Global Regulatory Viewpoint.

Richard Poska, Coordinator ]

FDA 2008 Process Validation
Draft Guidance—How to
Implement
Paul L. Pluta

“Global Regulatory Viewpoint” addresses various regu- • Understanding and control of potential sources of
latory and compliance topics including newly-published variation in manufacturing is a key emphasis of the
regulations from a global perspective. The content in guidance
this column is intended to be useful to those who deal • The process design stage defines the commercial
with pharmaceutical development, development of manufacturing process, including process under-
CMC dossier sections, and guidances for manufactur- standing and process control. It focuses on two main
ing, validation, and CGMPs. objectives: Process understanding and process con-
Reader comments, questions, and suggestions are trol strategy
requested. Readers are invited to submit manuscripts • The process qualification state confirms the work
for publication in this column. Please contact column of the process design stage by demonstrating that
coordinator Richard Poska at richard.poska@abbott. the proposed manufacturing process is capable of
com or journal coordinating editor Susan Haigney at reproducible commercial manufacture. Qualifica-
[email protected]. tion includes facility design and qualification of
utilities and equipment and performance qualifi-
KEY POINTS cation (PQ)
The following key points are discussed in this article: • The continued process verification stage comprises
• The US Food and Drug Administration issued a new activities to assure that the validated state of the pro-
Draft Guidance for Industry Process Validation: Gen- cess is maintained throughout routine commercial
eral Principles and Practices in November 2008 manufacturing
• The guidance applies to manufacturing of human • The guidance also addresses documentation and
and animal drug products including biological and analytical methods
biotech products, active pharmaceutical ingredients • The new draft guidance reiterates principles stated
(API), and the drug component of medical device in other guidances during the past 20 years, and
combination products attempts to integrate activities heretofore considered
• The guidance aligns process validation with Inter- as separate and distinct
national Conference on Harmonisation (ICH) Q8, • Implementing the new guidance will require organi-
ICH Q9, and ICH Q10 and embraces the product zations to embrace the lifecycle approach to process
lifecycle concept validation including enhanced organizational com-
• A new definition of process validation is provided munication, collaboration, and documentation
• The lifecycle approach to process validation com- • Other areas for implementation include making
prises three stages: Process design, process qualifica- sure performance standards throughout the product
tion, and continued process verification lifecycle are adequate, including emphasis on identi-

[
For more Author ABOUT THE AUTHOR
information, Paul L. Pluta, Ph.D., has more than 30 years of pharmaceutical industry experience. He can be
go to reached by e-mail at [email protected]. Richard Poska, RPh., the column coordinator, has 20
gxpandjvt.com/bios years of technical experience and can be contacted by e-mail at [email protected].

JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] 23

Global Regulatory Viewpoint.

