major change in any of these systems
could adversely impact the processing conditions,
thereby compromising the quality of the drug prod-
uct being manufactured.
Parts Change Control
Parts change occurs repeatedly in a manufactur-
ing environment as utility systems wear down with
use. Some parts changes are minor and have no

impact on the operation of the system. In other cases,
a critical part might have to be replaced, which could
have a major effect on the operation of the utility sys-
tem and the quality of its product and service pro-
vided to the operations. In most instances, such part
changes are addressed during validation of these
systems, clearly defining which part changes could
lead to a requalification of the system. This aspect is
usually covered under the validation change control
SOP that describes the criteria for such an option and
the review and approval process. In other words,
mechanics and technicians are not allowed to change
parts without prior approval from appropriate organi-
zational units, including quality assurance.
For each utility system there should be a mainte-
nance SOP in place, defining the parts change con-
trol and a list of approved parts or a reference to the
utility system equipment manual. Use of unapproved
change parts should be strictly prohibited, as it
could compromise the performance of the system.
Sometimes utility systems are underutilized and,
as the operational activities increase, the utility sys-
tems are expanded to meet the increased demand or
to supply a utility to another part of the operation. It is
a common practice to extend the water supply pipe-
lines or to add outlets for compressed air. These are
major changes and additional piping and outlets will
necessitate extensive cleaning of the pipes, etc., to
prevent contamination of the system as a whole. This
system extension should be strictly controlled, as it
can affect the overall operation of the utility system as
well as its validation status. Also, as part of this
change control system, the as-built drawings of the
system must be changed to reflect these extensions.
Operational Parameters
Each utility system operates within a predeter-
mined set of conditions or parameters. If these
operational parameters are changed, it could
impact the functioning of the system as a whole. It
could be the rate of feed water supply to a de-
ionizing tank in a water purification system or the
operating temperature for a compressed air sys-
tem. Such a change should be avoided at all costs,
as it can physically damage the system. But, if
such a change does occur, it should be addressed
immediately to control the damage and minimize
the impact on the quality of the drug products
involved. Every utility system is equipped with con-
trols, alarms, and emergency shutdown mecha-
nisms, which immediately trigger a chain of events
to control the situation. However, the operators and
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plant personnel should be aware of the general
operating conditions for each utility system and be
able to recognize any extraordinary circumstances.
Inter-Relationship of Utilities Functioning
Utility systems usually operate independently of
each other, but there are situations where two or
more utility systems function as a unit, and a
change in one system can impact the performance
of others. For example, the dust collection system
and HVAC system work in tandem to remove dust
from a manufacturing area while providing a given
amount of conditioned air and a certain amount of
air changes per hour to the particular room.
Likewise, humidifiers in HVAC systems help main-
tain a certain level of humidity in the conditioned air.
If the humidifier malfunctions, it will affect the perfor-
mance of the HVAC system by altering humidity lev-
els in the air supplied to the manufacturing areas
and, therefore, impact the quality of the drug prod-
uct being manufactured. Thus, while approving a
change in one utility system, other systems should
also be considered, as there might be an opera-
tional relationship between these systems. Such
relationships should be well defined and known to
the engineering and maintenance department along
with quality assurance and validation personnel.
Equipment Changes
Manufacturing/packaging/analytical equipment is a
major capital investment, and each piece is carefully
selected considering a company’s immediate and
long-term manufacturing needs. Usually, major pieces
of equipment are not changed very frequently, as is
evident from the fact that some manufacturing opera-
tions employ equipment that is 20 – 30 years old.
Although cGMPs refer to current technology, there is
no regulation barring the use of old equipment if it is in
good repair and qualified to perform the job required.
Another fact is that a number of old application prod-
ucts were approved with the old equipment available
at the time, and many companies find it very costly to
upgrade some of that equipment, as it will require a
number of regulatory submissions. However, some old
pieces of equipment are replaced by newer equipment
because of technological innovation or capacity rea-
sons. Such equipment change is usually very well
controlled, as it involves the qualification of new equip-
ment, including product specific process validation.
The first few lots manufactured with the new equip-
ment are placed on stability, either on concurrent CRT
Technical Guide 13
Shahid T. Dara
or under accelerated conditions, depending on the
regulatory status of the drug product and its stability
profile. If it is an NDA/ANDA drug product, FDA is noti-
fied either through a pre-approval supplement to the
application or as a changes being effective (CBE)
notice, along with process and stability data.
SUPAC (Scale-Up and Post-Approval Changes)
guidelines were developed jointly by FDA, industry,
and academia in response to the growing number of
changes that the pharmaceutical industry had expe-
rienced in manufacturing operations in recent years,
which resulted in an excessive number of submis-
sions to FDA for application drug products. Another
factor that contributed toward this effort was a rash of
mergers and acquisitions over the past decade,
which led to a considerable consolidation of manu-
facturing operations and technology transfers from
one plant to another. While addressing the questions
of process scale-up and how to handle post-approval
changes in manufacturing procedures and specifica-
tions, these guidelines also provide a definition and
listings of what is considered similar equipment,
based on the same design and operating principle
for immediate release drug products. Examples of
similar equipment include replacing a ribbon blender
from one manufacturer with a ribbon blender from
another manufacturer, as it will not present any
change in design or operating principle. Switching
from a ribbon blender to a V-blender is a change
involving different equipment based on their design
and operating principle. However, applicants should
review each equipment change case on its own
merit and make a judicious decision based on sound
scientific data. Switching from a ribbon blender to a
fluidized bed dryer and mixer is a major change that
affects the manufacturing process parameters. Try
not to justify this change as part of the SUPAC
Similar Equipment Guideline. These are useful refer-
ence guides and can be of tremendous value when
replacing equipment or transferring manufacturing
from one plant to another. There are some limita-
tions, however, which will be discussed later.
Equipment Usage
Routine usage of equipment also needs to be
managed from a change control perspective.
Possible variables, which could impact the quality
of the drug product, include:
■ Machine setups
■ Mixing speeds
■ Timers
14 Journal of GXP Compliance
■ Switching between similar equipment
■ Sprayer set up for both powders and liquids
■ Compression machine setup
There should be detailed instructions in the mas-
ter batch record describing what equipment is to be
used for a given batch size and what should be the
operating parameters for each piece of equipment at
every step of the manufacturing process. For a gran-
ulation, the batch record should describe which
mixer is used, at what speeds, and for how long. A
critical review of a completed batch record can easily
show if the equipment was used within its prescribed
parameters. If there is any deviation, it should be
reported immediately to appropriate organizational
units and approved by quality assurance according
to the deviation SOP. In some cases, however, the
deviation is discovered after the fact, like the failure
of a chart recorder on a drying oven during a cycle
lasting 12 hours or more. Here, the situation warrants
a critical review of the failure with special emphasis
on its impact on the quality of the product. Test addi-
tional samples to gather valuable data to decide the
fate of the batch involved, while mechanical failure is
addressed separately. The entire investigation, test
data, and corrective actions should become part of
this unplanned change event and reviewed and
approved by quality assurance before the drug prod-
uct involved is released for distribution.
Sometimes, there are planned or intentional
deviations from an approved procedure. This usu-
ally happens when the procedure has been revised,
while going through its routing, review, and approval
process, but the change usually involving procedu-
ral improvements or corrective actions has to be
implemented immediately. In either case, these
planned deviations or exceptions should be docu-
mented, reviewed, justified, and approved by appro-
priate organizational units according to the particu-
lar change control system.
Equipment Cleaning Practices
Equipment cleaning is a sensitive subject both
for the Agency and industry, and the sky seems to
be the limit when it comes to the definition of
“clean equipment” and “allowable residues.” There
should be detailed procedures available for each
piece of equipment or grouping of similar equip-
ment based on extensive cleaning validation data,
both equipment and product specific. Also, there
should be an SOP on approved cleaning agents
for product contact surfaces.

Equipment cleaning procedures should be fol-
lowed religiously, and cleaned equipment should be
inspected and released for use by quality assur-
ance. However, the biggest source of variation in
equipment cleaning sometimes is the cleaning pro-
cedure itself, as it may be vague. Another variable is
uncontrolled use of cleaning agents, as the individ-
ual procedures may not describe the dilution factors
and how to prepare a solution from concentrate. But
most of all, the manufacturing crew responsible for
cleaning might cause the biggest problem by not fol-
lowing the cleaning procedures, using incorrect dilu-
tions of agents and causing drug product contami-
nation. Thus, operator training in correctly following
the equipment cleaning procedures is as important
as knowing how to use the equipment.
If a drug product is contaminated due to inade-
quate cleaning of the equipment, the change control
system should immediately trigger the batch to be
placed on hold/quarantine until the investigation is
complete and a decision is made as to its disposition.
Such an investigation will focus on both the quality
failure of the product as well as failure of the cleaning
procedure itself. If the suspected drug product can be
proven to be safe and effective based on analytical
data and clinical toxicology of the potential contami-
nants, then it should be considered for release to dis-
tribution. Otherwise, it should be non-conformed and
processed according to the non-conforming materi-
als SOP. The cleaning procedures involved might
require extensive revision and follow-up training of
the operators. All such activities should be docu-
mented, reviewed, and approved by quality assur-
ance, and the revised SOPs and training records
made part of the change control investigation.
Critical Parts Change and Qualification Status
Parts change is part of a manufacturing environ-
ment as manufacturing and packaging equipment
wears down with use. Some parts changes are minor
and have no impact on the operation of the equip-
ment. In other cases, a critical part might have to be
replaced, which could affect the operation of the
equipment and the qualified status of the machinery.
In most instances, such part change issues are
addressed during validation of the equipment, clearly
defining which part changes could lead to a revalida-
tion of the equipment concerned. This aspect is usu-
ally covered under the validation change control SOP
that describes the criteria for such an option and the
review and approval process. In other words,
mechanics and technicians are not allowed to change
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parts without prior approval from appropriate organi-
zational units, including quality assurance.
There should be a maintenance SOP in place
for each major piece of equipment, defining the
parts change control and a list of approved parts or
a reference to the equipment manual. Use of unap-
proved change parts should be strictly prohibited,
as it could compromise the performance of the
equipment. All critical part changes should be
logged into the individual maintenance log for each
piece of equipment to maintain traceability. If the
equipment requires too many change parts too
often, it might be time to replace it.
Maintenance – Preventive and For Cause
Equipment maintenance could be preventive or
for cause. In either case, there should be preventive
maintenance SOPs in place for all key pieces of
equipment, detailing the methods, equipment, and
schedules of preventive maintenance. Such SOPs
should also describe disassembly and reassembly of
equipment for proper maintenance. All maintenance
orders should be reviewed by quality assurance and
the equipment inspected and released by quality
assurance before it is put back into service. Also,
there should be an SOP in place describing the
approved product contact lubricants that can be
used for repair and maintenance of manufacturing
and packaging equipment. Mechanics should be
thoroughly trained in these SOPs to avoid any sur-
prises. It is a common practice to declare each repair
a minor item to expedite the repair process, and
soon a given piece of equipment might have been
totally overhauled, without any consideration for its
revalidation or impact on the manufacturing process.
The employees, both operators and supervisory
staff, should be grilled in following the proper proce-
dures when it comes to equipment repair and main-
tenance to assure that the equipment used in manu-
facturing is always maintained in a qualified state.
Calibration Status
Equipment performance is controlled and moni-
tored by gauges and meters, which are calibrated at
regular intervals. Sometimes, the gauges have to be
removed from the equipment to perform calibration.
In the meantime, the gauge is usually replaced by a
similar gauge, which is still within its calibration. This
change is performed by the metrology department in
association with the maintenance staff, without verifi-
cation by quality assurance that the replacement
gauges are similar to the ones being replaced and
Technical Guide 15
Shahid T. Dara
are within calibration when installed. The change
control system should address these changes, as it
is a compliance requirement to have all critical equip-
ment and associated controls calibrated which could
have an impact on the safety, quality, purity, identity,
and strength of a drug product.
Equipment Breakdown
Equipment failure in the middle of a manufactur-
ing or packaging run is a critical but unplanned
change that needs to be carefully controlled to pro-
tect the integrity of the drug product. The product
or in-process materials should be quarantined
immediately to assess the impact of the break-
down and how long it will take to repair the
machine. The process time limit conditions for the
given operation should also be considered to
assure that these limits are not exceeded. If this is
the case, additional sampling and testing might be
required before proceeding further with manufac-
turing or packaging operations. This is more critical
for liquid preparations and those with natural ingre-
dients, as these drug products are more prone to
supporting microbial growth.
For parenteral drug products, if the equipment
breakdown exceeds the validated process time lim-
its, then the drug product has to be discarded.
There should be an SOP addressing equipment
breakdown change control situations, detailing the
steps needed to assure the integrity of the product,
including review and approval requirements and
follow-up actions. There should be a log of equip-
ment breakdown, recording each incident, cause,
and how long the equipment was out of commis-
sion. Also consider the extent of repair required
and its effect on the validated status of the equip-
ment. Frequent breakdown of equipment is a sign
of age or poor maintenance practices.
Automated Equipment
Automated equipment operation, repair, and main-
tenance pose a different set of issues from a change
control perspective. Whenever there is a change
involving the PLC boards or software code upgrades,
it should be carefully reviewed by information technol-
ogy and quality assurance personnel to assure that
the equipment will continue to perform within its vali-
dation parameters. All such changes should be docu-
mented, reviewed, and approved by quality assurance
according to the change control SOP. The equipment
should be fully tested before it is released for use.
Likewise, if there is a software code change, then all
16 Journal of GXP Compliance
the relevant parameters need to be tested to assure
that the changes do not compromise the validated sta-
tus of the software and the performance of the equip-
ment involved.
Component Changes
Components, containers, closures, labeling, and
packaging materials essentially comprise the build-
ing blocks for drug manufacturing. As discussed in
the product development phase, any critical
change in a component or container/closure sys-
tem will have far reaching quality implications for
the drug product involved. Most of the time, these
changes are planned to qualify alternate manufac-
turers. However, some changes are discovered
after the fact, and the manufacturer has to respond
accordingly. This section addresses potential
changes for chemical raw materials and packaging
components that come into direct contact with the
drug product and their possible impact on the over-
all compliance and quality status.
Raw Materials
Raw materials include both active pharmaceuti-
cal ingredients as well as excipients, and possible
changes could include the following:
Manufacturer Change
Alternate manufacturers are essential to main-
taining the reliable supply of a drug product. A
manufacturing change is either a planned change
to qualify an alternate source or to respond to an
emergency caused by a plant shut down due to
natural disasters or quality/compliance issues. In
either case, the formulation change control proce-
dure should be followed. The formulation has to be
re-evaluated, and the drug product has to undergo
additional stability testing to assure that the new
API has no impact on the purity, safety, efficacy,
and quality of the drug product. The stability testing
could be concurrent if the API from a new manu-
facturer proves to be identical to the original
source. Also, the impurity profile of the new API
and its stability characteristics must be established
to make it a viable source. Such a change requires
pre-approval by FDA prior to its implementation
and will be submitted to the Agency as a pre-
approval supplement to an NDA/ANDA drug prod-
uct with pertinent stability and process qualification
data. In this case, the API from a new source is
proven to be identical to the original and is a com-

