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What is 21 CFR Part 11
21 CFR Part 11:
 Allow the industry to use electronic records and signatures
alternatively to paper records and handwritten signatures
21 CFR Part 11 applies:
 To all FDA regulated environments
 When using computers in the creation, modification, archiving,
retrieval or transmission of data or records
 To records required by predicate rules - GLP. GCP. GMP – that
impact patient safety
 To new and old systems
21CFR
FDA, Code of Federal Regulations
21CFR Part ELECTRONIC RECORDS; ELECTRONIC,
11
SIGNATURES
21CFR58
GLP
21CFR210 GMP, Drugs (General)
21CFR211 GMP. Drugs (Finished Pharmaceuticals)
21CFR312 Inv. New drug Application (GCP)
21CFR314 FDA Approval of new drug (GCP)
21CFR6xx GMP. Biologics
21CFR820 GMP. Devices
21CFR
Food, nutrients and cosmetics
ALCOA++
ALCOA stands for Attributable, Legible, Contemporaneous,
Original and Accurate. ALCOA was then expanded to ALCOA Plus (ALCOA+),
by the addition of a few more concepts which are, Complete, Consistent,
Enduring, Available and Traceability.
The concept of ALCOA++ ensuring that data security and integrity
(data protection) are observed and maintained. ALCOA Plus has been implemented
and is in use by various big bodies, such as the FDA, WHO, and
GMP. ALCOA is all about data quality.
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ALCOA++
SUMMARY OF ALCOA++
Attributable – Record who wrote it and when with sign/date
Legible - Data should be readable after it is recorded
Contemporaneous - Record the data at the time it was generated (online)
Original - The data original should be preserved
Accurate - Data reflect its actual value / trueness, free from error
Available - Available for review at any time
Enduring - Making sure records exist for the entire period
Complete - Data in complete state to avoid recreation/ manipulation
Consistent - Data in sequential manner with a sign and date. Follow GDP
for consistency in documentation.
Traceability – Easy to traceable any type data.
What is Data integrity ?
Data may be generated by a paper-based record of a manual observation, or in
terms of electronic based record of equipment or instrument.
What is Data integrity
Data integrity refers to the completeness, consistency and accuracy of data.
OR
Data integrity is a concept and process that ensures the accuracy, completeness,
consistency, and validity of an organization's data. By following the process,
organizations not only ensure the integrity of the data but guarantee they have
accurate and correct data in their database.
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What is change control?
Change refers to any modification in equipment, manufacturing materials,
facilities, utilities, design, formulations, Processes, packaging/labelling,
computer system and all associated documentation
(SOP, s quality manual, etc.)
Types of change control
CHANGE CONTROL
Permanent
Change
Temporary
Change
Classify in 3 categories
Minor

Moderate
Major
Temporary Change Control
When we are making any temporary changes in some operation, procedure,
manufacturing facility, system, etc for certain period of time, after that it will
restored to its original condition.
This type of changes are handled through temporary change control.
• Example: In powder processing area pulverizer is not working, so in place
of pulverizer we are temporarily using multimill till pulverizer gets in
working condition.
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 Permanent Change Control
When we are making any permanent changes in some operation,
procedure, manufacturing facility, system, etc. for forever.
This type of changes are handled through permanent change control.
• Example: When we will upgrade system by installing auto system in
place of manually operated system, such type of changes are called as
permanent change.
Change Control classify in 3 categories
 Minor
 Moderate
 Major

 MINOR CHANGE CONTROL
•
•
•
•
•
•
•
Unlikely to have impact on the SISPQ [Safety, Identity,
Strength, Purity and Quality] of product.
Unlikely to have impact on the Quality or process
attributes of the product.
Does not alter process significantly.
May require minimum testing and revalidation
if applicable.
Has no impact on regulatory filings.
Is improvement in procedure.
 EXAMPLES OF MINOR CHANGE CONTROL
• Changes in the SOP's or any QMS document for merging
• of content, deletion of repetitive instructions, alignment
• changes, typographical error correction with supporting data.
• Change in secondary packing material without affecting
identification.
• Change in Qualification/ validation documentation due to
parameter supported by validation.
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 MODERATE CHANGE CONTROLS
• These change controls are usually taken for improvements
to process, product, materials or system.
