Required GMP Standards and Inspections

Required GMP Standards and Inspections Alain Kupferman Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

STATE OF CONTROL Equipment Personnel Drug meeting requirements Methods Premises State of Control State of Control:a drug firm is considered to be operating in a state of control when it can guarantee a finished drug product for which quality, strength and purity has been assured throughout production and that the product is compliant with its registration Definition of conditions under which drugs are manufactured, packed, tested, held

ELEMENTS OF COMPLIANCE EQUIPMENT COMPONENTS PERSONNEL FACILITIES PROCESS QUALIFICATION ANALYSIS TRAINING QUALIFICATION DEVELOPMENT VALIDATION PRODUCT APPROVAL BY AUTHORITIES

MONITORING OF COMPLIANCE SELF-INSPECTION INSPECTION

DEFINITIONS ComplianceThe state of conformity of a regulated party (including a corporation, institution, individual or other legal entity) or a product with a legislative or regulatory requirement. Compliance Monitoring Actions planned to maintain regular surveillance in order to evaluate compliance with applicable requirements of the National Regulatory Authority (NRA) and its associated Regulations. This includes a wide variety of fact gathering and assessment activities such as inspections, market surveys and a product sampling program. Compliance VerificationActions taken to verify compliance in response to information regarding known or suspected non-compliance with the applicable requirements of the NRA and its associated Regulations. This includes actions such as information gathering either off-site or via on-site visits.

DEFINITIONS Enforcement Actions that may be taken to induce, encourage or compel compliance with the NRA and its associated Regulations. Inspection On-site monitoring and assessment against the applicable requirements of the NRA and its associated Regulations. Inspections are routinely conducted on a predetermined cycle or as required to assess compliance. Inspector Any person designated as an inspector for the purpose of the enforcement of the NRA Investigation Actions taken to gather evidence to support a case referral for potential judicial determination regarding specific violations of the NRA and its associated regulations.

REASONS FOR INSPECTION • Regular schedule based on general GMP’s • Pre-approval inspections • Submission of a variation • Submission of an NDA • New products and/or manufacturing changes • Site changes • For cause inspections • Recalls or significant complaint • Past inspection history

TRENDS • Focus on Risk and Quality Systems • Doctrine of Liability for Executives • Process Analytical Technology

FOCUS ON QUALITY SYSTEMS & RISK Quality Systems Inspection Program Assess Firm's State of Control Systems Approach (6 systems) Executive Management Expected to Establish Effective Procedures and Controls to Ensure: Timely Investigations Supportable Decisions Are Documented

FOCUS ON QUALITY SYSTEMS • FDA Systems Approach (6 systems) • Quality System • Facilities System • Equipment System • Materials System • Production System • Packaging & Labeling System The idea underlying this approach is that deficiencies in one system will affect all other systems as well.

FDA FOCUS ON QUALITY SYSTEMS & RISK “Risk Based Pharmaceutical cGMP Initiative” Goals (GMPs for 21st Century) the most up-to-date concepts of risk management and quality systems approaches should be incorporated while continuing to ensure product quality (PAT); the latest scientific advances in pharmaceutical manufacturing and technology should be encouraged; the submission review program and the inspection program should operate in a coordinated and synergistic manner; regulation and manufacturing standards should be applied consistently; management of the program encourages innovation in the pharmaceutical manufacturing sector; and FDA resources should be used most effectively and efficiently to address the most significant health risks

WHY A NEW FOCUS ? • Increased number of pharmaceutical products and a greater role of medicines in health care • Decreased frequency of FDA (NRA) manufacturing inspections as a result of fewer resources available for pharmaceutical manufacturing inspections • FDA’s (NRA’s) accumulation of experience with, and lessons learned from, various approaches to the regulation of product quality • Advances in the pharmaceutical sciences and manufacturing technologies • Application of biotechnology in drug discovery and manufacturing • Advances in the science and management of quality • Globalization of the pharmaceutical industry

RISK ASSESSMENT

RISK ASSESSMENT COMPONENTS PRODUCT COMPONENT PROCESS COMPONENT FACILITY COMPONENT

PRODUCT COMPONENT 1. Intrinsic factors Factors such as sterility, medical gas, and the determination of prescription (Rx) versus over the counter (OTC) are crude methods to distinguish between products with higher and lower potential for public health consequence should there be a drug defect. If there is a quality defect, sterile drugs would have a higher public health consequence than nonsterile drugs; hence, sterile drugs should be given a higher weight. Specific products where there is a heightened risk of cross-contamination, such as sites manufacturing highly sensitizing agents (e.g., penicillin) and at least one other product using similar processing methods should be taken into account. 2. Past recalls for quality defects / Complaints Drug recall data provide information on past recalls for quality defects with potential for human health hazard.

