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Presented By: Aris Koumandaros

IVTs 2nd Validation Week Canada,

May 14 to 16, 2013

Plan for a Successful Gap

Assess Current Company
Develop an
Implementation Plan for
Correcting Deficiencies
Interactive Exercise

Audits versus Gap Analysis
Reasons for Conducting a Gap Analysis
Gap Analysis Preparation Plans

Gap Analysis & Audits

Gap Analysis


A technique that compares a

An audit is a systematic,

companys existing state to its

desired state (as expressed by its
long-term plans) to help
determine what needs to be
done to remove or minimize the
[Source: Christensen, Eldon H.,
Kathleen M. Coombes-Betz, and
Marilyn S. Stein. The Certified
Quality Process Analyst
Handbook, ASQ Quality Press,

independent and
documented process for
obtaining audit evidence and
evaluating it objectively to
determine the extent to
which audit criteria are
[Source: ISO 19011:2011
Guidelines for quality and/or
environmental management
systems auditing]

Audit versus Gap Analysis

An independent review
Decisions based on a
sample of data reviewed
Limited scope and time
Assess compliance or
lack of compliance to an
accepted standard

Audit versus Gap Analysis

Gap Analysis
Detailed review, identify
gaps in a program
Identify opportunities
for improvement, going
beyond compliance
Wider scope, examining
greater number of
More collaborative,
open environment

Why Audit?
Ensure compliance with company requirements
Ensure compliance with regulatory requirements
Ensure the quality system is effectively implemented

and maintained
Identify opportunities for improvement

Why Conduct a Gap Analysis?

Identify compliance issues and improve the quality

Proactive response
Continuous quality improvements
Reactive response to an internal or corporate audit or

regulatory audit
Response to serious regulatory findings (FDA warning

For example, conduct a gap analysis between the updated

Process Validation procedure and the validation documentation
associated with the equipment

ISO 9000 Quality Management

Principle 4Process Approach
A desired result is achieved more
efficiently when activities and related
resources are managed as a process
Principle 5System Approach to

Identifying, understanding, and

managing interrelated processes as a

system contributes to the organizations
effectiveness and efficiency in achieving
its objectives.
[Source: ANSI/ISO/ASQ Q9000-2000]

Gap Analysis Process

ProcessA group of
activities and
related resources
that transforms
inputs into outputs

Policy &

Gap Analysis
Resources &


Gap Analysis Methodology

Assess current system &

Identify weaknesses
Compare to best


Determine priorities
prioritization of tasks
Develop an

improvement plan
CAPA, Change Control

Gap Analysis Preparation Plans

Define Objective
What do you want to achieve with the gap analysis?
Define Scope
Identifies the items & activities to be examined
Define Team
Functional & Multi-functional teams
Define Standards/Requirements
Develop a technical understanding
Develop a Checklist

Preparation for a Gap Analysis

Read policies and procedures
Determine what has been established in comparison to the
Create questions, addressing 3 general conditions
Procedures established & meet requirements?
Procedures implemented?
Management support adequate to support procedures?
Create a sampling plan for collecting information
Training is up-to-date for personnel involved in process
Training in gap analysis process
Knowledge of documenting gaps
Know the requirements (policies, procedures, regulations)

Regulatory requirements
Elements of a validation program
FDA citations relating to validation

Validation Program
Extent of qualification /

validation & level of

Based on risk associated

with product quality

and patient safety
Complexity and novelty
of the systems
regarding the integrity
of the data

Validation Program Prerequisites

Have a quality system in place
Investigate root causes
Assure effective corrective & preventative actions
Implement effective change control
Validation supports the FDA quality systems approach
Quality System
Laboratory Controls System
Facilities & Equipment System
Materials System
Production System
Packaging & Labeling System

Validation Program Prerequisites

Principles for quality assurance involved in

Quality, safety, effectiveness must be designed and

built into the product

Quality cannot be tested into the finished product
Each step of a manufacturing process must be
controlled to ensure the finished product meets

