Quality Control - Stephen M. Pondell

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S. Pondell, Aug, 2008
Integrated BioTech Solutions
Steve Pondell
Director of Manufacturing, Encysive Pharmaceuticals
Principal, Integrated BioTech Solutions
August 8, 2008
Bio-Manufacturing Practices
Short Course in Biotechnology

S. Pondell, Aug, 2008
Integrated BioTech Solutions
Part 1:
Biotech Regulatory
Environment
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What is Biotechnology?

Webster’s definition:

The manipulation (as through genetic
engineering) of living organisms or their
components to produce useful usually
commercial products (as pest resistant crops,
new bacterial strains, or novel pharmaceuticals);
also
: any various applications of biological
science used in such manipulation
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What is Biotechnology?

Contemporary Examples:

Genetically-engineered drugs

Genetically-engineered crops

Small to medium size life science companies

Alternative fuels

Organisms for environmental control

Nanotechnology related to health care

Medical devices
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Regulatory Environment

Rules, guidelines or laws formulated by a
governmental agency to guide or control products in
the public realm

All companies operate in some type of regulatory
environment

Because of biotech’s potential impact to public health,
it tends to be more highly regulated that other
industries
S. Pondell, Aug, 2008
Integrated BioTech Solutions
U.S. Biotech Regulating Bodies

Food and Drug Administration (FDA)

Environmental Protection Agency (EPA)

Department of Agriculture

Patent and Trademark Office

Drug Enforcement Agency (DEA)
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Integrated BioTech Solutions
Foreign Agencies

EMEA (Europe FDA)

Therapeutic Products Division (Canada FDA)

Therapeutic Goods Administration (Australia FDA)

Ministry of Health (Japan FDA)
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Integrated BioTech Solutions
How Do Agencies Regulate?

Congress passes laws

Clean Water Act

Food, Drug and Cosmetic Act

Agencies create regulations

Mandatory

Agencies create guidelines

Strongly suggested

Agencies audit for compliance to regulations and
guidelines

Agencies take enforcement actions for non-
compliance
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Discovery / Screening
Discovery / Screening

Animal
Testing
Phase 2
Phase 3
Marketing
Appli
c
atio
n Re
v
i
ew
Mar
ke
t
i
ng Application Review
Post-marketing
Po
st
-
ma
rketi
ng
Pre-clinical
Pre-clinical
Research
Research
Clinical Studies
Clinical Research
Clinical Research
Phase 4



IND
IND
Phase 1
Development and Approval Process
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Typical Timelines
Discovery to Commercial

Alternate fuels
1 yr

Pesticide
3-5 yrs

Environmental remediator
3-5 yrs

Medical device
2-5 yrs

Small molecule drug
8-10 yrs

Biologic drug
10-12 yrs

Generic drug
2-3 yrs
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Compliance

GLPs (Good Laboratory Practices)

Pre-clinical, EPA

GCPs (Good Clinical Practices)

Clinical studies

GMPs (Good Manufacturing Practices)

Production and distribution of drugs and devices for human
use

Written into Federal Register – mandatory regulations
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Compliance

Guidelines

Non-mandatory

Provides acceptable ways to meet regulations

Guidelines can become regulations
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Compliance

Companies self-police

Quality Unit is responsible

Top management also held responsible

Procedures, documentation and training

Agencies audit on regular basis
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Enforcement

Non-compliance

Found during audit or review

Official notification

Withholding of approvals

Withdrawal of product from market

Seizure of product

Legal action

Consent decree

Personal liability of top management

Debar
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Part 2:
cGMP’s
current Good Manufacturing
Practices
S. Pondell, Aug, 2008
Integrated BioTech Solutions
History of FDA

In 1202, King John of England proclaimed the first
English food law, which prohibited adulteration of
bread with such ingredients as ground peas or
beans.

In 19
th
century, physicians were scarce and poorly
educated and many people put their faith in patent
medicines, pitched by traveling salesmen as drugs
and miracle cure devices.

Ingredients secret

Efficacy questionable in many cases

Food, Drug and Cosmetic Act of 1906 created FDA

Significant revision in 1936 and again in 1960’s
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What are cGMP’s?

current Good Manufacturing Practices

Developed from a series of manufacturing mishaps in
the 1960’s and 1970’s

Found in Code of Federal Regulations, Title 21, Parts
210 and 211 (for drugs) and Part 820 (for devices)

Applicable for drugs manufactured for human use,
including investigational drugs
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What do cGMPs do?

