CGMPs and Drug Quality Assurance

Richard L. Friedman, M.S.Associate Director

Office of Manufacturing and Product Quality Office of Compliance

FDLI “Understanding CGMPs” ConferenceJuly 10, 2013

TOPICS

• CGMP and the Consumer• Quality Systems

– Oversight of State of Control is basic requirement of GMP

– Examples• Pharmaceutical Quality in the 21st Century

– Paradigm shift

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CGMP and the Consumer

CGMP Objective:Assure Quality of Every Batch, Every Day

“We rely upon the manufacturing controls and standards to ensure that time and time again, lot after lot, year after year the same clinical profile will be delivered because the product will be the same in its quality… We have to think of the primary customers as people consuming that medicine and we have to think of the statute and what we are guaranteeing in there, that the drug will continue to be safe and effective and perform as described in the label.”

- Janet Woodcock, M.D.

Potential for Tension between Commercial and Public Health Interests

• “The probability alpha, also known as the producer's risk, is the risk that adequate product is rejected. The probability beta is known as the consumer's risk because defective product is accepted.”

• The associated risk probabilities will depend on “inspecting and scrapping good product” or “the [later] costs of shipping bad product.”

[Jim Colton, Quality Digest, Dec., 2011 “Statistical Tools for Pharmaceutical Manufacturing”]

Sources of Variability

Major factors that can affect manufacturing output and adversely impact drug quality:

– Materials (APIs, Excipients, etc.) – Equipment – Environment– Operators – Procedures (SOPs, master batch records, etc.)– Measurement Systems

CGMP: Framework for Industrial Quality Assurance

A drug manufacturer is responsible for implementing dependable daily operations that assure consistent drug quality. Management’s daily decisions on myriad issues involving equipment, materials, maintenance, staff qualifications, supervision, process control, and investigations will ultimately determine the quality of the drugs that are shipped from a given facility.

[Woodcock, J and M. Wosinska, Clinical Pharmacology & Therapeutics, “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortage,” Jan 2013]

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Key Ingredient: Top management support for major quality improvements

• Survey of 400 executives (many industries) found that most companies are willing to sacrifice long term economic value in order to deliver short term earnings.

• Quality-oriented leaders establish systems that detect problems (new or emerging risks)– Monitor for OOT instead of waiting for OOS– Early warning system that enables effective

management review (QA instead of reliance on QC)Mauboussion, M. “The True Measures of Success,” Harvard Business Review, Oct, 2012

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Quality Systems

Reliable Manufacturing

• …Clearly the responsibility for maintaining quality rests squarely with the manufacturers themselves...the widespread and successful adoption of six sigma and related quality management techniques in other manufacturing sectors would imply that reliable, high-quality manufacturing is also attainable in the pharmaceutical sector.

• We must ask ourselves, in an area where the stakes are so high, why is this not being achieved?

Dr. Janet WoodcockCommentary in May-June 2012 edition of PDA Journal

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Importance of an Effective Pharmaceutical Quality System

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.”

ICH Q10, Section 3.1.3 Commercial Manufacturing

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A Quality System creates real fixes

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• A robust quality system is:– Science and risk-based– At the core of Good Manufacturing Practice – Vigilant and Proactive – Culture-focused – Able to identify issues while they are still small– Responsible for assuring any contracted site is qualified to do the

function, and performed it satisfactorily– Supportive of business needs because it creates dependability

and sustainability, as well as efficiency and effectiveness!• It should not be:

– Reactive or defensive (issues should be surfaced)– Solely a procedural approach (not only“plan-do”)

GMP-Compliant Quality System:Effective Management Oversight & Controls Over Manufacturing

FDASIA Revision to FD&AC Act

ENHANCING THE SAFETY AND QUALITY OF THE DRUG SUPPLY. Section 501 (21 U.S.C. 351) is amended by adding:

“For purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.’

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Leadership and the Corporate Quality Culture

Quality/Compliance

Path

Choices

Unreliable Systems & Manufacturing Problems

Defects, Regulatory Actions, Business Failures

Strong Corporate Quality Culture & Manufacturing Consistency

Daily Decisions ...

… influence your direction

Adapted from Richard Davis (2004)

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How mature is your quality system?

Level 1: Small problems ultimately snowball into larger ones, and management becomes aware only when there is a crisis.

Level 2: Nearly always reactive, but there is some willingness to change. Patchwork corrections are the norm.

Level 3: More proactive. Increasingly surfaces major issues and makes lasting systemic improvements.

Level 4: Routinely acts preventively, and institutionalizes (rewards) meaningful process and system improvements.

1

2

3

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Good Decisionmaking Through Sound Quality Risk Management (QRM)

• The output/results of the risk management process should be reviewed to take into account new knowledge and experience.