Adequate personnel with the required experience,

knowledge and training

Regulatory Requirements (FDA)

Part 211 Subpart D Equipment
Sec. 211.68 Automatic, mechanical, and electronic
Part 211 Subpart F Production and Process

Sec 211.100 Written procedures; deviations
Sec 211.110 Sampling and testing of in-process

materials and drug products

Sec 211.113 Control of microbiological contamination

Part 211 Subpart I Laboratory Controls

Sec 211.165 Testing and release for distribution

Regulatory Requirements
Health Canada
C.02.004, Premises

C.02.014, Quality Control

C.02.005, Equipment

C.02.015, Quality Control

C.02.007, Sanitation

C.02.018, Finished Product

C.02.009, Raw Material

C.02.024, Records
C.02.027, Stability
C.02.029, Sterile Products

C.02.011, Manufacturing
C.02.012, Manufacturing

Elements of a Validation Program

Equipment Qualification

Aseptic Operations

Utilities Qualification
Computerized System

Process Validation
Cleaning Validation

Analytical Methods
Sterilization Validation
Filter Validation
Integrity Closure Testing

Quality Systems Model

Management Responsibilities
Validation plans, procedures, personnel
Qualification/validation, training
Manufacturing Operations
Define critical parameters, data
collection, addressing deviations
Evaluation Activities
Trends, risk management, CAPA

[Source: FDA, Quality Systems Approach to Pharmaceutical CGMP

Regulations, 2006]




Validation Equipment/Systems
Quality System
Document Management
Complaints System
Change Management System
Laboratory Systems
Materials Systems
Dispensary Systems

Production System
Sterile Filtration
Packaging/Labeling Systems
Artwork Systems
Packaging Equipment
Facilities/Equipment Systems
Building Automation System
Purified Water System

Validation Documentation
Validation Policy
Validation Planning
Validation Master Plans
Validation Plans
User Requirements
Technical Specifications

Validation Documentation (cont.)

Validation / Qualification

Protocols & Reports

Facilities, Utilities, Equipment
Computerized Systems
Cleaning Validation
Process Validation
Test Method Validation
Sterilization Validation
Filter Validation
Standard Operating Procedures
& Work Instructions

Revalidation Program
Sterilization &

Depyrogenation processes
Equipment Qualification
Computer Validation
Environmental Validation
Aseptic Processes
Analytical Test Methods
Process Validation
Cleaning Validation

Maintaining the Validated State

Change Control Management
Preventative Maintenance
Corrective & Preventative Action Plans
Statistical Process Controls
Management Reviews

Systematic approach to determining gaps in a validation

FDA citations related to validation

Techniques for Assuring a

Complete Gap Analysis
Include all system elements

Examine all functions at all

Use checklists to assure that
requirements are reviewed

Gap Analysis Approaches

Horizontal gap analysis
Assessment of one system/process
across several functional groups
Vertical gap analysis
Assessment of each function
(department) and conduct gap
analysis of all processes in each

Developing Checklists
Develop questions based on the

Open questions; closed questions

Aid in documenting assessment of

current practices
Adequacy, suitability,

effectiveness, compliance

Possible answers to each question

Meets requirements; does not
meet requirements; partial
requirement met; not applicable

I have six honest serving men.

They help in all I do.
Their names are:
Where, What and When, How,
Why, and Who.
--Rudyard Kipling

Checklist Question Examples

Does the company have a Validation

Master Plan (VMP)?

Does the document meet the company
requirements for layout and format?
Does the creation, review, approval and
control of the VMP comply with the
procedure for master GMP documents?
Does the VMP clearly state the
requirements for validation
documentation management?
Does the VMP provide details of the
overall expected timescales and
activities associated with validation of
equipment, utilities and systems?

