IF IT WAS NOT DOCUMENTED, THEN IT WAS NOT DONE” Fundamentals of US Regulatory Affairs Chapter 8

Objectives Understanding GMP Understanding basic quality system concepts and quality system regulations Overview of key GMP regulations Differences and similarities between pharmaceuticals and medical devices Concept of clean design and process validation

Objectives (cont) Basic elements of sanitary equipment design Effective cleaning and sanitation programs CAPA system (Corrective And Preventative Action) Cross-contamination risk within the manufacturing environment

cGMP (Current Good Manufacturing Practice) GMP should be “Designed” to be flexible to allow each manufacturer to decide individually how to implement the necessary controls by using scientific sound design, processing methods and testing procedures The “C” in GMP means current – up to date technologies Overall concept Quality should be built into the product Testing alone cannot be relied on to ensure product quality A product that is ‘fit for its purpose”

cGMP Principles Build QUALITY in - you cannot test or inspect quality in to a product – it must first be quality Have controls in place for each step of the process – increase the likelihood the product produced in safe and fit for its intended purpose Product the product from contamination and cross-contamination and prevent mix-ups.

cGMP Principles (cont) Know what you are doing in advance and document what really happened (document everything) Work towards consistency and control and monitor your system Have an independent Quality Assurance Group

GMP is global It is influenced by international bodies ICH International Organization for Standardization (ISO) cGMP Harmonization Analysis working group (FDA 2003) Modify 21CFR210 and 211 to meet ICH

GMP Regulations Non-biologics – FD&C Act section 501(a)(2)(b) Finished Pharmaceuticals – 21CFR211 – Clinical supply dosage forms (including placebo) and commercially marketed dosage form ICH Q7A GMP for Active Pharmaceutical Ingredients Biologic Drug Products – 21CFR 210 and 211; 21CFR 600-680; comply with BLA commitments and applicable standards Quality Systems - ISO9000, non-US Pharmaceutical quality management requirements FDA Quality Requirement System (QRS) Guidances and CPGM (Compliance Program Guidance Manuals) – for FDA GMP inspections – details cleaning validation, water systems, microbiological and QC labs, sterile bulk substance

cGMP Requirements (as many regulations as GCP) A Quality System (change control, validation, CAPA Qualified and trained personnel Fit for use buildings and facilities to meet the purpose Equipment that is suitable, clean, maintained and calibrated

cGMP Requirements (cont) Controls in place to prevent degradation or contamination of materials (raw, in process and final) Production and in-process controls for performance monitoring and deviations Proper packaging and labeling – ID and Protection Laboratory controls – specifications , samples, testing

Generic Drugs and GMP Is identical or bioequivalent to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use Analytical testing of the chemical composition of the generic is determined to be the same as the branded product

Medical Devices FD&C Section 501(h) and 520(f)(1) Amended in 1976 - Medical Device Amendment 1978- Device GMP initiated 1996 – Revised ‘Quality System Regulations’ Human factors techniques and data should be integral considerations in all medical device design control components Each manufacturer must establish and maintain procedures for verifying the design input Design validation must ensure devices conform to defined user needs and intended users and must include testing of production units under actual or simulated use conditions Design validation must include risk analysis and use error

Combination Products Utilize the capabilities of two or more different product types to provide effective health care (21CFR3.2(c)) and cGMP (21CFR Part4 Subpart A) The drugs and devices are still covered by individual regulations (21CFR210 and 211; 21CFR810 respectively)

cGMP for Phase 1 Investigational Drugs Guidance for Industry: Current GMP Practice for Phase 1 Investigational Drugs (July 2008) 21CFR201.2 – If the Phase 1 drug is already marketed or used in Phase 2 or 3 trials, then it is exempt from 21CFR211 Trial Materials need Well-defined and written procedures Adequately controlled equipment and manufacturing environment Accurately and consistently recorded data

cGMP for Phase 2 and Phase 3 Investigational Drugs Guidance: Preparation of Investigational New Drug Products (1991)

Adulterated Drugs or Devices A drug or device is considered adulterated unless it is manufactured in conformity with cGMP practices (newest industry standards) A robust quality system is required to provide the necessary framework for implementing Quality by Design, continuous improvement and risk management Whether documented on paper or electronic all data must be able to be traced back to the source and verified

Device Quality System Regulation (QSR) Quality System is the organizational structure, responsibilities, procedures, processes and resources for implementing process management Medical devices QSR are found in 21CFR820 ICH Pharmaceutical Quality System Q10 QSR states specific requiremnts for such key elements as management responsibility, quality planning, CAPA, design controls and purchasing control

