Quality Assurance: (PHTC 941)

Pharmacy and Biotechnology
Department of Pharmaceutical Technology
Quality Assurance
(PHTC 941)
Lecture 3: GMP; Documentation and Validation
Course Instructors:
Dr. Shahir Aziz
Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 1

Intended Learning Objectives (ILOs)
 Classify the types of documentation following general quality assurance guidelines.

 Recall and specify used terminology in the implementation of quality systems within
the pharmaceutical industry.
 Discriminate between validation, qualification, calibration and verification.
 Evaluate process from industrial case studies and recommend a suitable corrective
action plan.
 Recommend the correct validation or qualification approaches for specific processes.
 Communicate clearly by verbal means through open discussions over industrial case
studies

Outline
Recall: Premises and Personnel
Documentation
• Specifications
• Master Formulae
• Standard operating procedures
• Records
Validation
• Validation principles
• Validation Vs. Qualification
• Validation approaches
• Qualification Stages
• Calibration and Verification
• Change Control
Real time quality assurance case studies

Recall: Heating, ventilation and air-conditioning (HVAC) Premises
• Based on level of protection, Areas are classified into 3 main levels as shown in table.
Further sublevels can be introduced according to more specific standards such as the
number of airborne particulates and their sizes in micron (µm).
Level Condition Example of area
Area with normal housekeeping and maintenance (e.g.

Level 1 General
warehousing, secondary packing).
Area in which steps are taken to protect the exposed
pharmaceutical starting material or product from
Level 2 Protected
contamination or degradation (e.g. manufacturing,
primary packing, dispensing).
Area in which specific environmental conditions are
defined, controlled and monitored to prevent
Level 3 Controlled
contamination or degradation of the pharmaceutical
starting material or product.

Recall: Heating, ventilation and air-conditioning (HVAC) Premises
Some of the typical HVAC system parameters that should be qualified for
a pharmaceutical facility may include:
1) Temperature and Relative humidity 6)Microbiological air and surface counts
2) Return air or exhaust air quantities 7) Room air-change rates and

pressure differentials
3) Room airflow patterns and velocities

8) Room clean-up rates
4) HEPA filter penetration tests 9) Room particle counts
5) Operation of de-dusting 10) Warning/alarm systems
5
Recall: Safety, Hygiene and Training Personnel
Personnel
Qualified/
Safety
Trained
Hygiene
6
Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020
Documentation Types and Guidelines
Documentation Specifications
Manufacturing formula
• Must be approved,
and Process instructions
signed and dated by
authorized person.
• Continuously updated Operational Procedures

and arranged in
fashionably manner.
• Main source for Records

auditing and inspection
by quality personnel

Documentation Types and Guidelines
Batch production process

e.g.: Solid dosage forms Tablets Specifications
Manufacturing
formula and
Process instructions
Operational
Procedures
Records

Specifications Documentation
Is defined as the list of tests, analytical procedures, storage conditions and acceptance
criteria that define the standard quality of a given material (Raw, intermediate or finished
goods).
Manufacturer
Information
Name, code and

physicochemical
properties
Sampling or testing
directions
Qualitative and
quantitative
requirements
Storage Conditions
and shelf life

Master Formulae Documentation
WHO identifies manufacturing instructions as “Master Formula”

Other terms used in GMP guidelines and regulations are “Manufacturing
Formula”, “Master Production and Control Record”, but all mean the same thing.
A document or set of documents specifying the raw materials with their quantities and
the packaging materials, together with a detailed description of the procedures and
precautions required to produce a specified quantity of a finished product as well as the
processing instructions, including the in-process controls.
Guide to Master Formulae by WHO:

http://www.who.int/immunization_standards/vaccine_quality/guide_to_master_for
mulae_final_2012.pdf

Standard Operating Procedures (SOPs) Documentation
A step by step documentation for operating a certain process or to

perform a task. They can be categorized into;
1. Operational Procedures for specific equipment (e.g.: how to operate tablet

machine)
2. Maintenance/Validation Procedures (e.g.: how to clean/sanitize a room)
3. Personnel cautionary Procedures (e.g.: how to wear gown/protective clothes before

a clean area)
4. Sampling procedures (e.g.: how to take a certain amount of sample material to be

tested by QC)
5. Testing and analysis procedure (e.g.: how to analyze and compare samples to the
standard required specifications in QC)
6. Recalls, returns and complaint procedures

Records Documentation
Information that should be recorded at the time an action is taken and

completed. The record should be dated and signed in agreement by the
person responsible for the processing operations.
It is the approved copy of the master document with filled in

Batch production data entries, signatures, dates, production locations, operators,
Record (BPR) and lot number, records of all supporting data including;
equipment identification and calibration dates, in-process test
results, and QC results.
Batch Packaging The record should carry the batch number and the quantity of
Record bulk product to be packed.
A description of samples received for testing, including the

Laboratory control material name or source, batch number or other distinctive code,
Record date sample was taken, and the quantity of the sample. In
addition to the test results observed.
Validation principles Validation
It is the documented act of proving that any procedure, process,

equipment, material, activity or system actually leads to the expected
results.
Validation is an essential part of good manufacturing practices (GMP) and the

implementation of validation work requires considerable resources such as:
• Time: generally validation work is subject to demanding time schedules.
• Financial: validation often requires the time of specialized personnel and expensive
technology.
• Human: validation requires the collaboration of experts from various disciplines

(e.g. a multidisciplinary team, comprising quality assurance, engineering,
manufacturing and other disciplines, depending on the product and process to be
validated).