pendial material. This change in formulation could
be reported to FDA as a Changes Being Effective
(CBE) supplement.
A new manufacturing process or major change in
the manufacturing process of an API can have simi-
lar consequences. Such a change would again
require pre-approval by FDA prior to its implementa-
tion and submitted to the Agency as a supplement
to an NDA/ANDA drug product with pertinent stabil-
ity and process data. However, in some cases, this
can be a CBE supplement, if the change in manu-
facturing process is an improvement in the overall
quality of the API. Nonetheless, the drug product
manufactured with the new API has to be evaluated
for stability. This type of change has to be communi-
cated to the drug manufacturer by the API manufac-
turer and requires effective communication between
the two based on a recognized quality agreement,
mandating that any change in the manufacturing
process be reviewed and approved by the dosage
form manufacturer.
A change in physical characteristics of an API
can also have a critical effect on the drug product,
for example, particle size, crystal form, isomeric res-
olution, etc. These can impact the manufacturing
process, like mixing times for powders, dissolution
rates, drug delivery, and in-vivo bio-availability. Such
potential changes should be carefully monitored and
controlled via routine sampling and testing of the
API. A sudden change in physical characteristics is
a clear sign of a change or deviation in the manu-
facturing and purification process of the API. For
dosage form manufacturers, such changes can be
reported to FDA as part of an Annual Report, if the
data shows no adverse effects on the drug product.
A change in the impurity profile of the API
poses an equally serious challenge and could go
undetected if the incoming API samples are not
routinely checked for impurities. Potentially, this
could have fatal consequences for the end user
and be a major regulatory nightmare for the drug
product manufacturer. To avoid this situation, each
shipment of an API should be tested for known
impurities of consequence, and if the API fails its
specifications for impurities, it should be consid-
ered for rejection. It gets real interesting when
unknown impurities are found during testing of the
finished drug product while assaying for the API,
putting the drug product release in jeopardy. To
trace the source of an impurity is a monumental
task, and the culprit could be the API itself or the
manufacturing process, like a cleaning agent
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residue. Such instances should be duly investi-
gated, and the drug product disposition decision
should be made after considering all the relevant
facts, analytical data, regulatory consequences,
and above all, the consumer’s health and well-
being.
Excipients
Most excipients used in drug product formulation
are USP or NF grade and therefore, are, well charac-
terized chemical entities. It is common practice to
use more than one manufacturer of an excipient as
long as the raw material meets its compendial speci-
fications. Of course, formulations using different
sources of excipients have to be evaluated for stabil-
ity and overall quality of the drug product. However,
there is a potential that an unapproved source of an
excipient might find its way into a formulation, con-
tending that it is the same official grade material.
Chemical distributors have earned a reputation for
switching raw material manufacturers without notice.
In most cases, such a change should be caught at
the time of receiving the material, and if it goes
unnoticed, during the sampling/inspection process,
the material should be rejected. Sometimes, a
source change is inevitable due to natural disaster or
other reasons and that is where the change control
system should trigger the mechanisms to protect the
safety, efficacy, and purity of the dosage form.
A change in a critical excipient would have more
impact on the quality of the drug product compared to
a minor ingredient, especially if it has any bearing on
the dissolution or bio-availability of the dosage form.
In such a case, the formulation with the new excipient
should be carefully monitored for stability profile as
well as dissolution and bio-availability behavior. If the
new excipient has impacted any of these features, a
pre-approval supplement to the application might be
required. If it can be proved that the excipient from
the new manufacturer is equivalent to the original,
then such a change could be reported as CBE or
even as part of the Annual Drug Report.
Storage Conditions
Storage conditions for raw materials are equally
critical in maintaining the quality of a drug product.
This is especially true for biological derivatives and
those raw materials that are susceptible to heat,
humidity, or microbial infestations. Warehousing
practices and overall environment monitoring of the
facilities should have built-in change control mech-
anisms whenever the temperature/humidity condi-
Technical Guide 17
Shahid T. Dara
tions drift from the specified ranges. Storage condi-
tions are of critical importance for soft gel capsules
both empty and filled. If these are stored at very
high temperature or under extreme humidity condi-
tions, the soft gels become brittle and fail to per-
form during the capsule filling operation.
Packaging Components
Packaging components describe the immediate
container/closure system for the drug product and
usually include the following:
■ Bottles
■ Caps
■ Tubes
■ Cans
■ Vials
■ Ampoules
■ Stoppers
■ Filler
■ Desiccants
■ Blister materials (both base and lidding)
The USP is an excellent reference and has
detailed specifications and test procedures for all
types of container/closure systems used in packag-
ing of dosage forms. The container/closure system
is meant to provide adequate protection to the
drug product through its shelf life and during its
usage by the patient. The container/closure system
is selected based on the stability profile of the drug
product and is submitted as part of the CMC sec-
tion of an NDA/ANDA drug product. Any critical
change in the container/closure system requires
additional stability testing, followed by FDA pre-
approval or some notification of this change to the
Agency. Here are some of the changes that could
occur with a container/closure system and how to
handle these situations:
Container/Closure Materials of Construction
For HDPE and other plastic containers, the
material of construction quality and grade is of criti-
cal importance, as the drug product comes into
direct contact with the inner surface of the con-
tainer. For HDPE resin, for example, there might be
multiple grades of resin available from the same
manufacturer, with minor qualitative and quantita-
tive differences. For bottle manufacturers, such dif-
ferences might be of little consequence; however,
such changes must be communicated to and pre-
approved by the drug manufacturer as they could
18 Journal of GXP Compliance
adversely impact the stability of the drug product.
Bottle manufacturers should be required to submit
a Certificate of Compliance (COC) with each ship-
ment of bottles with lot traceability for the resin used.
Multiple resin manufacturers produce similar
grades of HDPE and other plastic materials that
meet the compendial requirements, yet HDPE from
two different manufacturers could have subtle dif-
ferences which could become apparent only after a
rugged stability testing regime. Bottle manufactur-
ers tend to switch HDPE from one manufacturer to
another, depending on supply and price. However,
a pharmaceutical manufacturer should have a
quality agreement in place dictating the approved
sources of resins for a given container, along with
additives. Any change must be reviewed and
approved by the drug manufacturer.
A change in resin manufacturer or grade
requires new stability studies for the drug product
involved and might also require a pre-approval sup-
plement to FDA, if it is a major change. However, if
it can be proved that the resin from the new source
or of different grade still meets all compendial
requirements and would have little impact on the
stability profile of the drug product, then it could be
an annual reportable event. Nonetheless, it will
require the change control system to kick in, and all
the safety features and drug product involved would
have to be placed on concurrent stability.
The closure material of construction is of equal
importance, especially the liner material, which
comes into direct contact with the drug product. Any
changes in material of construction has serious impli-
cations for the stability profile of the drug product
involved, and any change should be closely moni-
tored, as it requires new stability studies. Moisture
permeation and adhesive abilities of the liner material
are of special importance as it forms a protective
sealing against environmental elements. Possible
changes in construction of liner material include a dif-
ferent manufacturer or a grade of material. In either
case, the change should be processed per change
control SOP and requires a revision of the closure
specifications to reflect the change. Unless the new
material is deemed similar to the original, it will
require concurrent stability studies, and the change
reported to FDA as an annual reportable incident.
Storage Conditions
Like raw materials, packaging components should
be stored under controlled temperature and humidity.
Exposure to excessive heat and dry conditions could