Possible Quality Tools

Matrix diagrams
Pareto Analysis

Gap Analysis Results

Classification of gaps
Validation Requirement Matrix
Demonstrates regulatory requirements met
Tracking system for gaps
CAPA system

CAPA Concepts
Remedial corrections of an

identified problem
Root cause analysis with
corrective action
Preventive action

CAPA Process
Analyze process
Identify corrective and

preventative actions
Validate corrective and
preventative actions
Implement corrective
and preventative actions
Evaluate effectiveness

Aftermath of a Gap Analysis

Documenting results of the gap


Final report

Report Format
Executive Summary
Gap Analysis Design
Results & Discussion

Barriers to a Successful Gap

Insufficient management

Inadequate resources to
perform the task
Inappropriate assignment of
Unreasonable schedule
Inadequate follow-up to
CAPA plans

FDA Warning Letter Citation

Plans were put in place 12/1/94 to validate the processes in the
Chemical Manufacturing Operations (CMO)... However, the
CMO production summary indicates that since 1/98 CMO
routinely manufactured most of the major products scheduled
for validation. Our investigators spoke with selected members of
management and the CMO validation staff about the number of
projects scheduled versus the number of employees in that
Department. The Department currently has seven employees...
This department is responsible for all process, cleaning,
equipment validation, validation change controls, and all the
corresponding reports, data and protocols. This seems like an
inadequate number of trained employees... We feel that the lack
of adequate staff to perform validations has likely contributed to
the slow progression of validation activities over the past few

FDA Inspectional Observation

Your firms CAPA procedure allows corrective and preventive
actions to remain uninitiated for prolonged periods of
time. For example, CAPA 12307 was opened on 10/8/09 as a
preventive action to identify gaps in your firms previously
executed equipment cleaning validations. A Cleaning
Validation Gap Analysis status report identifying
deficiencies in these cleaning validations was issued in
April 2010. This report recommended that a Master
Cleaning Program be written... On 2/2/11, 10 months after
the cleaning validation deficiencies were identified,
another CAPA, 37944, was opened to create a Cleaning
Validation Master Plan (CVMP)... The CVMP... was
approved in July 2011, more than 15 months after cleaning
validation deficiencies were identified.

Management Review of a
Validation program
Review effectiveness of the validation


Internal & corporate audits

Change controls
Annual product reviews

Review gap analysis

Follow-up on CAPAs
Ensure timely actions taken
Review metrics
% critical/major/minor gaps
% requirements met

FDA Citations Related to Validation

Part 211 Subpart B Organization

and Personnel
Sec. 211.22 Responsibilities of

quality control unit

Part 211 Subpart D Equipment

Sec. 211.63 Equipment design, size,
and location
Sec. 211.67 Equipment cleaning and
Sec. 211.68 Automatic, mechanical,
and electronic equipment

FDA Citations Related to Validation

Part 211 Subpart J Records and

Sec. 211.192 Production record

Sec. 211.194 Laboratory records

Part 211 Subpart C Buildings and

Sec. 211.42 Design and construction

Sec. 211.46 Ventilation, air filtration,
air heating and cooling

FDA Citations Related to Validation

Part 211 Subpart E Control of

Components and Drug Product

Containers and Closures
Sec. 211.94 Drug product

containers and closures

Part 211 Subpart I Laboratory

Sec. 211.160 General

Sec. 211.165 Testing and release
for distribution

FDA Citations Related to Validation

Part 211 Subpart F Production

and Process Controls

Sec. 211.100 Written procedures;

Sec. 211.110 Sampling and testing
of in-process materials and drug
Sec. 211.111 Time limitations on
Sec. 211.113 Control of
microbiological contamination

FDA Warning Letter (21 CFR 211.22)

There were numerous and significant discrepancies in the

Process Validation Report, which was approved by Quality.

