Quality and Compliance Challenges for Biopharmaceutical Products

Ramon Rivera Gonzalez, Ph.D.

Director Quality Assurance

Amgen Manufacturing, Limited

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Outline Background Information

Regulatory and Process Challenges

Quality by Design

Risk Management

Process Analytical Technology

Key Quality Systems• Deviations/Nonconformities• Corrective and Preventive Actions

Biological Product Deviations

FDA and EMEA Observations

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Biotechnology

Biotechnology is a set of scientific techniques used to derive valuable products from living

organisms

Applications

biopharmaceutical drugs

agriculture

waste management

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Background information

FDA- “sterile drugs should be manufactured by aseptic processing only when terminal sterilization is not feasible”.

Parenterals -Drug administration other than by the mouth or rectum- ex. Injection, infusion or implantation.– Biological products (vials or syringes)

•solubility, stability, maintain activity

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Biotechnology

BIOLOGY

CHEMISTRY

ENGINEERING

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Biological Products Manufacturing

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Biological Products Manufacturing

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Bacterial Systems

(+)

– Grow fast

– Easy to maintain

– High yield

(-)

– Endotoxins

– Low expression or extracellular secretion

– No post-translational modifications machinery

E. coliE. coli

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Mammalian Cells

(+)

– Adequate conformation

– Post-translational modifications

– Preferred for complex proteins

(-)

– Grow slower than bacteria

– Maintenance is expensive

– Usually lower yield

– Limited manufacturing applications

CHOCHO

MammalianMammalian

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Quality and the Product Life Cycle Adherence to regulations

Control and maintenance of documentation

Quality of suppliers, components and raw materials

Reliability and consistency

Monitor/audit of the manufacturing process

Deviations, unexpected situations - product impact

Correction and prevention - CAPA

Lot release/rejection decision

Customer complaints

Continuous improvement

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Quality Systems Emphasis

Quality Management

Quality Assurance

Risk Management– Evaluation analysis and quality risk management

tools

Preventive Action

Promote product and process improvement (i.e., continuous improvement)

“Continuous Improvement” of the Quality System

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Regulatory Environment Challenges

Transfer of CBER products to CDER

GMPs for the 21st. Century

Aseptic Processing Guideline

Risk management

Increased scrutiny of product insert claims

Focus on patient safety

Process Analytical Technology (PAT)

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Regulatory Environment Challenges

Quality by Design

Bioterrorism

Animal-derived materials

Country-specific regulatory requirements– Mexico, Brazil, Saudi Arabia, Japan

Biogenerics in EU

State of the art technology– Isolators

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Major Process Challenges

• Sterile vs. Aseptic• Requires the application of microbiological contamination

control to prevent infectious organisms to be present in the sterile product

• Demonstrate “CONTROL” of the process, while technical complexity increases• Characterization to identify variability components• Application of science and new technologies

• Maintenance of the cell lines• Contamination risks

• Personnel as “incubators”• Source of microbial load

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“Quality can not be tested into products; it has to

be built in by design”

Product quality and performance requires efficient design of manufacturing processes

Product specifications based on deep understanding of how formulation and process factors impact product performance

It provides a framework for continuous "real time" assurance of quality and continuous Improvement

Quality by Design

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The importance of Design

Multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide an assurance of quality

Operating within design parameters will produce a product meeting designed quality attributes

Working within the design parameters is not considered a reportable change

Movement outside of design space is considered a change – subject to regulatory approval

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Risk Management

What are the potential hazards to process and product ?

• Identify potential hazards both prospectively and in a reactive mode

Applies to components, container closure, raw materials, dosing devices, manufacturing process, drug substance, intermediates

How these factors influence variability of process, product performance, product safety and efficacy?

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Risk Management

Risk management is a regulatory expectation for a modern quality system

Risk assessment, risk control, risk communication and risk review throughout product lifecycle

Decisions should be based upon process and product understanding

• Balance between the use of risk management and compliance with GMPs

Always include intended use, patient safety and availability

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Process Analytical Technology

“…any system for continuous analysis and/or control of manufacturing processes based on real-time measurements, or rapid measurements during processing.”