make certain plastic bottles brittle and even develop
cracks. Such conditions can also adversely affect the
liner material on closures, especially the pressure-sen-
sitive type. High humidity can also cause deterioration
of cotton, used as filler in packaging operations, by
making it soggy or facilitating microbial growth.
Storage conditions should be constantly monitored
with built-in alarms to trigger corrective actions if the
temperature/humidity conditions drift outside the pre-
determined specifications. Details of such a system
should be described in an SOP and be part of the
master change control system.
Labeling Components Change Control
Labeling components refer to the immediate label
on a drug product container, physician or patient
package insert, cartons, etc. Label development and
the approval process is tightly controlled within each
pharmaceutical organization. For NDA/ANDA drug
products, labeling is approved as part of the applica-
tion, and any post-approval changes in labeling com-
ponents usually require FDA approval. Labeling
development, revision, and the approval process
should be separate from its usage controls.
Labels and cartons should be stored in a limited
access area, and the storage should be organized to
prevent any mix-up of labeling components during
storage and issuance. Multiple versions of the same
label might be in inventory, especially in a use-up sit-
uation where the older version can be used until it is
gone. Such a change can be managed only if there
are mechanisms in place that provide version control
for labeling components at the time of issuance as
well as during its usage. Labeling errors are still one
of the leading causes for drug product recalls.
Process Changes
The manufacturing process generally consists
of a number of unit operations, e.g., tablet manu-
facturing involves blending, wet or dry granulation,
milling, drying, and compression as unit opera-
tions. Each unit operation has its own set of critical
parameters that determine the quality of the overall
manufacturing process. To fully understand the
complexity of a manufacturing process, all the unit
operations should be drawn up as a flow diagram.
Based on the sensitivities of the drug substance
involved and the dosage form being manufactured,
define the critical steps, which need to be moni-
tored against any change. Mapping of the manu-
facturing process is usually done during the pro-
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cess development phase. Most process-related
changes are unplanned and are handled as “devia-
tions,” and the resulting in-process material or drug
product is evaluated accordingly.
Process Parameters
Process parameters usually refer to machine
set-up, mixing speeds, mixing times, drying tem-
perature, sequence of addition of ingredients, etc.
They all usually have a predefined range described
in the batch record that is based on the process
qualification and validation data. Most of the time
these process parameters are followed religiously,
and the manufacturing operations go on smoothly.
However, once in a while, the granulation might be
over-mixed or dried at a temperature that was out
of its range for part of the cycle. Worst of all, many
of these digressions are not caught when they
happen, and they come to surface only when the
finished batch record is being reviewed by quality
control prior to its release for distribution. Now, the
granulation that was dried under the suspect dry-
ing cycle has already been compressed, as the in-
process test for moisture content was well within
specifications and the finished product also met all
its specifications. But this is a deviation nonethe-
less and a change that must be reviewed by
appropriate organizational units to pin down the
cause of deviation and its impact on the quality,
safety, and efficacy of the drug product and is eval-
uated according to the deviation SOP. The product
disposition should be decided based on the nature
of the deviation, product quality history, and the
available data.
Process Conditions
Process conditions refer to the manufacturing
environment, and it includes both the facilities as
well as the temperature/humidity conditions. De-
pending on the nature of the drug product, the envi-
ronmental controls can vary from simple tempera-
ture/humidity controls to extensive environment
monitoring schemes utilized for aseptic processes.
Most manufacturing operations are carried out
under controlled temperature and humidity condi-
tions. An occasional deviation from the settings
should be considered as part of the system opera-
tion and could be caused by extremes of external
environment. However, if the drug substance or unit
operation involved is temperature or humidity sensi-
tive, then it is a cause for investigation, and such a
change should be controlled. Again, such changes
Technical Guide 19
Shahid T. Dara
are usually noticed post-occurrence and, therefore,
fall under the category of unplanned deviations and
should be processed accordingly.
Reprocessing
Reprocessing is allowed under cGMP regula-
tions; however, it is a critical change in an other-
wise validated manufacturing process. It could be
a failure of an in-process material or the bulk fin-
ished drug product that could force a company to
consider a reprocessing option. There should be a
reprocessing SOP in place to address such a situ-
ation. First of all, the cause of the failure should
be investigated per quality failure investigation
SOP. The impact of reprocessing on the safety
and efficacy of the drug product involved should
be thoroughly studied. If it is an NDA/ANDA drug
product, regulatory implications of reprocessing
should also be carefully examined. Once all the
reviews are done and a decision is made to repro-
cess the material involved, a reprocessing proce-
dure should be prepared, reviewed, and approved
by manufacturing and quality assurance. The
reprocessing procedure should also detail any
additional sampling and testing to be performed. It
should define if the reprocessed batch is to be
placed on concurrent stability for long-term moni-
toring. A detailed investigation report should also
be prepared, focusing on the corrective actions,
particularly the need for revalidation of the manu-
facturing process. As the batch in question is
being considered for reprocessing, it should be
placed under quarantine according to the noncon-
forming materials SOP, so that it is not processed
any further.
CHANGE CONTROL
MANAGEMENT TOOLS
A master change control system is composed of
a number of individual procedures and systems
that are meant to control changes in various
aspects of the operational activities within a phar-
maceutical manufacturing operation. Such a sys-
tem should be interactive, managed by the quality
assurance function with due representation from
other functionary disciplines to address different
changes. An integral part of any change control
system is an effective quality failure investigation
procedure. This section details some of the tools
and procedures that should be implemented to
have an effective change control system.
20 Journal of GXP Compliance
Deviations
21CFR211.100 Written Procedures; Deviations
This section mandates that there will be written
procedures for production and process control to
assure the identity, strength, quality, and purity of
the drug product. However; if there is a deviation
from written procedures it shall be documented
and justified. The following discussion is a proce-
dural approach on how to handle any deviations.
Definitions
A deviation is any modification or temporary
change in any approved procedure, document, or
specification. The deviation request/report is a spe-
cific one-time use document that will modify docu-
ments contained within or referenced by the batch
record. It does not permanently change existing
specifications, SOPs, or other batch record docu-
ments. These documents could be revised according
to document change control procedures, if needed.
Types of Deviations
Deviations could be process or procedure
related, and the following types of deviations can
be found in a manufacturing operation.
Planned vs. Unplanned
A planned deviation is a proposed change to
any approved procedure, document, or specifica-
tion prior to execution. An example is the use of
water-for-injection instead of purified water to rinse
cleaned equipment.
An unplanned/in-process deviation is an unex-
pected event that requires a change to any
approved procedure, document, or specification. It
is usually discovered after the fact. An example is a
sudden change in temperature/humidity in the
manufacturing area, missed sampling points, or
temperature digression during a drying cycle out-
side the specified range.
Temporary vs. Permanent
A deviation could be temporary or permanent,
depending upon its impact. If the deviation is a
one-time occurrence, then it should be treated as
temporary. Otherwise, if the deviation is going to
result in permanent changes in an approved proce-
dure, document, or specification, then it is a per-
manent change and will require detailed follow-up
corrective actions to implement the required
changes, including employee training.

Lot Specific vs. Multiple Lots
A deviation is usually lot specific for a given
drug product but can also involve multiple lots.
Product Specific vs. Multiple Products
A deviation is generally product specific, but in
some cases, it can involve more than one drug
product. An example is a sudden failure of the
water system, impacting multiple drug products,
which might have used suspect-quality water for
equipment cleaning or product manufacture.
Potential Areas of Deviations
Following is a listing of potential deviation areas
and how each could influence the drug product
quality attributes.
Materials
Raw materials as well as labeling and packag-
ing components must meet their quality specifica-
tions before their usage in manufacturing. Yet there
will be situations when an unreleased material
might end up in manufacturing, or an unapproved
labeling component might be used in the label-
ing/packaging operation.
In either case, the impact on the quality/compli-
ance status of the drug product should be
reviewed in detail before deciding its disposition.
Equipment
The sudden breakdown or malfunction of equip-
ment is an unplanned deviation that could have an
adverse impact on drug product quality. Also, if the
equipment is beyond its calibration period and is
used in manufacturing, packaging, or testing of the
drug product, it will compromise its compliance sta-
tus. Such deviations may not have any apparent
effect on the quality, safety, and efficacy of the drug
product but still have compliance implications.
Another deviation could be replacing equipment by
similar or comparable equipment in the middle of a
manufacturing run. Such a change should be docu-
mented and justified at the time of occurrence and
be pre-approved by the quality assurance function.
Process
Deviations from both process parameters and
process conditions could affect the drug product.
Machine setups, mixing speeds, drying tempera-
tures, etc., all should remain within the preset lim-
its. Any digression would be a deviation and would
require an investigation, especially if the machine
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settings drift too far from the validation data.
Likewise, process conditions, like temperature,
humidity, and the microbial quality of the environ-
ment, should be maintained as any change would
be considered a deviation and could impact the
drug product quality.
Practices
If the written procedures are not followed
strictly, this will be a deviation as spelled out by the
regulations. For example, if sampling procedures
are not followed, the samples collected will
become suspect, and any data obtained from their
testing will not be of value to make any quality
decisions. Such a deviation requires resampling
and retesting of the materials along with other cor-
rective actions, including retraining of employees.
Documentation practices
cGMPs require that all quality/compliance
related documents be prepared, reviewed, revised,
and approved according to written SOPs. Likewise,
such documents should be used in a consistent
manner; if not, this will be a deviation that has to be
explained. Documentation practices are a cause for
concern throughout the company, and employees
should be trained and retrained on this subject.
Test Methods
Analytical test methods are qualified relative to
a given drug product and set of instruments.
Whenever there is a deviation from an approved
analytical procedure, it requires a detailed investi-
gation and sound scientific justification before the
data is accepted for any quality decision. Some
deviations are minor, yet these should be docu-
mented, while others could lead to a reevaluation
of the analytical method or the instrument used.
Sometimes deviation from an approved test
method is necessary because of compendial
changes, and the written procedure is yet to be
reviewed and approved by the organization.
Specifications
Specifications are based on sound scientific
data and are a direct result of drug product behav-
ior during the development process. Raw material
and packaging component specifications are either
based on the most current USP or supplier specifi-
cations. Deviations from approved specifications
result in failure and rejection or rework of the mate-
rials involved.
Technical Guide 21
Shahid T. Dara
Deviation Management
Whether a deviation is planned or unplanned,
there should be a change control system in place
to handle it. Essential elements of such a system
would include the following:
SOP
There should be a written procedure in place on
deviation processing, detailing all the steps neces-
sary in resolving a deviated scenario.
Deviation Report
A standardized deviation report form should be
part of the SOP. Such forms should be prenum-
bered for control and reference purposes and con-
trolled and issued by the quality assurance func-
tion. QA should also be responsible for the appro-
priate closure of each deviation report. The devia-
tion report form should detail all the steps neces-
sary to complete the investigation and resolution of
an incident.
Probable Cause
The deviation reporter or requester should pro-
vide information as to the probable cause of the
incident, especially if it is process related.
Otherwise, the quality/compliance review commit-
tee would have to find the cause of the deviation
as part of the investigation.
Review/Investigation (if needed)
Quality assurance and the rest of the
quality/compliance review committee should review
the deviation to make a determination if an investi-
gation is warranted or not, depending upon the
nature of the deviation. Such an investigation
should be in-depth and in writing.
Rationale for Acceptance/Rejection
As part of the deviation investigation, the rationale
for acceptance or rejection of raw materials and drug
products should be well defined and based on sound
scientific justification. If it involves a raw material, the
quality history of the material should be considered
and referenced in the decision-making process. If the
deviation was process related, process qualification
data and drug product quality history could be of
value in the review process.
Corrective Actions
The quality assurance function should consult
with the affected department(s) to determine if a
22 Journal of GXP Compliance
corrective action is required. If the answer is Yes,
then details of the corrective action plan should be
finalized and agreed upon with time lines for imple-
mentation. As part of the corrective action plan,
also determine if the deviation under review has
impacted any of the following areas and how that
affects the quality/compliance status of the drug
product involved:
■ Stability data: Is there a need for additional
stability testing? If yes, will it be concurrent or
prospective, and under what conditions?
Would this impact the current established expi-
ration date for the marketed drug product?
■ Validation: Is the revalidation of a manufac-
turing process or an analytical method
required? If so, what is the justification, and
how does it affect the qualified status of the
drug product involved?
■ Regulatory status: Will this deviation have
an adverse effect on the approval status of
the drug product?
■ Change request required: Will this deviation
require changes in approved procedures, batch
records, or specifications? If so, is the change
request initiated and by whom? From a regula-
tory perspective, is this change a pre-approval
supplement, changes being effective notice, or
an annual reportable event?
Responsible Personnel
Whenever a corrective action is required, the
corrective action plan should clearly define the
responsibilities and accountabilities with quality
assurance to oversee the effort. By naming the
individuals or departments, it becomes much eas-
ier to follow up on the progress of the project.
Deviation Disposition
Once the investigation phase is completed, a
decision needs to be made to decide the disposi-
tion of the materials or drug products involved.
Consider if the deviation is an isolated incident or
involves multiple lots of the same drug product or
multiple drug products. Due consideration should
be given to the stability profile of the product, as
most process-related deviations necessitate addi-
tional stability testing for the lot under review. Also
look into the regulatory/compliance status of the
drug product; the regulatory affairs department
should agree to the proposed disposition of the
product. All deviations should be reviewed periodi-

