Steve PondellDirector of Manufacturing, Encysive

PharmaceuticalsPrincipal, Integrated BioTech Solutions

August 8, 2008

Bio-Manufacturing Practices

Short Course in Biotechnology

Part 1: Biotech Regulatory Environment

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

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 biotech’s 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

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

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Pre-Pre-clinicalclinical

ResearchResearchClinical Studies

Clinical ResearchClinical Research

Phase 4

IND

IND

Phase 1

Development and Approval Process

Typical TimelinesDiscovery 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

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

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: cGMP’scurrent 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 1960’s

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

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 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

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 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

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 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

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 FDA’s 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 cGMP’s

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 Sigma Level 308,537 2 66,807 3 6,210 4 233 53.4 6

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 UnitAreas Covered Under the Quality Control Unit

1. Quality Unit2. Batch Release3. Change Management4. Deviation Management/ Failures Investigation5. 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.Stability11.Validation (status of required validation/ revalidation)12.Training/ Qualifications (related to the employee’s functions)

What Happens When You Don’t Follow GMP’s?► FDA-483► Warning Letter► Consent Decree