Reliability Vs. Validity Validation
Not Valid Reliable

Not Reliable Not Valid
Valid Valid
Not Reliable Reliable

Validation Vs. Qualification Validation
• Validation and qualification are essential components of the same concept.

• The term qualification is normally used for equipment, utilities and systems, and
validation is for processes.
• In this sense, qualification is part of validation.
• Qualification should be completed before process validation is performed. The

process of qualification should be a logical and systematic process.
• There should be qualification and validation Protocols and Reports describing the
qualification and validation study to be performed, including;
1) The objectives of the study

2) The site of the study
3) The responsible personnel
4) Description of SOPs to be followed
5) Equipment to be used
Approaches to Validation Validation
Prospective and
Retrospective
Concurrent
validation
validation
Based on evidence
Based on the
obtained through
analysis of historical
testing (before and
data (not preferred)
during production)
Applied for:
• New premises, equipment, utilities, systems, processes and procedures.
• At periodic intervals and when major changes have been made.
In accordance to:
Validation Master Plan (VMP) that reflect all the key elements of the validation
program.

Approaches to Validation Validation
When to apply Revalidation or

Requalification ?!
http://apps.who.int/medicinedocs/en/d/Js14057e/19.html#Js14057e

Qualification Stages Validation
1) Design 2) Installation 3) Operational 4) Performance

Qualification Qualification Qualification Qualification
(DQ) (IQ) (OQ) (PQ)
Provide Provide Provide provide

documented documented documented documented
evidence that the evidence that the evidence that evidence that
design installation was utilities, utilities, systems
specifications complete and systems or or equipment and
were met. (i.e.: satisfactory. (i.e.: equipment and all all its components
Specifications) Installation its components can consistently
Record) operate in perform
accordance with in accordance
Operational with the
Procedures. specifications
under routine
use.

Qualification Stages Validation
http://apps.who.int/medicinedocs/en/d/Js14057e/19.html#Js14057e

Change Control Validation
• The Change control process should be done under the coordination of a change control
management that gathers qualified and trained personnel for each specific change
type.
• Changes should be controlled in accordance with a SOP as changes may have an

impact on a qualified utility, system or piece of equipment, and a validated process
and/or procedure.

Change Control Validation
• The procedure should describe the actions to be taken, including the need for and
extent of requalification or revalidation to be done.
• Changes should be formally requested, documented, approved before

implementation and Records should be maintained.

Validation & Qualification Examples Validation
1. HVAC and water systems  Qualification
2. Cleaning  validation
3. Analytical methods  validation
4. Computerized system methods  validation
5. Systems and equipment  Qualification
6. Non sterile product process  validation

Calibration and Verification Validation
The set of operations under specified

conditions that establish;
• The relationship between values
indicated by an instrument or
system for measuring material
properties (e.g.: weight,
temperature and pH), and the
corresponding known values of a
reference standard.
• Limits for acceptance of the results
of measuring should be established.
Note:
Calibration and verification of equipment, instruments and other devices, as applicable,
used in production and quality control, should be performed at regular intervals (e.g.:
every 3 months).

Case Studies Quality Assurance
Case 1: (Change management/risk assessment)

• During a Secondary packaging process the line stopped and an alarm went on indicating a
certain failure or malfunction in the line.
• After extensive investigations and engineering team interferences, it was discovered that
a spare part needs to be changed ASAP to continue the packaging process.
• The engineering supervisor went straight ahead to the procurement team; raise a PO to
get this spare part immediately. Once this spare part was received it was installed and the
line worked normally fine and the batch was completely packed and finalized.
• The Quality assurance officer was reviewing this same batch to have it ready to be
released to the market, and he thoroughly examined all comments regarding the line
failure in the middle of the process and along with any other comments or related
incidents/ investigations to this batch.

Case 1: Answer
• The QA officer refused to release this batch. Why do you think this happened?
• This equipment change should be handled with a change control document.
• Any change that occurs within a GMP process needs to be documented with a change
control record for future tracking.
• In this case, the required spare part was changed without any documentation recording
this event, which is not accepted according to the GMP rules & regulations.
• Sometimes if the spare part required, is a critical part that would impact the product
quality in a way or another, a risk assessment document might be required to assess the
risk/s that could occur with such a change. In this case a risk assessment document is
derived from the change control record. In the above case the QA officer shall raise a
quality incident because the normal procedures were not followed and all required
documents shall be initiated and then finalized, to be able to release the relevant batch.

Case 2: (Training Management)
• A QA officer was having the daily tour around the production area, to make sure that all
processes are compliant with all procedures and instructions.
• Along his tour he found a new processing operator in one of the manufacturing rooms
working on a batch. The QA went in to get to know him, and throughout the discussion it
was clear enough that this new operator had more than 10 years of experience, which is
logically enough to start working from the very first day.
• Instead of just passing by, the QA officer decided to raise a Quality investigation/
Incident. Why do you think this has happened?

