GMP Fundamental.....

Good Manufacturing Practice
From Fundamentals to Applications
National Medicines and Poisons Board, Obaid Ali, R. Ph. Ph.D

Republic of Sudan June 2012
This communication constitutes an
informal communication that
represents the best judgment of the
speaker at this time but does not
constitute an advisory opinion and
also does not bind or otherwise
obligate or commit Agency, to the
views expressed.
Opening Message Material
Introduction Documentation
History and Background Complaints and Recalls
Premises Sanitation and Hygiene
Equipment Validation
Personnel API
Personnel API
Personnel API
What is GMP?
Ensures that products are consistently

produced and controlled
(State of Control)
Diminishes risks that cannot be controlled

by testing of products
e.g.
Contamination, Cross contamination
Mix-ups
GMP
Fundamental Principles of Quality Assurance
Quality, safety and effectiveness must be

designed and built into a finished drug
product;
Quality cannot be inspected or tested into

a finished drug product;
Each step of the manufacturing process

must be controlled to assure that the
finished drug product will meet its
specifications.
Why GMP
Pharmaceutical Manufacturers have the

responsibility of developing safe products
through the proper selection of
ingredients, product formulation and
manufacturing process.
To ensure identity, safety, strength,
quality and purity
To ensure traceability
GMP is good business practice , it provides
control, consistency and assurance about
the quality of the product.
GMP Scope
Pharmaceutical/
Biologicallyderived
products
Medical devices ………….
History and Complaints and Recalls

Background
Personnel API
GMP Scope
Already discussed by
Sultan Ghani Saheb
C in cGMP
C stands for current because the

interpretation is always
changing
(new details, dimension and

expectation are always added)
Basic Requirement for GMP
Facility design to control operations
Adequate documentation/records
Production and process controls
Quality control/assurance
Validation
Equipment calibrated/qualified
Personnel training & certification

Manufacturing processes are clearly

defined, validated and systematically
reviewed to ensure consistency and
compliance with specifications
Manufacturing processes are

controlled and changes to the
process that can impact on the
quality of the drug are validated
Instructions and procedures are written in

clear and unambiguous language
Operators are trained to carry out and

document procedures
Records are made, manually or by

instruments, during manufacture which
demonstrate that all the steps required by
the defined procedures and instructions
were in fact taken and that the quantity
and quality of the drug was as expected.
Deviations are investigated and
documented
Records of manufacture, including

distribution, which enable the complete
history of a batch to be traced are retained
in a comprehensible and accessible form
The distribution of the drugs minimizes

any risk to their quality
A system is available to recall any batch of

drug from sale or supply
Complaints about marketed drugs are

examined, the causes of quality defects
investigated and appropriate measures
taken in respect of the defective drugs and
to prevent re-occurrence
Personnel API
Premises
Premises must be located, designed,

constructed, adapted and maintained for
the operations:
Minimize risks of errors & cross-

contamination
Permit effective cleaning
Permit effective maintenance
Minimize build-up of dirt and dust
Eliminate any adverse effects on quality
Premises
Premises must be located, designed,

constructed, adapted and maintained for
the operations:
Minimize risks of errors & cross-

contamination
Permit effective cleaning
Permit effective maintenance
Minimize build-up of dirt and dust
Eliminate any adverse effects on quality
Premises
Principle
Premises must be located to

minimize risks of cross-
contamination.
Geography, climate, noise and economic factors
Neighbours
What do they do?
What impact can they have on the business?
Pollution/effluent control
Premises
Premises should be built to
Facilitate sanitation.
Be maintained and cleaned easily
Services availability
Protection against entry of insects or other
animals
Premises
Ancillary Areas
Rest and refreshment rooms
Changing, washing and toilet areas
Maintenance workshops
Animal houses
Premises
Design Principles
Process flow
Material flow
People flow
Premises
Warehouse
Storage areas of sufficient capacity for
Clean, dry and maintained within
acceptable temperature limits
Area under cover, protection from heat,
dirt, and rain
Areas clearly marked and access limited
for quarantine status good.
Premises
Warehouse
Storage areas of sufficient capacity for
QC sampling area with GMP standards

Segregated areas for rejected, recalled and
returned materials
Separate areas for highly active,
hazardous, narcotic materials
Printed materials storage
Premises
Weighing areas
Control systems
Environmental controls, dust control
Segregation
Smooth, impervious, durable, easy to

clean finishes
Cleaning and Documentation

Premises
Manufacturing and Packaging
Dedicated and self-contained facilities

for:
Logical flows of materials and people
Adequacy of working space & orderly

and logical positioning of equipment
Interior surfaces
smooth/crack-free/easy to clean
Premises
Other Areas
Personnel rest
areas/cafeterias/changing rooms:
away from operating areas
prevention of cross-contamination
prevention of operators going outside in
work clothes
provision of access control
prevention of visitors access to operating
areas
Premises
Other Areas
Maintenance service areas:
separated from production areas
whenever possible
Windows should not open to the

outside
Premises
Finish of Floors, Walls & Ceilings
Smooth, impervious, easy to clean
Resistant to operations and

materials in use
Windows not opening to the outside
Avoid sliding doors

Premises
Premises
Finish of Floors, Walls & Ceilings: Much better

Premises
Cross-contamination
1. Segregated areas
2. Airlocks and pressure differentials
3. Treatment of recirculated air
4. Protective clothing
5. Effective cleaning procedures
6. Closed production systems
7. Residue testing
8. Status labelling
Premises
Manufacturing and Packaging – I