For example, the results documented in the report
conflicted with the sterilization cycle descriptions outlined
in the report.
The Validation Policy procedure was not followed when a
change was made to the manufacturing process. A planned
deviation changed the tank mixer speeds and mixing times
used to make the batch of suspension product. The
Validation Department did not determine if the
modification was major or minor as per procedure. In
addition, the Validation Department did not address the
need to do additional testing to assure the product was
equivalent to that made by the validated process.

FDA Warning Letter (21 CFR 211.22)

An investigation of the test procedure for the impurity test

method conducted by the Quality Control Director revealed that

the procedure was unreliable and concluded that the method
should be revalidated. Despite this finding, the Quality Control
Director did not implement any corrective actions to remedy this
deficiency. Your QCU was aware of these issues and took no
corrective and preventative action with respect to the product on
the market.
There was inadequate oversight of the media fill process.
Furthermore, the responsibility section of the Validation of
Aseptic Manufacturing and Filling Process Using the PST
procedure makes no mention of the quality control unit having
an active role in the oversight of media fill studies.

FDA Warning Letter (21 CFR 211.22)

Your quality procedure (i.e., Responsibility of the

Quality Group) states that the Quality Group shall

have the responsibility and authority to direct all
operational groups with respect to compliance with all
CGMP requirements. However, your Quality Group:
Failed to establish valid test methods for raw materials

and drug products that assure components and drug

products conform to appropriate standards of identity
and strength prior to release.
Approved the validation of test method even though
the ruggedness and robustness elements do not meet
the acceptance criteria.

FDA Warning Letter (21 CFR 211.63)

You have not qualified the performance of manufacturing

equipment, including a lack of installation qualification,

operation qualification and performance qualification of
your autoclave, laminar flow hood, compounding
equipment and fillers.
Your firm failed to ensure your water system was of

adequate design. Your firm also has not performed a formal

validation of the purified water system, although you
collected data that indicates your firm is now apparently
producing purified water of adequate quality for your

FDA Warning Letter (21 CFR 211.63)

The calibration of thermocouples (TCs) used during the

validation of your terminal steam sterilizers is not

performed before or after the autoclave cycles... The
calibration of these TCs provides assurance of an accurate
reading of the temperature in the sterilizer.
Our review of the equipment qualifications for multiple
automated Tablet Testing System (TTS) machines, used to
conduct in-process tablet testing (weight, hardness and
thickness) revealed that performance qualification was not
conducted to ensure the accuracy of the machine at the
various available speed settings.

FDA Warning Letter (21 CFR 211.63)

The re-qualification of the... did not have clearly

defined acceptance criteria. In addition, there was no

discrepancy report to explain why equipment
drawings, equipment schematics, equipment manuals,
and purchase orders were not available, what steps had
been taken in an attempt to obtain these materials,
and why the re-qualification was acceptable without
this information.

FDA Warning Letter (21 CFR 211.67)

No documented evidence exists to demonstrate the

effectiveness of cleaning methods and agents used in

cleaning of all production equipment and utensils to
ensure that residues have been reduced to acceptable
levels. Cleaning validation is limited to only glassware.
Additionally, your firm failed to conduct
investigation(s) of out of specification results obtained
during the cleaning validation for lyophilization trays.
There is no cleaning validation for screens or wire
electrodes that have product contact during

FDA Warning Letter (21 CFR 211.67)

Your firm lacked adequate evaluation of possible migration

of potent compounds throughout the facility. Specifically,

the cleaning validation study... was inadequately performed
in that recovery studies have not been performed on
material coupons (samples of materials used for wall
coverings, countertops, ceiling, and stainless steel) to
demonstrate the ability to recover cytotoxic products from
surfaces and equipment used in production as required by
the protocol... Also, the sampling records failed to show
time of sampling, and the area cleaning records failed to
show the time of cleaning. Finally, the sampling locations
were not defined and evaluated as possible worst case

FDA Warning Letter (21 CFR 211.67)

