SIX SIGMA SYSTEM

INSPECTION MODEL

PRESENTED BY :
P . ESTHER RANI
REG NO : 220208
PHARMACUETICAL QUALITY ASSURANCE
SHRI VISHNU COLLEGE OF PHARMACY
BHIMAVARAM
 SIX SIGMA* is an organization-wide approach used to achieve
breakthrough improvements tied to significant bottom-line results.
 Unlike previous TQM approaches, Six Sigma specifies exactly how
the organization’s managers should set up and lead the effort.
 Key features are the use of data and statistical analysis, highly
trained project leaders known as Black Belts and Green Belts, project
selection based on estimated bottom-line results, and the dramatic
goal of reducing errors to about three per million opportunities.
 Six Sigma is a quality management methodology used to help
businesses improve current processes, products or services by
discovering and eliminating defects.
 The goal is to streamline quality control in manufacturing or business
processes so there is little to no variance throughout.
 THE SIX SIGMA APPROACH
 In 1981, Robert Galvin, who was the president of Motorola, issued a
challenge to his company: Improve performance tenfold over the next 5 years.
 Motorola developed and implemented Six Sigma Quality, a unique approach to
dramatically improving quality.
 Motorola responded and achieved the goal.
 That led the company to its next challenge. Galvin, by then versed in some work
being done in Motorola’s Communications Sector with the goal of Six Sigma
quality, called for 10 times improvement in each of the next 2-year periods, and
achieving
 In 1988, Motorola became one of the first winners of the new Malcolm Baldrige
National Quality Award.
 Because winners are required to share their methods, Six Sigma Quality
became public knowledge.
 Other companies began using and improving on it, especially GE and
AlliedSignal. In the 1990s and 2000s, it spread to thousands of other
organizations.
 Six Sigma programs have reported huge savings when applied to complex,
even organization wide problems that need breakthrough solutions.
 It is best focused on reducing variation in any major process from the
production floor to headquarters offices.
 Customer requirements, defect prevention, and waste and cycle time
reduction are the kinds of issues that Six Sigma addresses.
 Small or local problems do not need the major investment of a Six Sigma
project and are better handled by local or departmental teams.
 WHAT DOES SIX SIGMA MEAN?
 Sigma—written with the Greek letter σ—is a measure of a process’s
variation or spread. The process is improved by making that spread
smaller, producing output that is more consistent and has fewer defects or
errors.
 Under traditional quality standards, the spread is reduced until the
specification limit is 3s away from the process mean.
 With this standard, 0.135 percent of output still would be outside the
specifications. This unacceptable output generates cost of poor quality: lost
time, money, and customers.
 Common measures of performance in Six Sigma programs are
sigma levels and defects per million opportunities.
 The Six Sigma companies expect just 3.4 defects per million.
 It is important to note that the Six Sigma concept is a subset of
the broader concept of total quality.
 Six Sigma is a strategy within the context of total quality that
moves the target to a much higher level of quality than
organizations have achieved in the past.
 It is not a concept that supplants or replaces total quality.
 Rather, it is an innovative way to pursue a higher level of quality
under the broad umbrella of total quality.
 The central core of the Six Sigma concept is a six-step
protocol for process improvement.
 The six steps are as follows:
1. Identify the product characteristics wanted by customers.
2. Classify the characteristics in terms of their criticality.
3. Determine if the classified characteristics are controlled by
part and/or process.
4. Determine the maximum allowable tolerance for each
classified characteristic.
5. Determine the process variation for each classified
characteristic.
6. Change the design of the product, process, or both to achieve
a Six Sigma process performance.
 METHODS AND TOOLS
 Six Sigma prescribes an improvement process known as DMAIC: define, measure,
analyze, improve, control.
 DEFINE the improvement project’s goals, deriving them from customer needs or
wants.
 MEASURE the current process and establish metrics to monitor progress toward
goals.
 ANALYZE the current process to understand problems and their causes.
 IMPROVE the process by identifying and piloting solutions to the problems.