Pipework and other fittings sited to avoid
recesses
Drain design:
equipped to prevent backflow
open channels avoided
Effective air handling to suit product

temperature
humidity
filtration
monitoring
Premises
Manufacturing and Packaging – II

Specifically designed and laid out to
avoid mix-ups and cross-
contamination
Changing facilities to provide segregated
access
Prevention of cross-contamination
Suitable lighting levels

Premises
In-Process and QC laboratories

Located separate from but near
manufacturing
prevention of cross-contamination
separate biological , microbiological,
radioisotopic areas
Designed for the operations

being carried out
suitable storage space
Personnel API
Equipment
Equipment
must be:
-located
-designed
-calibrated
-monitored
-maintained
to suit their intended use

Equipment
Equipment layout and design must

aim:
-to minimize risks of error
-to permit effective cleaning
-to permit effective maintenance
And to avoid:
-cross-contamination
-dust and dirt build-up
-any adverse effect on the quality of
products
Equipment must be installed to:
-minimize risks of error
-minimize risks of contamination
Equipment
Equipment:
Instrument Calibration
Frequency based on:
-Nature/type of equipment
-Type/frequency of use
-Importance of measurement
Written and approved procedures

documented
Equipment
Equipment: Monitoring
-Monitored for performance
-Ensure proper functioning
-documented
-Use log
-traceability
Equipment
Equipment: Maintenance
Preventative
Scheduled and based on SOPs &
usage
Corrective
Malfunction/breakdown
Documented
Maintain log books near equipment
and available
Equipment
Types of equipment maintenance

-Scheduled preventative maintenance
There must be a procedure (SOP) in place
for the frequency and extent of the
preventative maintenance
-Procedure should provide step-by-step

instructions on how to perform the
preventative maintenance.
Preventative maintenance must be

documented
Equipment
Types of equipment
maintenance
Non-scheduled maintenance
Performed as needed (in cases where
equipment malfunctions/breaks down)
Non-scheduled maintenance must

be documented
Equipment
Equipment:
Modifications/Changes
Corrective or planned (maintenance
or for improvement)
Evaluated (may require revalidation)
Approved
Documented
Effective date noted
Equipment
-Defective and unused equipment

are removed from production and
quality control areas or are at least
clearly labeled as such
-Equipment usage logs are

maintained
Equipment
Possible Issues
-Poor design
-Lack of safety
-Poor quality finishes
-Lack of cleaning
-Lack of maintenance
-No usage log or record
-Use of inappropriate weighing
equipment
-Open-plan location of
compressing machines
Personnel API
Personnel
GMP and Personnel

Each person… shall have
education, training, experience
or any combination thereof, to
enable that person to perform
the assigned function
Personnel
Personnel
85% of quality problems due to

management and systems
-Poor managers
-Lack of information/communication
-Unclear job responsibilities
-Lack of training of staff/inadequate
training
Personnel
Personnel
People are the most critical element
in ensuring the quality of the
product – and that the application of
Good Manufacturing Practices
Continuous training of personnel is

an essential function
-For knowledge of GMPs
-For knowledge of specific job duties
Personnel
Training
Company organization, policies, etc.
Job function
Review formal training written plan
-Short & long term schedule

-Standards of performance &
evaluation criteria
-development
Personnel
Maintenance
Ongoing performance evaluation

-Development
-Self evaluation
Records
-documented
Continuing education
Personnel
Regulatory Interpretation
5 interpretations
-Required qualifications of manufacturers,
packagers/labelers/testers in charge of
manufacturing and quality control
departments
-Required qualifications of those

responsible for packaging operations
-Required qualifications of those in QC

department of importers, distributors and
wholesalers
Personnel
Regulatory Interpretation
5 interpretations (cont’d)
-Adequate number of personnel with

necessary qualifications and practical
experience appropriate to their
responsibilities are available on site.
-All personnel are aware of principles of

GMPs that affect them and receive initial
and continuing training relevant to their
job responsibilities
Personnel
Possible Issues-I
-Limited number of staff

-Inadequate qualifications
-Inadequate experience
-Lack of means to develop training

materials
Personnel
Possible Issues-II
-Unclear organisation diagram

-Staff movement
-Inadequate training records
-Illness
Personnel API
Material
Principle
Objective of the pharmaceutical
manufacturer:
-To produce finished products from a
combination of materials
Materials combined:
-Active Pharmaceutical Ingredients
-Auxiliary Materials(excipients)
-Packaging Materials
Material
General Requirements for Materials
All incoming materials and finished

products:
-quarantined after receipt,
until released for use or distribution
-stored
under appropriate conditions
orderly fashion (batch segregation)
materials management
stock rotation (FIFO)
Material
Starting Materials-I
Things to consider;
Purchasing of starting material
Suppliers of starting material
Delivery of starting material
Integrity
E.g. damaged containers
-seal
-order
-delivery note
-Supplier’s labels
Material
Starting Materials-II
Things to consider;
Cleaned and labelled
-name and internal code
-batch number(s), (supplier &
manufacturer on receipt)
-status
-expiry date or re-test date
Sampled containers identified
Material
Examples of Labelling of Starting Materials

