FOOD AND DRUG ADMINISTRATION
`COMPLIANCE PROGRAM GUIDANCE MANUAL
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`PROGRAM
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`7356.002A
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`CHAPTER 56 – DRUG QUALITY ASSURANCE
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`SUBJECT:
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`STERILE DRUG PROCESS INSPECTIONS
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` Revision Note: Program revised 09/11/2015 to update
`implementation date, completion date,
`organizational/procedural changes and program
`contacts.
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`IMPLEMENTATION DATE
`September 11, 2015
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`COMPLETION DATE
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`DATA REPORTING
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`PRODUCT CODES
`Industry codes 54, 56 and 60-66 inclusive
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`PRODUCT/ASSIGNMENT CODES
`Domestic / Foreign Inspections:
`56002A (Full Inspection)
`56002I (Abbreviated Inspection)
`Related PACs
`56002
`56002C
`56002M
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`FIELD REPORTING REQUIREMENTS:
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`Establishment Inspection Reports (EIRs) are to be created and filed electronically using the specific
`module in TurboEIR or replacement system that is accessible to both ORA and CDER.
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`For inspections of routine commercial manufacturing classified as Official Action Indicated (OAI) due to
`failure to comply with 21 CFR Part 210 and 211 Current Good Manufacturing Practice (CGMP) as they
`apply to sterile drug process inspections, submit advisory, administrative, or judicial action
`recommendations via MARCS-CMS in accordance with the Regulatory Procedures Manual (RPM).
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`Districts should immediately report significant issues according to current FACTS, Panorama and CMS
`procedures. This includes promptly filing and changing OAI notifications.
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`During an inspection, if you obtain information pertaining to inadequate adverse drug experience (ADE)
`reporting, unapproved drug issues, or post-approval reporting violations (application supplements, Field
`Alert Reports (FARs), etc.), report in accordance with directions provided in the applicable compliance
`programs and under separate captions in the EIR. Data system information about these inspectional
`activities should be reported under separate Program Assignment Codes (PACs). Expansion of coverage
`under these programs into a CGMP inspection should be reported under this compliance program.
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`Page 1 of 38
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`Novartis Exhibit 2054.001
`Regeneron v. Novartis, IPR2021-00816
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`7356.002A
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`The Districts are requested to use this compliance program for all sterile drug process inspections.
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`NOTE: Districts should assure that each operation performed by direction of this program circular is
`entered against the correct Product Code and Program/Assignment Code (P/AC).
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`PAGE 2 of 38
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`Novartis Exhibit 2054.002
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`TABLE OF CONTENTS
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`PART I
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`PART II
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`PART III
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`BACKGROUND ................................................................................................... 4
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`IMPLEMENTATION ............................................................................................. 5
`2.1 Objective ........................................................................................................ 5
`2.2 Program Management Instructions ................................................................ 5
`A. Strategy ............................................................................................... 5
`B. Inspection Planning ............................................................................. 6
`C. Profile Reporting ................................................................................... 6
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`INSPECTIONAL ...................................................................................................... 7
`3.1 Types of Sterilization....................................................................................... 7
`A. Terminal sterilization ........................................................................... 7
`B. Aseptic processing .............................................................................. 7
`3.2 Reporting .......................................................................................................8
`3.3
`Inspection Approaches ................................................................................. 9
`3.4 System Inspection Coverage ...................................................................... 11
`3.5 Quality System .............................................................................................. 11
`3.6 Facilities and Equipment System ................................................................. 13
`A. Facilities ............................................................................................... 13
`B. Equipment ......................................................................................... 14
`3.7 Materials System .......................................................................................... 19
`3.8 Production System ........................................................................................ 22
`3.9 Packaging and Labeling System .................................................................. 28
`3.10 Laboratory Control System ........................................................................... 28
`3.11 Sampling ....................................................................................................... 30
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`PART IV
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`ANALYTICAL ....................................................................................................... 32
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`PART V
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`REGULATORY/ADMINISTRATIVE STRATEGY .............................................. 33
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`PART VI
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`REFERENCES, ATTACHMENTS AND PROGRAM CONTACTS ..................... 35
`6.1 References ......................................................................................................... 35
`6.2 Attachments ..................................................................................................... 36
`6.2 Contacts ........................................................................................................ 36
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`PART VII
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`CENTER RESPONSIBILITIES ........................................................................... 38
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`ATTACHMENT A
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`.................................................................................................................A
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`[end Cover Page]
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`PAGE 3 of 38
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`Novartis Exhibit 2054.003
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`PART I - BACKGROUND
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`This program covers the manufacture and testing of all sterile drug products, including drugs that are
`sterilized by filtration or other means and aseptically processed, and drug products that are terminally
`sterilized. The type of products covered by this program include sterile bulk drugs, ophthalmic drugs,
`otic dosage forms, small volume parenteral (SVS) products for small molecule and licensed biological
`therapeutic drug products, large volume parenteral (LVP) products, and any other drug products
`required to be sterile or labeled as sterile. Center for Biologics Evaluation and Research (CBER)
`regulated products and veterinary drug products are excluded from coverage under this program.