 CONTROL the improved process with standardization and ongoing monitoring.
 DMAIC vs. DMADV
 The DMAIC and DMADV methodologies seem similar, but they have different use
cases. The DMAIC methodology is designed for existing process or products that
aren’t meeting customers’ needs or performing to standards. When a business needs
to develop a product or process that doesn’t already exist or when a product has been
optimized but still falls short, that’s when you want to use DMADV.
 Six Sigma DMADV
 For developing a new product or process or for processes that need total
overhaul, there is a modified version called Design for Six Sigma (DFSS).
 A process often used in DFSS is called DMADV: define, measure,
analyze, design, verify.
 DEFINE realistic goals that suit the customer’s requirements or the
business strategy.
 MEASURE and identify the customer’s critical to quality (CTQ)
requirements and translate them into clear project goals.
 ANALYZE multiple options and alternatives for the customer along with
the estimated total life cycle of the project.
 DESIGN the process at a high level before moving onto a more detailed
version that will become the prototype to identify errors and make
modifications.
 VERIFY that the final iteration of the product or process is approved by all
customers and clients — whether internal or external.
 SIX SIGMA IN THE ORGANIZATION
 Unlike Total Quality Management (TQM), the Toyota Production System and Lean,
Six Sigma has a defined organizational hierarchy of Six Sigma expertise and
experience for the organization implementing practices and operating Six Sigma
projects. These hierarchical levels are named as follows:
 Executive (CEO, Top Management). Establish Six Sigma vision for the organization.
Empower subordinate Six Sigma leaders. Provide necessary resources for the
implementation/projects. .
 Champion. Trained in Six Sigma methodology and selection of Six Sigma projects
that are aligned with business objectives. Executive designates Champions from
upper management to identify Six Sigma projects, align and integrate them with the
organization’s goals and vision. Select and mentor Six Sigma project leader “Belts.”
 Master Black Belt. Identified by Champions to be cross-functional in-house Six
Sigma consultants/facilitators/coaches. Assist Champions in identification of Six
Sigma projects. Has extensive project management experience, and thorough
mastery of Six Sigma methodology and tools. Guides and mentors Black and Green
Belts. Usually full-time Six Sigma employees.
 Black Belt. Has significant Six Sigma training. Primarily engaged in leading Six
Sigma project execution under the Master Black Belts.
 Green Belt. Has Six Sigma training. Project leaders engaged in Six Sigma
implementation/projects, operating under guidance from the Black Belts.
 SIX-SYSTEM INSPECTION MODEL
 The FDA's Drug Manufacturing Inspection Compliance Program, which contains
instructions to FDA personnel for conducting inspections, is a systems-based
approach to inspection and is very consistent with the robust quality system
model presented in this guidance.
 INSPECTION
 The inspection is defined as audit coverage of 2 or more systems, with
mandatory coverage of the Quality System
 Inspection options include different numbers of systems to be covered depending
on the purpose of the inspection.
 INSPECTION OF SYSTEMS
 Inspections of drug manufacturers should be made and reported using the
system definitions and organization in this compliance program.
 Focusing on systems, rather than profile classes, will increase efficiency in
conducting inspections because the systems are often applicable to multiple
profile classes.
 TYPES OF SURVEILLANCE
 SURVEILLANCE INSPECTIONS
Surveillance Inspections are inspections conducted without prior knowledge of a
violative situation
a) The Full Inspection Option
 The Full Inspection Option is a surveillance or compliance inspection which is meant to
provide a broad and deep evaluation of the firm's cGMP.
 This will be done when little or no information is known about a firm's cGMP compliance
(e.g., for new firms); or for firms where there is doubt about the cGMP compliance in the
firm (e.g., a firm whose history has documented short-lived compliance and recidivism);
or follow up to previous regulatory actions.
 During the course of a Full Inspection, verification of quality system activities may require
limited coverage in other systems.
 The Full Inspection Option will normally include an inspection audit of at least four of the
systems, one of which must be the Quality System (the system which includes the
responsibility for the annual product reviews).