cally to determine if there are any trends develop-
ing which could be indicative of systemic prob-
lems. In other words, what might appear to be an
isolated incident could prove to be an ongoing
quality issue that requires systemic changes, both
procedural and practical.
Final Reviews and Approvals
The deviation report form should be reviewed
and approved by the manufacturing, regulatory
affairs, and quality assurance departments. QA
has the ultimate responsibility to determine that
each deviation is resolved before a suspect lot of
a product is released or rejected.
Follow-up Actions
QA should follow up the resolution of each devi-
ation to determine that the corrective actions, if
needed, were implemented. The revised docu-
ments should be reviewed and approved and be
part of the investigation as it is closed. Also,
employee training records should be reviewed to
see if the operators were, in fact, trained in revised
procedures and practices.
Nonconformance Materials Control
21 CFR Part 211.84, 211.122, 211.188, and
211.192 mandate that only those components and
packaging/labeling materials can be used in manu-
facturing drug products which meet their pre-
approved specifications. Similarly, each lot of a drug
product manufactured must be produced in compli-
ance with cGMPs and meet all its in-process and
finished drug product specifications. If any of these
materials fail to meet their respective specifications,
they should be declared nonconforming and be
segregated and placed on hold/quarantine until a
disposition decision is made.
Definitions
Nonconforming material refers to a material that
fails to meet quality acceptance criteria or its pre-
defined specifications. A Nonconformance Material
Report (NCMR) is a specific onetime use report,
which documents the nonconformance material
and its disposition.
Material Review Board – refers to a group of
individuals within an organization representing
quality assurance, quality control, regulatory
affairs, operations, production planning, and pur-
chasing. This group is responsible for reviewing
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each nonconforming situation and deciding the dis-
position of the materials involved. This could be
part of the quality/compliance review committee.
Types of Nonconforming Materials
Components
Incoming raw materials could fail to meet specifi-
cations due to shipping damage, contamination,
and infestation or fail upon testing of a sample.
Sometimes raw materials can fail upon retesting of
an older lot or when an older lot cannot be retested
because it’s beyond its retesting protocol. Also
expired raw materials should be processed as non-
conforming materials and should be destroyed. In
any of these situations, the raw material involved
should be declared a nonconforming material
according to company policies and procedures.
Container/Closure
Incoming container(s) and closures could fail to
meet specifications due to shipping damage, con-
tamination, and infestation or fail upon testing of a
sample. In such situations, the container/closure
involved should be declared a nonconforming mate-
rial according to company policies and procedures.
Labeling Components
Incoming labeling components could fail to meet
specifications due to shipping damage, contamina-
tion, and, most serious of all, printing errors.
Sometimes, labeling changes are mandated by
FDA, and the existing stock of labeling compo-
nents can no longer be used and, therefore,
becomes nonconforming. In such situations, the
labeling components involved should be declared a
nonconforming material according to company poli-
cies and procedures.
In-Process Materials
In-process materials require further processing to
complete the manufacturing cycle and are sampled
and tested at critical points during the process to
assure that the process is functioning within its lim-
its. Sometimes the in-process materials fail to meet
specifications upon testing, and the material should
be declared nonconforming at this stage. It might be
resampled and retested or reprocessed depending
on the nature of the failure and its cause. But by
declaring it a nonconforming material, it is assured
that the material will not be processed further. Also
expired in-process materials should be processed
as nonconforming and be destroyed.
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Shahid T. Dara
Finished Drug Products
When a finished drug product fails to meet
specifications or alert limits, it should be declared
nonconforming at this stage to prevent its distribu-
tion unless the deficiency is corrected by repro-
cessing or repackaging. Also, expired drug prod-
ucts should be processed as non-conforming
materials and be destroyed.
Nonconforming Materials Management SOP
There should be a written procedure in place on
“Nonconforming Materials Handling,” detailing all
the steps necessary in deciding the disposition of a
nonconforming material.
Nonconformance Material Report (NCMR)
A standardized NCMR form should be part of
the SOP. Such forms should be prenumbered for
control and reference purposes and be con-
trolled and issued by the quality assurance func-
tion. The latter should also be responsible for
appropriate closure of each NCMR form and dis-
position of associated materials. The NCMR
form should detail all the steps necessary to
resolve a nonconforming situation and document
the disposition decision as well as actual dispo-
sition of the materials as to when and by whom.
Probable Cause
The nonconformance reporter should provide
information as to what materials are involved and
what could be the apparent cause of this nonconfor-
mance, such as shipping damage or sampling error,
etc. The material review board or Quality/Com-
pliance Review Committee can further investigate
the issue to define the most probable cause.
Review/Investigation (if needed)
Some nonconforming situations are self-ex-
planatory, like material contaminated with oil or
grease, while others require more in depth investi-
gation, especially those involving a raw material
sample test data, failure of an in-process material,
or a finished drug product. Quality assurance
should define if there is a need for further investiga-
tion in consultation with other departments. The
investigation phase could involve resampling and
testing of the materials involved in order to gather
more information. A review of the process validation
history and drug product quality profile might also
be required to determine the possible cause of fail-
ure and potential corrective actions, if possible.
24 Journal of GXP Compliance
Rationale for Acceptance/Rejection
Most nonconforming materials are usually
rejected because of the nature of the quality fail-
ure. However, in some instances where a sampling
technique could be a potential cause for sample
failure, a resampling or expanded sampling and
testing of material might be recommended before
deciding the eventual disposition. Likewise, for in-
process materials and finished drug products, the
reprocessing decision should be made after careful
consideration of all regulatory/compliance issues
as well as quality/stability attributes of the drug
product involved. Whatever the rationale, it must be
documented, reviewed, and approved by QA.
Corrective Actions
The quality assurance function should decide, in
consultation with other departments, if there is a
need for any corrective action. Based on the nature
of the quality failure, the potential corrective
actions might include one of the following options:
Resample/Retest
If sampling technique is a potential cause for the
quality failure, the material could be resampled and
retested to assure that a quality material is not
rejected unnecessarily. This is especially true for in-
process materials and finished drug products.
However, if the retest data meets specifications, this
should initiate another aspect of the change control
system, i.e., the out-of-specifications data investiga-
tion. Nonetheless, the rationale for the resampling/re-
testing decision should be justified and documented
in detail with review and approval by QA.
Reprocessing/Repackaging
In-process materials and finished drug products
could be considered for reprocessing or repackaging,
depending on the cause of the quality failure. Re-
processing is allowed by cGMP regulations; however,
consider the regulatory/compliance status of the drug
product when faced with such a decision. The repro-
cessing must not affect the safety, quality, purity, and
efficacy of the drug product. Repackaging might be
an option where a packaging error is the cause for
quality failure, e.g., incorrect lot number or expiration
date on the label. Like reprocessing, a repackaging
option should be carefully explored as to its potential
impact on the safety, quality, purity, and efficacy of the
drug product. In both cases, the reworked batch
should be considered for concurrent stability studies,
if so decided by the Quality/Compliance Review

Committee. There should be a rework procedure pre-
pared and approved by quality assurance before
reprocessing or repackaging is initiated and the
rework procedure becomes part of the batch record.
The justification for the rework decision should be
fully documented and become part of the NCMR file
for the drug product involved.
Reprocessing/repackaging is an example of a
temporary change control system that allows for a
one time deviation from the approved manufactur-
ing or packaging procedure to correct a quality
deficiency. Here, a normally processed batch has
to be reworked or repackaged to correct the prob-
lem. Once the situation is resolved, go back to the
originally approved manufacturing/packaging pro-
cedure or batch record.
Responsible Personnel
Whether a material is to be rejected or a drug
product has to be reworked, the responsibilities
should be clearly defined with QA interaction
throughout the process to assure proper disposi-
tion of the nonconforming materials and closure of
the NCMR form. The responsible personnel should
be indicated on the NCMR form.
NCMR Disposition
Once a disposition decision is made for a non-
conforming material, QA should be responsible for
assuring that the material is disposed of accordingly.
Release/Reject
If the material is to be released for use, its qual-
ity status should be changed accordingly. If the
material is rejected, it should be moved immedi-
ately to the rejected material storage area and be
marked for destruction.
Return to Vendor
If shipping damage is the cause for nonconfor-
mance or the raw material fails to meet specifica-
tions on testing, it could be returned to the vendor
for credit. For contract manufactured/packaged
drug products, a similar approach can be taken.
Inventory Adjustments
Inventory control and reconciliation of raw mate-
rials, container/closure, labeling components, as
well as in-process and finished drug products is
required by cGMP. Whenever a material is non-
conformed, inventory records should be adjusted
accordingly, with full explanation for the changes.
Shahid T. Dara
Final Reviews and Approvals
The completed NCMR form should have review
and approval signatures from all appropriate de-
partments. It should clearly indicate the disposition
of the material and who was responsible, along
with a QA double check.
Follow-up Actions
Quality assurance should follow up the resolu-
tion of each nonconforming incident to see if it is
an isolated situation or a symptom of systemic
problems. Also review the possible implication of
other batches of the same drug product or other
drug products as well. This could involve vendor
audits to ensure there has been no unapproved
changes in their shops.
A detailed review of the manufacturing process
and other control procedures in place should be
performed to determine if the process is still oper-
ating within a state of control, if there is a need for
process revalidation, or if the change control pro-
cedures need revisions with attendant employee
training. In any case, quality assurance should fol-
low up with all these activities to control the poten-
tial for nonconforming situations.
Hold for Release Issues
21 CFR 211.22 Responsibilities of the Quality
Control Unit dictates that all quality decisions
regarding a drug product and its components
should be made by an independent quality control
unit. The quality function in general is also implied
to assure the quality of components and pro-
cesses at each stage. As part of this responsibil-
ity, the quality function must have adequate
means to control the materials of questionable
quality/compliance status before their disposition
for use in manufacturing or release for distribu-
tion.
Definition
“Hold” is a questionable quality status of a drug
product or its components, or for any other rea-
son, which prevents further processing until it can
be determined whether to quarantine, release, or
reject the drug product or its component. In all
cases, the “Hold” status should prevent distribution
of drug products for marketing. Materials placed
on hold typically require further investigation or
testing and may result in return to vendor or
destruction.
Technical Guide 25
Shahid T. Dara
Types of Hold
Hold status could be invoked because of a
material’s failure to meet specifications or for reg-
ulatory/compliance reasons. Most questionable
quality status situations fall into one of the follow-
ing categories:
Planned vs. Unplanned
A planned hold status is when the reason for
questionable quality status is known and related to
a change in formulation, manufacturing process, or
container closure system for the drug product.
Such changes require additional process validation
and stability testing of the drug product to deter-
mine the effect of the change(s) on the safety,
quality, and purity of the drug product. Until these
studies are completed, the drug product cannot be
released for distribution.
An unplanned hold status is an unexpected
event resulting from a sudden failure of the mate-
rial to meet its specifications. This could happen to
an already released drug product or raw material,
e.g., a drug product complaint might force the
organization to put on hold its existing released
stock of particular drug product until the complaint
is investigated and resolved.
Temporary vs. Permanent
Hold status is usually a temporary situation,
and the material or drug product involved is
either released or rejected. However, under cer-
tain regulatory/compliance circumstances, a
company might be forced to put its drug prod-
uct(s) on permanent hold leading to rejection and
destruction. This could happen when FDA finds a
lack of cGMP compliance or other serious viola-
tions of the Act.
Lot Specific vs. Multiple Lots
Hold status could involve only one lot of drug
product or multiple lots.
Product Specific
Hold status should always be product specific
and, if more than one drug product is involved,
each should be placed on hold separately, and
documentation should reflect this.
Reason for Hold
Hold status is a result of a questionable quality
status and could be caused by one or more of the
following reasons:
26 Journal of GXP Compliance
Formulation/Packaging Components Change
Formulation changes are rare, but once these
occur, a number of concurrent activities need to be
completed before the drug product could be taken off
hold status. Potential changes in formulation include:
■ Active Pharmaceutical Ingredient
■ Major Excipient Change
■ Container/Closure Change
Either of these changes requires, at a minimum,
additional stability testing to determine the effect of
the change on drug product quality and stability. API
changes require submission of a pre-approval sup-
plement to FDA if it is a NDA/ANDA product. In either
case, the drug product should remain on hold until
these issues are resolved.
Equipment Change
Major equipment change necessitates a revali-
dation of the manufacturing process, unless it
could be proven that the change falls under similar
equipment criteria based on SUPAC guidelines.
The drug product manufactured with new equip-
ment, however, should be placed on hold until the
issue is resolved.
Process Change
A critical change in the manufacturing process
also requires a revalidation of the process and
additional stability testing for the drug product pro-
duced.
Again, the drug product has to be placed on
hold until these issues are resolved and the drug
product safety, purity, and quality can be proven.
Stability Data
On-going stability studies might reveal a sudden
negative trend in drug product potency, making the
expiration dating assigned to the drug product
questionable. In this case, the current stock of the
drug product should be put on hold and distribution
temporarily halted until this stability issue is
resolved.
Validation
Validation batches are completed much before a
validation study is completed, i.e., all the documen-
tation is signed off and a summary report is pre-
pared and approved by quality assurance. The vali-
dation batches should be placed on hold until the
validation is complete and successful. Other valida-

