Mary Oates, PhD Vice President, Global Quality Operations Pfizer Management of Outsourced Activities and Purchased Materials: Addressing the Interfaces Mary Oates, PhD Vice President, Global Quality Operations Pfizer

Product Quality and Patient Safety Product quality is the responsibility of all parties involved in the development, manufacturing, testing, packaging, distribution and regulation of materials that make up the clinical or commercial drug product Who is ultimately responsible?

Q10 Provides the Answer “The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials.” Based on global regulations Eudralex Volume 4 Chapter 7, Outsourced Activities”, says the “contract giver is ultimately responsible…” 21 CFR 200.10 says that FDA regards independent contract facilities “as an extension of the manufacturer's own facility. “

Questions Remain Why is this important? How is “control” achieved? What are possible consequences of a failure of control?

Risks to Product Quality Two fundamental types Material made under non-GMP conditions Intentionally adulterated material for the purpose of economic gain Heparin, melamine Counterfeits (imitation product sold under “authentic” label) Both can result in risk to patient safety

Greater Risks Today Two fundamental reasons Increased fragmentation and globalization of the clinical and commercial supply chain Every pharmaceutical manufacturer/manufacturing authorization holder (MAH) relies on many others for activities and materials, which may include the finished product itself Explosion of participants Expansion in markets with emerging regulatory expectations

Greater Risks Today (continued) Results in Inconsistent understanding and application of global expectations and regulations across the product lifecycle Numerous hand-offs increase opportunities for both GMP issues and adulteration Difficulty in maintaining oversight of the entire supply chain

Greater Risks Today (continued) Increased emphasis on cost control Affects supply chain participants across the lifecycle in all parts of the world Domino effect Can affect product quality if focus on the fundamentals that protect patient safety is lost

Supply Chain Risk: Change in Philosophy Firms have developed their historical supply chain controls under the assumption that all parties in the supply chain are both ethical and understand and adhere to globally accepted standards It has been believed that an audit of a supplier by the purchasing firm and/or a regulatory authority inspection combined with routine incoming testing of the material was sufficient to assure acceptable quality It has been believed that it was necessary to understand the supply chain from a certain point forward, usually to the firm from which the purchase was being made

The Benefit of ICH Q10 Defines proactive Quality Assurance controls that do not rely on Quality Control to “test in” product quality Process performance and product quality monitoring system Corrective and preventive action system Change management system Management review of process performance and product quality The contract giver must ensure that these comprehensive systems and controls are in place and effective at their contract receivers

Q10 Expectations of the Contract Giver Processes should incorporate QRM and include “Assessing prior to outsourcing…the suitability and competence of the other party…” (e.g., audit program) “Defining the responsibilities and communication processes for quality-related activities…included in a written agreement between the contract giver and contract acceptor” “Monitoring and review of the performance…or the quality of the material…and the identification and implementation of any essential improvements” “Monitoring incoming…materials to ensure they are from approved sources using the agreed supply chain”

Keys to Managing the Interface Knowledge (e.g., due diligence, audits, trend reviews, notification of issues) Control (e.g., quality agreements, ongoing oversight) Continuous improvement (based on knowledge gained) Risk management (e.g., drives supplier selection, extent of oversight)

Criticality of Quality Culture The single most important indicator of a firm’s ability to consistently provide a quality service or product A firm can have all the SOPs, systems and controls required but, without quality culture, product quality and business continuity are not assured Must be measured as a separate element of due diligence Management’s attitude towards compliance and their engagement and proactive commitment to systemic problem resolution Identification, trending and communication to employees of quality metrics Willingness of employees to bring issues forward Number of deviations from procedures or expected results Are there too many or too FEW?

Criticality of Quality Culture (continued) Without a strong quality culture at a contract receiver, risks to product quality cannot be fully mitigated Testing, person in plant, review of deviations by the contract giver are not enough Quality culture cannot be externally imposed Quality culture cannot be changed in the near-term

Case Studies Demonstrating Risks API Supplier 1 API Supplier 2 Intermediate Supplier Contract Manufacturer

API Supplier 1: How Far Back in the Supply Chain Should a Firm Go? Sole supplier of an API, used in a global product made by a contract manufacturer for the MAH Quality Agreement required contract manufacturer to maintain oversight of their supply chain MAH had no business relationship and no Quality Agreement with API supplier

API Supplier 1 (continued) Inspection by a health authority found numerous significant violations of GMPs, e.g., Drums of a critical starting material were stored routinely in the yard with no protection from the weather. The drums were corroded and the status of the material could not be determined. Recalls were required in four countries No further material could be used from this supplier Significant patient and business impact

API Supplier 2: Impact of Cost Pressures Annual audits of supplier prior to 2008, including in 2007, found no significant GMP issues Audit in 2008 found that the supplier had begun using a “shadow factory” after the 2007 audit Crude material was being purchased from a chemical company and was then purified by the supplier in a non-GMP facility Supplier was experiencing significant business challenges, resulting in cash flow issues

API Supplier 2 (continued) Business impact due to inability to use API on hand, WIP or manufacture future product Demonstrates the value of business intelligence Gained through surveillance of local conditions, both in the general business environment and specific to contract receiver

Intermediate Supplier: Importance of Local Conditions Long-time, trusted supplier of API intermediate Due to local circumstances, could not manufacture as promised Manufactured later and back-dated the records to make it appear that the material was made when promised Discovered through review by the contract giver of electric bills for the months in question Supplier did not want to lose respect by acknowledging that they could not keep their commitment Material could not be used

Contract Manufacturer: Quality Culture Due diligence identified the need to improve quality systems before product supply was initiated Changes were implemented over the course of one year Additional testing, person in plant and high level of review of deviations, changes, etc put into place

Contract Manufacturer (continued) Post-manufacturing inspection of containers from one product lot found a high number of a specific defect The contractor removed the containers with the defect and released the lot without investigation Previous information on this type of defect in other lots (inspection data, complaint reports, etc.) was not reviewed The defect did exist in earlier released lots and, when discovered, resulted in a patient-level recall of all lots on the market

Why Did This Happen? Failure of deviation investigation system at contract manufacturer but more importantly Failure of quality culture at the contract manufacturer Risk mitigation activities by the contract giver did not prevent the issue Can only react to what you know The contract receiver must have a quality culture that ensures that the right decisions will be made by employees at all levels of the organization at all times

MAH and the Manufacturer MAH and the contract giver both have the responsibility for the product No longer always the same firm (e.g., licensing deals) Although regulatory reporting responsibilities are clear, quality-decision making responsibilities may become complex Release to market Recall decisions

Management is Responsible Management at the contract giver must be actively engaged to ensure product quality across the entire lifecycle of the contract Must accept or reject potential partners based on thorough due diligence Must know about issues and trends that may affect product quality via a strong notification process Must ensure that controls and systems for both contract giver and receiver are maintained and enhanced using knowledge gained Must recognize the criticality of quality culture at all contract receivers and acknowledge that, without it, significant risks cannot be mitigated Management at the contract receiver is responsible for fully implementing an effective quality system (including assuring full compliance with GMPs at their site), as well as meeting the requirements of the Quality Agreement

Summary There are many reliable, high quality outsourcing partners around the world ICH Q10 enables the contract giver to identify these firms, enhance the partnership and assure product quality through implementation of proactive, risk-based Quality Assurance controls