Topic 3: Apply
(1) good documentation practice and
(2) records keeping
APH3011
Current Good Manufacturing
Practice & Process Improvement
(cGMPP)
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Topic 3 – Part 2
learning objectives
1. Need for procedure documentation – SOP (is a very important
documentation in cGMP)
2. A typical appropriate format of SOP
3. consequences of failure to follow standard operating procedure
(SOP).
4. Deviation in Processes affecting SOPs
5. Change control management
•
changes and improvement in SOP which is affected by cGMP QMS processes.
2
What is procedure? E.g. SOP
Type 1 of documentation - instructions (directions, requirements)
• Regulatory Agencies require written
(1) Quality Policy
procedures for all systems and
operations which impact the quality
(1) Quality Manual/ Site
and safety (ISPE) of pharmaceutical
Master file – SMF/ QM
products.
(1) Procedures (SOP)
• Standard Operating Procedures
(SOPs) provide the main forum for the
(1) Work Instructions/ work
procedures, Forms, protocol,
documentation of a company's
master formulae, etc., (WI / WP)
systems and operations.
(2) – Records/ Reports
• are therefore the most popular
documents audited by Regulatory
Agencies during GMP inspections.
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How do you know what SOP is required to
established? In your plant?
• Check against cGMP (PICs) requirements/ ICH or WHO
guidance or any regulatory requirements.
• Mandate by law for processing nuclear/ biological
agents and toxins materials (e.g. MOH BATA)
• (Critical) Process/ equipment and facilities that affects
ISPE if not controlled.
• Operation of Equipment/ Instruments which impacts to
test and inspection results.
APH3011 – cGMPP
Where you
manufacture?
What you
manufacture?
Where you sell?
written policies, procedures, protocols
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Validation and qualification of processes, equipment and systems;
Equipment assembly and calibration;
Technology transfer;
Maintenance, cleaning and sanitation;
Personnel matters including signature lists, training in GMP and technical matters, clothing and
hygiene and verification of the effectiveness of training;
Environmental monitoring;
Pest control;
Records of each key process has
Complaints;
to be maintained. To discuss in
Recalls;
topic 3-2
Returns;
Change control;
Investigations into deviations and non-conformances;
Internal quality/GMP compliance audits;
Summaries of records where appropriate (e.g. product quality review);
Supplier audits.
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In general for cGMP and some healthcare gmp codes
(A)Technical & Analysis SOPs
-
Usually such critical “Work Process” requires,
verification/ validation to formalise into SOP ensuring
repeatable, reproducible, consistency and accurate as
they affect product quality/ patient safety.
APH3011 – cGMPP
(B) QMS (procedural)
“Management” SOPs
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QMS (procedural) “Management”
CATEGORY
Such SOP can range from
• Document and Record Control explain exactly which types of SOPs
exist, what the outline is of each type of SOP and how the SOPs
must be written.
• Change Control
• to performing management review.
• Contract agreements
• Training and Administration
• Purchasing and inventory Management
• Internal Auditing, Supplier Auditing
• CAPA, Complaints handling & Recalls
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“TECHNICAL” (SOP)
CATEGORY PROCEDURES
1.
2.
3.
4.
5.
6.
Clear operating procedures should be available for
key processes and major items of manufacturing
and test equipment.
Receipt of materials: for the receipt of each delivery of each starting
material, (including bulk, intermediate or finished goods), primary,
secondary and printed packaging materials
Production methods and process preparation, operations and
monitoring, maintenance and cleaning.
Internal labelling, quarantine and storage of starting materials, packaging
materials and other materials, as appropriate.
Sampling, which include the methods and equipment to be used, the
amounts to be taken and any precautions to be observed to avoid
contamination of the material or any deterioration in its quality
Testing materials and products at different stages of manufacture,
describing the methods and equipment to be used.
release and rejection procedures should be available for materials and
products, and in particular for the certification for sale of the finished
product by the Authorised Person(s).
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Records of each key process has
to be maintained.
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What are the Components in an SOP?
format
No ONE right
of an SOP, a good SOP generally
contain the following Components
1.
2.
3.
4.
5.
6.
7.
8.
Objectives
Scope
Responsibilities
Procedures
Materials/ Equipment
Records
Associated documents or References
Appendices (if any)
APH3011 – cGMPP
should
Some examples of SOP/ procedures/ protocol document section
heading descriptions
1. Title: or name of the process / activity detailed by the SOP
2. Scope: The departments where the current SOP is applicable
3. Objectives: Overall objectives / purpose of the SOP
4. Procedures: Detailed procedures of the process / activity
5. Materials: All materials (chemicals / raw materials / packaging material) required to
complete the procedures
6. Equipment: All equipment required to complete the procedures (Note: can be
combined with Materials section to form “Materials and Equipment” section.