Name of
Material and/or
internal code
Control/
Batch No.
Quarantined/Released/Rejected
Status
(Colors may be used)
Expiry date or
retest date
Date Sign a t u r e
Material
Starting Materials-III
Use only released material
Dispensing:
-designated persons
-written procedure
-accurately weighed
-clean, labelled containers
Independent checks
-material and weight
Dispensed material:
-kept together and labelled
Material
Packaging Materials-I
Primary and printed materials:

-as for starting materials
purchasing, handling and control
No unauthorized access
Storage and transport
-avoid mix-ups
-issue and return: SOP
Material
Packaging Materials-II
Specific reference number for batch

or consignment
Packaging department checks:

-quantity, identity and conformity
Outdated or obsolete material

Material
Intermediate and bulk products
Appropriate conditions
Purchased:
-as starting materials
Material
Finished Products
Quarantine until released
Storage conditions
Evaluation and documentation

-product release
Material
Rejected and Recovered Materials

Rejected materials
-Clearly marked
-Stored separately in restricted
areas
-Action
Reprocessing:
-exceptional
-procedure and records
-batch number
-additional testing
Recovery:
-prior authorization
-additional testing
Material
Recalled Products and Returned

Goods
Recalled products:
-identified
-stored separately
-access controlled
-fate
Returned goods:
-SOP: decision regarding the fate
-nature of product, storage conditions
-history, time lapse
-records
Material
Reagents
Recorded upon receipt or

preparation
-preparation in accordance with SOP
label:
concentration, standardisation factor,
shelf-life, date that re-standardisation is
due, storage conditions
signed and dated

Material
Reference Standards
Official reference standards
-use only as per monograph
-storage
Reference standards prepared by the
producer:
-tested, released
-stored in same way as official reference
standards
Secondary or working standards:
-appropriate checks and tests
-regular intervals
-based on official reference standards
Personnel API
Documentation
AN INSPECTOR ONCE ASKED…..

“Tell me….
WHAT you did and WHY you did it…
And then….
PROVE IT”
Documentation
What is proof?
DOCUMENTED EVIDENCE
“proof is evidence that tends to
establish the existence of a fact”
Canadian Law Dictionary

Documentation
Inspectors want to see…..

THE PROOF!!!
-Written standards (SOPs) & specifications
-Records
Work (BPRs, logs, worksheets, notebooks,

etc)
Qualifications (people, equipment,

building, materials, etc)
Documentation
Who is involved?
Anyone and everyone implicated in
any of the procedures noted
-Production, filling and packaging staff

-QC, QA & RA staff
-Maintenance, cleaning, shipping, receiving
staff
-Staff involved in storage and distribution
ANYONE WHO “TOUCHES” THE PRODUCT
Documentation
Why Document?
-to ensure that there are specifications for
all materials and methods of manufacture
and control
-ensure all personnel know what to do and

when to do it
-ensure that authorized persons have all

information necessary for release
-provide audit trail

Documentation
Document Hierarchy?
Quality Policy SOPs

-May also include procedures
-key quality/compliance rules &
responsibilities
Procedural SOPs
-Detailed work instructions
Records of Work
-Forms
-Logs
Documentation
Types of Documentation
Written Standards
-SOPs and Specifications (RM, pkg)
-Protocols (validation)
Blank Templates
-QC worksheets, log books, cleaning logs,
etc.
Documentation
Records
Completed templates (BPR)
Product protocols
-All relevant records for review and release
Reports
-Validation, audit, non-conformity, product
review/trending
-Signature verification
-Personnel training
Documentation
What are SOPs?

Canadian GMP definition:
“An authorized written procedure
for performing operations not necessarily
specific to a given product or material but
more general in nature (e.g., equipment
operation, maintenance and l\cleaning…)
Certain SOPs may be used to supplement
product-specific master and batch
production documents”
Documentation
What are SOPs?
Written Instructions
How to do something
-Describe WHAT is actually done
Performance/standards of
performance
To ensure consistency
Documentation
What are SOPs?

Required for both…
-specific tasks & other tasks affecting the
product
Authorized document
Act as official documents

-Promise to the regulatory authorities
-Entire SOPs and references to SOPs are
made in all license submissions
-Special handling requirements
Documentation
Why do we need SOPs?

Consistency and control
Document quality (clarity/

understandability)
Regulations and requirements are

met
-Ensures technical accuracy
Documentation
Why do we need SOPs?

Responsibilities/standards are clear
-Who does what & level of performance
Provides authority to implement

(once signed off)
Documentation
What SOPs are needed?