• Once a quality risk management process has been initiated, that process should continue to be utilized for events that might impact the original quality risk management decision, whether these events are planned (e.g., results of product review, inspections, audits, change control) or unplanned (e.g., root cause from failure investigations, recall).

• The frequency of any review should be based upon the level of risk. Risk review might include reconsideration of risk acceptance decisions (section IV.D.4). [ICH Q9]

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Risk Management: Some Information That May Trigger Risk Review or CAPA

Nonconformances, discrepancies, deviations, failures, recalls Product Quality Data Process monitoring results

e.g., trend analyses from process performance and product quality monitoring

Equipment or Facility issues Raw Material Issues Regulatory Findings (local or at another site) Audits and self-inspections Complaints/Returns Stability Testing results

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• “After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.” (FDA PV Guidance)

• State of Control: A condition in which the set of controls consistently provides assurance of continued process performance and product quality. (ICH Q10)

• FDA’s CGMP inspection program began evaluating state of control using the quality systems approach in 2002.

Effective monitoring & control systems

• FDA’s 2011 Process Validation Guidance:– An ongoing program to collect and analyze product and process

data that relate to product quality must be established. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

– Scrutiny of intra-batch as well as inter-batch variation is part of a comprehensive continued process verification program (lifecycle stage 3).

FDA Warning Letter

• When preparing your SOPs, please note that a CGMP-compliant quality system supports a sustainable state of control. This includes but is not limited to systems to ensure proper raw materials, vigilant quality monitoring, and appropriate corrective and preventive actions. FDA expects your firm to perform a comprehensive assessment of manufacturing operations to ensure that drug products conform to FDA requirements.

Contracting Risks and Complexity

“Not only are buyers unable to observe manufacturing quality,but firms that contract out manufacturing of their productoften do not have the same level of insight into or oversight ofthe contract manufacturer’s quality systems as they would haveinto their own. Over-commitment on manufacturing capacityby a contract manufacturer can lead to an unsustainably highnumber of products on each line and substandard oversight ofthe process.”

[Woodcock, J and M. Wosinsksa, Clinical Pharmacology & Therapeutics, “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortage,” Jan 2013]

Your firm failed to thoroughly investigate several non-sterility complaints. For several weeks spanning April-May, your firm received complaints from multiple customers (sponsors) informing you that USP IV bags were contaminated with a swirling mass in LVP bags, and provided the identity of fungi and bacterial contaminants. Your firm did not adequately investigate the root causes of the problem, or address other lots that were impacted by the problem. You ultimately found that sharp edges on stereos used in your LVP bag labeling operation caused a recurring problem with pinhole punctures in bags. This loss of container closure integrity led to the contamination. However, your firm originally failed to address other impacted lots beyond those with specific complainants… Your firm also submitted late Field Alerts regarding these serious nonsterility issues.

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Warning Letter LVP Contract Manufacturer

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“OOS results may indicate a flaw in product or process design. For example, a lack of robustness in product formulation, inadequate raw material characterization or control, substantial variation introduced by one or more unit operations of the manufacturing process, or a combination of these factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of the product or process be undertaken to ensure reproducible product quality.”

- FDA Guidance on Investigating Out-of-Specification Test Results for Pharmaceutical Production (2006)

Design

Top 10 Drug Observation in Turbo EIR (since 2000)Count CFR No. Citation Text

1656 21 CFR 211.22(d) The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. Specifically, ***

1089 21 CFR 211.100(b) Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance]. Specifically, ***

1035 21 CFR 211.160(b)

Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. Specifically, ***

1023 21 CFR 211.192 There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. Specifically, ***

999 21 CFR 211.100(a) There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, ***

991 21 CFR 211.110(a) Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Specifically, ***

783 21 CFR 211.165(a) Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release. Specifically, ***

770 21 CFR 211.25(a) Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations]. Specifically, ***

750 21 CFR 211.67(b) Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, ***

729 21 CFR 211.188 Batch production and control records [are not prepared for each batch of drug product produced] [do not include complete information relating to the production and control of each batch]. Specifically, ***

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Pharmaceutical Quality in the 21st Century

Pharmaceutical Quality in the 21st Century• Regulatory paradigm shift to:

– Performance and Management-Based • Establish performance standards (e.g., metrics)

– Lifecycle focus• Evaluate capability of firm’s quality system to consistently

meet performance standards, including determining:– whether state of control is maintained throughout

lifecycle– determining how effectively the facility manages risks

• Allow flexibility for technological advancement and continual improvement

Pharmaceutical Quality in the 21st Century

• Industrial paradigm shift to:– Quality Systems approach, with strong process

performance and quality monitoring programs, and a proactive quality culture

– Engaged Senior Managers who create and reinforce the quality culture, through both policies and actions

– Scientific risk management throughout lifecycle, with CAPA and continual improvements made based on knowledge gained