Assure the following:

Identity

Purity

Safety

Effectiveness

Potency

Of drug products

Assure that these qualities are met

Consistently

Over life of product
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Sections of cGMP’s for Drugs

A. General Provisions

B. Organization and Personnel

C. Buildings and Facilities

D. Equipment

E. Control of Components and Drug Product Containers and
Closures

F. Production and Process Controls

G. Packaging and Labeling Controls

H. Holding and Distribution

I. Laboratory Controls

J. Records and Reports

K. Returned and Salvaged Drug Products
S. Pondell, Aug, 2008
Integrated BioTech Solutions
A. General Provisions

Minimum requirements

Applies to drug products

Additional detail for biologically derives products

Parts 600-680

Additional detail for products derived from human cells or
tissue

Part 1271

Over-the-counter drugs exempted

Nutraceuticals exempted
S. Pondell, Aug, 2008
Integrated BioTech Solutions
B. Organization and Personnel

Must have “quality unit”

Must have adequate laboratories

Must have adequate personnel for task, trained to
perform task, and trained in GMP’s

Supervisors must have adequate education, training
and experience to perform task

Adequate clothing and personal hygiene so as not to
compromise product

Consultants must have adequate education, training
and experience to perform task
S. Pondell, Aug, 2008
Integrated BioTech Solutions
C. Buildings and Facilities

Adequate number and size

Good product flow so as to avoid mix-ups or
contamination

Adequate lighting, ventilation and plumbing

Adequate sewage, refuse, washing and toilet facilities

Sanitation

Maintenance
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Integrated BioTech Solutions
D. Equipment

Design, size and location suitable for task

Constructed of materials that are non-reactive with
product

Maintained to avoid product contamination

Control of computer systems to assure consistent
operation

Appropriate filters to avoid product contamination or
reaction
S. Pondell, Aug, 2008
Integrated BioTech Solutions
E. Control of Components and Drug
Product Containers and Closures

Components received, tested and stored to prevent
contamination

Each batch tested and approved prior to use

First in/first out

Retested periodically

Containers and closures provide appropriate
protection for product and are non-reactive
S. Pondell, Aug, 2008
Integrated BioTech Solutions
F. Production and Process
Controls

Written procedures – written and followed

Approved batch record describing manufacturing
process

Calculate yields at appropriate steps

Equipment identified as to status

Product appropriately sampled and tested

Time limits on production activities

Control of microbial contamination

Reprocessing controlled
S. Pondell, Aug, 2008
Integrated BioTech Solutions
G. Packaging and Labeling
Controls

Appropriate controls during receipt and storage to
prevent mix-ups

Issuance controlled, and quantities reconciled

Correct labels applied to product

Lot number, expiration date

Tamper-evident packaging for OTC

Inspected and sampled during production

Expiry date supported by testing
S. Pondell, Aug, 2008
Integrated BioTech Solutions
H. Holding and Distribution

Warehousing

Control of quarantined product prior to release

Appropriate temperature and humidity controls as needed
by product

Distribution

First in/first out

Traceability of lot distribution in case of recall
S. Pondell, Aug, 2008
Integrated BioTech Solutions
I. Laboratory Controls

Specifications, standards, instruments as necessary
to assure identity, safety, efficacy, potency and purity
of product

All product tested and released prior to distribution

Products routinely tested for stability

Reserve samples

Penicillin contamination avoidance
S. Pondell, Aug, 2008
Integrated BioTech Solutions
J. Records and Reports

Production and laboratory records must be
maintained for life of product

Equipment cleaning and use logs

Lot records regarding quantity, test results and labels

Master production and control records

Batch-specific production and control records

Record review

Laboratory records

Distribution records

Complaint files
S. Pondell, Aug, 2008
Integrated BioTech Solutions
K. Returned and Salvaged Drug
Products

Returned product must be held and evaluated prior to
re-distribution

Must have assurances of proper storage

Packages must be intact
S. Pondell, Aug, 2008
Integrated BioTech Solutions
International Harmonization

cGMPs exist in all major markets

Europe

Japan

US

International Conference on Harmonization has
aligned cGMPs between major markets

Interpretation can still be issue

Emphasis different from market to market
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What is Validation?

Definition

Documented evidence that provides a high degree of
assurance that a specific process, facility, or support
system will consistently produce a product meeting its
predetermined specifications and quality attributes.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Part of cGMP’s?

Biologics and Pharmaceuticals – NO

CFR 210/211

Medical Devices – YES

CFR 820

BUT, FDA expects and requires validation in all
cases

Validation helps assure that products are pure, safe
and effective
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Where did it come from?

Originally from need to consistently control
sterilization cycles for injectable solutions

Expanded over years to include utilities and
equipment

Further expansion to processes, methods and
computers

Latest expansion has been cleaning of equipment
S. Pondell, Aug, 2008
Integrated BioTech Solutions
The Parts of Validation

Design qualification

Installation qualification

Operating qualification

Process qualification

Re-qualification
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What Gets Validated?

Facilities

Utilities

Equipment

Computer Control Systems

Test Methods

Process

Cleaning

Operators?
S. Pondell, Aug, 2008
Integrated BioTech Solutions
The Parts of a Qualification

Protocol

Written pre-defined acceptance criteria

A description of procedures (and tests) to be conducted,
data to be collected, and methods to be utilized.