tion-related issues, which would necessitate the
use of this procedure, could include the following:
■ Change in process
■ Cleaning validation
■ Test method
■ Packaging configuration
■ Facility/utility changes
■ Quality issues
Other quality issues might force a drug product
to be placed on hold, e.g., periodic review of the
reserve samples might reveal a container/closure
defect, or a critical product complaint from the field
could make the drug product suspect. As part of
the investigation, the first step should be to place
the drug product on hold to show due vigilance by
the company.
Regulatory Issues
Regulatory/compliance reasons could also
dictate that a drug product should be placed on
hold until resolution of these concerns. A change
in an API requires a pre-approval supplement to
the FDA, and until that is approved, the drug
product lots involved cannot be released for mar-
keting.
Hold for Release Management
Whether a hold status is planned or unplanned,
there should be a change control system in place
to deal with questionable quality status of raw
materials, containers/closures, or drug products.
Essential elements of such a system include:
SOP
There should be a written procedure in place on
Hold for Release issues, detailing all the necessary
steps in controlling and resolving the situation.
Hold for Release Report (HFR) Form
A standardized Hold for Release report form
should be part of the SOP. These forms should be
prenumbered for control and reference purposes
and be controlled and issued by the QA function.
The latter should also be responsible for appropri-
ate closure of each HFR form. The HFR form
should detail all the steps necessary to complete
the investigation and resolution of a questionable
quality status. It should also refer other change
control documents involved, like a deviation report
or an NCMR form.
Shahid T. Dara
Quantity Placed on Hold
For inventory purposes, the quantity placed on
hold should be clearly marked and adjustments
should be made accordingly.
Reason
Reason for hold should be clearly defined, refer-
ring to any source documents involved, especially
for planned hold situations. For unplanned quality
failures leading to a hold decision, the probable
cause should be defined, as it will be the starting
point for the investigation by the Quality/Com-
pliance Review Committee.
Review/Investigation (if needed)
Quality assurance and other members of the
Quality/Compliance Review Committee should
review the questionable quality status to make a
determination if an investigation is warranted or
not. Such an investigation should be in-depth and
properly documented.
Rationale for Acceptance/Rejection
The rationale for an acceptance/rejection decision
should be well defined, based on solid scientific
data, considering the quality history of the drug prod-
uct, process qualification data, and stability profile.
Corrective Actions
Quality assurance should determine if the correc-
tive actions carried out to resolve questionable qual-
ity status are sufficient or if there is a need to rectify
these deficiencies on a broad systemic basis.
Corrective actions could involve the following:
■ Additional stability testing
■ Validation considerations
■ Regulatory considerations
■ Employee training issues
Responsible Personnel
Whenever a corrective action is required, the
plan should clearly define the responsibilities and
accountabilities with QA to oversee the effort.
If it is a multidisciplinary effort, then it is even
more important to define all the participants roles
in carrying out the project.
Hold for Release Disposition
Based on analytical data or regulatory approval
of a supplement, the material or drug product
involved can be released for use or distribution;
Technical Guide 27
Shahid T. Dara
otherwise, the material might have to be rejected.
Care should be taken that all necessary validation
or stability testing is completed, and a final report
is written up before the drug product is released.
Final Reviews and Approvals
The HFR form should be reviewed and
approved by the hold requester, regulatory affairs,
and QA. QA has the responsibility that each HFR
incident is resolved, and the drug product involved
is disposed of accordingly.
Follow-up Actions
Quality assurance should follow up the resolu-
tion of each hold incident to determine if additional
corrective actions are needed or if the reason for
the hold incident is a symptom of systemic prob-
lems. If such is the case, then all concerned qual-
ity/compliance systems should be reviewed and
revised accordingly. This might require revision of
documents and additional training for the person-
nel involved.
Out-of-Specifications Investigations
Out-of-specification (OOS) data investigation is at
the top of the current list of issues facing industry and
FDA. Not that it is a new subject, as it has always
been part of the cGMP regulations, 21 CFR 211.194,
but the issue has assumed a new significance since
the infamous Barr Decision. The old school of testing
a product till it passed was supposed to be gone with
the introduction of cGMP regulations. However, this
monster still lives on in some pharmaceutical manu-
facturers. Like any other compliance issue, OOS is
part of analytical reality in any organization, and how
to investigate and resolve a situation involving OOS
data should not be the subject of deep philosophy
and considered right up there with universal meta-
physical forces in action. The simple truth is that
every drug manufacturer is responsible for investigat-
ing OOS data according to a written procedure, with
due review and an approval process in place. The fol-
lowing discussion is a procedural approach on how to
handle any OOS investigation.
Definitions
■ “GMP data” means data upon which a quality
or GMP decision is made and includes data col-
lected in determining the disposition (release or
rejection) of a raw material, intermediate or in-
process material, or drug product, as well as data
28 Journal of GXP Compliance
collected to determine expiration dates or valida-
tion of processes.
■ “Out-of-specification” is any GMP data which
is outside the boundaries of predetermined specifi-
cations.
■ “Laboratory error” occurs when an analyst
commits an error while following an analytical
method (e.g., incorrect standard preparation, miscal-
culation of data, incorrect sample preparation, etc.).
■ “Inconclusive laboratory error” occurs when the
analytical method is followed correctly, but the data
generated is questionable. Upon retest, the results
show that the material is within specifications, and a
reason for the OOS data cannot be determined.
■ “Process error” happens when the manufac-
turing process itself is found to be the cause of the
OOS data.
■ “Nonprocess related error” occurs when
human or mechanical errors cause a failure, result-
ing in questionable GMP data.
■ “Retest of original sample” means the reanaly-
sis of the material involved from the initial sample
taken from the bulk. For stability studies, this means
the initial sample that was removed from its proper
storage condition. Re-injection of the initial
HPLC/GC vial also qualifies as retesting the original
samples. A freshly diluted sample prepared from an
original tablet grind is also considered valid.
■ “Resample of material for analysis” means
physically removing a new sample from the bulk
material.
Barr Decision
In 1992, Judge Wolin made a landmark decision in
U.S. vs. Barr Laboratories, clarifying the issues of
OOS data and the practice of retesting the drug prod-
uct until it passes. cGMP regulations imply that the
drug manufacturer should conduct a failure investiga-
tion when a drug product fails to meet test specifica-
tions. The Barr decision made it clear that it is a legal
requirement for every manufacturer to address the
OOS data investigation in a systemic way, and written
procedures should be in place to define the course of
action. It also emphasized the fact that quality cannot
be tested into a drug product, rejecting the practice of
testing till it passes. The OOS data should not be
summarily dismissed, and it should be part of the
analytical results along with the retest data and justifi-
cation for the retesting of the original sample or
resampling and retesting of this sample.
The Barr decision had a far-reaching impact on
the pharmaceutical industry, as Judge Wolin’s

opinion was the first established detailed explana-
tion of how an OOS situation should be handled.
FDA has incorporated this explanation into its
inspection guidelines and expects industry to follow it.
Types of Data Involved
Analytical data pertaining to raw materials, in-pro-
cess tests, finished drug product analysis, validation
test results, and stability study samples are utilized to
make quality decisions about drug products.
Whenever these results are outside the predeter-
mined specifications for any of these tests, the OOS
investigation must be performed. Even if a raw mate-
rial or drug product is going to be rejected based upon
retest data, the investigation must be carried out, as it
could involve more than the quality and purity of the
material involved. In a Quality Control Laboratory one
can encounter the following types of data which could
require an OOS investigation including:
■ Component test data
■ In-Process test data
■ Finished product test data
■ Stability studies test data
■ Validation studies test data
■ Analytical method validation
■ Process validation
■ Cleaning validation
Management of OOS Data in the Investigation
An OOS incident is never planned; however,
there should be a system in place to investigate it.
Essential elements of such a system should
include the following:
SOP
There should be a written procedure in place for
the OOS investigation, detailing all the steps neces-
sary for completing a timely investigation of GMP
data which is considered out-of-specification.
Laboratory management should train all analysts in
this SOP and make sure that all OOS incidents are
investigated and resolved in a timely fashion. The
SOP should define the time period allowed for initi-
ation and disposition of an OOS incident. Once an
analyst has determined that the GMP data gener-
ated does not meet specification, he or she should
immediately inform management to start the inves-
tigation. At this time, an OOS investigation report
should be initiated, and all original samples and
solutions prepared should be kept and stored under
appropriate conditions for later analysis if needed.
Shahid T. Dara
OOS Investigation Report
A standardized OOS investigation report should
be part of the SOP. Such forms should be pre-
numbered for control and reference purposes and
controlled and issued by quality control. An OOS
investigation log should be maintained to record
the following information:
■ OOS report number issued
■ Name of the material in question
■ Lot number
■ Initial analyst
■ Investigation initiation date and the
conclusion date
■ Disposition of the material
The following details should be recorded on the
OOS Investigation Report:
Material Involved
List name and lot number of the material
involved. If it is a stability study sample, detail the
storage conditions and test interval as well. For
validation samples, specify whether the sample is
for process, cleaning, or method validation.
Sampling Information
Sampling information should include the con-
tainer number from which the particular sample
was taken, thereby forcing the company not to
composite the samples, as required by the
cGMPs. For purified water samples, the sampling
outlet designation and time of sampling are also
important.
Analytical Method
The analytical method used should be refer-
enced, along with the analyst’s name and labora-
tory notebook references, as a measure of trace-
ability and good record-keeping.
Initial Results vs. Specifications
Record the initial test results vs. the specifica-
tions in an unambiguous manner.
The author has seen many confusing ways of
expressing the OOS data, which immediately
raises a red flag for an investigator.
Probable Cause
Define the probable cause if it is immediately
known; otherwise, let the investigation take its
course. Avoid speculation without hard evidence.
Technical Guide 29
Shahid T. Dara
Investigation Team
Members of the investigation team should
include the analyst, his/her supervisor, representa-
tives from regulatory affairs, production, and QA.
A quality/compliance review committee might be
entrusted to make a final decision based on the
recommendations of the investigation team.
Review/Investigation
The investigation should focus on the following:
■ Analytical method validation status
■ Data/calculations verification
■ Instrument
■ Performance/calibration/maintenance history
■ Instrument output/raw data
■ Reference standards
■ Analyst training records
■ Review of batch records
Define Cause
The investigation should result in narrowing down
the cause for OOS data, and a brief summary of the
reasoning behind this decision should be prepared.
Probable causes of OOS data could include:
■ Laboratory error
■ Inconclusive laboratory error
■ Nonprocess related error
■ Process related error
■ Stability degradation
Corrective Actions
The corrective action plan should be defined to
address the following:
■ Retest plan
■ Retest of original sample
■ Resample of material for analysis
■ Predetermined testing procedure to define the
source of retest sample and the number of
samples to be retested for statistical signifi-
cance of data
■ A second analyst to perform the analysis, when
necessary, to verify the ruggedness of method
■ Evaluation of retest data
Related Batches/Drug Products
Related batches of the same raw material or
drug product or related drug products should be
evaluated to establish an analytical history of the
material involved. This review is necessary to
30 Journal of GXP Compliance
determine, with reasonable assurance, if the inci-
dent is an isolated event or a systemic problem. If
the OOS data is a result of the quality system’s
deficiencies, like lack of proper process validation,
then the investigation scope takes on a whole new
meaning, and the QA function should act accord-
ingly to correct the problems.
Conclusion
Once the investigation is completed, a decision
has to be made as to the disposition of the mate-
rials involved. The material could be released or
rejected, and that should close the investigation
for the particular OOS incident. However, some-
times the original and retest data are submitted to
experts within the company, along with key mem-
bers of management, to make a decision. The
assistance of outside experts might also be
sought. All these activities must be documented
to maintain a level of control desired by cGMPs.
Final Reviews and Approval
The OOS investigation report should be
reviewed and approved by QC Lab personnel,
appropriate manufacturing representative (if
needed), regulatory affairs, and QA. Final approval
should be obtained from a senior member of man-
agement to maintain communication at all levels of
the organization.
Validation Change Control Issues
Validation is establishing, to a high degree of
assurance, thoroughly documented evidence that a
given process will consistently produce a product
that will meet its predetermined specifications and
quality attributes. Validated systems and processes
by definition should be maintained and operated
within a state of control that assures that any
changes will be carefully evaluated and monitored
so as not to compromise the validated status of a
system or process, thereby assuring the quality of
the drug product so produced. The pharmaceutical
industry is experiencing rapid changes, the pace of
which has increased tremendously over the past
few years in response to hard economic realities
and market forces. Equipment changes are more
frequent than in the past and so are the changes
to the manufacturing/packaging processes. Both
are being done to improve the economic efficien-
cies of the operations as well as to achieve better
compliance. Part of this trend involves technology