PROCESS COMPONENT Some processes are more complex and more susceptible to problems than others. A primary goal of CGMP inspections is to ensure that processing operations are in a state of control. Two types of process-related factors were identified for inclusion in the risk-ranking model: 1. Factors associated with maintaining process control 2. Factors associated with potential vulnerability to product or environmental contamination

PROCESS COMPONENT It is important to arrive to a risk-ranking (i.e., from high to low) of the probability of a loss of a state of control and, independently, the vulnerability of the process to contamination for a product category and processing operations associated with that product category. It is necessary to survey on risks associated with commonly employed manufacturing operations (e.g., measuring, mixing, compression, and filling) and for a variety of product categories (e.g., immediate and modified release solid-oral drugs, sterile liquids, metered dose inhalers, and active ingredients by chemical and fermentation processes).

PROCESS COMPONENT: RISK MANAGEMENT ICH Q9

FACILITY COMPONENT The facility component of the US FDA risk ranking model includes 4 factors: 1. History of violation (e.g., CGMP deficiencies have higher weights) 2. History of inspection (e.g., no prior inspection, newly registered/ licensed or no CGMP inspection in the past 2 years have higher weights than those with recent CGMP inspection) 3. Estimated volume of production output (surrogate for exposure, e.g., higher volume and production output, higher weights) 4. Type of establishment (e.g., manufacturer, repacker, contract lab)

MANAGEMENT CONTROLS Strict Liability Requires Diligence & Management Controls to: • Prevent Violations • Detect Problems When They Occur • Correct Root Cause Issues Corporations Act Through Individuals Individuals Can Be Held Accountable • The FD&C Act • “…dispenses with the conventional requirement for criminal conduct -- awareness of some wrongdoing.“ • “…a positive duty to seek out and remedy violations when they occur … and …, a duty to implement measures that wil ensure that violations will not occur.” • “…and permits conviction of responsible corporate officials, who … have the power to prevent or correct violations”

PROCESS ANALYTICAL TECHNOLOGY PAT • PAT is considered to be a system for • designing , • analyzing, and • controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”

PROCESS ANALYTICAL TECHNOLOGY 1. PAT Tools 2. Process Understanding 3. Risk-Based Approach 4. Integrated Systems Approach 5. Real Time Release

PROCESS ANALYTICAL TECHNOLOGY • 1. PAT Tools • Multivariate data acquisition and analysis tools • Modern process analyzers or process analytical chemistry tools • Process and endpoint monitoring and control tools • Continuous improvement and knowledge management tools • 2. Process Understanding • A process is generally considered well understood when • all critical sources of variability are identified and explained; • variability is managed by the process; and, • product quality attributes can be accurately and reliably predicted over the ranges of acceptance criteria established for materials used, process parameters, and manufacturing environmental and other conditions. • The ability to predict reflects a high degree of process understanding. • Although retrospective process capability data are indicative of a state of control, these alone may be insufficient to gauge or communicate process understanding

PROCESS ANALYTICAL TECHNOLOGY 3. Risk-Based Approach Within an established quality system and for a particular manufacturing process, there is an inverse relationship between the level of process understanding and the risk of producing a poor quality product 4. Integrated Systems Approach Development, manufacturing, quality assurance, and information/knowledge management functions 5. Real Time Release Real time release is the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process analytical data

PROCESS ANALYTICAL TECHNOLOGY and ICH

Error Precursors

Human Errors Organizational / systemic: For example, when the work culture priority in the company is efficiency and productivity.Of course, efficiency and productivity are important, but so is quality. So there has to be a balance. Some companies put quite too much emphasis on productivity; managers lead by example and people are just cutting corners the same as the managers, and they are therefore taking product and regulatory risks to reduce cost and increase profits. Some companies have gone so far as to say that they would take the risk of doing this or that, because they don’t expect the NRA to catch them doing it. Procedural (SOPs): Sometimes SOPS are not clear, or the instructions are contradictory. It was not the operator’s fault, it is the company’s fault, because the SOPs are not clear in the first place. How do you train someone in SOPs that are not clear? Careless work: That is another type of human error, where people are forgetful. They are not paying attention to what they are doing, or they are careless. Sometimes people have serious personal problems, they have a lot of stuff in their minds. This happens. But also the work environment may have an influence on these types of errors. For example if you have an operation where you have to rely on the person’s memory to execute some steps correctly, you [may be] setting that person up for failure. Voluntary / intentional: The SOP is inadequate and the employees know the SOP is wrong and they just don’t follow it.Many times we see that employees do backdating, sometimes following instructions from managers. Involuntary: Errors due to human variability. We know there are going to be errors. We are just human. We are all human. But what can we do to minimize them?