Unsure whether an SOP is needed?
-Ask yourself “If the task is performed
inconsistently, will there be an effect on
safety, quality or performance?”
Err on the safe side and write one

-Be prepared to justify your position either
way (especially for procedures not needing
SOPs – document why)
Speak to QA to get their opinion/advice

Documentation
WHO should write SOPs and

WHY?
-Supervisors/Managers?
-Consultants
-QA
-Technical Staff?
Documentation
SOP Format
SOP System Needs
-Standard format policy and handling

procedures
-Document control group
-Master document file (originals)

Documentation
SOP Format
-Identification and control (numbering)

-Cover page
-Distribution list
-Headers & pagination
-Fonts & multi-level bullets
-Text style
-Organization
Documentation
SOP Format
Identification & Control: SOP number and revision
1 QP - 001 - 02
-1 = Volume (dept. specific)
1 = QA, 2 = QC, 3 = RA, 4 = Filling
-QP = Section name (usually an acronym for the type of SOP)

CS = Compliance System, QP = Quality Policy, CT = Chemical Test, FP =
Filling Procedure
-001 = Document number (unique identifier)

-02 = Revision Number (change control)
Documentation
SOP Format
-Text Style
-Active verbs/direct statements
-Relevant procedures
-Simple wording
-Clear and concise
Can it be understood, will it be followed?
Focus on WHAT is to be done
Documentation
SOP Format
Organization
-Beginning
Title, introduction & lists (equipment,
materials, people)
-Body
procedures
-End
References, attachments/appendices
Documentation
SOP Format
Organization: Beginning
-Title (descriptive of the procedure)

-Introduction (overview, purpose)
-Scope (who does the procedure apply to)
-Lists (materials & equipment)
Note specifications
Details of reagent preparation
-Responsibilities (who does what)
Documentation
SOP Format
Organization: Body
Detailed procedures (critical tasks)

-Chronological/step by step
-Safety procedures
-Calculations
-Documentation requirements
-STANDARDS OF PERFORMANCE
Documentation
SOP Format-Standards of Performance

Poor Wording Examples
For a few minutes
Add a few drops at a time
Store in the freezer
Incubate
Spin down the sample

Documentation
SOP Format
Organization: End
-References
-Internal (other SOPs or documents)
-External (regulations, technical papers, etc.)
-Attachments/Appendices
Attach complex tables, flow charts, blank forms or
other blank documents, copies of completed
documentation, etc.
Documentation
RECAP
There is no perfect SOP
SOPs must describe what is actually done

-SOPs MUST be followed at ALL times
The technical staff should write the SOPs
SOPs must follow the corporate format

Documentation
Finishing the Process
-Printing
-Authorizations
Departmental
QA/RA
-Distribution and document control
-Life span
-Annual reviews/revisions
Documentation
Printing and Authorization

-Type the material into the computer
Original SOPs have a “-00” revision number
-Review the text internally

All the people involved in the process
-Sign off the cover page (authorization)

Originator (select one person) + supervisor
Documentation
-QA Authorization
-Single QA review by the relevant QA auditor
-Any comments are made in writing

Speed up the process with face to face
meetings
Documentation
Distribution & Document Control
Document Control:
-Makes copies
-Applies official stamp
-Distributes copies
Only “official” stamped copies can be
used?
Documentation
Distribution & Document Control
-Detailed records are kept of all recipients

A copy of the SOP must be in the work area
If additional official copies are made, this is documented
-All original documents and supporting information

is kept FOREVER!
Documentation
Life Span
-SOPs generally last for 2 years
Based on effective date
Unless there are changes to the procedure
All changes must go through the revision process

BEFORE the procedure changes
Documentation
Revisions
-If changes have occurred, the SOP must be revised
Regardless of the ”expiry date” of the SOP
-All changes must be:

Documented
Justified
Reviewed and approved
The basic SOP writing and approval procedures
are followed
Documentation
Revisions
-The old SOPs are recalled and destroyed
-All documentation is retained FOREVER
All previous SOP editions, review forms and
supporting documentation
The current outdated SOP, the SOP review form and

the newly revised SOP (original)
The distribution list

Documentation
Batch Production Records

The BPR is completed, as the information becomes
available during process:
-Name of the product

-Number of the batch being manufactured
-Dates and times of commencement and completion of significant

intermediate stages, such as blending, heating, etc
Documentation

BPR contents, continued
-Batch number and quantity of raw materials actually weighed and

dispensed
-Confirmation by a person of each ingredient added to a batch
-Identification of personnel performing each step of the process and

of the person who checked each of these steps
Documentation

BPR contents, continued
-Actual results of in-process quality checks performed at appropriate

stages of the process and identification of the person carrying them
out
-Actual yield of the batch at appropriate stages of processing and the

actual final yields, together with explanations for deviations from the
expected yield
-Notes on special problems with signed authorization

Documentation
Basic Documentation Procedures
-Common problems
Real citations
7 deadly sins
-Fixing these problems

Standards and training
Designing standard forms that work
Documentation
Common Documentation Problems
-Incomplete batch & test records

Steps not verified
Lab results not included
Equipment not identified
-Not reviewed or revised periodically
-Inadequate documentation of deviations

Source: The Gold Sheet – June 1997, pp. 11-12
Documentation
Other documentation issues

-SOPs missing, inadequate, out of date or not being
followed
-Equipment cleaning/use logs not maintained
-Missing or inaccurate logs
-Training records inadequate
Source: The Gold Sheet – June 1997, pp. 11-12
Documentation
-Raw data not recorded in an accountable fashion

-Inadequate manufacturing directions
-Inadequate traceability
-Batch records do not state reason for deviation
-No documentation indicating time limits
-In-process lab results not kept with BPRs
-Inadequate QA review of records
Source: BioQuality 1997 (all vol.)
Documentation