Case 2: Answer
• Training, Training, & training… No matter how experienced an operator, analyst,

technician…etc.
• Training has to be completed ahead of touching any machinery or starting any product
analysis. Whether it is an on-job training, or a documentation training. The operator in
the above case is not allowed to start working on any machine unless he’s trained on the
entire process on the relevant SOP’s, instructions and records, in order to be able to
demonstrate the perfect practice and adhere to the common practice of this area. In this
above case, the batch this operator worked on, might be rejected or risk assessed for it’s
suitability. That’s why an investigations with area supervisor is required to question why
this operator worked ahead of training, and prevent this happening in the future by
placing the proper proactive measures.

Case 3: (Documentation and validation)
• A warehouse operator had a very good idea that could save a lot of time during the
receiving process; he went and asked his line manager and QA officer to update the
required document to reflect these changes. The warehouse operator applied the
changes immediately to his daily routine to save up the agreed upon time, and
simultaneously the document was being updated.
• Do you find anything wrong with what the warehouse operator did?

Case 3: Answer
Any new process, method or initiative needs to be validated & documented ahead of
application. This warehouse operator got excited about his idea and forgot that he cannot
apply this change without having the relevant instruction or working procedure updated &
approved by quality, to make sure it has no quality impact, and have his colleagues and the
required personnel trained on this new process.

References
1. EUROPEAN COMMISSION - HEALTH AND CONSUMERS DIRECTORATE-GENERAL. 2012. The

Rules Governing Medicinal Products in the European Union. Brussels : EUROPEAN
COMMISSION, 2012. Ref. Ares(2012)778531 - 28/06/2012.
2. GAD, SHAYNE COX. 2008. PHARMACEUTICAL MANUFACTURING HANDBOOK; Regulations

and Quality. New Jersey : John Wiley & Sons, Inc., 2008. ISBN: 978-0-470-25959-7.
3. World Health Organization. 2007. Quality assurance of pharmaceuticals : a compendium of

guidelines and related materials. Geneva : WHO Press, 2007. ISBN 92 4 154708 1.
4. World Health Organization. 2009. Handbook: good laboratory practice (GLP): quality
practices for regulated non-clinical research and development -. Geneva : WHO Library,
2009. ISBN 978 92 4 154755 0.
5. U.S. Department of Health and Human Services Food and Drug Administration. 2009.
Guidance for Industry Q10 Pharmaceutical Quality System. Silver Spring : Food and Drug
Administration (FDA), 2009.

“If you are not willing to learn, no one can
help you. If you are determined to learn, no
one can stop you.”
-Zig Ziglar
THANK YOU

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Pharmacy and Biotechnology

Department of Pharmaceutical Technology

Lecture 3: GMP; Documentation and Validation

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 1

 Classify the types of documentation following general quality assurance guidelines.

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 2

Real time quality assurance case studies

Level Condition Example of area

Area with normal housekeeping and maintenance (e.g.

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 4

1) Temperature and Relative humidity 6)Microbiological air and surface counts

2) Return air or exhaust air quantities 7) Room air-change rates and

3) Room airflow patterns and velocities

4) HEPA filter penetration tests 9) Room particle counts

5) Operation of de-dusting 10) Warning/alarm systems

• Continuously updated Operational Procedures

• Main source for Records

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 7

Batch production process

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 8

Name, code and

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 9

WHO identifies manufacturing instructions as “Master Formula”

Guide to Master Formulae by WHO:

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 10

A step by step documentation for operating a certain process or to

1. Operational Procedures for specific equipment (e.g.: how to operate tablet

2. Maintenance/Validation Procedures (e.g.: how to clean/sanitize a room)

3. Personnel cautionary Procedures (e.g.: how to wear gown/protective clothes before

4. Sampling procedures (e.g.: how to take a certain amount of sample material to be

6. Recalls, returns and complaint procedures

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 11

Information that should be recorded at the time an action is taken and

It is the approved copy of the master document with filled in

A description of samples received for testing, including the

It is the documented act of proving that any procedure, process,

Validation is an essential part of good manufacturing practices (GMP) and the

• Time: generally validation work is subject to demanding time schedules.

• Human: validation requires the collaboration of experts from various disciplines

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 13

Not Valid Reliable

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 14

• Validation and qualification are essential components of the same concept.

• Qualification should be completed before process validation is performed. The

1) The objectives of the study

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 16

When to apply Revalidation or

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 17

1) Design 2) Installation 3) Operational 4) Performance

Provide Provide Provide provide

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 18

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 19

• Changes should be controlled in accordance with a SOP as changes may have an

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 20

• Changes should be formally requested, documented, approved before

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 21

1. HVAC and water systems  Qualification

3. Analytical methods  validation

4. Computerized system methods  validation

5. Systems and equipment  Qualification

6. Non sterile product process  validation

Dr. Shahir Aziz – QA course (PHTC 941) – Winter 2020 22

The set of operations under specified