 SELECTING THE FULL INSPECTION OPTION : The Full Inspection Option will
include inspection of at least four of the systems as listed under the STRATEGY
section in Part II, one of which must be the Quality System.
 Select the Full Inspection Option when the firm has a history of fluctuating into and out
of compliance. To determine if the firm meets this criterion, the District should utilize all
information at their disposal, such as, inspection results, results of sample analyses,
complaints, Three-day NADA/ANADA Field Alert Reports, recalls, etc. and the
compliance actions resulting from them or from past inspections.
 Evaluate if important changes have occurred by comparing current operations against
the EIR for the previous Full Inspection. The following types of changes are typical of
those that warrant the Full Inspection Option:
1) New potential for cross-contamination arising through change in process or product
line.
2) Use of new technology requiring new expertise, significant new equipment, or new
facilities.
 The Full Inspection Option will satisfy the biennial inspection requirement.
b) The Abbreviated Inspection Option
 The Abbreviated Inspection Option is a surveillance or compliance inspection which is
meant to provide an efficient update evaluation of a firm’s cGMP.
 The abbreviated inspection will provide documentation for continuing a firm in a
satisfactory cGMP compliance status.
 Generally this will be done when a firm has a record of satisfactory cGMP compliance,
with no significant recall, or product defect or alert incidents, or with little shift in the
manufacturing profiles of the firm within the previous two years.
 The Abbreviated Inspection Option normally will include an inspection audit of at least
two of the systems, one of which must be the Quality System (the system which
includes the responsibility for the annual product reviews). The Investigator should
ensure that the optional systems are rotated in successive Abbreviated Inspections.
 SELECTING THE ABBREVIATED INSPECTION OPTION.
 The Abbreviated Inspection Option normally will include inspection audit of at least two
of the above systems, one of which must be the Quality System. During the course of
an abbreviated inspection, verification of quality system activities may require limited
coverage in other systems.
2) COMPLIANCE INSPECTIONS
 Compliance Inspections are inspections done to evaluate or verify
compliance corrective actions after a regulatory action has been
taken. The coverage given in compliance inspections must be
related first to the areas found deficient and being corrected.
 In addition a determination must be made on the overall
compliance status of the firm after the corrective actions are
taken.
 The Full inspection option should be used for a compliance
inspection, especially if the Abbreviated Inspection Option was
used during the violative inspection.
 Compliance Inspections include For Cause Inspections.
 The For Cause Inspections are compliance inspections which are
done to investigate a specific problem that has come to the
attention of some level of the Agency.
 The diagram above shows the relationship among the six
systems:
 The quality system and the five manufacturing systems. The
quality system provides the foundation for the manufacturing
systems that are linked and function within it.
 The quality system model described in this guidance does not
consider the five manufacturing systems as discrete entities,
but instead integrates them into appropriate sections of the
model.
 Those familiar with the six-system inspection approach will see
organizational differences in this guidance; however, the inter-
relationship should be readily apparent.
 One of the important themes of the systems based inspection
compliance program is that you have the ability to assess
whether each of the systems is in a state of control.
 The quality system model presented in this guidance will also
serve to help firms achieve this state of control.
 QUALITY MANAGEMENT SYSTEM
 Assessment of the Quality System is conducted in two phases. The first
phase is to evaluate whether the Quality Control Unit has fulfilled its
responsibility to review and approve all procedures related to production,
quality control, and quality assurance and assure the procedures are
adequate for their intended use. This also includes the associated
recordkeeping systems.
 The second phase is to assess the data collected to identify quality
problems and may link to other major systems for inspectional coverage.
 For each of the following, the firm should have written and approved
procedures and documentation.
 The firm’s adherence to written procedures should be verified through
observation whenever possible.
 These areas are not limited only to finished products, but may also
incorporate starting materials and in-process materials.
 These areas may indicate deficiencies not only in this system but also in
other major systems that would warrant expansion of coverage.