-Training records lack information on specifics
-No formal training program for micro lab workers
-Training not documented as required in SOP
-No records kept of failing WFI chemical tests
-Data from contract lab not reviewed or evaluated
-Yearly SOP reviews not carried out
-Inadequate change history
-Substitution of a method without supporting doc.
Source: BioQuality 1997 (all vol.)
Documentation

-Use of uncontrolled documents
-Discrepancies noted but not explained
-Calculations not signed for or checked
-Missing signatures/dates
-Blanks on BPRs
-BPRs not detailed enough/not sequential
-Too many corrections
Documentation
7 “Deadly Sins” of Documentation

-Non-concurrent entries
-_____ (missing information)
-Improper corrections
-Illegible writing
-Improper documentation
-Inconsistencies within documents
-Poorly designed BPRs/worksheets
Documentation
Non-Concurrent Entries
-Hard to find
Documents filled in before the event
Documents filled in after the event
-Re-audit after finding blanks
-Inconsistencies in the records

Different writing “perfect” data
Documentation
Fixing Non-Concurrent Entries

-Have the people who did the work fill in the information
Only if they remember the work
-Note the reason why
-Initial and date
-Have the supervisor review, sign & date
-Write a deviation report

Documentation
Missing Information
-Signatures/initials
-Dates/times (am/pm)
-Information/explanations
-Steps not carried out were left blank

Documentation
Forgotten Entries
-Leave the information blank
-Inform the appropriate people

Supervisor, QA, etc.
-File a deviation report

QA/RA review of the product in question
Documentation
Blank Areas
-Acceptable but make sure it is clear that no information is

expected
-Put a diagonal line through the area

Initial and date
-Or design the form to make it clear

Documentation
Improper Corrections
-Missing initials and dates
-The “write over”
-The “scribbler”
Documentation
Making Proper Corrections
-Cross out the error with a single line

It is necessary to see the incorrect data
-Enter the correct information
As close as possible to the proper place
-Initial and date the correction (+ time)
Provide an explanation if necessary
Documentation
Illegible Writing
-Tricky issue to deal with
-The “bottom line”

If it can’t be understood = no record
-Illegible initials & signatures are OK

Have a signature verification sheet
Printed name, employee ID, signature, initials, date
For the entire department & verified by the
supervisor
Documentation
Improper Documentation Practices
-Use of “white-out” or “liquid Paper”
-Erasure of incorrect entries
-Use of pencil on official documents
-Use of colored and/or water based inks
-Use of “post-it” notes, paper towels, etc

Documentation
Prevention
-Training
-Restrict access
-Have a specification for pens

Black/blue permanent ink
-Well designed BPRs/worksheets

Documentation
Inconsistencies
-Different date/time formats

i.e. Feb 17, 1998 vs. 02/17/98 vs. 17/02/98
i.e. 7:00 pm vs. 19:00
-Decimal places & rounding off

i.e. pH 7.2 vs. 7.23
-Dates/times don’t match

Dates/times don’t match
Documentation
Prevention
-Policy SOP
Clear standards of performance
-Training
-Adequate resources
-Have good forms

Keep them updated
Documentation
Documentation Policy SOP
-Ensures consistency
Clear procedures for documentation
-Procedures on how to deal with problems
-Foundation for training

One of the primary QA SOPs
Documentation
Suggest to include:
-Scope (types of records)
-Basics (pens, legibility, completeness, concurrent,
data/time formats, etc.)
-Dealing with problems (making corrections and
non-concurrent entries)
-Record reviews
-Record keeping, retention & retrieval
Documentation
-Ensure it references back to the GMPs
-Cross reference other related SOPs

Change control, writing SOPs, deviations, etc.
-Involve production, packaging & testing staff in its

development
-Have all major divisions sign it

Documentation
Essential Systems/ Policies
-Basic documentation practices
-Control of
Written standards
Blank templates
Work records/reports
Documentation
Document Control
-Writing/updating
Change control
-Review and approval

Includes effective date
-Distribution and storage

Copy control
Documentation
Any System
-Policy SOP
Clear standards of performance
Responsibilities clear
-Procedure SOPs
-Standard Forms
Easy to fill out
checklists
Documentation
Change Control
-Purpose: to ensure the most current element is in use

Multiple copies of documents on site
Documents on file with Regulatory Agencies
-Ensures changes are:

Reviewed, justified, documented and approved
Implemented after a review of its implications
Documentation
Summary
-Documentation should be everyone’s primary activity

Proof the work was performed
Proof of meeting specifications/compliance
Proof of product quality
Documentation
Proper Documentation Practices
-Document your work in full at the time it occurs
-The person(s) doing the work must do the documentation

Double check all critical entries
Including calculations
-Sign & date as required

Documentation

-Document any deviations
Note why it occurred and sign & date it
Including any unusual observations (SPC)
-Make corrections properly
-Follow standard date/time formats

Documentation
-Maintain all records (including training)

-Review the work in a timely manner (24 hrs?)
-Update your documents
(BPRs, specifications, worksheets, SOPs, etc)
-Communicate issues with your supervisor and QA

-Use a permanent ink pen
Preferably black
-Be consistent (i.e. decimal places)
History and Background

Complaints and
Recalls
Personnel API
Complaints
Complaints
-General comments & questions
Unrelated to product quality (late delivery)
-Product quality related problems

