“Evolving Critical Documents – Part 3”

Session – 5
(90 minutes)

Organized by:
Pharma Institute of GMPs

9/5/2019 1
 Points Covered
 What is a Change Control?
 Developing SOP for Change Control
 Regulatory & GMP linkages
 Examples
 Exercise!!

9/5/2019 2
Management of Change Control
 Do not misunderstand !
 The Requirements have always been there,

 It is just that "Change Control"

is now a

CENTER STAGE
(Source: PIGMP)

9/5/2019 3
Management of Change Control
 Q1 Change Control System : What it is?
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 Managing to control a change in a
process/procedure/system through proper and
scientific justification, review, approval,
implementation, follow-up and closure
 Q2 What is the objective of Change Control
System ?
 To provide mechanism for on-going process
optimization / system improvement and ensure a
continuing state of process control
9/5/2019
(Source: PIGMP) 4
Management of Change Control
 Q3 What types of changes can be covered?
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 Proposed changes to :
 Processing Steps
 Specifications & Test Procedures
 Facilities and equipment
 Support Systems (Includes computer hardware and
software)
 Key / starting materials (includes vendor)
 Packaging materials / configuration
9/5/2019 (Source: PIGMP) 5
 Purpose of Change Control
 Q4 What is the purpose of the Change Control
Program?
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 To prevent unauthorized modifications to a validated
system,
 To evaluate proposed changes against development and
technology transfer documents,
 To identify and evaluate all proposed changes to assess
their potential effects on the manufacturing process,
and
 To determine if, and to what extent, revalidation is
needed
9/5/2019 (Source: PIGMP) 6
 Purpose of Change Control
 Q4 continued…..
------------------------------------------------------------------
 To ensure that all documents affected by changes
are promptly revised and,
 To determine the impact of changes on the
critical chemical, physical and microbiological
attributes of the product, such as :
- assay, impurity profile, stability, and physical
characteristics
(Source: PIGMP)

9/5/2019 7
 Purpose of Change Control
 Q5 What could be the probable effect of
changes to improve process yields?
------------------------------------------------------------------
 Such proposed changes should be evaluated
carefully to determine if they result in new or
higher levels of impurities/degradation products
- The impurity / degradation profile of resulting
batches should be comparable
(Source: PIGMP)

9/5/2019 8
 Purpose of Change Control
 Q6 Could process changes affect analytical
methods?
------------------------------------------------------------------
 Yes ! Process changes should also be evaluated to
ensure that these do not have an adverse affect on
analytical methods
 The effect is due to increased interference caused by
new or higher levels of impurities / degradation
products and by-products
 Analytical methods should be modified as necessary to
ensure that they are capable of detecting and
quantifying impurities / degradation products
9/5/2019 (Source: PIGMP) 9
 Purpose of Change Control
 Q7 What follow-up is required after changes to
manufacturing process are implemented?
------------------------------------------------------------------
 In case, the manufacturing process changes affect
the critical attributes of the API,
1. Notify dosage form manufacturers,
2. Notify Regulatory bodies, if mfg process is
filed,
3. Revalidation (where required),
4. Prompt revision of other documents affected,
(Source: PIGMP)

9/5/2019 10
 Purpose of Change Control
 Q7 continued……
------------------------------------------------------------------

5. Careful evaluation of the first few batches

produced/tested under the change,

6. Generate data on stability profile, impurity

profile, crystal form, particle size, residual
solvents, etc.
(Source: PIGMP)

9/5/2019 11
 Purpose of Change Control
 Q8 Do we have guidelines to classify or categorize
Changes?
------------------------------------------------------------------
There are no clear guidelines !
a) The change control program should provide for a
classification scheme to evaluate changes in :
- Raw Materials, Intermediates, Packing Materials
- Manufacturing Sites
- Scale of Manufacturing
- Manufacturing Equipment
- Production processes
- Specifications-STPs
- Editorial changes (Source: PIGMP)
9/5/2019 12
 Purpose of Change Control
 Q8 continued…….
------------------------------------------------------------------
b) The classification procedure should be used to
determine what level of:
- testing,
- validation, and
- documentation
is needed to justify changes to a validated process
(Source: PIGMP)

9/5/2019 13
 Purpose of Change Control
 Q9 How do we, therefore, categorize
changes?
------------------------------------------------------------------
 We can categorize into Minor, Moderate or Major,
depending on the nature and extent of the changes,
and the effects that these Changes could impart on
the process/product