• Source; FDA Human Drug cGMP Notes, Q1 2002

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Process Analytical Technology

“At line” - the sample is removed, isolated from, and analyzed in close proximity to the process stream

“On-line” - the sample is diverted from the manufacturing process, and may be returned to the process stream

“In-line” – the sample is not removed from the process stream and can be invasive or non-invasive

• Source: FDA PAT Guidance

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PAT - Benefits

Enhancement of process understanding Sources of variability identified and

explained Meet requirements for validating and

controlling process Quality attributes can be accurately and

reliably predicated Continuous improvement Integration of development, manufacturing,

QA and knowledge management Acceptability of in-process materials and

final product based on process data

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Management Controls

Written quality policy and objectives

Management reviews – regulations and quality objectives– attendance documented– results, action plans/corrective actions

documented

Internal audits – auditors no direct responsibility for matters

being audited

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Deviations/Nonconformities

Classification based on impact/risk

Investigations need to be thorough, stand-alone– Root cause analysis– Product impact

• Stability data, intrinsic vs. extrinsic, historical data

– Toxicological/health hazard evaluations based on route of administration to patient

– Corrective and Preventive actions

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Corrective and Preventive Actions(CAPA)

Corrective = correct existing nonconformity

Prevention = potential recurrence of nonconformity

Regulatory expectations:– Identify sources of problems/nonconformities

• Unfavorable trends

– Prioritize based on risk– Defined action plans– Timely implementation– Measure and document effectiveness– Reviewed by Management

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If a deviation/nonconformity involves distributed product…

Evaluate per 21CFR600.14 – Biological Product Deviation (BPD)

“must report any event and any information relevant to the event associated with the manufacturing, to include testing, processing, packing, labeling or storage, or with the holding or distribution, of a licensed biological product if the event meets the following criteria:

(1) Either;(i) Represents a deviation from cGMP, applicable regulations,

applicable standards, or established specifications that may affect the safety, purity or potency of that product; or

(ii)Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and

(2) Occurs in your facility or a facility under contract with you; and(3) Involves a distributed biological product

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Some points regarding BPDs

Distributed = biological product has left the control of the licensed manufacturer

• Contract manufacturing

The decision to report should be based on whether the event had the potential to affect safety, purity, or potency of the product

The license holder is required to file at a date not to exceed 45 calendar days from the date that you, your agent, or another person, acquire information reasonably suggesting that a reportable event has occurred

Must report even if the investigation determined that there was no impact

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BPD- Reportable Examples

Raw materials that failed specifications used in manufacturing

Aseptic processing not performed according to procedures

Stability testing not performed at required interval

Missing information in label (product type, lot number, storage temperature, concentration)

Distributed product prior to completion of required testing

Product release prior to validation of manufacturing process

Biological Drug Substance stored at the incorrect temperature

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BPD – Non-reportable Examples

Raw material did not meet specification and was rejected prior to its use

Testing performed incorrectly, invalidated and repeated and found acceptable prior to distribution

Product labeled with a shortened expiration date (not due to failure to meet specification)

Product shipped to the incorrect facility

Customer order filled incorrectly (wrong product, wrong amount), but labeled correctly

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EMEA Observations

Critical = give rise to product that could be harmful to patient

Major = result in product not meeting marketing authorization, major deviation from EU GMP

Other = usually lack information to be classified

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EMEA 1995 - 2005

Critical• Design and maintenance of premises • Potential for microbiological or

chemical/physical contamination

Major/Other• Potential for microbial contamination• Documentation- Quality system

elements/procedures • Unauthorized activities requiring regulatory

filing• Design and maintenance of equipment and

premises

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FDA Observations (1996-2006)

Failure Investigations (Nonconformities)

– Failure to conduct investigations– Failure to extend investigations to related

batches and products– Averaging OOS results with in-specification

results to support release– Delays in starting the investigation– Incomplete investigation into root cause– Failure to take immediate corrective action– Failure to address product impact

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FDA Observations (1996-2006)

Record keeping– Batch Production and Control records do not

include complete information– “post-it” notes with hand-written original data– Lack of procedures– No revision history for procedures

Validations– Discrepancies against Master Validation Plan– Inadequate cleaning validation – Inadequate process validation– Inadequate validation of analytical methods

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In Summary

The successful application of quality systems for the manufacturing of biological products requires the comprehensive synergy between: regulations, science/new technologies, process knowledge, Management accountability and efficient risk management

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Questions?