FINDINGS FROM INSPECTIONS Source:MHRA (MCA)

FINDINGS FROM INSPECTIONS

FINDINGS FROM FDA INSPECTIONS

INSPECTION RESULTS • Buildings and Facilities • Not of adequate size or capacity for intended activities • Failure to provide separate or defined areas to prevent contamination, cross-contamination or mix-ups • No appropriately cleaned or maintained • Effectiveness of sanitation has not been established • Poorly designed air handling systems or not appropriate for intended activities • Not monitored for temperature or humidity • Poorly designed water systems • Poor hygienic zone system • Use of low quality building fabrics leading to easily damaged walls and doors which become difficult to clean • • Incorrect airflows and pressure differentials to prevent cross contamination • • Sterile area changing rooms insufficient in size or bqd lqyout • • Goods receipt areas of insufficient size

INSPECTION RESULTS • Equipment • No or improperly maintained cleaning and usage logs • No expiration dating of cleaned equipment • No or inadequate cleaning validation • Not identified as to use or status • No or insufficient SOP for use • Not or incorrectly identified in batch record • Inadequate calibration program • Preventative maintenance program not in existence or inadequate

INSPECTION RESULTS • Raw Materials and Components • Poor labeling or mislabeling • Poor segregation to prevent mix-ups • Inadequate sampling conditions and testing procedures • Incomplete SOPs for receipt, storage, sampling and disposition • No or inaccurate inventory system or log • • Insufficient assurance of supplier adequacy • • No evidence that APIs have been manufactured to GMP • • TSE risks inadequately controlled • • No vendor recertification or secondary/backup to suppliers • • No system to address problems with suppliers, e.g. audit or increased testing • • Poor sampling facilities • • Insufficient identification testing (Annex 8)

INSPECTION RESULTS • Quality Management Systems, Records and Reports • Incomplete batch and test records: • - Steps not verified • - Laboratory results not included • - Equipment not identified • Not reviewed or revised periodically • Inadequate documentation of deviations and OOS • Incomplete or tardy recording and investigation of complaints and incidents • • No regular management review of quality indicators • • Lack of quality improvement / CAPA processes • • Insufficient change control • • Ineffective self-inspection systems • • Recall systems incomplete and untested • • Non-compliance with previous inspection commitments • Inadequate recording of training and effectiveness • Insufficient documentation of maintenance and calibration activities

INSPECTION RESULTS • Laboratory Controls • Not based on scientifically sound and appropriate (specific) specifications • Test methods not appropriately validated • Standard Operating Procedures (SOP) • Not in existence. • Incomplete or not in sufficient detail • Not followed or deviations not justified • Not periodically reviewed and updated

INSPECTION RESULTS • Procedures and Process Controls • Aseptic processing principles not applied or validated: • - Not all aseptic processes are included in challenge studies. • - Product exposed to environment that is not properly controlled. • - Failure to validate aseptic connection. • - Failure to follow SOP. • Investigations following excursions not performed, documented or are inadequate: • - Do not include other batches associated with failure. • - Are not completed in timely manner.

INSPECTION RESULTS • Procedures and Process Controls • In-process hold times not validated or incorporated into stability program • Sterilization procedures not appropriately validated or revalidated • No or inadequate process validation studies or in-process testing • Inadequate changeover procedures for multi-purpose areas • No time limits for completion of time-sensitive production phases

INSPECTION RESULTS • Environmental Monitoring • Not performed during manufacturing operations • Appropriate limits: • - Not based on trends • - Do not consider nature of the product • Inadequate monitoring frequencies • Improper location of sampling devices or monitoring locations not identified • No viable monitoring close to point of fill for aseptic products • Poor handling and positioning of settle plates in critical zones • Poor or no continuous particle monitoring in critical zones • Inadequate personnel monitoring • Wash bays, cold stores and water systems not monitored microbiologically • • No monitoring during or following building work • • No assessment of recovery or growth promotion • Sampling procedures not representative of usage procedures • Data not linked to manufacturing process • Investigation following excursions are no performed,not documented, or inadequate: • - Are not complete, do not consider impact on product, are not completed in timely manner • Procedures allow for consecutive out of specification results before taking action

CONCLUSION Adopt the mindset Be prepared and compliant all the time, NOT just at the time of the inspection Conduct at regular intervals Inspection Readiness Training Self Audits Integrate audit program with overall system based GMP program.

Required GMP Standards and Inspections