fication of potential input variation and routine use A new definition of process validation is provided in
of statistical methods the guidance as follows: “Process validation is defined as
• The new guidance and its clarified expectations will the collection and evaluation of data, from the process
be great challenges for industry—there is agreement design stage throughout production, which establishes
on the direction of this effort. scientific evidence that a process is capable of consistently
delivering quality products” (1).
INTRODUCTION A lifecycle approach to process validation is described
The US Food and Drug Administration issued the Guid- in the draft guidance that encompasses the following
ance for Industry, Process Validation: General Principles and three stages:
Practices, Draft Guidance (1) in November of 2008. After • “Stage 1—Process Design: The commercial process is
approval, this document will ultimately replace the previ- defined during this stage based on knowledge gained
ous 1987 process validation guidance (2). While the new through development and scale-up activities.
draft process validation guidance was presented for public • ”Stage 2—Process Qualification: During this stage,
comment and was not technically official at the time this the process design is confirmed as being capable of
article was written, this article discusses new or notewor- reproducible commercial manufacturing.
thy elements in the draft guidance. It also specifically • ”Stage 3—Continued Process Verification: Ongoing
addresses compliance with guidance recommendations. assurance is gained during routine production that
Topics addressed in this article include the following: the process remains in a state of control” (1).
• Guidance overview
• Specific stage activities and other guidance A key section of the draft guidance clearly lays the
recommendations foundation for what may be the essence of successful
• Are these new requirements? pharmaceutical manufacturing—understanding and con-
• Implementing the new draft guidance. trol of potential sources of unexpected variation in manu-
facturing. Manufacturers should do the following:
GUIDANCE OVERVIEW • Understand and control the sources of variation
The draft process validation guidance applies to manu- • Detect the presence and degree of variation that is
facturing of human and animal drug products including abnormal for the system
biological and biotech products, active pharmaceutical • Understand the impact of variation on the process
ingredients (API), and the drug component of medical and ultimately on product attributes
device combination products. The guidance aligns process • Control the variation in a manner commensu-
validation with ICH Q8, ICH Q9, and ICH Q10 (3,4,5) and rate with the risk it represents to the process and
embraces the product lifecycle concept. This approach product.
links product and process development, performance
qualification of the commercial manufacturing process, SPECIFIC STAGE ACTIVITIES
and ongoing maintenance of the process during routine The key message of the guidance is that process validation
commercial production. The guidance emphasizes sci- should be an ongoing and coordinated effort through-
ence-based manufacturing, innovation, and continuous out the organization. Process validation begins during
process improvement. the design and development of the product, API, etc.,
The 2008 draft guidance is consistent with the 1987 and continues throughout the entire product lifecycle.
guidance, but adds elements of risk analysis, new technol- The guidance discusses recommendations and specific
ogy, and quality systems. It is consistent with basic quality expectations for validation programs and for the respec-
principles that a drug should be fit for its intended use as tive stages of the lifecycle. The collaboration of relevant
supported by the following basic tenets: organizational groups including manufacturing, quality
• Quality, safety, and efficacy are designed or built into assurance, formulation, engineering, analytical, statistics,
the product and other groups is recommended. The availability of
• Quality cannot be adequately assured merely by in- expertise and relevant information from these groups
process and finished-product inspection or testing with appropriate analysis will be useful to maintain
• Each step of a manufacturing process is controlled continued successful manufacturing throughout the
to assure that the finished product meets all design product lifecycle.
characteristics and quality attributes including
specifications.
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 Richard Poska, Coordinator.

Process Design Before conformance lots can be manufactured, the

The process design stage is the initial stage of the product facility, equipment, utilities, and associated control sys-
lifecycle. Work in this stage defines the commercial manu- tems must be demonstrated to be functioning properly
facturing process. It focuses on two main objectives: Pro- (i.e., they must be qualified). The information in this
cess understanding and process control strategy. The main activity is fairly standard IQ/OQ/PQ information. Risk
source of process understanding information lies in the management should be used to prioritize efforts. The
product development effort which in addition to original draft guidance lists specific expectations for qualification
experimentation can rely on previous knowledge. Tradi- of utilities and equipment including:
tionally, this information was warehoused in the research • Studies or tests to use
and development (R&D) area by scientists. It is now a key • Criteria appropriate to asses outcomes
part of the regulatory submission. The publishing of ICH • Timing of qualification activities
M4 (6) mandated the inclusion of specific development • Responsibilities
information in global regulatory submissions. The pro- • Procedures that document and approve the
cess design stage provides the basis for the manufacturing qualification
process as manifest in master batch records and in-process • Requirements for evaluation of changes
controls. The information developed (e.g., identification • Documentation including summaries with conclu-
and understanding of the relationship of the important sions that address acceptance criteria
formulation and process variables) during this stage sup- • Approval by the quality unit.
ports manufacturing throughout the entire product life-
cycle. The application of statistical experimental designs Specific details of PQ are discussed in the draft guid-
associated with the quality-by-design (QbD) initiative ance. These included the PQ approach, PQ protocol,
is helpful to determine relationships and multifactorial and protocol execution and report. This stage describes
interactions, design space limits, etc. Experimental work what many organizations currently understand to be the
should be focused on appropriate highest risk processes entire concept and practice of validation. The PQ should
as identified by risk analysis. be successfully completed before product is released for
Development of a process control strategy has its founda- commercial distribution. The guidance specifically recom-
tion in the identification of the critical quality attributes. mends that statistical metrics be used to achieve adequate
It should also reflect the understanding of the effects of assurance of acceptable processes. The PQ should have a
various formulation and process variables on the quality higher level of sampling, additional testing, and greater
attributes. Inclusion of process controls should minimize scrutiny of process performance.
the reliance on end-product specification testing. Identify- Specifics recommended in the draft guidance for the
ing potential sources of variation is another key element of PQ protocol include the following:
the process design stage. Without control of input variables, • Manufacturing conditions including operating param-
successful manufacturing will not be possible. Often there eters, processing limits, and raw material inputs
is little experience with input variation at this stage of the • Data to be collected and evaluated
product lifecycle. However, the potential for variation from • Tests to be performed and acceptance criteria
equipment, different material lots, different production • Sampling plan including sampling points, number
operators performing manual processes, environmental of samples, and frequency of sampling
variation, and measurement systems in the production • Number of samples should be adequate to provide
facility should be evaluated. Use of process analytical tech- statistical confidence of quality within and between
nology (PAT) enables processing adjustments and is helpful batches
to minimize output variation (7). • Confidence level can be based on risk analysis
• Sampling should be more extensive than in routine
Process Qualification production
The second stage of the product lifecycle is the process • Acceptance criteria should specify statistical
qualification stage. This stage confirms the work of the methods
process design stage and demonstrates that the proposed • Provision for addressing deviations and handing non-
manufacturing process is capable of reproducible com- conforming data
mercial manufacture. The process qualification phase • Data should not be excluded from the PQ without a
describes facility design and qualification of utilities and documented science-based justification
equipment and performance qualification (PQ). • Approval by the quality unit.
JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] 25
Global Regulatory Viewpoint.