Your cleaning validation was limited to the cleaning

process of a plastic 55-gallon drum used in the

manufacture of Hydroquinone Skin Lightening Formula.
You have not established an adequate rationale, including
determining whether this product is the most difficult
product to clean. The validation also does not include other
equipment used in the manufacture and packing of this
Layers of chemical powders were observed covering the lids
of mixing tanks and equipment. Cleaning procedures have
not been validated to assure the adequacy in preventing

FDA Warning Letter (21 CFR 211.67)

Cleaning validation involved testing for residues of the

cleaning compound but not for residues of the various

products for which the beakers, stir bars, and homogenizer
had been used.
Disposable silicone tubing sets are cleaned with isopropyl
alcohol and distilled water between uses and then reused
to fill liquid oral drug products. There is no documentation
that your firm performed studies to ensure, for example,
that this cleaning procedure (a) is sufficient to effectively
remove residues of the drug product from the tubing and
(b) does not adversely affect the quality of the tubing for
its re-use.

FDA Warning Letter (21 CFR 211.68)

The process control computer monitoring system that

is used to monitor various production and processing

operations (e.g., operation conditions, equipment and
component status, historical trending of collected
data) is not validated to the current corporate
Your firms laboratory analysts have the ability to
access and delete raw chromatographic data located on
the ... used to conduct HPLC testing. Due to this
unrestrictive access, there is no assurance that
laboratory records and raw data are accurate and valid.

FDA Warning Letter (21 CFR 211.68)

Your firms custom software for your Master Batch

Production record, referred to as the I-131 Database,

has not been validated. This software is responsible for
generating the batch production record, performing
calculations to produce varying concentrations of drug
product, and generating label information for
customer vials.
The accuracy of calculations performed by the
Spectrophotometer has not been verified.

FDA Warning Letter (21 CFR 211.68)

The initial qualification for the Cutting and Packaging Machine was

completed on June 7, 2007. Approximately 25 major and minor changes

were implemented between June 14, 2007, and July 15, 2010, before your
approval of the re-qualification report for the equipment.
The data acquisition system for the UV/Visible spectrophotometers
allows your analysts to modify, overwrite, and delete original raw data
files. The spectrophotometers are used for dissolution testing of
finished product, stability samples, and process and method validation
studies. All laboratory personnel were given roles as Managers, which
allowed them to modify, delete, and overwrite results files. This system
also does not include an audit trail or any history of revisions that
would record any modification or deletion of raw data files. Your
laboratory computer system lacks necessary controls to ensure that
data is protected from tampering, and it also lacks audit trail
capabilities to detect data that could be potentially compromised.

FDA Warning Letter (21 CFR 211.192)

You failed to investigate environmental monitoring data

recorded in your aseptic processing suite, which failed to

meet your established limits... You have not investigated
the cause of the environmental monitoring results that
exceeded the limits on your Performance Qualification
Data HVAC Validation and Routine Environmental
Monitoring worksheets, nor have you justified your
assessment of the product impact caused by those
Your investigation regarding the media fill failures for eye
wash aseptic filling suite is inadequate because it was
attributed solely to improper aseptic techniques during the
filling operation without scientific justification to support
this conclusion.

FDA Warning Letter (21 CFR 211.192)

Low OOS assay results for... were noted in mixing samples

during process validation of... A clearly assignable cause for

the OOS result was not found. Your firm prepared samples
again and retested the lot. Only the passing retest results
were reported.
Out-of-limit (OOL) results obtained during the in-process
fill weight examination for validation batches were not
investigated. Specifically, you reported 31 in-process fill
weight OOL results for validation batch..., while reporting
11 and 3 OOL results for batches..., respectively... In
addition, the batch record does not contain any evidence
that you evaluated the in-process results to determine the
impact of the out-of-limit fill weight results in product

FDA Warning Letter (21 CFR 211.194)

Your firm has not evaluated the HPLC method used in

assaying Cetylpyridinium Chloride in Tech 2000

Dental Rinse, to assure that it meets proper standards
of accuracy and reliability, or that the test method was
verified under actual conditions of use. Identification
and assay methods for Cetylpyridinium Chloride
Topical Solution are contained in the current revision
of the United States Pharmacopoeia.