transfer from one plant to another, creating more
challenges for the change control systems.
Validation change control applies to all validated
systems and processes, including facilities, utilities,
equipment, and manufacturing/packaging pro-
cesses. However, routine preventive maintenance
should not be confused with a change in the vali-
dated status of a system. This discussion is meant
to provide an overview of validation change control
and how to manage it in day-to-day operations.
Definition
Validation change control can be defined as the
process by which each critical or major change in
a validated system or process is evaluated to
determine if the proposed change impacts the vali-
dated status of the system or process involved.
Due consideration should be given to the possibil-
ity of the revalidation of the system or process.
These potential changes include equipment
upgrade, change of critical parts of a utility system,
major changes in manufacturing process, etc.
Types of Validation Changes
Planned vs. Unplanned
Planned changes in a validated system are
meant to improve operation. Such changes usually
have been thoroughly studied and agreed upon by
different organizational units. However, distinction
should be made for planned routine maintenance
activities, as these are extensions of the original
validation of the equipment or system.
Unplanned changes, on the other hand, are a
result of an emergency and have to be made to
keep operations going. Many times the review pro-
cess starts after the fact, and the drug product
manufactured has to be evaluated for compliance
with all its regulatory and quality specifications.
Potential Areas of Validation Change
Pharmaceutical manufacturing is conducted in a
controlled environment, and, anything that could
have an impact on the safety, identity, quality,
purity, and strength of a drug product should be
validated. This validated status must be maintained
throughout the life of the system involved. Any criti-
cal or major changes in any of the following sys-
tems must be carefully reviewed and evaluated for
its impact on the system individually and as part of
the manufacturing cycle for the drug products
involved.
■ Facilities
Shahid T. Dara
■ Utility systems changes
■ Equipment change parts
■ Process parameters
■ Procedural issues
■ Test methods
■ Specifications
■ Computer systems
■ Hardware changes
■ Software changes
Validation Change Control Management
Validation change control is meant to manage
the proposed changes in a way that a system or
process maintains its validated status after imple-
menting the changes and could require a revalida-
tion. As part of an effective master change control
system, there should be a subsystem addressing
validation change control and, within this subsys-
tem, designated procedures for each set of vali-
dated systems and processes within an organiza-
tion. Essentially, such a system should detail the
following:
SOP
There should be a written procedure in place to
assure that any changes in a validated system or
process are evaluated for their effect on the vali-
dated status of the system or process involved
before their implementation.
Validation Change Control Report
A standardized validation change request/con-
trol report form should be part of the validation
change control SOP. Such forms should be pre-
numbered for control and reference purposes and
controlled and issued by the quality assurance
function. The latter should also be responsible for
appropriate closure of each proposed change in a
validated system, in cooperation with the validation
function. The form should ask for all the pertinent
information in order to review and dispose of any
proposed changes.
The validation change request could be initiated
due to one of the following reasons:
■ Procedural changes
■ Utilities modifications
■ Equipment calibration
■ New equipment/replacement of equipment
■ Maintenance frequency
■ Engineering study for process improvement
■ Change in API/major excipient source
Technical Guide 31
Shahid T. Dara
■ Production/packaging process changes
■ Deviations
■ Nonconformance reports
Reason for Change
The sponsor of a validation change request
should provide the reason and justification for the
proposed change along with any technical informa-
tion and drawings of current and proposed systems.
Review of Proposed Change
Operations, engineering, QA and validation
should review the change request. The review pro-
cess should consider the following:
■ Validation status of system/process
■ Drug product(s)
■ Stability issues
■ Regulatory status
■ Isolated vs. systemic issues
Quality assurance and validation must evaluate
the impact of the proposed change on the vali-
dated system or process, and if the opinion is that
the validated status is affected by said change, a
decision is made as to revalidation of the system
or process involved. All proposed changes do not
lead to a revalidation of a system or process, and it
is possible that the impact on the validated status
is minimal, and therefore, corrective actions might
involve additional sampling and testing. There
could be situations where a change request might
be denied altogether for lack of justification, both
technical and financial for the organization.
Rationale for Acceptance/Rejection
Rationale for acceptance or rejection of a pro-
posed change in a validated system or process
should be documented in detail, referring to all the
appropriate documents, including initial validation
documents for the system involved. A change for
the sake of change is not an acceptable practice,
as each change costs money.
Corrective Actions
If a decision is made to revalidate the system or
process concerned, define all the documents that
are impacted, and would have to be revised or pre-
pared as new. These include:
■ Validation protocol
■ SOPs
32 Journal of GXP Compliance
■ Manufacturing batch master records
■ Preventive maintenance procedures
A decision has to be made as to the status of the
drug product manufactured utilizing the changed sys-
tem or process. Should it be placed on hold until the
validation study is complete and all documentation is
reviewed and approved by the organization. This
decision is based on the nature of the change and
extent of the sampling and testing performed on the
impacted drug product and the test results obtained.
Some critical changes in manufacturing equip-
ment or process require additional stability studies
for the drug product manufactured before it can be
marketed. This is necessary to ascertain the stability
profile of the product under a different set of process-
ing conditions. There might be a system or manufac-
turing process improvement situation which has no
impact on the overall quality of the drug product and,
therefore, will not have to be placed on hold.
Pre-Approval
The validation change request should be pre-
approved by validation and quality assurance,
authorizing that the proposed change can be made.
Validation Change Execution
Once it is decided that the change has to be
made and the system/process needs revalidation,
the following activities should occur in succession:
■ Protocol preparation, review, and approval
■ Protocol execution
■ Data collection
■ Final report and conclusion preparation
■ Review and approval of final report and con-
clusion
■ Release of the drug product(s) involved (If
placed on hold pending completion of revali-
dation)
The final review and approval should be by the
same individuals who conducted the pre-approvals
of the protocols. Having a senior VP sign off on a
completed validation study does not add any more
credibility to it than otherwise. Another important
aspect is to review the issues related to the just-
implemented change if there is collateral damage to
other systems. Although this should have been con-
sidered up front when the change was proposed,
some effects will only manifest after the fact.
Therefore, be prepared for all contingencies.

Follow-up Actions
Validation is not an event but an on-going cycle
that ends only when a system is retired or the drug
product is removed from the market. An astute vali-
dation professional understands that the systems
and processes qualified at one point in their life have
to be monitored periodically to assure that they are
still operating within the same validated parameters.
QUALITY FAILURE/INCIDENT
INVESTIGATIONS
Quality systems and procedures are imple-
mented to minimize quality defects, with the aim to
create a zero-defect manufacturing environment. In
reality, there is no such thing as a perfect system.
Quality defects and failures are part of any
manufacturing operation, and pharmaceutical man-
ufacturing is no exception. cGMPs require that all
quality failures/incidents be investigated, docu-
mented, and corrective actions implemented to
prevent recurrence. Most pharmaceutical manufac-
turers have established detailed procedures on
how to investigate out-of-specification data origi-
nating in the analytical laboratory following the Barr
Decision. However, there is a need to have sepa-
rate procedures to address other operational qual-
ity issues, i.e., quality failure/incidents. The quality
failure/incident investigation procedures offer a
number of benefits, such as:
■ Standardized investigation format
■ Useful communication and training tool
■ Improved processes and procedures
■ Long-term cost savings
■ Enhanced overall compliance
■ Timely resolution of quality issues
This article provides an overview of such an
SOP, with special reference to water quality failure
investigation, both during validation and routine
monitoring of the system.
Quality Failure/Incident
Investigation Procedure
What is a Quality Failure/Incident?
Quality failure refers to a situation where a fin-
ished drug product, process, or service does not
meet its expected attributes or specifications. A
quality incident, on the other hand, is a failure of
the quality system practices which may or may not
Shahid T. Dara
lead to a quality failure of a product, process, or
service. Both cases, however, should be fully
investigated and documented.
Quality Failure/Incident Investigation Procedure
A quality failure/incident investigation procedure
should address the following areas as appropriate,
(see Figure 1 for a summarized list):
Define Quality Failure/Incident
It is important that the quality failure/incident be
defined in a clear and concise manner, detailing
exactly what happened.
Define Quality Significance of the Failure/Incident
Most quality failure/incidents can be classified
as critical, major, minor, or for information only. In
some cases, the quality data is also measured
against alert and action limits, e.g., total aerobic
count for an environmental monitoring sample for a
given area. This classification can be a useful tool
in determining the extent of the investigation as
well as the scope of corrective actions needed,
including disposition of the drug product or prod-
ucts involved.
Figure 1
Failure/Incident Investigation
Procedure
Elements of Quality Failure/Incident
Investigation Procedure
Define quality failure/incident
Define quality significance of the failure/incident
Define the cause of the quality failure/incident
■ Facilities
■ Utilities
■ Components
■ Equipment
■ Process
■ Drug Product
■ Analytical
■ Personnel
Quality failure/incident investigation
■ Facilities
■ Utilities
■ Components
■ Equipment
■ Process
■ Drug Product
■ Personnel
■ Procedures and documentation practices
Corrective action plan
Summary, conclusion, and sign off
Technical Guide 33
Shahid T. Dara
Define the Cause of Quality Failure
A quality failure/incident could be caused by
one or more of the following; however, use the pro-
cess of elimination to narrow down this list as
much as possible;
■ Facilities
An example of facilities as a possible cause of
quality incident/failure could be improper
cleaning/sanitization of manufacturing areas lead-
ing to increased bioburden in the environment with
the potential for drug product contamination.
■ Utilities
A malfunction of any of the following utility sys-
tems can cause a quality failure/incident leading to
a drug product failure. They include:
• HVAC system
• Water purification system
• Compressed air system
• Dust collection system
■ Components
Both chemical raw materials and
packaging/labeling components can cause a qual-
ity failure/incident.
■ Equipment
Equipment breakdown as well as improper
cleaning can lead to a quality failure/incident.
■ Process
The manufacturing process as well as process
conditions can contribute to a quality failure/incident.
■ Drug Product
Failure to meet drug product specifications is
the ultimate quality failure/incident.
■ Analytical
Most analytical laboratory quality issues are
related to analytical data and are usually investi-
gated according to an out-of-specification data
investigation SOP. An OOS investigation will likely
involve some of the aspects discussed here.
■ Personnel
Personnel expertise and level of training can
also significantly contribute to quality failures.
This list should not be considered all inclusive,
and there could be other factors involved. Review
34 Journal of GXP Compliance
all possibilities, and attempt to define the most
probable cause(s) of the quality failure/incident.
Quality Failure Investigation
A quality failure/incident investigation should
include a review of the following, depending on the
most probable cause(s). Concentrate on those
areas that may have contributed to a given quality
failure/incident. The investigation phase is in fact
already underway as the probable cause(s) of a
given quality failure/incident are being defined and,
therefore, the two cannot be totally separated from
each other. Quality assurance must lead the inves-
tigation phase in cooperation with other depart-
ments, as these findings are the basis of any cor-
rective action plan.
■ Facilities
If facilities are a possible cause of the quality
failure/incident, review the state of repair of manu-
facturing and packaging areas as well as the tem-
perature and humidity conditions in the plant.
Also, if the microbial environment is monitored,
the data for the particular incident should be
reviewed along with data for the past four to six
weeks to identify any adverse trends.
■ Utilities
If any of the utility systems is a potential cause for
a quality failure incident, review the system in question
in detail. Items to be checked if one or more of the fol-
lowing utility systems is under suspicion include:
HVAC system: Temperature/humidity profile of the
area and potential temperature/humidity exposure
of the components and drug product(s) involved.
Water purification system: Both chemical and
microbial quality of purified water and water-for-
injection can impact the quality of the finished drug
product. The quality failure investigation for a water
purification system is discussed later.
Compressed air system: Possible presence of oil
droplets in an oil-free compressed air system can
cause contamination.
■ Dust collection system
Malfunction of a dust collection system can
cause excessive dust in the area, with potential for
cross contamination, especially where conditioned
air is recirculated.