• May have an impact on the quality or process attributes of
the product, however proper evaluation is necessary for
implementing these changes.
• May not affect regulatory status of the product.
 EXAMPLES OF MODERATE CHANGE CONTROL
• Transfer of fixed manufacturing equipment from one line to
other line.
• Change in source of any excipient which may have impact on
the final quality requirement of the material.
• Change in Qualification / validation documentation due to
revision of guidance or harmonization practices.
 MAJOR CHANGE CONTROLS
SISPQ [Safety, Identity, Strength, Purity and Quality]. Requires
definite
additional / major tastings and suitable revalidation
studies to justify the change.
• These changes are likely to have an impact on the critical
attributes of the process, procedure or product.
• Major changes could shift the process significantly,
affecting the quality yield, stability, impurity profile etc.
• May affect the regulatory status of the product / process.
• May affect the facility or system.
 EXAMPLES OF MAJOR CHANGES
• Relaxing acceptance criteria or deleting a test for raw
material or drug product.
• Change in primary packing material.
• Change in test methods having impact on previous
method validation.
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Change Control Working on ICH Q7 section 13
• A formal change control system should be established to
evaluate all changes that could affect the production and
control of the intermediate or API. (13.10)
• Written procedures should provide for the identification,
documentation, appropriate review, and approval of changes
in raw materials, specifications, analytical methods, facilities,
support systems, equipment (including computer hardware),
processing steps, labeling and packaging materials, and computer
software. (13.11)
• Any proposals for GMP relevant changes should be drafted,
reviewed, and approved by the appropriate organizational
units and reviewed and approved by the quality unit(s). (13.12)
• When implementing approved changes, measures should
be taken to ensure that all documents affected by the
changes are revised. (13.14)
• After the change has been implemented, there should
be an evaluation of the first batches produced or tested under
the change. (13.15)
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What is Deviation?
Definition: Deviations are the measured differences between
Observed and expected or normal values for a product or process
Condition.
OR
Departure from a documented Standard or procedure
WHY DEVIATIONS OCCURS
 GMP Mistakes or Error
 V Performing an activity without proper training
 Failure to follow written SOPs or approved Batch record instructions
 V Reprocessing or Rework
 V Unapproved changes
Deviation
Planned Deviaon
Unplanned Deviaon
Classify in 3 categories
Minor
Critical
Major
Deviation is just like Iceberg. Visible part is near to 30% But about 70% part is
hidden under the water.
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Types of Deviation
• Planned Deviation
• Unplanned Deviation
 What is Planned Deviation?
Planned deviations, which are described, and pre-approved
deviation from the current operational document/system,
covering a specified period of time or number of batches.
• All changes should be evaluated for product impact,
significance
• The need for requalification or revalidation
• Changes ultimately approved or rejected by QA
• Examples:
 Calibration or validation is not carried out of any
Instrument of equipment as per schedule due to delay
for various reasons.
 Change in batch size of any product.
 Product release without complete microbial
results (under micro release)
 What is Unplanned Deviation?
Unplanned Deviations can be defined as any uncontrolled
event in the form of the designed system or procedure
at any stage of manufacturing, packaging, testing, holding
and storage of drug product due to system.
• Examples:
• Any failure of utility (HVAC)
• Any failure of parameter (fluctuation in Rh or Temperature)
• Any Failure of equipment (sudden break down).
Deviation classify in 3 categories
 Minor
 Critical
 Major
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 MINOR DEVIATION
• When the deviation does not affect any quality attribute,
a critical process parameter, or an equipment or
instrument critical for process or control, it would
be categorized as Minor deviation.
• Such deviations treated as such by the applicable procedure.
Examples:
• Skip of FEFO principle.
• Inadequately trained personnel to perform cleaning activities.
• Minute error in art work
• Etc.
 CRITICAL DEVIATION
• When the deviation affects a quality attribute, a
Critical process parameter, an equipment or instrument
Critical for process or control, of which the impact to
Patients (or personnel or environment) is highly probable,
Including life threatening situation, the deviation is
Categorized as Critical deviation.
• Such deviations requiring immediate action,
Investigation, and documentation as such by the appropriate SOP.