FDA Warning Letter (21 CFR 211.42)

There is no documentary evidence of in-situ air pattern

analysis (e.g., smoke studies) conducted at critical areas to

demonstrate unidirectional airflow and sweeping action
over and away from the product under dynamic conditions.
Your firm failed to demonstrate that the appropriate design
and controls are in place to prevent turbulence and
stagnant air in the critical area. It is essential that you
evaluate airflow patterns for turbulence that can act as a
channel for air contamination. The studies should be well
documented within written conclusions, and should
include an evaluation of the impact of aseptic
manipulations (e.g., interventions) and the equipment

FDA Warning Letter (21 CFR 211.42)

Your firms cleaning validation studies demonstrate the

selected cleaning agent is not effective on spore forming

microorganisms. However, spore forming microorganisms
have been detected in the environmental monitoring
samples, personnel monitoring samples, and sterility test
samples of final product.
Disinfectant effectiveness studies against representative
microorganisms and/or specific in-house isolates were not
conducted for cleaning agents used in your facility to
disinfect production areas, including aseptic areas.

FDA Warning Letter (21 CFR 211.42)

For parenteral operations, smoke studies were not

conducted to demonstrate unidirectional airflow and

sweeping action over and away from the product under
dynamic conditions during numerous aseptic operations in
classified areas of the vial filling facility. For example:
Various manual operations performed with the... such as

dispensing sterile API and connecting equipment to this...

were not included in smoke studies.
Other significant manual aseptic activities that can affect
airflow, including opening and closing the fill equipment
access panels during routine aseptic filling operations, were
not evaluated in smoke studies.

FDA Warning Letter (21 CFR 211.46)

API products sold as dry powders are manufactured in

a suite... solution drug product is manufactured. There

have been no studies showing whether contamination
of the solution drug product by the dry powders
cannot occur when doors to the manufacturing suites
are opened at the same time. The air handling system,
including the air filters and filter combinations, have
not been qualified to demonstrate that the drug
product does not become contaminated with the dry
powders. There are no diagrams showing the flow of
air through the rooftop vents, fans, and air return

FDA Warning Letter (21 CFR 211.94)

Your unfilled vial depyrogenation process has not been

demonstrated to provide a 3-log reduction in bacterial

endotoxins for 3cc and 10cc vials, which represent all
vial sizes that are aseptically filled in your facility. You
have never performed quantitative recovery studies
from 3cc and 10cc vials. Additionally, you did not
document that the applied endotoxin solution was
allowed to air dry. Therefore, you have not
demonstrated that the worst-case conditions were
challenged to validate depyrogenation of all vial sizes
that are aseptically filled at your facility.

FDA Warning Letter (21 CFR 211.160)

Your firm failed to prove that the methods used to perform

the bacteriostasis and fungistasis tests on Povidone-Iodine

Gel Swab Sticks are equivalent to or better than the USP
methods. The test methods used to evaluate the inhibitory
effects of the Povidone-Iodine on the ability of the ... to
support microbial growth lacked the requirements to use...
as part of the validation test as well as adequate incubation
times and temperatures.
The validation data for several laboratory methods was
incomplete or unavailable (i.e. total viable aerobic count for
the API, total viable aerobic plate count of raw materials,
and bacterial endotoxin testing for... However, you
approved the validation for these methods without the
complete data in place.

FDA Warning Letter (21 CFR 211.160)

During cleaning validation of the ... the specification

was a maximum of ... micrograms per swab and the

result was 41.9 micrograms per swab . The cleaning
validation was not repeated and the cleaning
procedure was not changed until after the inspection.
The biological indicators are not stored in accordance
with the manufacturers requirements for temperature
and relative humidity.

