Career Guidance in Quality

Assurance

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History of Pharma GMP

 Pharmaceutical regulations and GMP requirement were

created and put in place as response to tragic circumstances
and to prevent future tragedies.
1941 Initiation of the GMP

• 1901-children who received antitoxin for diphtheria treatment died

of tetanus because the horse serum that had been used to prepare
the antitoxin was contaminated with tetanus.
• Response : 1906 Pure Food and Drug act-first selected dangerous
ingredients to be labeled on all drugs.

• 1930s-the wrong raw material and an elixir of sulfanilamide, anti –

infective drug used in 1935.diethylene glycol, a poisonous solvent
as a antifreeze, in oral elixir.
• Response: Federal Food ,Drug and Cosmetic Act,1938.first time
companies were required to prove that their products were safe
before marketing them.
Continue…
 In 1941, nearly 300 people were harmed by one company’ s
sulfathiazole tablets, a sulfa drug tainted with the sedative
phenobarbital.
Response: That incident caused FDA to drastically revise
manufacturing and quality control requirements, leading
to what would later be called GMPs.
 1960s- Thalidomide was marketed in Europe as a sleeping pill and
to treat morning sickness. it turned out to be teratogenic : it
caused serious deformities in developing fetuses.
Response: Manufactures must prove efficacy of the products
before marketing them and strict control over drug testing.
 1970s- the 1972 Devonport, UK, incident resulted in at least
five deaths when drug products designed to be sterile became
contaminated and recipients developed infections. An
unwritten change to autoclave operation, communicated
orally between operators, resulted in dextrose IV solutions
that were not uniformly sterile.
Response: GMPs for drugs(21 CFR Parts 210 and 211) were
made final in 1978. They were intended to help ensure the
safety and efficacy of all products.
 Part 210 –Current Good Manufacturing practice in
manufacturing, processing, packing, or holding of drugs;
general part 211 -current good manufacturing practice for
finished pharmaceuticals
Continue..

 1974-allergic reaction due to extremely small traces of

penicillin in other drug products lead to demands for
separation of penicillin and non-penicillin production.
 1980s- Poisoned acetaminophen capsules . In 1982,12 year old
Mary Kellerman died after taking an extra-strength Tylenol
acetaminophen capsule, Six other people died after taking the
same drug. Recall of 31 million bottles .
Continue..

 Response: FDA issued tamper-resistance packaging regulations

for all OTC human drug products and incorporated them into
the GMPs.
 FDA passed the federal Anti-Tampering Act in 1983, making it
crime to tamper with packaged consumer products.
Continue..
 In the 1980s, FDA began publishing a series of guidance
documents that have had a major effect on our interpretation
of current GMPs.
 Issuance of Guidance on General Principles of process
Validation in 1987 outlined current thinking or expectations of
process validation for drugs and devices.
Continue…
 In 1989, an outbreak of toxic reactions to over-the –counter l-
tryptophan, a dietary supplement, resulted in 38 deaths and
probably thousands of less severe reactions. The event was
the result of a manufacturing process change that increased
the level of a harmful by products. Doses that had previously
been safe now caused toxicity.
 Response : clarification of requirements for characterizing drug
impurities and new requirements for evaluation of minor
impurities.
Continue…
 https://www.slideshare.net/KostasSkopelitis/the-role-of-qa-in-
pharmaceuticals
 1989 EU publishes its Directive on the “ Approximation of
provisions for GMP in the European Community”, i.e. A legal
basis is established for Pharmaceutical GMP within European
community.
 1996 PIC accepts the European industry’s GMP guide.
Continue…
 1998” GMPs for Staring Materails” is added to the ICH work
programme to be decided by an Expert Working Group.
 2001 ICH Q7A API guidance ICH’s “ Good manufacturing
Practice Guidance for Active Pharmaceutical Ingredients(APIs)
 2001 –issuance of directive 2001/83/EC of the European
Parliament and of the Council on the Community code
relating to medicinal products for the human use.
What is quality of Product
 “It delivers the properties described on the label and is not
contaminated” – Dr. Woodcock
 "fitness for intended use“
 “freedom from defects”*
 "meeting or exceeding customer expectations“*
 “customer's definition of quality is the only one that matters
Define quality of drug :
 The degree to which a set of inherent properties of a product,
system or process fulfils requirements specifically for quality of
the drug substance and drug product. (ICH Q9)
 The suitability of either a drug substance or drug product for
its indented use. This term includes such attributes as identity,
strength and purity (ICH Q6)
QUALITY ?
For a Drug Product, Typically the Patient Cannot “See” Quality!