Examples:
• Expired or rejected API component used.
• Sterilization of an aseptic filling process not available/performed.
 MAJOR DEVIATION
• When the deviation affects a quality attribute, a
Critical process parameter, an equipment or
Instrument critical for process or control, of which
The impact to patients (or personnel/environment)
Is unlikely, the deviation is categorized as Major Deviations.
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• Such deviations also requiring immediate action,
Investigation, and documentation as such by the appropriate SOP.
 What is incident ?
An Incident is an unplanned and unexpected event which
which may result in an injury or damage to the plant,
equipment, machinery, material or both or the consequences thereof.
Some examples of incidence:
• Eating food in the production area.
• Spillage of material on the floor.
• Break down in any machine during processing.
• The mix-ups of two batches.
• Wrong material added in batch etc.
EXAMPLE
DEFINIATION
DIFFERENCE BETWEEN INCIDENT & DEVIATION
Incident
Deviation
Any event that may or may
Departure from an approved
not affect our quality but that instruction or established
is against the CGMP
standard.
OR
Type of deviation
Operational event which is not
1.Planned Deviation
part of standard operation
2.Unplanned Deviation
(GAMP)
Someone is found without
gowning in the production
area
Any insect is found in
processing area.
Eating food in production
area.
Manufacturing instructions are
not followed.
wrong batch details are printed.
SOPs or methods of testing not
followed during analysis.
Spillage of material on floor. Inadequately trained personnel
to perform sterility tests.
Break down in any machine Gross misbehavior of staff in a
during processing.
critical aseptic process.
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Mix-up pf two batch etc.
Pressure differential out of
established limits in aseptic fill
areas.
Accident
Skip of FEFO principle (first
expired-first out) in raw
material handling.
Fire
Line clearance is not taken
from QA
OUT OF SPECIFICATION OUT OF TREND
OUT OF SPECIFICATION
Definitions: Results that falls outside predetermined specification.
OR
If the analytical results of a batch or material is falling out side of the
established specification ranges, is called Out of Specification.
Example- Specification: 90% to 110%. Results: 88.5%
OUT OF TREND
Out of trend: Result is not out of specification but show significant
variation from historical data.
OR
A result that does not follow the expected trend, either in comparison
with other stability batches or with respect to previous results collected
during a stability study.
Example- Specificatio:90% to 110%. Normal range - 97% to 103%.
Results: 91.5%
ICH GUIDELINES FOR STABILITY STUDIES
Q1A (R2)
Q1B
Q1C
Q1D
Q1E
Stability Testing of New Drug Substances and Products.
Stability Testing: Photostability Testing of New.
Drug Substances and Products.
- Stability Testing for New Dosage
Forms.
Bracketing and Matrixing Designs for
Stability.
Testing of New Drug Substances and
Products.
Evaluation of Stability Data.
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Q1F
Stability Data Package for Registration
Applications in Climatic Zones III and IV.
ICH QUALITY GUIDELINES
Q1A –
Q1F
Q2
Q3A Q3D
04 - Q4B
Q5A Q5E
Q6AQ6B
Q7
Q8
Stability
Analytical Validation
Impurities
Pharmacopoeias
Quality of Biotechnological Products
Specifications
Good Manufacturing Practice
Pharmaceutical Development
Q9
Quality Risk Management
Q10
Q11
Q12
Q13
Pharmaceutical Quality System
Development and Manufacture of Drug Substances
Lifecycle Managen
Continuous Manufacturing of Drug Substances and Drug
Products
Q14
Analytical process Development
IMP
IMPORTANT FULL FORMS
 CFR: - Code of federal regulations.
 USFDA: - United state food & drug administration.
 ICH: - International conference harmonization.
 MHRA: - Medical and Healthcare Products Regulatory
Agency
 FDA: - Food and Drug Administration
 DEA: - Drug Enforcement Administration
 ONDCP: - Office of National Drug Control Policy
 CDSCO : - Central Drugs Standard Control
Organization(India)
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CPP- Which is direct impact on attribute or quality of product. (ICH Q8)
Exp. Like Temperature of any sampling point
CQA- Critical Quality Attribute – Which is impact on physically,
chemically & biologically impacted. (ICH Q8)
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