FDA Warning Letter (21 CFR 211.165)

Your firm failed to validate the specificity of the test

procedures used to analyze finished product stability

samples to ensure that the methods are stability-indicating.
For example, your firm determined the content of salicylic
acid in... stability samples by titration. Your firm has not
demonstrated the specificity of the method for degradation
products. The method may not allow you to detect the
presence of degradation products that may indicate
deterioration of the drug product.
Your firm employs a microbial limits test for Total Aerobic
Count (TAC) and Total Yeast and Mold (TYM) that differs
from the compendial procedure outlined in USP <61> and
has not validated the altered method.

FDA Warning Letter (21 CFR 211.165)

Failure to use fully validated computer spreadsheets to

calculate analytical results for in-process and finished

product testing. For example, the computer
spreadsheets used to calculate analytical results for...
have not been validated.

FDA Warning Letter (21 CFR 211.100)

Lot #79298AF00 was one of the batches included in the process

validation study for this product. This lot was not produced using the
manufacturing process discussed in the validation study protocol. Lot
#79298AF00 was subjected to several reconditioning steps, due to
particulate contamination, that were not listed in the master batch
record. Some of the actions taken with respect to this lot, such as the
hand pouring of the granules from a drum ... were steps that were
performed for the production of the two additional lots used in the
validation study.
Three initial process validation batches failed the dissolution test
specification... Your investigation concluded that the dissolution
results were affected by the order in which the excipient... was added
during the... process. Appropriate process design studies were not
conducted to scientifically establish the correct order of adding
excipients... to ensure proper dissolution of the drug product.

FDA Warning Letter (21 CFR 211.100)

Your manufacturing process, has not been validated for repeated

changes to the drying time parameter of the oven dryers in the...

granulation. The changes were implemented in an attempt to ensure
granulation is not too dry without establishing a minimum
specification and without an assessment of product quality.
You conducted validation with batches of 1,550,000 tablets. For
subsequent lots, you scaled up to 2,400,000 tablets, then 3,500,000
tablets... The manufacturing instructions in all Master Batch Records
had identical blending times of... even though the batch size was
increased... Your firm failed to provide validation protocols that
evaluated the impact of the increasing batch sizes on product quality.
You failed to conduct a study to demonstrate at what point each batch
size is uniformly blended. You have not conducted any analysis
comparing data between your validation batches.

FDA Warning Letter (21 CFR 211.100)

Written procedures do not define how process validation

will be conducted or documented.

No written validation plan or written validation
protocols were available at the time of the inspection.
Your firm has failed to validate a number of procedures
and processes used in the manufacture of your drug
products. Specifically, your firm does not have data to
verify that the mixing times used for bulk drug products
are adequate to produce homogeneity. Further, you have
not provided any data to demonstrate that your bulk
drug products can be stored for extended periods of time
under ambient conditions without altering their identity,
strength, quality, and purity.

FDA Warning Letter (21 CFR 211.100)

The process validation conducted for Fentanyl

Transdermal System is inadequate in that your final

process validation report failed to include and
evaluate the impact of all the combined deviations
that occurred during process validation. The report
failed to include such deviations as (1) the discovery
of brown particles in a laboratory sample of Fentanyl
Adhesive Mass Solution, (2) aborting the
cutting/packaging operations during the first
process validation lot due to a broken cutting and
packing machine, and (3) setting of the IR gauge
value below specification during the coating process
for the first validation lot.

FDA Warning Letter (21 CFR 211.110)

During the process validation... your firm failed to

reject tablets that were Out-of-Specification (OOS) for

Your firm does not have data to support the
temperature range of... used during the granulation
process... During the validation studies for the
granulation process, your firm established a
temperature range of... Your process validation study
does not provide any data to support the process range
allowed in the Master Batch Records.