 Scientific judgment should determine what

additional testing and validation studies are needed
to justify a change in a validated process
9/5/2019 (Source: PIGMP) 14
 Purpose of Change Control
 Q10 What is a Minor Change?
------------------------------------------------------------------
MINOR CHANGE is that change which :
* Is unlikely to have a detectable impact on the critical
attributes of the API / Drug Product
* Does not shift the process in any discernible manner
* Can be implemented with minimal testing and
revalidation
* Can be reviewed and approved by QA at the facility level
* Is reported in Annual Reports and does not require FDA
approval
(Source: PIGMP)
9/5/2019 15
 Purpose of Change Control
 Q10 continued…..
------------------------------------------------------------------
 Few examples of MINOR CHANGES :
a. Like-for-Like equipment replacements,
b. Non-critical process parameters,
c. Revision of specifications (non-critical attributes) as per
Process capability,
d. Revised Quantity of reagents/excipients,
marginally,
e. Editorial changes
(Source: PIGMP)

9/5/2019 16
 Purpose of Change Control
 Q11 What is a MAJOR CHANGE?
-----------------------------------------------------------------
MAJOR CHANGE is that change which :

* Is likely to have a detectable impact on the critical

attributes of the API/drug product, significantly

• Could shift the process in a discernible manner

(quality, yield, stability, impurity/degradation
profile, crystal form, particle size)
(Source: PIGMP)
9/5/2019 17
 Purpose of Change Control
 Q11 continued…… MAJOR CHANGE
------------------------------------------------------------------

* Warrants definite additional/major testing

and suitable revalidation studies to justify
changes,
* Reviewed by QA at the facility level and
approved by Corporate Groups, and
* Requires prior FDA approval
(Source: PIGMP)

9/5/2019 18
 Purpose of Change Control
 Q11 continued…… MAJOR CHANGE
------------------------------------------------------------------
* Few examples of MAJOR CHANGES:
 Change in type of solvent used for final
crystallization (affects impurity profile, physical
attributes and other CQAs of API),

 Replacement of equipment with different kind (not

like-to-like)
(Source: PIGMP)

9/5/2019 19
 Purpose of Change Control
 Q11 continued….. MAJOR CHANGE
------------------------------------------------------------

 Change in Critical Process Parameter(s),

 Revision of Critical Quality Parameter
(specification), such as Assay limit, Related
Substances limit

(Source: PIGMP)

9/5/2019 20
 Purpose of Change Control
 More Examples of Major Changes:
--------------------------------------------------------------
 Revision of STP for Assay (potentiometric to
HPLC), for Related Substances (TLC to HPLC),
for Residual Solvents (GC to Head Space)
- Change in facility (site of manufacturing),
- Change in route of synthesis for API,
- Change of key RM/excipient source,
- Change in sequence of operations
(Source: PIGMP)

9/5/2019 21
 Purpose of Change Control
 Q12 What is a MODERATE CHANGE?
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 MODERATE CHANGE is that change which:
 Is usually for Improvements to process, materials,
product or procedure;
Therefore, no reason to wait!
 Does not require prior approval by the Regulatory
/ FDA before implementation,
 The Agency will want to review it!
 Can go in Annual Reports to FDA
(Source: PIGMP)
9/5/2019 22
 Purpose of Change Control
 MODERATE CHANGES:
------------------------------------------------------------------

 Can be evaluated by QA at the facility*

These are called

"CHANGES BEING EFFECTED“

(Source: PIGMP)

9/5/2019 23
 Purpose of Change Control
 MODERATE CHANGES:
------------------------------------------------------------------

 Few examples of Moderate Changes include:

- Improvements in yield,
- Improvements in CQAs,
- Improvements in Process capability/efficiency,
- Cost-effectiveness
(Source: PIGMP)

9/5/2019 24
 Status of Change Control
 Q13 Explain STATUS of Change
Control Management!
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a) MATERIALS: (Change of Vendor, MOC,
Configuration, Dimension)
* Do not happen - Mostly Unreported?
b) EQUIPMENT:
* Most obvious changes are reported
* However, maintenance changes – Mostly
unreported !!
(Source: PIGMP)
9/5/2019 25
 Status of Change Control
 Q13 continued…
----------------------------------------------------
c) PROCEDURES:
* Usually well documented and controlled
* However, not well communicated

(Source: PIGMP)
9/5/2019 26
 Status of Change Control
 Q13 continued…
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d) ANALYTICAL TEST METHODS:
* Usually well documented and controlled,
* Because changes come from pharmacopoeia or
corporate/higher authority,
* Prompt thorough notification,
* Affects a small group only
(Source: PIGMP)

9/5/2019 27
Management of Change Control

Make No Mistake!
Change Control Is No Easy Task!

It Is Fraught With Peril!

It Must However Be Done!
----------------------------------------------
You Are Your Change Agent
(Source: PIGMP)
9/5/2019 28
 THANKS!
For inquiries please contact –
Sumant Baukhandi, PhD

Director - Pharma Institute of GMPs

Director - pharmaACCESS

7, Phase-1, Vasant Vihar,

Dehradun-246 006
Uttarakhand State (India)
Landphone: 91-135 276 3092
Cellphone: 91- 99970 10901
Email ID: [email protected]; [email protected]
Website: www.pigmp.com

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