Bio-Manufacturing

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

Part 1:
Biotech
Regulatory Environment

What is Biotechnology?
Websters

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

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

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 biotechs potential impact to public
health, it tends to be more highly regulated
that other industries

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)

Foreign Agencies

EMEA (Europe FDA)

Therapeutic Products Division (Canada FDA)
Therapeutic Goods Administration (Australia
FDA)
Ministry of Health (Japan FDA)

How Do Agencies Regulate?

Congress passes laws

Agencies create regulations

Mandatory

Agencies create guidelines

Clean Water Act

Food, Drug and Cosmetic Act

Strongly suggested

Agencies audit for compliance to regulations

and guidelines
Agencies take enforcement actions for noncompliance

Development and Approval

PreProcess
Clinical Research
clinical
Research

Animal
Testing

Post-marketing

Phase 3

Marketing Application
Review

Clinical Studies
Phase 2

IND

Discovery / Screening

Phase 1

Phase 4

Typical Timelines
Discovery to Commercial

Alternate fuels
Pesticide
Environmental remediator
Medical device
Small molecule drug
Biologic drug
Generic drug

1 yr
3-5 yrs
3-5 yrs
2-5 yrs
8-10 yrs
10-12 yrs
2-3 yrs

Compliance

GLPs (Good Laboratory Practices)

GCPs (Good Clinical Practices)

Clinical studies

GMPs (Good Manufacturing Practices)

Pre-clinical, EPA

Production and distribution of drugs and devices for

human use

Written into Federal Register mandatory

regulations

Compliance

Guidelines

Non-mandatory
Provides acceptable ways to meet regulations
Guidelines can become regulations

Compliance

Companies self-police

Quality Unit is responsible

Top management also held responsible
Procedures, documentation and training

Agencies audit on regular basis

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

Part 2: cGMPs
current Good Manufacturing
Practices

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 19th 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 1960s

What are cGMPs?

current Good Manufacturing Practices

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

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

Sections of cGMPs 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

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

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 GMPs
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

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

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

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

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

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

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

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

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

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

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

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.

Part of cGMPs?

Biologics and Pharmaceuticals NO

Medical Devices YES

CFR 210/211
CFR 820

BUT, FDA expects and requires validation in all

cases
Validation helps assure that products are pure,
safe and effective

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

The Parts of Validation

Design qualification
Installation qualification
Operating qualification
Process qualification
Re-qualification

What Gets Validated?

Facilities
Utilities
Equipment
Computer Control Systems
Test Methods
Process
Cleaning
Operators?

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

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

Part 3:
Quality
Assurance/
Quality Control

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

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

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 FDAs eyes, for assuring that
products manufactured are safe, pure and
efficacious.

Types of Quality Systems

QbD Quality by Design

ISO 9001/14001 More generic than cGMPs

Apply to variety of industries

TQM Total Quality Management

Six Sigma

Originally developed for electronics industry

(Motorola)

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
308,537 2
66,807 3
6,210 4
2335
3.4
6

Sigma Level

A Six Sigma Process

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.

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

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.

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.

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.

Quality Control Unit

Must have one

Approve or reject:

Components
Drug product containers
Closures
In-process materials
Packaging and labeling
Final product

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.

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

Personnel Qualifications

Must be an adequate number of people to do

the job

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

Consultants

Must have education, training and experience

to advise
Records of consultants must be maintained

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 employees functions)

What Happens When You Dont

Follow GMPs?

FDA-483
Warning Letter
Consent Decree