FDA Warning Letter (21 CFR 211.110)

The manufacturing process does not include in process controls

to monitor and confirm that the filtration step is effective. We

note that your complaint investigation for particulate matter in
two bottles of... concluded that the subject particles present in
the complaint sample are inert organic sediment, and you have
not provided supporting documentation to confirm the
Your process validation, which consists of compounding, vial
washing/depyrogenation, filling, capping, sterilization, and
visual inspection resulted in a high vial rejection rate .
Additionally, a lack of non-viable particle (NVP) monitoring
with out-of-limit (OOL) results was reported, as well as fill
weight discrepancies. This is all an indication of deficient
process controls in a non-validated manufacturing process.

FDA Warning Letter (21 CFR 211.111)

Your firm has not validated your bulk or process hold

times assigned for most products... The assigned...

hold time limits for solutions and... day limits for
suspensions are largely unsupported. Your firm also
lacks data to support the adequacy of your process
hold times even though some of your products
contain... that are known to be absorbed by your
Your firm has failed to provide a justification for the
hold times... used in current batch records for sterile
ophthalmic eye drop products.

FDA Warning Letter (21 CFR 211.113)

Your firm has failed to conduct a media fill representative

of the different packaging configurations of your drug

products for the past two years. Your firm has been using a
volume of... for media fills; however, commercial products
are available in... In addition, you have not established
maximum aseptic fill duration.
Your firms qualifications of the Getinge Model 4300
autoclave and the Grieve CLE-500 oven are inadequate in
that you have not qualified this equipment with
representative loads. Your firms practice is to qualify the
equipment using minimum loads as opposed to actual
loads during routine operation (e.g., Grieve CLE-500 oven
was qualified to depyrogenate glass vials using... tray when
the actual load is a maximum of 60 trays).

FDA Warning Letter (21 CFR 211.113)

You have not conducted bacterial filtration retention

validation for all of your aseptically filled products.

Your firm failed to adequately document air flow (smoke)
studies to demonstrate unidirectional airflow under
dynamic conditions. Your firms air flow patterns procedure
lacked specific acceptance criteria. Your airflow study
documentation included hand drawings that provided
insufficient information to determine whether HEPAfiltered air used in the manufacturing area (and sterility
test laboratory) robustly sweeps away particles and
maintains unidirectional airflow protection under dynamic
production conditions.

FDA Warning Letter (21 CFR 211.113)

Your firms purified water system that provides water for

the production of liquid and semisolid drug products has

not been validated to show that it produces water that
meets the necessary specifications for objectionable
microorganisms with sufficient consistency to justify the
sampling frequency employed.
Steam sterilization cycles for the... lack adequate
validation. There was no justification provided for selection
of the worst case maximum load for the PREVAC1 used for
sterilization of aseptic manufacturing equipment loads and
terminally sterilized drug product equipment loads.
Furthermore, a minimum load was not established.

Closing Remarks
Going beyond traditional

internal audits

Identify all deficiencies to

be corrected on a systemic

Planning the gap analysis

is the key to a successful

validation program
Leads to continuous


Practice is the path to


Review lessons learned

Before Proceeding to the

Group Exercises...

Thank you for your attendance!

Contact Information:
Next Step: Interactive Exercises

Section 1 : Group Discussions

Section 2: Gap AnalysisEquipment Qualification

Group Discussion
Validation Requirements on Like-for-Like

During review of the maintenance records as part of the

gap analysis, you noted the following like-for- like

changes (same model replacement):
Replacement of the vacuum pump in the Sterilizing Autoclave
Replacement of the water distribution pump in the RO Water

Replacement of Mixer Motor

As per company policy, like-for-like changes do not

require revalidation. Is this a gap?

What is the extent of validation required, if any, in the
above situations?

Gap Analysis: Equipment

Qualification Program
This gap analysis is intended to assess the
companys current equipment qualification
program as compared to regulatory requirements
and identify gaps between the companys current
practice and the expectations of regulatory
Identify the scope (and what is not in scope) of the gap

Develop a gap analysis checklist. (Consider a minimum
of 5 questions based on the scope of this gap analysis).