 AREAS OF OBSERVATION DURING AUDITING
 Batch production and control record review and approval prior to distribution of
batches.
 Discrepancy and failure investigations related to manufacturing and testing:
documented; evaluated; investigated in a timely manner; includes corrective action
where appropriate.
 Change Control: documented; evaluated; approved; need for revalidation assessed.
 Reprocess/Rework: evaluation, review and approval; impact on validation and
stability
 Complaint reviews (quality): documented; evaluated; investigated in a timely
manner; includes corrective action where appropriate.
 Complaint reviews (medical): Check the firm’s written procedures describing how
Adverse Drug Experience (ADE) Reports are investigated, evaluated and submitted
to FDA, and determine whether they are followed.
 Determine if 15-Day reports, required from serious, unexpected ADEs are submitted
to FDA within 15 working days.
CAUSES TO IMPOSE REGULATORY ACTIONS
 Pattern of failure to review/approve procedures.
 Pattern of failure to document execution of operations as
required.
 Pattern of failure to review documentation.
 Pattern of failure to conduct investigations and resolve
discrepancies/failures/deviations/ complaints.
 Pattern of failure to assess other systems to assure
compliance with GMP and SOPs.
 PRODUCTION SYSTEM
 For each of the following, the firm should have written and
approved procedures and documentation.
 The firm’s adherence to written procedures should be
verified through observation whenever possible.
 These areas are not limited only to finished products, but
may also incorporate starting materials and in-process
materials.
 These areas may indicate deficiencies not only in this
system but also in other systems that would warrant
expansion of coverage.
 When this system is selected for coverage in addition to the
Quality System, all areas listed below should be covered;
however, the depth of coverage may vary depending upon
inspectional findings.
 AREAS OF OBSERVATION DURING AUDITING
 training/qualification of personnel
 identification of equipment with contents, and where appropriate phase of
manufacturing and/or status
 calculation and documentation of actual yields and percentage of theoretical
yields
 contemporaneous and complete batch production documentation
 established time limits for completion of phases of production
 prevention of microbiological contamination of drug products purporting to be
sterile, including the validation of any sterilization process
 prevention of objectionable microorganisms in non-sterile drug products
 adherence to preprocessing procedures (e.g., set-up, line clearance, etc.)
 equipment cleaning, maintenance and use logs
 process validation, including validation and security of computerized or
automated data handling system
 documented investigation into any unexpected discrepancy
CAUSES TO IMPOSE REGULATORY ACTIONS
Pattern of failure to establish/follow a control system
for implementing changes in the production system
operations.
 Pattern of failure to document investigation of
discrepancies
 Lack of process validation.
 Lack of validation of computerized systems.
Pattern of incomplete or missing batch production
records. Pattern of nonconformance to established in-
process controls, tests, and/or specifications.
 FACILITIES AND EQUIPMENT SYSTEMS
 For each of the following, the firm should have written and
approved procedures and documentation.
 The firm’s adherence to written procedures should be verified
through observation whenever possible.
 These areas may indicate deficiencies not only in this system but
also in other systems that would warrant expansion of coverage.
When this system is selected for coverage in addition to the
Quality System, all areas listed below should be covered;
however, the depth of coverage may vary depending upon
inspectional findings.
AREAS OF OBSERVATION DURING AUDITING
 Facilities
 cleaning and maintenance
 facility layout and air handling systems for prevention of cross-contamination
(e.g. penicillin, beta-lactams, steroids, hormones, cytotoxics, etc.)
 specifically designed areas for the manufacturing operations performed by
the firm to prevent contamination or mix-ups
 general air handling systems
 control system for implementing changes in the building
 Equipment
 equipment cleaning, maintenance and use logs
 equipment installation and operational qualification where appropriate
 adequacy of equipment design, size, and location
 equipment surfaces should not be reactive, additive, or absorptive
 appropriate use of equipment operations substances, (lubricants, coolants,
refrigerants, etc.) contacting products/containers/etc.
 cleaning procedures and cleaning validation
 controls to prevent contamination, particularly with any pesticides or any
other toxic materials, or other drug or non-drug chemicals
CAUSES TO IMPOSE REGULATORY ACTIONS
 Contamination with filth, objectionable microorganisms, toxic
chemicals or other drug chemicals, or a reasonable potential
for contamination, with demonstrated avenues of
contamination, such as airborne or through unclean equipment
 Pattern of failure to validate cleaning procedures for non-
dedicated equipment. Lack of demonstration of effectiveness
of cleaning for dedicated equipment.