The Patient Expects Quality!!

Patients and caregivers assume that their drugs
Are safe, efficacious, and have the correct identity

Deliver the same performance as described in the

label

Perform consistently over their shelf life

Are made in a manner that ensures quality

Will be available when needed

What really assures Quality?
The Real Assurance of Quality
A robust pharmaceutical quality system!!!

1. QS Elements / Framework - ICH Q10

2. FDA Evaluation – Inspection & Review

3. Standards& Expectations – Regulations & CGMPs

Background: ICH Q10 -Pharmaceutical Quality System
Objectives:
• Achieve product realization
• Establish and maintain a state of control
• Facilitate continual improvement
• Facilitate effective knowledge transfer and Management

Enablers:
• Knowledge & Quality Risk Management
The pharmaceutical quality system “assures that the desired
product quality is routinely met, suitable process performance is
achieved, the set of controls are appropriate, improvement
opportunities are identified and evaluated, and the body of
knowledge is continually expanded.”
• Foundation of Q10 - Regional GMPs, ICH Q7 and ISO QMS
• Augments GMPs by describing specific quality system
elements...helping industry and regulators achieve
harmonization...
Pharmaceutical Development
• DS development; DP formulation\ development
• Manufacturing process development and scale-up
• Analytical method development

Goal – design a product and process that consistently

delivers intended performance and meets needs of
customer
Technology Transfer
• New product transfers during development through
manufacturing
• Transfers within or between manufacturing and testing
sites for marketed products

Goal – transfer product and process knowledge to achieve

realization
Commercial Manufacturing
• Acquisition and control of materials
• Provision of facilities, utilities, and equipment
• Production (including packaging and labelling)
• Quality control and assurance (including release, storage,
distribution)

Goal – achieving realization, establishing and maintaining a

state of control and facilitating continual improvement
Product Discontinuation
• Continued product assessment and reporting
• Document archiving; sample retention

Goal – manage terminal stage of lifecycle effectively

Four Pharmaceutical QS elements:
1. Process performance and product quality monitoring
system
2. Corrective action and preventive action (CAPA) system
3. Change management system
4. Management review of process performance and product
quality
• Management Responsibility
• Leadership and commitment to quality
• Quality Planning
• Resource Management
• Internal communication
• Management Review
• Oversight of Outsourced Activities
QS assessment is two phased

• Quality (Control) Unit has fulfilled responsibilities – review &

approve
• Assess Data collected to ID quality issues link to other systems
• Facilities & Equipment
• Materials
• Production
• Packaging & Labelling
• Laboratory Controls
Product Reviews – at least annually [product review, trending – 21
CFR 211.180 (e)]

Product Issues - Complaint Reviews (quality & medical),

Discrepancy & Failure Investigations, Reprocess/ Rework, Returns /
Salvage, Rejects, Stability Failures, Quarantine

Lifecycle – Validation, Training / Qualification, Change Control &

Product Improvement Projects
Quality Control Unit:
Any person or organizational element designated by the firm
to be responsible for the duties relating to quality control.

Does this mean only the QC Unit is responsible for quality?

a) Responsibility and authority to:
• Approve or reject
• Approve or reject drug product “processed” under contract
by another company
• Review production records (e.g., identify errors)
• Have the errors fully investigated (if errors occur)
b) Responsible for having adequate laboratory facilities for testing
and approval or rejection
c) Responsible for approving or rejecting all procedures or
specifications impacting the quality of drug product
d) Responsibilities must be in writing and followed.
Quality Assurance Quality Control
QA aim is to prevent the defect. QC aim is to identify and improve the defects.

QA is the technique of managing the quality. QC is method to verify the quality.

QA does not involve executing the program. QC always involves executing the program.
All team members are responsible for QA. Testing team is responsible for QC.
QA means Planning for doing a process. QC Means Action for executing the planned
process.
QA makes sure you are doing the right things. QC makes sure the results of what you’ve done
are what you expected.

