ExcipientFest

April, 2016

Richard L. Friedman, M.S.

Deputy Director, Science and Regulatory Policy

Office of Manufacturing Quality

FDA/CDER/OC

The Importance of Ingredient Quality

Agenda

State of Control

• Quality Assurance needed throughout the Supply Chain

• Reliable Manufacturing = Reliable Supply

Oversight of Manufacturing and Quality

• Lifecycle Vigilance enabled by strong Quality System at both Ingredient Suppliers and Drug Product Manufacturers

• Quality Risk Management routinely uses accumulated lifecycle information and converts it into knowledge

Examples

• Impact of Raw Material Variation

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State of Control

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Management Oversight of the Supply Chain

In 2012, the FDASIA legislation amended the statutory GMP Definition in the FD&C Act 501 as follows:

“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.”

“Section 711: Enhancing the safety and quality of the drug supply” specifies management oversight from Raw Materials to

Intermediates to Finished Product

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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)

Daily Quality Assurance State of Control

PQRI: Process Robustness (2006)

• Capability: “It is upon transfer to Manufacturing that assessment of the true process capability and robustness as well as any process improvement or remediation will begin…”

• Variation: “When the product is transitioned to Manufacturing, it will most likely encounter a much wider range of variation on the parameters than seen in development.”

For example, regarding the impact of Raw Material Variability:

“For example, [drug product] attribute variability may increase due to a wider range in incoming raw material parameters that cannot feasibly be fully studied in R&D.”

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“Process Robustness- A PQRI White Paper,” PharmEng, May 2006

Compliance and Quality Assurance Is it Compliant to be Reactive?

Q: Is it compliant to delay corrective action until a major manufacturing problem recurs, or a regulatory agency cites the problem?

A: The 1978 preamble discusses why the phrase “designed to prevent” is used throughout the regulations. It explains that the regulatory intent is that operations will be designed and conducted in a manner that “precludes a deleterious effect” on product quality.

Waiting for a regulatory citation or a defective product to act on a problem is not compliant.

Internal systems should identify and address manufacturing quality issues proactively. Effective systems detect signals of adverse drug quality on an early basis, and drive sustainable fixes.

If an entity requires Regulatory Agency Intervention to affect change, it is very likely that their quality system maturity is low.

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Satisfied Customers (Patients)

Supply

Dependability

Consistent

Product Quality

Manufacturing

Reliability

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Quality System Oversight of

Manufacturing and Quality

A Robust Quality System Assures a State of Control

•The Pharmaceutical Quality System:

– Drives Sound Lifecycle Decision-making

– Uses Scientific and Risk-Based Approaches

– Establishes and Maintains a State of Process Control

• Monitors process performance & product quality

• Assures reliable processes and products through Vigilant Management Oversight (checkpoints, escalation) throughout the supply chain

• Creates real “fixes” to problems (long term, systemic)

ICH Q10 Pharmaceutical Quality System

GMP

Pharmaceutical

Development

Commercial

Manufacturing Discontinuation

Technology

Transfer

Investigational products

Management Responsibilities

Process Performance & Product Quality Monitoring System

Corrective Action / Preventive Action (CAPA) System

Change Management System

Management Review

PQS

elements

Knowledge Management

Quality Risk Management Enablers

Daily QRM: Moving from QC (Reactive) to QA (Proactive)

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]

Quality Risk Management (ICH Q9 Guideline)

• Technology focus

– Increase process capability

– Focus on critical control points

• Product

– Stabilize manufacturing steps (decrease variability)

– Guarantee shelf-life

• People

– Result in behaviours that promote superior performance of the Quality System

• Customer

– Reduce deviations

– Reduce market complaint rate

– Reduce technical-related adverse events

ICH Concept Paper (Osaka, November 2003)

Risk Management: Do you connect the dots in your Supply Chain?

Results of

Audits &

Inspections

Knowledge Management – Are you able to“connect the dots” in your Supply Chain?

• “We’re not even talking about connecting the dots, we’re just talking about the overload of having that many.”

