Lifecycle Product Quality Risk Management

Size: px

Start display at page:

Download "Lifecycle Product Quality Risk Management"

Marian Burke
6 years ago
Views:

1 Lifecycle Product Quality Risk Management Richard L. Friedman, M.S. Associate Director Office of Manufacturing and Product Quality Office of Compliance IFPAC Annual Meeting (Arlington, VA) January, 21-24, 2014

2 TOPICS Management Responsibility to Address Lifecycle Risks Importance of the 3 rd word in QRM (Quality Risk Management)! Senior Management is ultimately responsible Modernization Use of contemporary, capable technology Quality Assurance Robust IT Supports Effective QRM Managing Lifecycle Quality Risks Through More Effective Investigations

3 Management Responsibility to Address Lifecycle Risks

4 Senior Management Support is at the Core of Effective Lifecycle QRM Strong Senior Management Engagement and Commitment to: support surfacing of issues review potentially serious adverse information (very clear escalation policy) and inquire into cause of the problem oversee overall adequacy of both processes and systems (e.g., process/quality performance monitoring, CAPA, change management) remediate identified areas of process or system deficiency by allocating all appropriate resources Includes ensuring suitable manufacturing technologies, and well qualified staff (training, education, experience) who understand the technologies and failure modes. 4

5 GMP Definition Includes Effective Risk Management SEC. 711, 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. 5

6 Modernization

7 Gradual Industry Transformation Current facilities have been built using technologies and processes from the 1950s and 1960s Inefficient Not always capable Needed Capabilities: Modern facilities and technologies, as well as relevant staff competencies A more highly skilled manufacturing organization will be required to deal with the new technologies; however the improved automation and process control should bring staff [FTE] cost savings. ILF GPS Document, Published by ISPE, May 2012

8 Pharmaceutical Quality for the 21 st 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 responsive systems and improvements made based on knowledge gained (i.e., Knowledge Management)

9 Pharmaceutical Quality for the 21 st Century Regulatory paradigm shift to: Performance and Management Based Evaluate against performance standards Lifecycle focus Evaluate capability of firm s quality system to consistently meet performance standards, including determining: whether state of control is maintained throughout the lifecycle determining how effectively the facility manages risks Allow flexibility for technological advancement and continual improvement

10 Robust IT Supports Lifecycle QRM

11 State of Control = Daily Quality Assurance 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) 11

12 Leveraging Information Technology: Decreased Risk Metric Extent and use of IT Effect on Performance Increases manufacturing performance, Increases deviation performance Better data analysis, better risk assessments, better decisions to enhance process control (Macher Nicherson Study)

13 Ubiquitous IT: Better Data Management Leads to Better Control Improved systems to manage data will be required to ensure patient safety, product quality, and cost containment. The Pharmaceutical Quality System must be able to collect, analyze, trend, and store data generated from process control instrumentation and applications. The PQS must be able to to update and support periodic calibration and maintenance of NIR models. [ISPE Global Positioning Strategy, ILF Document, 2012]

14 Ubiquitous IT: Better Detection and Control Systems These systems will improve process control, including: Parameter feedback adjustment into manufacturing process [to] minimize rejects, scrap, and reprocesssing Reducing production cycle times by using on, in, or at line measurements and controls Increased automation to improve operator safety and reduce human errors Facilitating continuous process improvement, managing variability, and improving process efficiency Facilitating the implementation of real time release testing and continuous quality verification [ISPE Global Positioning Strategy, ILF Document, 2012]

15 Ubiquitous IT Continuous Quality Verification CQV should be designed to: React to process [e.g., input materials] and equipment parameter variation, or perturbations Utilize process control systems and online monitoring of CPPs and quality attributes to correct or shutdown the system and to divert non conforming materials Bring the process back into control once the source of the variation or perturbation has been addressed [ISPE Global Positioning Strategy, ILF Document, 2012]

16 Managing Lifecycle Quality Risks Through More Effective Investigations

17 Some Common Investigation-Related Deficiencies 1. Failure/OOS SOPs are good, but not followed 2. OOS s are tested into compliance 3. Complaints not substantively investigated (rote process) 4. Adverse complaint trend not detected or investigated 5. Scope of Investigations (see ): isolated issue or recurring? 6. Appropriate Expertise (SMEs) to investigate/diagnose/correct 7. Handling failures at contracted sites (CMO, contract lab) 8. Handling stability failures 9. Root Cause identification and correction 10. Effectiveness Checks 11. Resources to make lasting correction, not patchwork 12. Technology choice at launch was not actually capable enough

