In Industry there are lots failures related to the routine process, Equipment and System by one or other means. So one must analyze control such failures in manner that it will not affect your ultimate output and obviously that is your Product and its Quality.

1. QUALITY SQUARE INDUSTRY
TOOLS OF CONTINUOUS
IMPROVEMENT
By : Hardik Mistry

2. Goal of the Quality system
Ideal
A. NO Deviation
B. NO Out Of Specification
C. NO Failure
D. Beneficial Change
Real
A. Less & Effective Deviation
B. Less & Effective Out Of Specification
C. Fruitful Change
D. Fruitful Failure
Quality Product

3. System Development Cycle
Specificatio Confg/Impl Qualificatio
Design Operation
n e. n
User
Requirements, Detailed FAT
Functional Spec SAT
spec. Validation
Planning
IQ, OQ, PQ
Maintenance
Deviation , OOS
Change Control
Periodic Review

4. Deviation
A. Departure from a standard or norm.
B. Statistics : The difference between one of a set of
values and some fixed value, usually the mean of
the set.
C. Navigation : The error of a magnetic compass, as
that of a ship, on a given heading as a result of local
magnetism.
E. Optics : Diffraction. the bending of rays of light
away from a straight line.
F. Departure or divergence from an established dogma
or ideology.

5. Deviation & Incident
 Deviation - A departure from the approved instruction
or established standard or normal practice.
For example, the lack of a certain raw material that
could be substituted with another raw material.
 Incident - Unexpected event occur outside the scope
of the process or matter but willing to affect the
quality.
Example : Unexpected events related to maintaining
plant operations, safety, regulatory compliance, or
security.

6. Deviation & Change Control
A. Deviation is after done task
You came to know the effect after the deviation
B. Change Control is before done task
You know the possible effect before the doing
change & intention
to do something different and favorable in the future.
“A process that ensures that changes to materials, methods,
equipment and software are properly documented, validated,
approved and traceable”
- Change Control (PS 9000:2001, § 3.7)

7. Deviation & OOS results
A. Deviation is after done task
You came to know the effect after the deviation
B. OOS results is also after task
OOS are the deviations in testing results
“Test results, laying outside of the specifications” - Out Of
Specification

8. Deviation & Failure
 Deviation - A departure from the approved instruction
or established standard or normal practice.
For example , the lack of a certain raw material that
could be substituted with another raw material.
 Failure – Fail to achieve the targeted one.
“Deviation, Incident and OOS results are also type of
the failure”
“ The state or condition of not meeting a desirable or intended
objective ting, or a customer complaint. “ - Failure

9. Our Target : Our Specification

10. Deviation

11. Change Control

12. Out Of Specification
Results

13. Failure

14. Incident

15. Example 1:
Student obtaining less than 40 marks in one subject is
under deviation & Student obtaining less than 40 marks
in more than one subject is under Failure and that is
Out of Specification for paper checker.
Example 2 :
 My recently purchased centrifuge sets to run at 1000 ±
2 RPM.
 Yesterday it runs at 1030 RPM instead of 1000 RPM. –
Deviation
 Today my centrifuge starts but it doesn’t run…. –
Failure
 During calibration using tachometer I noted it runs on

16. Examples of Deviations
 Process Deviation :
In the process if someone adds Potable water instead of
W.F.I.
 Equipment deviations would include:
 A temperature setting spiking in a dryer
 Temperature profile curves not being followed in a
lyophilizer
 Pressures in a reaction vessel trending out of a normal
setting
Examples of Incidents
 An unexpected chemical release that requires a
report to the EPA.
 An equipment incident such as a failure of a newly

17. Future of the
Deviation, Batch
failure, Incident, OOS
CAPA
Corrective and Preventive action
CI
Continuous improvement
Quality

18. Change Control
• It is essential to maintain interrelationship between
quality, safety and efficacy. So that all changes are
evaluated before being introduced.
• It is intended that not only any changes to the way of
producing or analyzing the product should be covered
by the Change Control System (CCS), but also this
should also cover the changes to for examples
Buildings and Equipment, Utilities, Supplier of starting
materials, Document, Process, etc.
• It is a planned activity to bring about for better GMP
compliances.

19. Cont….
 It can be for shorter period of time or it can be
permanent. It must be intimated to all the concern
departments for official approval of Change Control.
“ Changes in any part of the quality system should not
be confused with DEVIATIONS .”