 Pattern of failure to document investigation of discrepancies
 Pattern of failure to establish/follow a control system for
implementing changes in the equipment.
 Pattern of failure to qualify equipment, including computers.
 LABORATORY CONTROL SYSTEM
 AREAS OF OBSERVATION DURING AUDITING
 adequacy of staffing for laboratory operations
 adequacy of equipment and facility for intended use
 calibration and maintenance programs for analytical instruments and
equipment
 validation and security of computerized or automated data handling
system
 complete analytical records from all tests and summaries of results
 quality and retention of raw data (e.g., chromatograms and spectra)
 correlation of result summaries to raw data; presence of unused data
 adherence to an adequate Out of Specification (OOS) procedure which
includes timely completion of the investigation
 adequate reserve samples; documentation of reserve sample
examination
 stability testing program, including demonstration of stability indicating
capability of the test methods
 CAUSES TO IMPOSE REGULATORY ACTIONS
 Pattern of failure to establish/follow a control system for
implementing changes in the laboratory operations.
 Pattern of failure to document investigation of discrepancies.
 Lack of validation of computerized systems and/or automated
data collection systems.
 Pattern of inadequate sampling practices.
 Lack of validated analytical methodologies.
 Pattern of failure to follow approved analytical procedures.
Pattern of failure to follow an adequate OOS procedure.
 Pattern of failure to retain raw data.
 Lack of stability indicating methods.
 Pattern of failure to follow the stability programs.
 MATERIALS SYSTEM
 AREAS OF OBSERVATION DURING AUDITING
 storage under quarantine until tested or examined and released
representative samples collected, tested or examined using
appropriate means
 at least one specific identity test is conducted on each lot of each
component
 a visual identification is conducted on each lot of containers and
closures
 testing or validation of supplier's test results for components,
containers and closures
 rejection of any component, container, closure not meeting
acceptance requirements. Investigate fully the firm’s procedures for
verification of the source of components.
 appropriate retesting/reexamination of components, containers,
closures
 first in-first out use of components, containers, closures - quarantine
of rejected material
 CAUSES TO IMPOSE REGULATORY ACTIONS
 Release of materials for use or distribution that do not
conform to established specifications.
 Pattern of failure to conduct one specific identity test for
components.
 Pattern of failure to document investigation of
discrepancies. Pattern of failure to establish/follow a
control system for implementing changes in the materials
handling operations.
 Lack of validation of water systems as required depending
upon the dosage form.
 Lack of validation of computerized systems.
 PACKAGING AND LABELING SYSTEM
 AREAS OF OBSERVATION DURING AUDITING
 control of issuance of labeling, examination of issued labels and reconciliation of
used labels
 examination of the labeled finished product
 adequate inspection (proofing) of incoming labeling
 use of lot numbers, destruction of excess labeling bearing lot/control numbers
 physical/spatial separation between different labeling and packaging lines
 monitoring of printing devices associated with manufacturing lines
 line clearance, inspection and documentation
 adequate expiration dates on the label
 validation of packaging and labeling operations including validation and security of
computerized or automated data handling system
 documented investigation into any unexpected discrepancy
 CAUSES TO IMPOSE REGULATORY ACTIONS
 Pattern of failure to establish/follow a control system
for implementing changes in the packaging and/or
labeling operations.
 Pattern of failure to document investigation of
discrepancies.
 Lack of validation of computerized systems.
 Lack of control of packaging and labeling operations
that may introduce a potential for mislabeling.
 Lack of packaging validation.