Specifics recommended in the draft guidance for pro- errors should be tracked to measure the quality of train-
tocol execution and report include the following: ing programs; to identify operator performance issues;
• Protocol execution should not begin until protocol and to look for potential batch record, procedural, and/or
has been reviewed and approved process improvements to help reduce operator errors. The
• Commercial manufacturing process and routine pro- quality unit should periodically meet with production
cedures must be followed under normal conditions staff to evaluate data, discuss trends, and coordinate cor-
and by normal manufacturing personnel rections or follow-up actions by production. Production
• Final report should discuss all aspects of the protocol, operators are often good sources of information and are
summarize and analyze all data, evaluate unexpected usually overlooked.
observations and non-conformances, and describe Maintenance of the facility, utilities, and equipment is
corrective actions or changes to existing procedures also mentioned in the guidance as important to process
and controls control. Qualification status must be maintained by routine
• State a clear conclusion that the process met expecta- monitoring, maintenance, and calibration programs.
tions. If it did not, discuss future actions planned to
complete the PQ. Other Guidance Recommendations
• Approval by the quality unit. Two other areas briefly discussed in the new guidance
include documentation and analytical methods. Docu-
Continued Process Verification mentation during the entire product lifecycle is essential.
Continued process verification comprises activities to A system that enables the ability to retrieve documentation
assure that the validated state of the process is maintained for use throughout the product lifecycle is equally impor-
throughout routine commercial manufacturing. Current tant. Design and development information generated
good manufacturing practice (CGMP) currently requires during product development should be used as needed
a system to collect and assess product data, and specifi- throughout commercial manufacturing so that science
cally to detect process drift. The draft guidance states that underlies process decisions. Process qualification docu-
data collected should include relevant process trends and mentation and process monitoring documentation are
quality of incoming materials or components, in-process mandated by CGMP and are generally easily accessible.
material, and finished products. Data should be statisti- FDA recommends use of process flow diagrams through-
cally trended and reviewed by personnel trained in statisti- out the development and commercial process to facilitate
cal methods to confirm that critical quality attributes are comparison and evaluations for comparability.
well controlled. Procedures should describe how trending The guidance discusses the importance of accurate and
and calculations are done. These data can help to identify precise analytical results throughout the product lifecycle.
process and product variability and cause improvements Validated analytical methods are not required during
to be initiated. The use of statistical methods to deter- product development activities. However, scientifically
mine variation, characterize it, and identify root causes sound methods must be used, and analytical equipment
is recommended. Also recommended is the scrutiny of must be functioning properly. This is especially impor-
intra-batch and inter-batch variation. tant when attempting to correlate development data and
The draft guidance recommends continued monitoring commercial product data.
and/or sampling at PQ levels until sufficient data are avail-
able to generate significant variability estimates. Thereaf- ARE THESE NEW REQUIREMENTS?
ter, sampling can be adjusted to a statistically appropriate Although the new process validation guidance was issued
level. Other areas for monitoring identified in the draft in November 2008, the content of the guidance was gener-
guidance include the following: ally well known prior to actual issue. The comprehensive
• Product complaints and integrated lifecycle approach to process validation
• Out-of-specification (OOS) findings has been clearly discussed in recent regulatory presen-
• Process deviation reports tations, and the various specific topics associated with
• Process yield variations the approach have also been published for many years.
• Batch records Essentially, everything stated in the 2008 draft guidance
• Incoming raw material records should have been expected by industry professionals.
• Adverse event reports. FDA representatives have clearly presented the lifecycle
Production line operator and quality staff feedback approach for several years (8,9,10). These presentations
on process performance should be solicited. Operator have included comments on factors indicating the need
26 JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] iv thome.com
 Richard Poska, Coordinator.