Corrective And Preventive Action (CAPA) Each Device manufacturer must maintain history files, a device ,aster record and a device history record for each type of device Every company must have quality plans and quality system records that define its quality practices Device Manufactures are required to establish purchasing controls and institute post-distribution device failure investigations and CAPA for defects or recurring technical problems

Pharmaceutical Quality System Guidance for Industry: Quality Systems Approach to Pharmaceutical cGMP Regulations (June 2006); 21CFR210 and 211 The six-system inspection model Quality system Facilities and equipment system Materials system Production system Packaging and labeling system Laboratory controls Robust Quality System will have SPOs Training Records and good documentation practive

QC vs. QA Quality Control vs. Quality Assurance The QC unit monitors overall compliance with cGMPs The QA units supplies oversight by auditing the functions They identify and investigate OOS (Out-of-Specification) results, deviations and failures in both production and the analytical laboratory.

Facilities and Equipment System Areas are designated as clean and dirty, Physical separation, equipment and staff for each operation Specify personnel protection equipment and to prevent contamination by humans Areas must operate to a single standard - GMP or non-GMP Need to have designed into areas Building materials, air handling, temperature, microbiology

Records Distribution records must be maintained to aid in recalls Environmental Controls, Support systems, Alerts, Action Limits must be established The environment must be controlled and monitored to prevent product cross-contamination and contamination by harmful microorganisms or extraneous matter (filth)

Microbiology Effects on product Causing human illness Product Discoloration Malodors Production of gasses that can lead to package swelling or busting Breakdown in viscosity or elasticity Otherwise unable to perform as intended Types: contact or airborne/ bacterial, yeast or mold Resistance to product preservative system or sanitizers (think antibiotic resistance) Classic Microbiology – takes 48-72 h for aerobic bacteria; 72-120 h for yeast or mold

Microbiology – areas of risk Heat exchangers Air compressors Pumps Water systems (Grades of water – WFI) Valves Ancillary Equipment (O-rings, pipes, clamps, gaskets Effective Cleaning and Sanitation (C&S) Autoclaves, sanitizer, alcohol, steam generators CIP – Conducted on assembled equipment COP – Conducted on dissembled equipment

Material System The measurement and activities to control finished products, components containers and closures Inventory Control Process Drug Storage Distribution Controls and Records Written procedures for the receipt, storage, testing and approval or disapproval of raw materials components, products, containers and closures

Production System Quality and manufacturing process and procedures (and changes to them) must be defined, approved and controlled. Batch numbering and maintaining proper traceability is required Track batch, equipment use records and labeling used, personnel, raw material controls are traceable Verification of all steps including sign-off are required for critical process steps. All batch records must be reviewed na d have QA approval before the product is released

Package and Labeling System FDA ‘recommends’ as part of the design process and before commercial products that the controls for all processes within the packaging and labeling systems be planned and documented with written procedures. Discriminating features of different products/strengths Distribution of all labels to manufacturing unit Reconciliation is performed between label issued, applied and returned (damaged) to insure 100% accountability

Laboratory Control system Laboratory Controls and written documentation Analytical Methods validation and laboratory equipment qualification Scientifically sound stability program to support labeled expiration dating Sampling program Statistical models to determine sample scheme Proper training of QC staff to collect samples Batch, water, microbiology, etc. Retesting conditions

Critical Elements of Subsystems SOPs Describes how the company complies with the drug or device regulations and are critical to GMP compliance See GLP review on overall view of SOPs Change Control System – to prevent unintended consequences to product quality Training Records

Verification, Qualification and Validation apply to both Drugs and Devices All operational methodologies and procedures utilized in manufacturing and testing be validated to demonstrate they can function as intended Validation activities must be conducted I accordance with approved protocols and appropriate guidances Process validation ensures that product quality, safety and effectiveness are designed and built into the final product (batch to batch output uniformity)

Process Validation Guidance for Industry: Process Validation: General Principles and Practices (January 2011) Stage 1 – Process Design: The commercial process is based on knowledge gained through development and scale-up activities Stage 2 – Process Qualification: The process qualification is confirmed as being capable of reproducible commercial manufacturing Stage 3 – Continued Process Verification: Ongoing assurance that the process remains in a state of control during routine production. Requires an ongoing program to collect and analyze product and process data that relate to product quality (21CFR211.180(e)) Requires an interdisciplinary team approach (process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics “Begin with the end in mind”

Method Validation Draft Guidance for Industry: Analytical Procedures and Methods Validation – Chemistry Manufacturing and Controls Documentation (August 2000) Generics - USP Each method used to analyze the drug or biologic must have associated validation to support the documentation of drug substance, product identity, strength, purity, and potency

Key GMP Concepts

Key GMP Concepts (cont)

Key GMP Concepts (cont) IF IT WAS NOT WRITTEN DOWN, THEN IT WAS NOT DONE