■ Components
Always review the sampling/inspection and
release processes if a component is a potential
cause for a quality failure/incident. Sample manipu-
lation can have a potential negative impact on the
quality of the material being sampled. Both active
and inactive raw materials can have a direct bear-
ing on the drug product quality if these are not of
desired quality or their quality is compromised
either during sampling process or due to improper
storage conditions.
Packaging/labeling component quality defects
can cause potential stability concerns as well as
mislabeling situations. Almost one-third of all drug
product recalls in recent years were due to misla-
beling of drug products, per FDA enforcement
reports.
■ Equipment
If manufacturing/packaging equipment is a
potential cause for a quality failure/incident, review
the following:
■ Cleaning and sanitization records
■ Calibration status of critical equipment
■ Maintenance records
■ Performance history
■ Equipment qualification records
■ Process
Review the manufacturing process in detail to
see if there were any deviations or anomalies.
Also, review the process conditions, like tempera-
ture, humidity, machine speed setups, order of
addition of ingredients, process time limits, etc. A
review of process validation records might also be
in order, if considered necessary.
■ Drug Product
Review other batches of the same drug prod-
uct to see if this is a product-specific quality issue
or an isolated incident. Review batches of related
drug products manufactured under similar sets of
conditions. This will help determine if other drug
products are also involved.
This part of the investigation demands
extreme diligence on the part of the quality man-
agement team, as it can have far-reaching impli-
cations. In recent years, FDA has repeatedly
cited pharmaceutical manufacturers for failure to
perform an in-depth investigation of quality fail-
ure/incidents.
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■ Personnel
This is a subjective issue that is difficult to mea-
sure as it tends to indirectly validate the effective-
ness of the employee training program. Ensure that
the individuals involved in all phases of a given
quality failure/incident have the knowledge, exper-
tise, and training to carry out their assignments,
and there is documented evidence to support this
claim. If not, an isolated quality failure incident
could be an indication of a major systemic quality
problem within the organization.
Procedures and Documentation Practices
A review of the SOPs, batch records, analytical
procedures, etc., is also required to complete this
investigation. This assures that the procedures are
detailed enough and easy to follow for the opera-
tors. If not, revisions might be needed.
Corrective Action Plan
Quality assurance management, in collaboration
with other appropriate departments within the
organization, should develop a corrective action
plan with definite time lines for implementation.
Such a plan should clearly define the responsibili-
ties and accountability profile of assignments and
should include:
■ Does the incident/failure fall under an OOS
investigation? If so, is there a need for a sep-
arate investigation?
■ In such cases, the two investigations should
complement each other in resolving the issue
■ Identifying procedural changes required
■ Identifying documentation to be revised
■ Identifying additional training requirements
■ Disposition of the drug product(s) involved
Summary, Conclusion and Final Sign Off
A critical step in the successful conclusion of
any investigation is that a summary report and con-
clusion is written up. Before finalizing such a report,
QA should verify that all the corrective actions have
been (or are being) implemented per their time
lines. The effectiveness of completed corrective
actions can be evaluated by verification that the
procedures and systems were revised, and the
employees were retrained by responsible person-
nel, the new equipment was purchased, or there
was a change in a raw material supplier, etc.
Documentation supporting that a given corrective
action was completed should be reviewed and ref-
Technical Guide 35
Shahid T. Dara

erenced or attached to the investigation report, like assurance and may also involve manufactur-
employee training records, copies of the purchase ing, if needed.
order, copy of the approved change control, etc. ■ The investigation team should discuss all
The report should be reviewed and approved by findings of the investigation before designing
the appropriate departments within the organiza- a corrective action plan and deciding the dis-
tion. QA and other pertinent departments should position of the drug product(s) involved.
sign off on the report, and sign off responsibilities
should be delineated in an SOP. The summary Water Quality Failure Investigation
report should be used to inform upper manage- A water quality failure investigation should
ment of any critical quality issues, especially those address the following areas, as appropriate (see
which would involve capital investments as part of Figure 2 for a summarized list):
their corrective action plan.
Define Water Quality Failure/Incident
Water Quality Failure Investigation Procedure A water quality failure/incident could involve one
Water purification systems are designed and or more of the following scenarios:
qualified to assure a consistent supply of purified
water of the desired quality. However, despite our
best efforts, a water sample may fail to meet its Figure 2
specifications. The water quality failure/incident has
far-reaching implications as purified water and water- Water Quality Failure Investigation
for-injection are used widely in drug product manu-
Elements of Water Quality
facturing and facilities and equipment cleaning. Failure/Incident Investigation
This is a detailed overview of a water quality fail-
ure investigation procedure, both during validation Define water quality failure/incident
and routine monitoring of the water purification sys- ■ System malfunction
tem and is based on the author’s personal experi- ■ Chemical
■ Microbiological
ences in handling them.
In order to accomplish a comprehensive investi- Define quality significance of the water quality
failure/incident
gation of a water quality failure incident, it is impor- Define the cause of the water quality failure/incident
tant that different aspects of the investigation be ■ Purification system
assigned to different departments according to their ■ Sampling
expertise. This is especially true if the incident hap- ■ Analytical issues
pens during validation or major revalidation of a Quality failure/incident investigation
water purification system. The investigation team ■ Purification system
should include the following: Source water
Pretreatment
Purification system
■ Engineering and maintenance, along with val- Storage and distribution
idation, should review the water purification Controls, alarms etc.
system for physical and functional integrity Sanitization cycle
from an engineering and validation point of ■ Sampling
view. Sampling procedure
■ Quality assurance should review the procedu- Sampling technique
Sample container prep
ral and training issues, as well as the drug
■ Analytical procedures
product(s) involved, from a compliance point Instruments
of view. Analytical procedures
■ Quality control should review the chemical Analyst training
and microbiological testing issues as well as Sample prep
the water sampling techniques. Media prep and tracking
■ Drug product(s) involved
■ Drug safety and information should review the ■ Personnel
safety concerns to decide the disposition of ■ Procedures and documentation practices
affected drug product(s). Corrective action plan
■ The investigation should be led by quality Summary, conclusion, and sign off

36 Journal of GXP Compliance


■ Purification system malfunction
■ Chemical
■ Microbiological
In most instances, it is the failure of a water sam-
ple for chemical or microbiological specifications
which triggers an investigation. Since purified water
is constantly being used in production, there is
always a chance that the suspect quality water might
have been used in equipment cleaning or manufac-
ture of a drug product, thereby putting it at risk.
Define Quality Significance of the Water Quality
Failure Incident
Water quality failure incidents can be classified as
critical, major, minor, or for information only, depend-
ing on the nature and severity of the incident. For
microbiological tests, the quality data is measured
against alert and action limits, e.g., total aerobic count
for a purified water sample. If the water sample fails
pH specification or total organic carbon (TOC), and
the purified water was used to manufacture a solid
oral dosage, the impact on quality, strength, identity,
and safety of the drug product will be much less if the
water sample fails for microbiological specifications
and is used to manufacture a liquid or sterile drug
product. This classification can be a useful tool in
determining the extent of the investigation as well as
the scope of corrective actions including disposition of
the drug product(s) involved.
Define the Cause of the Water Quality
Quality Failure/Incident
A water quality failure/incident could be caused
by one or more of the following; however, try to
narrow down this list as much as possible:
■ Purification System
Each water purification system is designed per
individual plant requirements but does have some
constants which should be looked into when inves-
tigating a water quality failure/incident.
Source Water
The quality of source water as supplied by local
water authorities changes with the time of the year
and geographic location of the plant. Microbial qual-
ity and the total dissolved solids in source water
play a vital role in determining the capability of a
given water purification system. Source water test
data should be part of the validation file for a given
water purification system. Sudden changes in
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source water quality can cause purified water fail-
ure, especially after natural disasters, like floods.
Source water test data from the local water
authority and in-house periodic source water test
results should be reviewed to determine any sud-
den change in source water quality. This review
should also indicate any trends that might be
developing over recent weeks, especially after
heavy rains or floods in the area, as they can affect
the composition of natural water reservoirs.
Pretreatment
Source water is pretreated to minimize the level
of both organic and inorganic impurities before
water is actually processed through the final purifi-
cation step. If pretreatment steps are not precisely
controlled and routinely monitored for performance
within preset limits, these could cause quality fail-
ure of the water produced.
■ Chlorination
Chlorine is added to the source water to
decrease its bio-burden. It also helps to minimize
microbial growth in pipes and storage equipment.
Local water authorities usually add a chlorine gas
generating chemical to wate like sodium hypochlo-
rite to produce one to two PPM of chlorine gas.
However, there is a downside to the presence of
chlorine in water, as it tends to corrode stainless
steel surfaces and will deteriorate reverse osmosis
membranes. Therefore, it is important that chlorine
be removed from water before it actually reaches
the purification and storage stage.
However, if there is insufficient or no chlorine in
the source water, the purification system down-
stream may not be able to remove all the microbial
contaminants, thereby causing a quality failure of
the water produced.
■ Depth Filters
Source water is passed through a series of
coarse filters to remove suspended solids. The fil-
tration media could be different grades of sand.
However, such filters tend to harbor microbes and
should be periodically back-washed to remove all
trapped waste. If left unsanitized, these filters could
contaminate the water with microbes, causing fail-
ure of the water produced after purification.
■ Water Softeners or Deionizers
Water softeners or deionizers are used to
remove heavy metal ions from source water to
Technical Guide 37
Shahid T. Dara
avoid scaling downstream during the purification
process. Deionizing resins need to be regenerated
periodically, and the regeneration process should
be controlled to ensure that a deionizer tank does
not sit idle for long periods of time after regenera-
tion, as it could promote microbial growth. If such a
tank is used in water purification, it might overbur-
den the system, and the water produced could fail.
■ Carbon Filter
Activated carbon filters are used to remove dis-
solved chlorine and other gases from source water,
along with organic materials, before water is sub-
jected to the final purification process. However, car-
bon filters can promote microbial growth and, there-
fore, foul the downstream components. Frequent
monitoring and sanitization of carbon filters should
be carried out to prevent this situation. Nonetheless,
carbon filters can be a cause of water quality failure.
Purification System
■ Deionization
Deionization is not considered by FDA to be an
acceptable water purification process to produce
Water-for-Injection (WFI); however, it is used to
produce purified water. Cation, anion, and mixed
bed resins are used to remove ionic impurities
from source water. The quality of these resin beds
can be monitored by determining the conductivity
of effluent water. A sudden increase in effluent
water conductivity indicates that a resin bed needs
to be regenerated. Ion exchange resin tank regen-
eration should be controlled, and regenerated
tanks should not sit idle, as this can promote
microbial growth. Also, if there is leakage of
sodium ions from a cation exchange resin, the
water produced will have a higher pH – greater
than 7.0.
■ Reverse Osmosis
Reverse osmosis membranes are an efficient
water purifier when used in series. However, these
can harbor microbial growth, as they are chlorine
sensitive and, therefore, can produce water of sus-
pect quality. Also, if the membranes are not period-
ically backwashed, they become overloaded and
enable organic and inorganic impurities to pass
through.
■ Distillation
Distillation is the method of choice for producing
WFI, assuming it is a continuous process. If, for
38 Journal of GXP Compliance
some reason, the system is idle for a period of
time, the feed sections of the still can become
dead legs and promote microbial growth. On start
up, if used unsanitized, this could produce WFI
with high endotoxins.
Storage and Distribution
Storage tank, distribution piping, and associated
controls are critical to maintaining the quality of the
water being produced. If there are leaks in the sys-
tem, these could contaminate the entire system.
Likewise, the vent filter on the storage tank
should be checked for integrity and to see that it is
not harboring any microbes in the condensate, as
both could compromise the quality of water. There
should be a procedure in place for changing the
sterile vent filter on the storage tank. Many times
water quality is compromised by the addition of for-
eign material during filter change over. Typically, fil-
ter change is followed by a complete sanitization
cycle. The heating and cooling system is another
critical part of this puzzle, as the water quality is
totally dependent on its storage temperature before
it is used.
Sanitization process
Water purification systems are periodically sani-
tized to remove any biofilm and organic build up on
different water contact surfaces. If a chemical sani-
tizing agent is used, there is potential for residual
chemicals in the purified water, unless the system
is thoroughly flushed and drained.
■ Sampling
Water samples are drawn during validation and
routine monitoring of a water purification system.
This step is critical and can cause water quality
failure if sampling procedure(s) are not strictly
adhered to. Details are discussed under the inves-
tigation section of this document.
■ Analytical issues
Both chemical and microbiological testing have
their own set of variables which could cause a water
sample to fail. It could be the instrument, sample
prep, or the procedure. Details are discussed under
the investigation section of this article.
Water Quality Failure Investigation
A water quality failure/incident investigation
should include a review of the following, depending
upon the probable cause. Concentrate on those