20. Governing Authorities
A. EC Guide to Good Manufacturing Practice, Chapter 5
(5.15)
B. 21 CFR 211.192 and Multiple Other Provisions within
211
C. ICHQ7A, GMPs for Active Pharmaceutical Ingredients
D. United States V. Barr Laboratories, Inc. 1993
Described Requirements for Investigations
E. Governing Authority, EU Commission Directive
2003/94EC (replaces 91/356/EEC)

21.  EC Guide to Good Manufacturing Practice, Chapter
5
“Any deviations from instructions or procedures
should be avoided as far as possible. If a deviation
occurs, it should be approved in writing by a
competent person…”
 21 CFR 211.192 and Multiple Other Provisions within
211
“Any unexplained discrepancy…shall be
thoroughly investigated…The investigation shall
extend to other batches …that can have been
associated with the specific failure or discrepancy.
A written record of the investigation shall be made

22.  ICHQ7A, GMPs for Active Pharmaceutical Ingredients
“Any deviation from established procedures should
be documented and explained. Critical deviations
should be investigated, and the investigation and its
conclusions should be documented.”
“All deviation, investigation and OOS reports should
be reviewed as part of the batch record review before
the batch is released.”
 United States V. Barr Laboratories, Inc. 1993
Described Requirements for Investigations
Specifies Content of Failure Report;
Requires Listing and Evaluation of Lots Potentially
Affected;
Elements of “Thoroughness” Vary Depending on

23.  The pharmaceutical industry did not hear much about the enforcement of this
paragraph, or the term out-of-specification, prior to the early 1990s. Then, Barr
Laboratories decided to sue the FDA because its founder, Edward Cohen, believed
it was not being treated fairly due to its part in what is often called the “Generic
Scandal.” The FDA saw this as an opportunity to air some of its frustrations and
bring legal weight to its regulatory actions through a judicial decision and
countersued. The two issues were settled in one trial that ended in 1993.
 One of the issues was how Barr Laboratories — and the industry as a whole—
handled initial test results that were outside of predefined limits (OOS
observations). At the beginning of the trial, the FDA’s position was that when the
laboratory gets a test result that is outside of product specification, the batch fails
and should be rejected immediately. Barr Laboratories took the position that the
possibility that the observation was the result of a laboratory makes it appropriate to
investigate in order to confirm or refute the original value.
 During the proceedings, Judge Alfred M. Wolin stated, “An out-of-specification
result does not constitute a failure.” His written decision states, “An out-of-
specification result identified as a laboratory error by a failure investigation
or an outlier test, or overcome by retesting is not a failure. Thus, the Court is
unwilling to adopt the government’s view of failure.”3
 OOS suddenly became a permanent part of the pharmaceutical industry lexicon.
Although Wolin’s decision supported Barr’s view that it is appropriate to challenge
an OOS observation with an investigation, he was critical of the firm’s investigation
process. The FDA began to scrutinize how firms handled OOS observations. (For

24. Change can be…
Major Changes
• Addition or deletion of a step or addition of an
alternative/new
step in the formulation manufacturing process.
• Addition of a new manufacturing site with modification
of the formulation manufacturing process described
in the original dossier/document.
• Change in input quantities of formulation
manufacturing process.
• Changes in the quality of raw material(s) or key
intermediate(s) used in the formulation manufacturing
process.

25. Cont….
Minor Changes
• Change in the administrative references
(name/company name, address) of the certificate
holder.
• Change in the references (name/company
name, address) of the manufacturing site.
• Change in the specifications of the substance.
• Change in supplier of starting and packing material.
• Change in the batch size.
• Change in the documents like SOPs etc.

26. Consequences of
Unapproved/Unappointed Change
 Detected at receipt/ inspection/testing of incoming
component / material by the customer.
 Worst Case: unapproved changes to
component/material causes final product failure in the
field.
 Result in lack of quality
 Customer may recall product
 Wastage of time and resources
 Miss the great chance of improvement

27. Scope of Change Control
– Raw materials suppliers
– Raw material suppliers’ processes
– Raw materials
– Sub-contractors
– Facilities/Utilities
– Manufacturing sites
– Manufacturing processes
– Packaging Processes
– Components’ documentation
(specifications, filings, drawings, etc.)
– Computer hardware/software packages affecting
product