Abnormal appearance, packaging component
deficiencies
-Adverse events
Side effects (expected and unexpected)
pharmacovigilance
Complaints
Complaints
Why does a Company Respond?
-Regulatory requirement (due diligence)
-Provide assurance of product safety/quality
-Act on and investigate problems

Minimize risk (injury and legal)
Minor through to product recall
-Identify areas for improvement/customer service
-REPUTATION
Complaints
Complaints
What should we do?
-Have a formal complaints handling system

Ensures uniform processing of information
Document and investigate
Report & trend

Complaints
Complaints
Elements
-Defined program
Designated complaint handling unit
Written procedure
-Complaint documentation
Logs and reporting forms
Complaints
Complaints
Elements (cont’d)
-Regulatory Review
-Investigation
Returned product review
-Customer follow-up
-Trending
Complaints
Complaint Handling System
Designated Handling Unit

Receipt
Maintain logs
Monitor progress
Create reports & trending
Monitoring/metrics
RA or QA group
Customer service, marketing and/or sales may be
primary contact/reporters
Medical departments may also be involved
Complaints

Complaint Procedure
Policy SOP
Departments and responsibilities
Classifications
Time limits for procedures
Specifications for reporting to regulatory authorities
Complaints

Procedural SOPs
Receipt & log-in

Investigation and reporting
Testing and reporting
Trending and reporting
Feedback to complainant
Documentation requirements
Complaints
Complaint Documentation
Standard blank template

Ensures all relevant data collected
Date and time received
Product and lot# involved
Name/address/phone # of complainant
Nature and details
Complaints
RA/ QA Review
Review & evaluate course of action

Investigation
If no, document only
Medical involvement
Notification to regulatory bodies (FDA field reports)
Complaints
Adverse Events/side effects

Unexpected/severe events
Close monitoring required
Minor/major/critical
Dependent on the drug involved
Parenteral example;
Minor: redness/swelling at injection site
Major: fever & convulsions
Critical: death
Complaints

Investigation
Root cause ID
Time limits for completion
Testing
Auditing
Records and/or process
Complaints

Follow up
Monitoring of Progress
Notification and reporting

• QA/ RA/ Medical
• Customer/ Complainant
Decisions/ Actions
• Nothing thru to recall
Recalls
Recalls
Removal of product from the market
Due to quality, safety, efficacy, etc. problems.
Suspected or confirmed
Reduce/remove risk/hazard to consumers
From complaint/adverse event/stability failure
Regulatory requirement
Destroy affected product

Recalls
Recalls
Mandatory
Actual or probable risk

Complaints/adverse events
Quality/safety risk
Labeling problems (#1)
Stability failures (dissolution testing)
Sterility/contamination
Recalls
Recalls
Voluntary
Potential risk
-Complaint but not a hazard
-Expiry dating issue

Projected failure to meet expiry potency but still fine now
-Asthetic issues
Recalls
Recalls
System Requirements (C.02.012)
-Prompt action
-Formal recall plan

Implementation regardless of the time of day
-Detailed distribution records
-Special handling of returned goods

Recalls
Recalls
Formal Plan
-Key responsible individual)s) identified
-Crisis/recall team membership

QA/QC/RA + Medical + Legal (trained staff)
-Communication requirements
-In writing (SOP)

Recalls
Recalls
Communication
-Regulatory Agency
Informed early
Review of plan and letters
-Wholesalers, importers, distributors

Stop distribution/sales
-Customers (everyone who received the product)

Press releases
Standard questions and answers
Recalls
Recalls
-Detailed documentation of every vial, bottle,
tablet/capsule, device, etc
Who received what, how much and when
Manufacturer, wholesaler, importer and distributor records
Customer level: print or media notices
Health Canada alerts to Doctors, Pharmacists, etc
-Request return of all in-stock material

Authorized destruction and documented
Recalls
Recall Process
-Monitoring
Close scrutiny by the regulatory bodies
Clear documentation requirements
Enforcement action (inspections) may result
-Closure
Return of all product possible
Complete documentation & destruction
Final report prepared
Recalls
Summary: Recalls
Formal system required

Regulatory requirement
Recalls vs. withdrawals
Prompt removal product from market

Remove risk to consumer
Generally return of all stock to manufacturer
Destruction of returned material
Recalls
Top Reasons for Drug Recalls
-Stability Data does not support expiration date

-Super-potent Product
-Labeled mix up
-GMP deviation
-Sub-potent products
-Microbial contamination
Premises
Sanitation and
Hygiene
Personnel API
Sanitation and Hygiene
Scope
-All aspects of manufacturing

-Personnel
-Premises
-Equipment
-Apparatus
-Production materials and container
-Products for cleaning and disinfection
-All potential sources of cross-contamination
Design of Premises
Design
Walls, floors, ceilings, ledges, drains, air supply, dust
extraction
Prevention of build-up of dirt and dust to avoid

unnecessary risks of contamination
Cleaning programme, appropriate cleaning, cleaning records
Design of Premises
Effective cleaning and disinfection
choice of materials and chemicals, validation
Drains
Protection from insects, vermin and weather

from receipt of raw materials to despatch of released product
Avoidance of Cross-contamination-I
-Segregated areas
-Ventilation systems and airlocks
-Clothing
-Closed processing systems
-Cleaning and decontamination
Avoidance of Cross-contamination-II
Segregated areas and separate facilities for
-live vaccines and other biological materials
-penicillin products
Avoidance of Cross-contamination-III
Ventilation systems
-design of ventilation system