for the lifecycle approach. The lifecycle approach over- Consistency With Other Regulatory
comes the “checklist” mentality to process validation in Guidances
which process validation is considered to be a singular The 2008 draft process validation guidance is consistent
event. Encouraging comprehensive process understanding with ICH Q8, Q9, and Q10 documents. These documents
improves technical analysis if manufacturing problems provide current global thinking on various aspects of the
occur. Successfully manufacturing three validation lots product lifecycle from development through commercial-
does not provide good assurance that future manufactur- ization. They provide a comprehensive and integrated
ing will be reliable. The 2004 revision of FDA Compliance approach to product development and manufacturing
Policy Guide (11) clearly states that manufacturers should to be conducted over the lifecycle of the product. ICH
have enough data and knowledge about the commercial Q8 discusses information for regulatory submission in
production process to support post-approval product dis- the ICH M4 Common Technical Document format. ICH Q8
tribution. Also, the manufacturer should identify and con- describes a comprehensive understanding of the product
trol all critical sources of variability prior to conformance and manufacturing process that is the basis for future
batches and commercial manufacturing. commercial manufacturing. ICH Q9 provides a systematic
Some of the key concepts in the 2008 draft process approach to quality risk management through various risk
validation guidance are actually mentioned in the 1987 assessment tools. ICH Q10 complements Q8 and Q9, and
guidance. For example, the 1987 guidance mentions “... discusses the application of the various quality system
adequate product and process design...”, “...quality, safety, elements during the product lifecycle. Elements of the
and effectiveness must be designed and built into the prod- quality system include process performance monitoring,
uct...”, and “During the research and development (R&D) corrective action and preventive action (CAPA), change
phase, the desired product should be carefully defined control, and management review. These quality system
in terms of its characteristics, such as physical, chemical, elements are applied throughout the various phases of
electrical, and performance characteristics.” In addition the product lifecycle.
to discussing actual validation protocols, the document The 2000 ICH Q7 (15) Good Manufacturing Practice Guide
mentions several post validation considerations: “...qual- for Active Pharmaceutical Ingredients discusses activities
ity assurance system in place which requires revalidation conducted prior to and post validation. For example, ICH
whenever there are changes in packaging, formulation, Q7 states that critical parameters and attributes should be
equipment, or processes which could impact product identified during development, and these critical process
effectiveness or product characteristics, and whenever parameters should be controlled and monitored. Non-
there are changes in product characteristics. The quality critical parameters should not be included in validation.
assurance procedures should establish the circumstances Regarding post validation, there should be periodic review
under which revalidation is required”(2). of validated systems.
The various FDA guides to inspections (12,13,14), all
issued during the 1990s, further the concepts of the 1987 IMPLEMENTING THE DRAFT GUIDANCE
guidance. They emphasize the development phase of the At the time this article was written, the 2008 draft pro-
validated process. This includes documented experiments, cess validation guidance had been presented for public
data, results, control of the physical characteristics of the comment and was not technically official; however, sig-
excipients, particle size testing of multi-source excipients, nificant changes in this document were not expected. As
and determination of critical process parameters. Devel- described previously, the content of the guidance does not
opment data serves as the foundation for the manufactur- suggest any new requirements by FDA—it is primarily a
ing procedures, and variables should be identified in the restatement of previous requirements from earlier FDA
development phase. Raw materials were identified as documents, ICH quality guidance documents, and FDA
a source of lot-to-lot variation. The 1987 guidance also presentations. There are, however, several areas that have
mentions post validation considerations such as evalua- received increased emphasis.
tion of changes in packaging, formulation, equipment, The following two general areas need to be discussed
or processes, which could impact product effectiveness regarding compliance with the 2008 draft guidance:
or product characteristics (i.e., the validated state must • Lifecycle approach to process validation.
be maintained). Acceptance of this concept will require enhanced
organizational collaboration, communication, and
documentation.
• Performance standards throughout the prod-
JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] 27
Global Regulatory Viewpoint.