7. Records: Specify all records and forms that have to be completed as a result of
performing the tasks.
8. Associated documents: Cross reference to all documents related to the tasks. E.g.
MSDS, equipment datasheet, other SOPs, work instructions
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Not following / (Deviation from) – SOPs
<Examples>
• Use of non-approved SOP
• Use of pre-dated, out-dated or backdated SOP and
forms
• Changes in Technical SOP not validated/ qualified
before use.
• Omits essential manufacturing processes
• Alters procedures without being reviewed
approved.
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Deviations from cGMP
• Products
– Mix-ups
– Contamination/ Cross-contamination
– Poor handling and improper storage
– Loss / Lack of traceability
– Poor documentation
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Deviations from cGMP
• Production equipment
– Major equipment is not tagged or labelled
– Lack of status for equipment or not reflected in a
centralized equipment log
– Cleanliness of equipment is not checked prior to
production
– Major equipment or parts changed without proper
change control
– Equipment is not duly calibrated or maintained
– Poorly maintained equipment log
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Deviations from cGMP
• Environment
– Environment condition not maintained to specifications (e.g..
Particle count, temperature, etc.)
– Environment monitoring and control equipment not duly
calibrated and/or maintained
– Poorly maintained cleaning log
– Waste material is not disposed of in a timely and hygienic
manner
– Environmental cleaning is not being performed according to
pre-determined schedule and/or methods
– Improper gowning/de-gowning
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What is DEVIATION?
Why is it important to follow SOP?
Baxter Heparin 2008
http://nolan-law.com/practice-areas/pharmaceuticals/baxter-heparin-contamination/
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Consequences of failure to follow
standard operating procedure (SOP)
• Increase the chance of mix-up and errors in the manufacture of
products.
• Prone to mistakes
• Impact on quality and safety of products manufactured as increased
risk of having inconsistent quality of company’s product.
• Production outcome different from expected thus affects
production schedule, wastage of resources .
• and causing hazards to working environment and personnel.
These Deviation from SOP Increase risk of non-compliance with
the cGMP requirements. – DEVIATION to requirements which may lead
to …. Patient’s risk due to inadequate safety, quality or efficacy.
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Follow Up Actions to Deviations
 Alert relevant personnel (and QA) if a deviation may / can affect
the process
 Record any deviation and action taken to correct deviation
 Carry out investigation through CAPA
We will discuss CAPA in topic 7-2
One of the most critical importance of Good Manufacturing Practice is that
People can admit a mistake at once without fears of being reprisal.
This will ensure that any mistake can be identified and damage that could result are kept
to a minimum.
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CHANGE
CONTROL
cGMPP APH 3011
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PIC(s) Part II Chapter 13
SOP needed!
Changes activity be
tracked by e.g. change
request/notification
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Deviation & Change Control
Reference: WHO conference workshop 2009 Nanjing China

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Is it
different
from
deviation?
Are changes
allowed?
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START
Typical Change Control Process
Initiate Change Request and fill up Change
Control Request Form (CCF):
• New / change,
• rational,
• preliminary impact assessment,
• implementation plan
Submit to
supervisor who
will do initial
impact
assessment
CCB will:
• Perform detail impact assessment (Regulatory, EHS,
product efficacy & stability, quality, impact on
downstream processing )
• Decide change classification
• Decide extent of validation
• Decide implementation & validation schedule
CCB
approves?
Yes
Pass
Validation
•
•
Submit to QA who will:
• Record in Change
Control Log (track
change number)
Update various document
Perform training
Fail - report CCB for discussion
Write and submit
Change Control
Report to CCB
CCB
approves?
No
QA logs it down
Change number
Close Out
Change
Request
Case
closed
Yes
Forms the CCB:
•
Subject Matter Experts (E.g.
Production, Engineering, R&D,
Purchasing, QC
•
QA (QP)
•
Other stakeholders
Implement
Change
No
Supervisor
approves?
QA logs it down
Change number
Yes
No
END
APH3011 – cGMPP
Please note that change control process flow may differs from organization
in accordance to cGMP requirements.