-incoming air should be filtered
-pressure differentials and air extraction
-airflow patterns and equipment design
-recirculation versus 100% fresh air supply
Avoidance of Cross-contamination-IV
Clothing
-protection of operator and product
-highly potent products or those of particular risk - need for

special protective clothing
-personnel should not move between areas producing different

products
-garments need to be cleaned

Avoidance of Cross-contamination-V
Closed Processing Systems
-For example: totally enclosed water purification systems
-tanks fitted with appropriate filtration - without

removable lids
-present special cleaning difficulties, sometimes use

clean-in-place (CIP)
Avoidance of Cross-contamination-VI
Cleaning and Decontamination
-procedure for removing soil and dirt
-remove all cleaning chemical residues or disinfectant

residues
-must remove or reduce micro-organisms

Production Operations – Sanitation – II
Simultaneous operations
-not permissible to process different products in different
areas with a common ventilation system
-permissible to carry out secondary packaging activities for

different products within a packing hall with adequate
physical separation
Production Operations – Sanitation – III
Area clearance checks
Process of checking
-all materials and documentation from the previous batch removed
-all plant and equipment thoroughly cleaned and appropriate status

labelling
-checklist useful
Production Operations – Sanitation – IV

Area clearance checks
The area clearance check should be carried out by two people

-between batches of same product, acceptable for both
checks to be carried out by production personnel
-for product changeover, second check carried out by QC staff
-all checks carried out in accordance with written SOP and

results recorded on the batch documentation.
Production Operations – Sanitation – V

Cleaning and cleaning validation
-degree of cleaning depends on whether consecutive batches
are of same or different product
Check cleaning agent is fully removed
-If possible hot water alone used for cleaning
all cleaning and disinfecting solutions carefully prepared and expiry dated
-Final rinse with purified water, or water for injection (for sterile
products)
-Full records kept

Production Operations – Sanitation – VI

Maintenance and repair
-activities inevitable in manufacturing area.
-Should present no risk to product
-Whenever possible, all planned maintenance outside normal

operating hours
-Emergency work in working area followed by thorough clean down

and disinfection before manufacturing recommences
-Area clearance by QC
Personal Hygiene-I
Health examinations
On recruitment for direct operators , repeated on regular basis
Training - check
induction training for new operators includes basic personal hygiene
training
written procedures - to wash hands before entering a

manufacturing area
signs in changing rooms to reinforce hand washing

Personal Hygiene-II
Illness
staff with illness or open lesions should not handle starting materials,
intermediates or finished products
Adverse conditions
operators trained to recognize risks
willingness to report illness to the area supervisor
Personal Hygiene-III
Contact between product and operator

-avoid direct contact
-if direct handling unavoidable, gloves should be worn
-check glove disinfection (for sterile production) and disposal

Personal Hygiene-IV
-Smoking, eating and drinking should not be allowed in any
manufacturing area, including laboratories and storage rooms.
-Chewing of gum should be banned.
-There should be no plants kept inside any factory areas.
-Rest and refreshment areas should be separate from manufacturing

areas.
-Toilets should not open directly into production or storage areas.

Personnel API
Validation
Definition
Validation is the documented act of proving that any

procedure, process, equipment, material, activity or system
actually leads to the expected result
Validation
Types of Process Validation

-Experimental approach
Prospective validation
Concurrent validation
-Analysis of historical data

Retrospective validation
-Revalidation
Periodic revalidation
Revalidation after change
Validation
Stages of Validation
-Design qualification (DQ)
-Installation qualification (IQ)
-Operational qualification (OQ)
-Performance qualification (PQ)

Validation
Priorities for Process Validation
Type of Process Requirement

New
Every new process before approval for routine
Existing
Start with major processes, equipment
All critical functions/parameters

Validation
Validation Master Plan (VMP)
Validation protocols (VP)
Validation reports (VR)
Standard Operating Procedures (SOPs)

Validation
The Validation Master Plan could consist of:
-Approval page and table of contents

-Introduction and objectives
-Facility and process description
-Personnel, planning and scheduling
-Responsibilities of committee members
-Process control aspects
-Equipment, apparatus, processes and systems to be validated
-Acceptance criteria
-Documentation e.g. validation protocols and reports
-SOPs
-Training requirements
Validation
Protocol
-Objectives of the validation and qualification study

-Site of the study
-Responsible personnel
-Description of the equipment
-SOPs
-Standards
-Criteria for the relevant products and processes
Validation
Report
-Title
-Objective of the study
-Refer to the protocol
-Details of material
-Equipment
-Programmes and cycles use
-Details of procedure and test methods
Validation
Possible situation-I
-Refurbishment of a liquids department, producing a single product

on an established site with an existing purified water system.
-Ventilation system
Equipment and process
Training
Validation
Possible situation-II
-New product introduced into an existing tablet manufacturing site,

with 20 products already being produced
Process Cleaning
Training
Validation
Possible situation-III
A new liquids manufacturing building on an existing site
which will produce 2 products.
-Ventilation
-Equipment and process
-Cleaning
-Training
Validation
Possible situation-IV
An existing sterile suite producing 5 products that are
terminally sterilized
-Sterilizers
-Ventilation and other environmental aspects
-Equipment and process
-Cleaning
-Training
Personnel API
Active Pharmaceutical Ingredients
General Considerations
-Overall control
-Consistent uniform batches
-Compliance with GMP
production
quality control
-General guidelines
-Co-operation in production
-Human and veterinary preparations
Personnel
-Qualified and competent
production and quality control
sufficient number
education, knowledge, experience
-Organizational chart with responsibilities
-Written job description or instructions