28. Scope touches multiple disciplines
– Formula Development
– Design Engineering
– Process Engineering
– Regulatory
– Quality Assurance
– IT
– Operations
– Laboratory
– Purchasing

29. Responsibility
– It is the Responsibility of the system owner together wit the end-
user
– There is No universal procedure & more than one procedure may
Role Responsible
Department Description/Responsibility
be appropriate
Change Quality Assurance. Receives and validates Change Control
Control Production, Quality Requests from the Originator of the
Team Control, Engineering Change Control request
Dept., Management Ensures the Change Control Plan is
system followed, and that all Change Control
administration task are completed
Ensures all change control requests are
impact assesses (instructs the Impact
Assessor).
Originator Concerned person or The person who originates the change
Department request.
Representative
Assessor Quality Assurance & The person who is responsible for the
Quality Control impact analysis of the Change Request.
The person who is responsible for
Modifier Process owner & ensuring approved changes are included.
Quality Assurance The Modifier must inform Change Control
team when the change is complete.
Has final decision making authority if the
Approver Quality Assurance Change Control board cannot reach a
consensus.

30. Procedure for Change
1) Raising a Change Control
 The client or individual initiates change by making a
formal request for something to be changed.
 The change control team then records and
categorizes that request. This categorization would
include estimates of importance, impact, and
complexity.

31. Cont….
2) Assessment of the proposed Change
 The impact assessor or assessors then make their
risk analysis typically by answering a set of
questions concerning risk, both to the business and
to the process, and follow this by making a judgment
on who should carry out the change.
 If the change requires more than one type of
assessment, the head of the change control team will
consolidate these.
 Everyone with a stake in the change then must meet
to determine whether there is a business or technical
justification for the change. The change is then sent
to the delivery team for planning.

32. Cont….
3) Change Approval /Action Plan
 If Change Control Team agreed.
 Applicant/Change requester will seek approval and
request a time and date to carry out the
implementation phase.
 Responsibility of Quality Assurance
Note : All Change Control team members must agree to
a time, date and cost of implementation.

33. Cont….
4) Change implementation/Action Plan
 After getting approval from Quality Assurance
department usually one with the specific role of
carrying out this particular type of change.
 The team's first job is to plan the change in detail as
well as construct a regression plan in case the
change needs to be backed out.
Following implementation, it is usual to carry out a post-
implementation review which would take place at
another stakeholder meeting.

34. Exit Criteria
 COMPLETE:
The Change Request and associated impact has
been approved and implemented
 REJECTED:
The Change Request has been rejected by the CCB.
 CANCELLED:
The Change Request has been cancelled by the
Approver or the Originator.
 APPROVAL:
The approval of the control change can be done
finally with signature of the members of the change
control team.

35. Policy, Design, and Functional Operational Use and Sustaining Effort Performance, Test & Evaluation, etc.
Requirement Requirement Requirement
Change Proposal Change Proposal Change Proposal
Change Control Board
Evaluation of Change Impact:
• Affects on Yes Development of a
Is the
Performance, Effectiveness, Life-Cycle
Change Change
Costs, etc.
Feasible?
Implementation Plan
• Proposed incorporation date, ensuing
affected requirements, etc.
• Resources required to implement the No
change
• Cost of implementing the change No Further Action
Etc.
Return to
Develop Change Incorporate
Yes
Procedures Continuing
Approved Change Is Change
Operational
Adequate?
Status
Update Documentation Dispose Residue
No
and Database
Redesign
Required

36. Benefits of Change management
 Movement in a New direction – New opportunities. Try
not to do the same old things over and over, you will
get the same results.
 Small changes helps to the bigger changes that are to
come
 Reduce the time required for NDA, INDA.
 More robust impact analysis is possible
 Improved time to market
 More reliable trend analysis
 Ease in adherence to quality system.

37. Selected References
 Proposed US FDA Rule, cGMP: Amendment of Certain
Requirements for Finished Pharmaceuticals (Federal Register
61(87) 3 May 1996, page 20104)
 US FDA Guide to Inspection of Quality Systems
 Investigating OOS Test Results for Pharmaceutical Production
(FDA, draft 9/1998)
 US Department of Energy Guideline, Root Cause Analysis
Guidance Document, February 1992
 US FDA Compliance Program Guidance Manual, 7356.002
37

38. Change always comes bearing gifts. - Price Pritchett
Hardik Mistry