areas believed to have contributed most to a given
quality failure incident.
Source water
Source water test data from the local water
authority and in-house periodic source water test
results should be reviewed to determine any sud-
den changes in source water quality. This review
should also indicate any trends that might be
developing over recent weeks, especially after
heavy rains or floods in the area, as they can affect
the composition of natural water reservoirs.
Pretreatment
Review all the pretreatment steps to see if the
quality of source water was compromised at any
stage. Also check for leaks or malfunction of any
alarms, controls, or autoregeneration of deionizing
tanks, etc.
Chlorination
Review the source water data to see if there
was sufficient chlorine in the water. Also, review
the residual chlorine level of pretreated water pro-
cessed downstream, especially in case of a
reverse osmosis water purification system.
Depth Filters
Check the backwash records to see if the depth
filters were backwashed and sanitized per require-
ments, as these can cause both microbial and
chemical contamination of the water being purified.
Water Softeners or Deionizers
Review the regeneration procedure and sched-
ule for water softener and deionizing tanks to
detect any deviation, especially if the tanks were
sitting idle for a long period of time after regenera-
tion, promoting microbial growth, thereby causing
contamination of water.
Carbon Filter
Review the monitoring data for the post-carbon
bed to determine if there was any proliferation of
microbes which could have contaminated the sys-
tem downstream.
Purification System
■ Deionization
Review the regeneration procedure and sched-
ule for cation, anion, and mixed bed resin tanks to
detect any deviation, especially if the tanks were
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sitting idle for a long period of time after regenera-
tion, thereby causing microbial contamination of
water. Also, the conductivity data for effluent water
should be reviewed to determine if the tanks were
changed as per schedule and are not totally
exhausted before replacement.
■ Reverse Osmosis
The reverse osmosis membranes should be
checked for integrity if these were exposed to high
chlorine source water. Also, the membrane back-
flushing procedure should be reviewed to deter-
mine if it is effective in removing all the build-up.
The reverse osmosis system sanitization proce-
dure and frequency should be checked to deter-
mine if they need any revisions, both in procedure
and frequency.
■ Distillation
Ensure that the system was in operation per
approved specifications. If there was a shutdown,
was the system sanitized before start up? Check to
determine if all alarms and controls are functioning
and are within calibration. Look for any dead legs
in the system as potential breeding grounds for
microbes.
Storage and Distribution
Check the storage tank, distribution piping, and
all points of use for leaks or other physical defects.
Examine the vent filter on storage tanks for
integrity and to see if it is harboring any microbes
in the condensate. Check the heat exchanger and
chiller controls for proper function to assure the
water is maintained at its desired storage and cir-
culation temperature.
If plastic pipes are used, like PVDF etc., these
should be checked, as they tend to sag over time,
leading to potential deadlegs and, therefore, could
promote microbial growth. The drain pipe from the
storage tank should have at least a two-inch gap or
twice the pipe’s diameter, whichever is greater,
between pipe and floor drain to prevent “back
siphon” of the floor drain.
Controls, Alarms
Today’s water purification systems have a number
of controls and alarms to operate the system within
specifications while controlling costs. Review all the
controls and alarms in case of a water quality failure/
incident to determine if these were functioning prop-
erly and are within calibration, where applicable.
Technical Guide 39
Shahid T. Dara
Sanitization Process
Review the water purification system sanitiza-
tion procedure and frequency to determine if they
could be contributing factors in water quality fail-
ure, especially when residual chemicals or high/low
pH values are detected.
Sampling
Multiple water samples are drawn on a daily
basis during validation and routine monitoring of a
water purification system. The sampling procedure
and the individual sampler’s technique are key to
obtaining uncompromised water samples. While
investigating a water quality failure/incident, the
sampling process should be scrutinized in detail.
Review the following to determine if there is any
chance to compromise the integrity of the sample.
Sampling Procedure
The sampling procedure should be reviewed to
determine the level of detail and clarity of state-
ment for a nontechnical person to understand it.
Also, review the training requirements spelled out
in the SOP and audit training records.
Sampling Technique
If sampling is a potential cause for water quality
failure, QA should review the sampling technique
and perhaps have a microbiologist watch the indi-
vidual sampler do the actual sampling under real
time conditions. This provides a wealth of informa-
tion as to the effectiveness of the sampling tech-
nique as described in the sampling procedure and
how people are trained. The sampling procedure
should simulate actual practice when the system is
used to draw water for manufacturing or cleaning
activities, i.e., flush the system for 10 seconds
before withdrawing water, etc.
Sample Container Preparation
Water sample containers are specially pre-
pared. Microbiological samples are taken in ster-
ile containers, while chemical samples are taken
in containers which have been specially cleaned
and rinsed with WFI to minimize contamination.
While investigating a water quality failure/incident,
also review the sample container prep practices.
This could involve reviewing cleaning procedures
and any studies done on these containers after
cleaning to determine the effectiveness of the
cleaning procedure. If presterilized containers are
obtained from an outside vendor, have access to
40 Journal of GXP Compliance
the vendor’s sterilization procedure and support-
ing validation documents. Nonsterile sample con-
tainers have been blamed for false failures of
water samples.
Analytical Issues
Chemical and microbiological tests are usually
performed by the quality control laboratory, and this
phase of the investigation is best accomplished if a
chemist and a microbiologist are asked to review
different aspects of the analytical work. In particular,
the following should be closely examined:
Analytical Instruments
Review analytical instruments to determine if
they are within calibration and performance limits.
Also, check for any unusual repair or maintenance
activity that might have affected the performance of
the instrument.
Analytical Procedures
Analytical procedures should be reviewed for
both chemical and microbiological testing to deter-
mine if there are any issues and if the procedures
adequately guide the analyst in a step-by-step pro-
cess to execute the test.
Analyst Training
Review training records for the analyst to make
sure they were qualified to perform the test under
review.
Sample Storage and Preparation
Water samples are usually transported to the
quality control laboratory where they might sit for
awhile before testing is conducted. Review sample
storage conditions as well as the time elapsed
before testing was performed. Some companies
refrigerate water samples upon receipt and may
test them after 24 hours or so. This practice should
be discouraged, as it could result in suspect data.
Also, review the sample preparation techniques in
the laboratory to assure that they do not compro-
mise the integrity of the sample.
Testing Time Limits
Water samples should be tested as soon as
they are received by the quality control laboratory.
However, if the company has a practice that allows
the samples to be stored for a limited time before
analysis, review the records to determine if the
samples were tested within the time limit.

Media Preparation and Storage
For microbiological testing, media preparation,
storage, and expiration dating issues are critical in
defining the success or failure of a test. Review
media preparation procedures as well as the expira-
tion date assigned to a given lot of in-house pre-
pared media to assure that media is used within its
expiration date. Other issues to be considered when
reviewing microbiological testing should include:
■ Incubation conditions
■ Qualification status of incubator
■ Use of positive/negative controls
■ Isolation and speciation of the microbial
contaminants
Drug Product(s) Involved
As part of the investigation, the drug product(s)
manufactured with suspect water should be
reviewed to determine if the safety, quality, and effi-
cacy of the drug product has been compromised.
The following points should be considered in this
review:
■ Dosage form of the drug product involved
■ Route of administration
■ Therapeutic class
■ Presence or absence of a preservative sys-
tem in the drug product
■ Safety history of the drug product(s)
Personnel
This part of the investigation should define if
there are any deficiencies in the training program
and also, if the people are qualified to perform their
assignments.
Procedures and Documentation Practices
All the procedures and documentation involved
should be reviewed to determine if there is a need
for revisions or if new procedures should be pre-
pared to supplement ones already in existence.
Also, a determination should be made to assess
whether all critical data is being reviewed by the
appropriate people to make critical decisions (if
needed).
Corrective Action Plan
Once all the facts are known, QA should
develop a corrective action plan in consultation
with other departments, as appropriate. The cor-
rective action plan could involve one or more of the
Shahid T. Dara
following, depending upon the cause of the water
quality failure/incident:
■ If the water purification system is operating
within specifications, additional water sam-
ples should be taken from source water, stor-
age tank, and all points of use for three to five
days and the system released if all samples
meet specifications.
■ If part(s) of the water purification system
need to be replaced, a determination should
be made if this change is covered under a
system parts change program or if it necessi-
tates a requalification of the system.
■ Revise water sampling procedures and
retrain employees.
■ Revise the analytical procedures.
■ Recalibrate the instruments, etc.
Summary, Conclusion and Sign Off
A summary report should be prepared detail-
ing the water quality failure/incident, probable or
definite cause, corrective action plan, and dispo-
sition of the drug product(s) involved. Such a
report should be prepared by quality assurance
and reviewed and approved by appropriate mem-
bers of management. The investigation report
along with a summary should become part of the
water purification system file. However, a brief
management summary might be prepared to
inform upper management, if the situation so
warrants.
Last Word
The management of change is an on-going bat-
tle and, like perpetual motion, we have yet to de-
velop a perfect change control system that foresees
all possible changes. There will always be unfore-
seen circumstances that will force one to rethink
their approach to maintaining a level of control.
Document change control and contract manufac-
turer/packager-related change control issues have
been deliberately omitted from this discussion
because of the enormity of the two subjects. ❏
About the Author
Shahid T. Dara is the president of Compliance
Consulting, Inc. He has over 17 years of experi-
ence in the areas of product development, manu-
Technical Guide 41
Shahid T. Dara

facturing, quality assurance, and validation. He has

held senior management positions with leading
pharmaceutical manufacturing companies. His
special interests are the development and imple-
Lights • Camera • Action
mentation of quality systems and management of
validation projects. He holds MS degrees in
Medicinal Chemistry and Industrial Pharmacy. He
Introducing
can be reached by phone at 972-423-6788 or by
e-mail at fskm93@aol.com. the Training
Suggested Reading Video Collection
1. Food & Drug Administration, “21CFR Part 210 and
211, Current Good Manufacturing Practice for Finished
Pharmaceuticals,” 1995, Rockville, Maryland.
2. Food & Drug Administration, “21CFR Part 210 and
211, Proposed Current Good Manufacturing Practice CHANGE CONTROL AND
Regulations for Finished Pharmaceuticals,” Federal
Register, May 03, 1996, Rockville, Maryland.
VALIDATION VIDEOTAPES
3. Food & Drug Administration, “21CFR Part 820, Current
Good Manufacturing Practice for Medical Device – A four-part comprehensive series on the
Quality System Regulations,” October 06, 1996, fundamentals of Change Control and
Rockville, Maryland.
4. Food & Drug Administration, “Guidance for Industry, Validation including:
Manufacturing Equipment Addendum to the Guidance ■ An Introduction to Change Control.
for Industry for Scale-Up and Post Approval Changes:
Immediate Release Products (SUPAC – IR), Draft ■ Change Control and Process Validation.
Guidance,” February 1997, Rockville, Maryland. ■ Change Control and Its Impact on Stability.
5. Food & Drug Administration, “Guide to Inspection of
Pharmaceutical Quality Control Laboratories,” July
■ A Model Program on Change Control.
1993, Rockville, Maryland.
6. Food & Drug Administration, “Guide to Inspection of These videotapes include:
Dosage Form Drug Manufacturers – cGMPs,” October ■ Practical approaches to change control sys-
1993, Rockville, Maryland. tems with equipment, materials and manufac-
7. “U.S. vs. Barr Laboratories,” USDC, D. NJ, Civil Action
No. 92-1744, February, 1993. turing processes
8. D. M. Stephon, “Considerations in Effectively Managing ■ FDA concerns
Change Control Issues,” Journal of cGMP Compliance,
Vol. 2, No. 4, July 1998. ■ How to determine if changes are major, minor
9. J. Stromp, “The Management of Change Control” or an improvement.
Journal of cGMP Compliance, Vol. 2, No. 1, October
1997. These are high quality tapes that are essential for
10. D. E. Jones, “The Training Side of Change Control,” any training program, with instructors that have
Journal of cGMP Compliance, Vol. 2, No. 4, July 1998. over 25 years experience in the pharmaceutical
11. J. L. Morgan, “cGMPs in Early Clinical Development,”
Journal of cGMP Compliance, Vol. 1, No. 1, October industry.
1996.
12. D. R. Dills “Handling Out-of-Specification Conditions Call today!
with Finesse,” Journal of cGMP Compliance, Vol. 2,
No. 3, April 1998. Purchase
13. N. Hakim “A Practical Approach to Investigating Out- entire seriesthe
of-Specification Results,” Journal of cGMP Compliance, individual tap or
Vol. 3, No. 1, October 1998. es
14. G. Amer, “Validation and Change Control,” Journal of
Validation Technology, Vol. 5, No. 4, August 1999.

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42 Journal of GXP Compliance