QA Defines standards and methodologies to QC ensures that the standards are followed while
followed in order to meet the customer working on the product.
requirements.

QA is responsible for full software development QC is responsible for software testing life cycle
life cycle.
Training

Reviewing training records to check if on-the-job and induction

training is taking place according to the schedule, and whether QC
(Quality Control) analysts are being validated.
Market complaint:

Logging and responding to customer complaints, supervising the

investigation into the cause of the issue, providing an investigation
report to the customer, etc.
Recalls:

Initiating, documenting and investigating market returns,

reprocessing (for API batches) or destruction (for finished
batches), and informing regulatory authorities about defects
found after distribution.
Definition:

Complaints When a customer or any other party (internal or external) has

reported a product defect or adverse event with any of the company's
marketed products.

Product complaints are usually concerned with the quality of the product
such as its physical properties, or condition of its packaging. Complaints
(internal or external) could be made to the manufacturer, verbally or in
writing by consumers or distributors.

Recall a procedure of retrieval or withdrawal of products known or

suspected to be defective, promptly and effectively, from the market.
An FDA "Class I Recall" is the most urgent type of recall
that the FDA will issue.
In an FDA Class I Recall, there is significant and immediate danger
of death or other serious injury from the use of the product being
recalled. Class I recalls are pretty rare, but they should be obeyed
as soon as you become aware of them.

In the case of Class I Recall, the FDA will develop an individual plan
that is specific to the manufacturer and the product involved, to
make sure that compliance with the recall is complete and that the
recall of the items involved is trackable.

The objective here is to be sure that all of the affected items are
removed from the market, and from people's homes.
An FDA "Class II Recall" is an intermediate threat
level recall.
A Class II recall is issued where there is no immediate danger of
death or other serious injury linked to the product, but the risk
of death or a serious injury is still present.

A Class II recall is more preventative in nature, but there are still

health and safety risks involved.

As in a Class I recall, the FDA will work with the manufacturer to

help get the word out about the recall, as well as to create a
plan to make sure that all of the recalled items are pulled from
the market as quickly as possible.
An FDA "Class III Recall" is the least serious of all
recalls.

A Class II recall is typically issued where there is no immediate or

perceived danger of any health issues, but where items have
been released that are in violation of FDA regulations.

An example of a Class III Recall is the 2010 recall of children’s

medicines that were potentially contaminated with small pieces
of plastic during the manufacturing process.
The importance of handling complaints and recall
appropriately:

• Identifying and addressing the root cause of complaints will help to

prevent the recurring of complaints.

• Reviewing trends of complaints can help to tackle systemic issues

before it got worse.

• A decreasing trend of complaints also shows customer satisfaction or

trust in the product/service.

• Appropriately handled complaints can help to retain or get more

customers and ensure customer satisfaction.

• If there are serious quality problems and there are potential harm to
consumer, product recall shall be considered.
Reviewing and Approving

Manufacturing records and QC testing data before any

intermediate, API or finished batch is released, as well as
periodic trending of this data.

Initiating an OOS (out of specification) and OOT

investigation and reviewing the QC test if any raw material,
packaging, intermediate or stability sample does not meet
established and approved specification during the latter
QA System: The Backbone of Pharma Quality
While the development, manufacturing and marketing of products
may involve more than one unit or department, the quality unit is
usually independent of production processes.

You could also use specialized departments incorporated in an

organizational network to handle the quality system and its related
duties.

In such a scenario, the QA unit would take on the task of

provisioning suitable systems as well as defining them in SOPs
(standard operating procedures) and higher level instructions.
Cycle for rational new drug discovering and application
of artificial intelligence
Cloud computing
storing and accessing data and programs over the Internet
instead of computer’s hard drive.
Anti-Counterfeiting World Serialisation Implementation
Map
Benefits of QR codes as artificial intelligence
Greater storage
Encode: numeric, capacity
Quick response
alphanumeric, compared to
code
byte/binary and kanji standard UPC
barcodes.

Uses: product tracking, item

Help in serialisation
identification, time tracking,
tracking which help
document management and
during recall
general marketing.
 Thank you
Nirvi Gandhi
Nulife Pharmaceuticals