- Mark R. Rosekind, Administrator, National Highway Traffic Safety Administration, on the agency’s inability to keep up with the number of consumer complaints

[New York Times, Dec. 3, 2014]

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Examples

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Drug Excipient Quality

• Quality characteristics of excipients significantly influence the quality of the drug products in which they are used

– content uniformity failures, stability failures (e.g., assay, dissolution), microbial contamination, extrinsic physical contamination

• Drug product manufacturers – rely on excipient manufacturers to provide excipients of uniform

quality, physical, and chemical characteristics

– need to qualify sources of excipients to ensure vendor capability and suitability of materials

S. Hoag, Excipient Fest Americas IPEC (2011)

Supply Chain Management

19 Xavier Good Supply Practices Concept Paper, 2015

Recognizes it is a failure of both

the Vendors and the Manufacturer’s

Supplier Management

Program when a the latter is

unaware of a problem or imminent change at the supplier that may affect quality. (This knowledge is a necessity to be able to do effective risk management.)

Ongoing Supply Chain Oversight: Selection, Qualification, Monitoring and Risk Review

20 Xavier Good Supply Practices Concept Paper, 2015

Impact of Raw Material Changes

• What happens when variation in ingredient attributes exceeds development and production experience?

“An API manufacturer changed the site of manufacture... This change was not

reported to the client. Although the process did not change, the move to a new

manufacturing location caused a slight change in pH. Since there was no

specification for pH, this change went undetected until the ingredient was used

in the finished product, causing it to fail. Corrective actions were put in place to

add pH as part of the specifications of the API process and to add the

manufacturer's site address as part of the [contract] reporting requirements.”

• Ingredient Supplier: Do you notify you customer of changes?

• Drug Product Manufacturer: Do you know when your vendor makes major changes?

21 PharmTech (Feb, 2007) “Risk Management in Pharmaceutical Outsourcing”

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Immediate Release Tablet Formulation:

Initial Risk Assessment and studies conducted

Formulation Attribute

DP CQA

Filler

type

& amount

Glidant

amount

Disintegrant

type

& amount

Lubricant type

& amount

Coating

formulation

Assay Low Low Low Low Low

Impurities Low Low Low Low Low

Content

Uniformity Low Medium Low Low Low

Dissolution Medium Low High Medium Low

Disintegration Medium Low High Low Low

Vary type & amount in studies (control strategy: optimized and fixed)

Initial risk assessment:

fix at high level based on prior knowledge

Vary type & amount in studies

(Control strategy: optimized and fixed)

Adapted from Y. Joshi, Teva, ISPE 2011 Annual Meeting

Quality Culture: Reported Mindsets that Led to “Non-compliance”

• We aimed for the lowest manufacturing standards, nothing more, in order to meet production goals. We produced drugs at a quality that we thought we could “get by” with

• Management wanted us to cut corners and play “Russian Roulette.” They were willing to risk that a regulator would not find the major deficiency in an inspection.

• Quality and Operations repeatedly told the responsible corporate executive that the process was not robust and could lead to supply shortfalls. But executive did not want to upgrade old facilities and equipment.

• Quality was considered a cost only. For example, a “speakup” or “preventive culture” was thought to waste valuable time (although it ultimately brought us huge improvements).

• Learning from failures and deviations was minimized. We did not look for root causes or at similar problems on other lines. The issues continued.

Summary

• Basic management role in today’s globalized industry

– Excipient quality plays a critical role in drug product performance

– Understanding intended use is critical to supplying appropriate excipients

– Senior management is responsible for assuring an effective Quality System, at both ingredient and drug product manufacturers

– Ongoing vigilance by both excipient producers and drug product manufacturers is critical to assuring predictable drug quality

“There is no longer such a thing as an American drug supply; there is a global drug supply…We know that, every day, some of those in the manufacturing and distribution chains for these products cut corners in small or large ways. They gain a competitive advantage or a monetary windfall from this non-compliance. But, they put our citizens at risk, and we cannot tolerate that.”

– Commissioner Hamburg, PIC/S Keynote (2011)