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Change Control CC/Request Form or Notice)
•
•
•
•
Current system (problem statement)
Proposed new/changes and rationale
Reasons and Justification
Impact of the changes
– Risk analysis
– Results and data
– impact assessment by various personnel
• Change Control Board decision
– Classification of changes
– Validation extent and schedule
CC Reference tracking or Change Control
number or Document changes DC References
Approved changes have the tracking reference indicated on
affected change history table on controlled document. E.g. SOP
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Application of Change Control
• cGMP processes:
Throughout cGMP if any
new or changes added affecting CPP & CQA
– Raw materials
– Process steps
– Production equipment
– Labelling and packaging
– Analytical test procedures
Self Directed learning Videos
https://www.youtube.com/watch?v=InICcEBF5QM
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Application of Change Control
Throughout cGMP
- CPP & affecting CQA
• Product/operation process related changes (e.g. CN - Change Notices)
– Raw materials, solvent and any ingredient or component in bill of
materials, process parameters, process control packaging materials
labels and introduction of new product
• Engineering Changes (e.g. ECN – Engineering Change Notices)
– Changes in facility design, equipment type, hardware, maintenance,
parameters, utilities.
• System Changes
– Software/Firmware or it’s configurations etc.
– Controlled documents (e.g. Document CN): Standard operating
procedures, Specification sheets, documentation forms and
templates
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Possible Causes of Changes
•
•
•
•
•
Updates from experiences from developmental or transfer phases.
Results of process monitoring or statistical process control.
Audit/Inspection findings.
Outcome of Continuous improvement processes (CIP)
Strategic considerations.
– Change of supplier of raw materials
– Product/Technology transfers
• Customer requests.
• Regulator requirements (legal changes, official requirements)
• Plant modifications to incorporate new processes or accommodate
increased production volumes.
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Change Control Classification
Major
Moderate
• Changes considered to
• Changes considered to
have a substantial
have a moderate
potential to have an
potential to have an
adverse effect on
adverse effect on the
“Quality” ISPE of a drug.
“Quality” ISPE of a drug
• Notification to agency is
required.
Minor
Changes considered to have a
minimal potential to have an
adverse effect on the “Quality”
ISPE drug.
EXAMPLES
•
•
•
•
•
•
A move to a different
manufacturing site
Changes in sterilization method
Changes to processing steps
Changes in source material
Adding a new product
Resignation and new
appointment of Qualified
person
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•
•
A move to a different
manufacturing site using preapproved test procedures
Replacement of equipment
with a different design that
does not affect process
methodology or process
parameters
•
•
•
•
•
•
Change / substitution of equipment
part
A move to a different site for
labelling
Tightening of acceptance criteria
Change in packing style or
secondary packing materials
Format of labels, deletion of
products
Packing of batch size
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Thanks that’s end of Part 2 for topic 3-1.
Before we proceed to Topic 3-2 Records
Please reflect what have we learnt
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Self check Questions (1)
• In a typical SOP template, what will be the section
headings providing clarity to the reader?
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Self check Questions (2)
Which of the following statement is not
consider as deviation in cGMP.
A.
B.
C.
D.
Use of pre-dated SOP.
Raise change request for a Technical SOP and plan for
pre-implementation validation and training after
change approval.
Omits essential manufacturing processes in approve
SOP.
Alters SOP without being approved by QA.
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Self check Questions (3) case study
Watch this (25mins) video “You’ll Soon
Feel Better” and identify the deviations
from all 3 scenes.
This is a remake of classic training video “You’ll Soon Feel Better” was produced for the
Association of British Pharmaceutical Industries (ABPI) in 1987 to highlight what can
happen when GMPs are not followed.
Scene 1
Scene 2
Scene 3
Review the video : https://www.youtube.com/watch?v=e5hg9cieiEQ
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Self check Questions (4)
4a) What is CCB?
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Self check Questions (continue 4)
4b) Who should be members of CCB?
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Self check Questions (4 continue)
4c) What will be the steps after changes
has been approved by CCB?
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Self check Questions (5)
Major / Moderate / Minor?
a) Changing the supplier of a certain cell culture media
component.
b) Changing the pH set point of production bioreactor from
7.2 to 7.15.
c) Changing the make and model of a conductivity probe
used in monitoring buffer preparation.
d) Using a different template of datasheet to record inprocess control data.
e) Version update of a software used in electronic
documentation management.
f) Introducing an additional step in personnel gowning
procedure.
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Self direction learning – Do it yourself!
Checklist
Check you have understood the Learning Objectives of the
topics
Study tutorial questions.
Check out PIC(s) 1 Chapter 4 & PIC(s) II Chapter 6,
requirements of handling deviation is stated throughout
PICS part 1 & II
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