18 Case Studies (Note: Warning Letters are paraphrased) 18

19 Warning Letter Endotoxin Contamination (Unsuitable Materials) Failure to subject each lot of a component with potential for microbiological contamination that is objectionable in view of its intended use, to microbiological tests before use [21 CFR (d)(6)]. For example, your firm has not tested each lot of raw materials used in the manufacture of Injectable Emulsion finished products to determine the presence and levels of bacterial endotoxin. Your firm's responses, state that your firm will subject each lot of incoming raw material to full microbiological testing, including endotoxin testing. Failure to thoroughly investigate failure of a batch or any of its components to meet any of its specifications For example: Your firm's analysis of pooled samples from customer complaint vials of finished product lot revealed an endotoxin concentration of. Your firm failed to identify a root cause and failed to implement a corrective action. 19

20 Warning Letter Endotoxin Contamination (Unsuitable Materials) 41 Adverse Events reported Some individual units produced by firm for injection contain elevated endotoxin, while others pass specification CDC issues health advisory: Clinicians Advised to Halt Use of from Tainted Lots. The Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) have been investigating recent cases of febrile reactions among patients undergoing endoscopy in the United States. This investigation has revealed that all of the case patients received the anesthetic from 100 ml vials manufactured by Pharmaceuticals. Testing done by the FDA has found that two lots of this product that were in use in facilities reporting febrile reactions were positive for elevated levels of endotoxin. The lots are and. [The firm] is initiating a voluntary recall for these lots, and clinicians are advised to immediately stop using these lots... 20

21 21 Warning Letter Stability Failures Multiple assay stability failure investigations for cream. Reason: separation of formulation components in the finished product during its shelf life. Investigation concludes that reformulation is indicated. However, the firm decided not to pursue this as a corrective action plan. Firm response to the Form 483 states that there is no need for reformulation of the topical product. Firm s rationale is that stability failure of 3 out of 24 batches was not very significant. FDA Warning Letter Issued. Discusses lack of CAPA: We are concerned that you have not taken any action to reformulate, reduce the shelf life, or withdraw this product, which is not supported by stability data.

22 Warning Letter OOS Low dose, therapeutically significant drug. Release assay spec of %. Product assays at 92.8%. Firm s investigation report said nothing in the lab investigation was found to invalidate this original assay result. Retest yields 93.3%. Firm says this confirms accuracy of first result. Testing of new sample yields an average of 95.6%, including one result at 95.1% (i.e., retest results still atypically low, and marginally passing) Batch Released. Lab error assumed. Investigation considered complete. Lacked Manufacturing Investigation. For example, what weaknesses/events in production may have caused the low assay results? No CAPA, and batch not placed on stability program. 22

23 Warning Letter Stability Issue (Manufacturing Root Cause Not Identified) For over 5 years, highly potent hormone tablet is not meeting assay at various stability testing intervals (RT/ambient conditions). Recent field alert shows assay failure at 9 months. FDA is concerned that your current stability data does not support your labeled expiration date. Significantly, your firm failed to identify the root cause of the problem and has been unable to implement appropriate corrective and preventive actions (CAPA), but has continued to produce and release these products that may be subpotent. Firm purchased the product from another company. Excess residual solvent after drying can lead to oxidation. Firm modified endpoint of drying process to temperature based (instead of drying time). However, 2 of 3 validation lots failed RT stability using the new process.

24 Recurring Dissolution Recalls Tablet Product: Highly Potent Hormone Tablet Recurring dissolution failures discovered by stability program for several years, resulting in many recalls Hundreds of commercial lots produced / year Minimal lots on stability Formulation includes shellac as a major ingredient High variability, and apparently affected by water content, age In process formulation also often shipped a long distance between manufacturing sites, potentially adding to variability Firm begins to test many other lots on stability, and more lots are found to fail dissolution Firm ultimately reformulates. Changes include adding a more suitable polymer excipient that reliably controls release rate Shellac no longer used 24

25 Warning Letter Basic Flaws in Quality System 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 (CAPA) actions. FDA expects your firm to perform a comprehensive assessment of manufacturing operations to ensure that drug products conform to FDA requirements.

26 Final Thought: PAT Enables Better Lifecycle Decisionmaking Advantages of using process analytical technology: Reducing production cycle times by using on-, in-, and/or at-line measurements and controls Preventing rejects, scrap, and re-processing Real time release Increasing automation to improve operator safety and reduce human errors Improving energy and material use and increasing capacity Facilitating continuous processing to improve efficiency and manage variability For example, use of dedicated small-scale equipment (e.g., 26 same scale eliminates often challenging scale- up issues)

Laboratory OOS Investigations The Missing Link

Laboratory OOS Investigations The Missing Link India Pharmaceutical Alliance Carmelo Rosa, Psy.D Director Division of Drug Quality I November 6-17, 2017 Indian Pharmaceutical Alliance DISCLAIMER: The views