-Trained
-Health
diseases
open lesions
Premises
General
-suitable construction and environment
-adequately adapted and sufficient size
-mix-ups or contamination
-logical work flow

Premises
Hygiene
-clothes, washing, toilets
-eating, drinking, smoking

Equipment
Design, construction, location and maintenance

intended use, cleaning, contamination
validated operation
Cleaning
sterilised, used, maintained: SOPs, records and checks
Equipment
Process monitoring and control

calibrated, checked
records
Defective equipment
removed or labelled
repaired, documented
Sanitation
-Written programmes
validated for premises and equipment
quality standard for water
hygiene , health and clothing practices
waste disposal
-Implementation and training

-Practices not permitted:
eating, smoking
unhygienic practices
Documentation
Master formulae
written instructions
master formula contents
authorisation
outdated documents
amendments
Batch documentation
batch manufacturing record contents
contract production
data recording
Record and Reference Sample Retention
Activities are traceable

Retention of records and samples

retention period
Production
Processing procedures
-master formula
-critical steps defined and validated
-supervision
-labelling
vessels, containers, equipment
Production (continued)
Starting materials
receiving, quarantine, sampling
testing
release, reject, storage, labelling
dispensing SOP
exceptions for hazardous materials
Intermediates
testing
labelling
storage
Active pharmaceutical ingredients

meet specifications
limits for residue and reactants
sterile APIs
Packaging
-packaging material selection
-procedures to prevent error
-labelling, including:
Product name
Quality
Batch number
Expiry or retest date
Warnings, if required
Storage conditions
Names of manufacturers and suppliers
Quality Control
Independent unit
Duties: Approve, reject or release
specifications and methods
sampling, sanitation and hygiene
reprocessing
stability
complaints
Laboratory access and requirements
Contract laboratories
Stability Studies
Written programme
stability indicating methods
Samples
containers
storage conditions
Expiry or retest date

Self-Inspection and Quality Audits
Regular independent inspection

expert or team of experts
Records
Storage
-Suitable conditions based on stability studies
-Distribution records for each batch

written SOP
facilitate recalls
Complaints and Defects

Written instructions
Prompt action and investigation
record facts
Product review system
Reject materials
Written procedures
starting materials, intermediates, packaging materials
identified
storage pending fate
Possible Issues
Manufacturers supplying various types of industries
Imports through brokers
Hazardous processes
Commercial secrecy
Unsatisfactory final facilities

Possible Issues
-The interpretation of the meanings of expiry dates and re-test dates

-The use of APIs close to their expiry date
-Blending of rejected APIs
-Reprocessing, recovery and/or reworking of APIs
-Recycling and treatment of solvents
-Addition of impurities to batches of APIs
-Trace-ability, repacking and re-labelling

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Good Manufacturing Practice

From Fundamentals to Applications

National Medicines and Poisons Board, Obaid Ali, R. Ph. Ph.D

History and Background Complaints and Recalls

Premises Sanitation and Hygiene

History and Background Complaints and Recalls

Premises Sanitation and Hygiene

History and Background Complaints and Recalls

Premises Sanitation and Hygiene

Ensures that products are consistently

Diminishes risks that cannot be controlled

Fundamental Principles of Quality Assurance

Quality, safety and effectiveness must be

Quality cannot be inspected or tested into

Each step of the manufacturing process

Pharmaceutical Manufacturers have the

History and Complaints and Recalls

C stands for current because the

(new details, dimension and

Facility design to control operations

Production and process controls

Personnel training & certification

Manufacturing processes are clearly

Manufacturing processes are

Instructions and procedures are written in

Operators are trained to carry out and

Records are made, manually or by

Records of manufacture, including

The distribution of the drugs minimizes

A system is available to recall any batch of

Complaints about marketed drugs are

History and Background Complaints and Recalls

Premises Sanitation and Hygiene

Premises must be located, designed,

Minimize risks of errors & cross-

Premises must be located, designed,

Minimize risks of errors & cross-

Premises must be located to

Premises should be built to

Rest and refreshment rooms

Changing, washing and toilet areas

QC sampling area with GMP standards

Environmental controls, dust control

Smooth, impervious, durable, easy to

Cleaning and Documentation

Manufacturing and Packaging

Dedicated and self-contained facilities

Logical flows of materials and people

Adequacy of working space & orderly

Windows should not open to the

Finish of Floors, Walls & Ceilings

Smooth, impervious, easy to clean

Resistant to operations and

Windows not opening to the outside

Avoid sliding doors

Finish of Floors, Walls & Ceilings: Much better

Manufacturing and Packaging – I

Effective air handling to suit product