uct lifecycle. This includes specifics mentioned in entire product life, with ongoing collaboration and com-
the guidance as well as increased emphasis on iden- munication among all relevant organizational areas.
tification of potential input variation and widespread Collaboration, communication, and documenta-
use of statistical methods. tion. The lifecycle approach to process validation requires
enhanced organizational communication, collaboration,
Lifecycle Approach to Process Validation and documentation. The scientific and technical work of
In contrast to the prevalent business model today, orga- R&D, which is the basis for the formulation and process,
nizations must embrace the lifecycle approach to process should be accessible throughout the entire product life-
validation. This will require a comprehensive view of cycle. R&D and development personnel must be aware
validation rather than focus on the performance of the that their development data and reports will be used to
usual three conformance lots. Many firms organize their support process parameters and changes throughout the
operations in distinct silos (e.g., R&D, manufacturing, entire manufacturing life of the product. R&D and devel-
validation, and quality). The silos create barriers to com- opment personnel should be encouraged to write final
munication and cooperation. The R&D organization reports with summaries and conclusions rather than have
develops the product; once development and approval is data only located in R&D. The expertise of R&D should
completed, the product is transferred to manufacturing. be used to evaluate product performance and initiate or
Manufacturing then makes the process ready for validation support product improvements. All development work
and routine commercial manufacturing. The validation and subsequent quality reviews must be documented;
function coordinates process validation. After the con- this contributes to the entire body of product and pro-
formance lots are successfully completed, the validation cess knowledge. This information should be available as
effort is finished. Manufacturing then continues routine needed to all groups within the organization as well as to
commercial production with oversight by the quality unit. external auditors. Documentation systems are essential,
There is usually minimal ongoing interaction between especially the ability to retrieve documents quickly.
R&D, validation, manufacturing, and quality.
The new draft guidance and the lifecycle approach Performance Standards Throughout the
to validation are clearly different than the previously- Product Lifecycle
described situation. Product development personnel The draft guidance states specific expectations for the
should approach their work as supporting the entire prod- various stages in the lifecycle approach. Organizations
uct lifecycle, including commercial manufacturing, and should assess their level of compliance with these spe-
should be involved in the monitoring and maintenance of cific expectations. For example, in process qualification,
the validated state. Their work should provide the techni- do the PQ protocols specify the data to be collected and
cal basis or justification for all aspects of manufacturing how they should be evaluated, tests to be performed and
including any changes that are needed during the product acceptance criteria, and sampling plan including sampling
lifecycle. The validation group should not only coordi- points, number of samples, and frequency of sampling?
nate the process qualification stage of manufacturing In conformance lots, are the commercial manufactur-
based on the technical development work, but should ing process and routine procedures the same as those
also actively participate in the identification of the criti- to be followed under normal conditions and by normal
cal process variables and control thereof. Manufacture of manufacturing personnel? In continued process verifica-
the conformance lots should be considered a “snapshot tion, are product complaints, OOS findings, deviations,
in time,” and not the final word or action on validation. yields, and adverse event reports regularly monitored?
The validated state must then be maintained through Is production line operator and quality staff feedback on
process monitoring, technical data evaluation, and change process performance regularly solicited? Are operator
control. Manufacturing “fixes” or “tweaks” should be errors tracked? Does the quality unit periodically meet
evaluated by technical people, and should be made only with production staff to evaluate data, discuss trends,
when supported by robust data sets or control charts. R&D and coordinate corrections? Are all equipment, utilities,
should be involved in process improvements and provide facilities, and analytical methods adequately validated?
the technical justification for these improvements. The Are all of the testing and generated data designed to sup-
aforementioned silos should be minimized and work port the proposed control strategy?
should be matrixed across functional areas. Organiza- Identification of potential input variation. The
tions should foster development of a continuous business identification and control of potential input variation
process beginning in R&D and continuing throughout the was specifically emphasized in the new process valida-
28 JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] iv thome.com
 Richard Poska, Coordinator.