Criteria by which a successful validation will be judged
S. Pondell, Aug, 2008
Integrated BioTech Solutions
The Parts of a Qualification

Results and Report

Written compilation of results

Actual, traceable data

Evaluation against pre-defined criteria

Explanation and justification of deviations

Conclusion supporting or refuting a successful validation
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Part 3:
Quality Assurance/
Quality Control
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What is Quality Assurance
(QA)


Quality Assurance (QA)
is

the activity of providing evidence needed to establish
confidence among all concerned,

that the quality-related activities are being performed
effectively.

All those planned or systematic actions necessary to
provide adequate confidence that a product or service will
satisfy given requirements for quality.

Quality Assurance is a part and consistent pair of quality
management proving fact-based external confidence to
customers and other stakeholders that product meets
needs, expectations, and other requirements.

QA (quality assurance) assures the existence and
effectiveness of procedures that attempt to make sure - in
advance - that the expected levels of quality will be reached
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What is Quality control (QC)?


Quality control (QC)
is

a procedure or set of procedures intended to ensure that a
manufactured product or performed service adheres to a
defined set of quality criteria or meets the requirements of
the client or customer.

Refers most commonly to a department which analyses
raw materials, intermediates, and final product
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Role of Quality assurance in the
pharmaceutical industry


Quality Assurance is a vital part of drug development
in the small pharmaceutical environment. It is the
department which is responsible for ensuring that all
the appropriate procedures have been followed and
documented so that clinical progress can be made.

Quality Assurance and Management are responsible,
in FDA’s eyes, for assuring that products
manufactured are safe, pure and efficacious.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Types of Quality Systems

QbD – Quality by Design

ISO 9001/14001 – More generic than cGMP’s

Apply to variety of industries

TQM – Total Quality Management

Six Sigma

Originally developed for electronics industry (Motorola)
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Sigma
Sigma is a metric or mathematical/statistical term which defines
how often a process fails to meet requirements.
Six Sigma is defined as a process which produces only 3.4 product
defects per million opportunities (DPMO) to produce a defect.
DPMO
or
PPM

Sigma Level

308,537
2

66,807
3

6,210
4

233
5
3.4
6
S. Pondell, Aug, 2008
Integrated BioTech Solutions
A Six Sigma Process
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Six Sigma

A defined methodology for reducing process
variation and a mathematical term for defining the
number of defects produced by a process
compared to the number of opportunities to create
a defect.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
How does it work?

Utilizes data to statistically determine where and to what
extreme process variability exists.

Step wise improvements are established to generate savings by
reducing process variability.

Focus is on:


Reducing the cost to produce

Reduce cycle time or downtimes


Improve yields


Reduce variability


Manufacturing costs


Customer needs
S. Pondell, Aug, 2008
Integrated BioTech Solutions
DMAIC Process
Lean Six Sigma methodology utilizes a rigorous procedure called
DMAIC on each input of a process and thereby controls the final
output or product.
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Integrated BioTech Solutions
Metrics

The organization and charting of collected data to
determine how well a process is performing.

Typically each key process input is measured to
determine how the actual compares to the expected.
(i.e. theoretical, average, goal)

The sequential charting of multiple data points
determines the trend and variability of the process.

Key Process Inputs and Key Process Outputs are
measured.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Ways to Improve Efficiency

Decrease variability.

Decrease defects.

Decrease time span.

Process variability and defects are the prime enemies
of efficiency.

Time waste is different from material waste in that
time waste can never be salvaged.


Process time traps must be identified and removed.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Quality Control Unit

Must have one

Approve or reject:

Components

Drug product containers

Closures

In-process materials

Packaging and labeling

Final product
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Quality Control Unit

Must have adequate laboratory facilities to perform
testing

Responsible for approving/rejecting all procedures
and specifications

Must have procedures, and they must be followed.
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Personnel Qualifications

Must have education, training and experience to do
job

Must be trained in GMP

Training must be conducted by qualified individuals

Training must be ongoing
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Personnel Qualifications

Must be an adequate number of people to do the job
S. Pondell, Aug, 2008
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Personnel Responsibilities

Apparel appropriate to protect product from
contamination

Good sanitation and health habits

Authorized access only to limited-access areas

Those with illness or open lesions that may affect
product quality must be excluded from direct contact
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Consultants

Must have education, training and experience to
advise

Records of consultants must be maintained
S. Pondell, Aug, 2008
Integrated BioTech Solutions
Quality Control Unit
Areas Covered Under the Quality Control Unit
1.
Quality Unit
2.
Batch Release
3.
Change Management
4.
Deviation Management/ Failures Investigation
5.
Product Reviews (at lest annually: APRs)
6.
Product Complaints
7.
Reprocess/ Rework (impact on validation and stability)
8.
Returns/ Salvages (assessment, investigation, disposition)
9.
Rejects (investigation and corrective actions)
10.
Stability
11.
Validation (status of required validation/ revalidation)
12.
Training/ Qualifications (related to the employee’s functions)
S. Pondell, Aug, 2008
Integrated BioTech Solutions
What Happens When You Don’t
Follow GMP’s?

FDA-483

Warning Letter

Consent Decree