tion guidance. This includes identification of the varia- communicated as part of the QbD initiative. The draft
tion each unit operation is likely to encounter, as well guidance specifically identifies statistical applications in
as the range of expected variability. Process inputs with the process qualification stage. The number of samples
important sources of variation may include materials, should be adequate to provide statistical confidence of
equipment, processes, measurement systems, manufac- quality within and between batches. Acceptance criteria
turing staff, and the manufacturing environment. R&D should specify statistical methods. Statistical methods
personnel should strive to develop a robust process that are also specifically mentioned in the continued process
will yield acceptable product despite reasonable variation verification stage. Monitoring data collected throughout
in process inputs. Material inputs including the char- the product lifecycle should be assessed and trended to
acteristics of active drug and inactive excipients may be detect process drift. The draft guidance states that data
difficult to control, especially physical properties such as collected should include relevant process trends and
particle size. These attributes may have great influence quality of incoming materials or components, in-pro-
on the manufacturing process. If the active drug is quan- cess material, and finished products. Data should be
titatively a minor part of the formulation, it may be more statistically trended and reviewed by personnel trained
important to control the particle size of major inactive in statistical analysis to confirm that critical quality attri-
excipients to assure a repeatable process. Knowledge and butes are well controlled. Procedures should describe
control of input variables is necessary to minimize risks how trending and calculations are done. These data
to product and process reliability. Technology transfer can help to identify process and product variability and
to commercial operations necessarily involves greater cause improvements to be initiated. The use of statisti-
quantities of materials, greater variation in materials, cal methods to determine variation, characterize it, and
global sources of materials, and so on—all of which identify root causes is recommended. Also recommended
contribute to process variability. The use of these varied is the scrutiny of intra-batch and inter-batch variation.
materials by greater numbers of production personnel in The use of industry accepted methods such as control
commercial manufacturing further exacerbates poten- charting provide the basic tools needed to interpret data
tial process variation. Personnel who influence process to make them meaningful over extended periods of time.
parameters and variables and who operate equipment The use of statistical indices (e.g., cPk) can also be used
may be another source of process variation depending on to predict the robustness of the process as measured by
the level of automation in the process. Ongoing moni- each proposed control.
toring and training of personnel is critical to minimize
human factor effects on processes. CONCLUSIONS
Strategies to control raw material variation, equipment Although FDA issued the new draft process validation
performance variation, process testing requirements, per- guidance in 2008, the information therein is not really
sonnel variables, and other sources of variation must be new. Pharma professionals who are aware of ICH guid-
developed. Enhanced incoming material specifications, ances and FDA CMC initiatives including the QbD effort
processes to eliminate borderline material, more frequent should not be surprised by the content of the draft guid-
in-process testing, and PAT are part of the strategy to ance. Also, they should be gratified to see FDA embracing
control variables. There must be careful recognition of these principles in terms of their application to process
process steps with conflicting outputs (e.g., increasing validation. These requirements have long been signaled.
drying conditions to minimize API degradation may Most of these requirements have also been previously
cause particle size reduction that negatively impacts published in documents over the past 20 years. The new
processing). The resulting output may sometimes neces- guidance recommends a coordinated and comprehensive
sitate additional, discrete process steps to accommodate effort in validation as opposed to addressing validation
the output characteristics. Without good control of input as a distinct and singular event.
variables and understanding of all potential effects on The primary challenge for industry to implement the
processing, relationships determined in development recommendations of the new draft guidance is to develop
will not be meaningful. coordinated systems in their organizations. These sys-
Statistical methods. The use of statistical methods tems should support a multi-disciplinary approach to
is also specifically mentioned in several areas of the draft product development that is supportive to robust product
guidance. Statistical methods including screening studies manufacturing through its lifecycle. The information and
and design of experiments (DOE) are commonly used in activities recommended in the guidance are generally
product development. Their applications have been well already in place; however, the appropriate “warehousing”
JOURNAL OF VALIDATION T ECHNOLOGY [WINTER 2009] 29
Global Regulatory Viewpoint.

of this information is not always as obvious. What will 8. McNally, Grace E., “Lifecycle Approach Process Valida-
be needed is increased communication between organi- tion,” GMP by the Sea, Cambridge, MD, August 26, 2008.
zational groups, greater availability of technical reports, 9. McNally, Grace E., “Lifecycle Approach Process Valida-
coordinated decisions involving appropriate organization tion,” GMP by the Sea, Cambridge, MD, August 29, 2007.
experts, and so on. Organizations must also be sure 10. Famulare, Joseph, “Benefits of a Pharmaceutical Quality
they are compliant with standards as stated for the three System,” PDA/FDA Joint Conference, Bethesda, MD, Novem-
lifecycle stages of validation. Special emphasis should ber 2, 2007.
be placed on identification, control, or input variation 11. FDA, Compliance Policy Guide 7132c.08, Section 490.100,
and on the application of statistics in all phases of the “Process Validation Requirements for Drug Products and
product lifecycle. Active Pharmaceutical Ingredients Subject to Pre-Market
The new draft guidance and its clarified expectations Approval” (CPG 7132c.08), 2004.
should help organizations focus on key areas. There is 12. FDA, Inspection Guidelines, “Oral Solid Dosage Forms,”
definite consistency in the messages of US and interna- January 1994.
tional guidelines. The challenges ahead are great, but at 13. FDA, Inspection Guidelines, “Topical Drug Products,” July
least there seems to be good agreement on the direction 1994.
of this effort. 14. FDA, Inspection Guidelines, “Oral Solutions and Suspen-
sions,” August 1994.
ACKNOWLEDGMENT 15. ICH, Q7A, Good Manufacturing Practice Guide for Active Phar-
Helpful discussions with Richard Poska and J. Ambrose maceutical Ingredients, August 2001. JVT
Van Wert are appreciated.
ARTICLE ACRONYM LISTING
API Active Pharmaceutical Ingredient
REFERENCES CAPA Corrective Action and Preventive Action
1. FDA, Guidance for Industry, Process Validation: General CGMP Current Good Manufacturing Practice
Principles and Practices, Draft Guidance, November 2008. CMC Chemistry, Manufacturing, Controls
2. FDA, Guideline for General Principles of Process Validation, DOE Design of Experiments
May 1987. FDA US Food and Drug Administration
3. ICH, Q8A, Pharmaceutical Development, May 2006. ICH International Conference on Harmonisation
4. ICH, Q9A, Quality Risk Management, June 2006. IQ Installation Qualification
5. ICH, Q10, Pharmaceutical Quality System, May 2007. OOS Out-of-Specification
6. ICH, M4, The Common Technical Document, September OQ Operational Qualification
2002. PAT Process Analytical Technology
7. FDA, PAT—A Framework for Innovative Pharmaceutical Cur- PQ Performance Qualification
rent Good Manufacturing Practice Regulation, September QbD Quality by Design
2004. R&D Research and Development

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