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`The guidance information in this program is tailored to sterile manufacturing operations and should be
`used in conjunction with the Compliance Program for Drug Manufacturing Inspections (CP 7356.002).
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`In 2004, Food and Drug Administration (FDA) published the Guidance for Industry Sterile Drug
`Products Produced by Aseptic Processing-- Current Good Manufacturing Practice, which is referred to
`throughout this Compliance Program as FDA’s “2004 Aseptic Processing Guidance.” The document
`represents FDA’s current thinking on Current Good Manufacturing Practices (CGMPs) for aseptically
`processed drugs.
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`The Guidance for Industry does not establish mandatory requirements and should not be referred to as
`the justification for an inspectional observation. Justification for inspectional observations originates
`from the CGMP regulations, 21 CFR Parts 210 and 211.
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`Manufacturers who follow the 2004 Aseptic Processing Guidance are generally considered compliant
`with CGMP regulations. However, alternate approaches may be used if such approaches satisfy the
`requirements of 21 CFR Parts 210 and 211.
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`For technical questions and unusual circumstances encountered during an inspection, investigators are
`encouraged to contact their District, ORA Office of Medical Products and Tobacco Operations/Division
`of Medical Products and Tobacco Program Operations and/or CDER for consultation. For questions
`concerning microbiological analysis, sterility and related sampling concerns, contact ORA Office of
`Regulatory Science/Medical Products and Tobacco Scientific Staff.
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`[end Part I]
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`PAGE 4 of 38
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`Novartis Exhibit 2054.004
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`PART II - IMPLEMENTATION
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`2.1 OBJECTIVES
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`The primary objective of this program is to provide guidance for conducting inspections of
`manufacturers of sterile bulk1 and sterile finished dosage drug products to determine compliance with
`the Food, Drug, and Cosmetic Act and the Current Good Manufacturing Practice Regulations (CGMPs),
`Title 21, CFR Parts 210 and 211.
`
`Other objectives include:
`• Obtain information on operations impacting on sterility, to identify areas for improvement and
`correction.
`• Evaluate current good manufacturing practices in the sterile drug industry.
`Initiate appropriate action against manufacturers observed to be out of compliance.
`•
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`2.2 PROGRAM MANAGEMENT INSTRUCTIONS
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`A. STRATEGY
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`(1) Inspection of Systems
`Inspections of drug manufacturers should be made and reported using the system definitions and
`organization in this compliance program. Focusing on systems will increase inspection efficiency
`because the systems are often applicable to multiple profile classes. The selection of the system(s) for
`coverage will be made by the District Office based on the firm’s specific operation, previous coverage,
`compliance history, or other priorities determined by the District Office.
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`The inspection should normally result in a determination of acceptability or non-acceptability for all
`profile classes. Coverage of a system should be sufficiently detailed, i.e., select an example of each
`profile class, so that the conclusion about the system’s state-of-control applies to all the profiles classes.
`However, the determination that a system is adequately controlled for one profile class can be extended
`to another profile class(es) even if that other profile class(es) was not specifically reviewed. The lead
`Investigator must consider the uniqueness of the various manufacturing situations at the plant and use
`their best judgment when selecting profile classes to review.
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`Selecting specific areas unique functions within a system will be at the discretion of the lead
`Investigator.
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`The options for system coverage are described in CPGM 56002. Any given inspection need not cover
`every system. See Part III - Inspectional.
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`Complete inspection of one system may necessitate further follow up of some items within the activities
`of another system(s) to fully document the findings. Such follow up does not constitute full coverage of
`the other system (and cannot be reported as such in FACTS); nor does that follow up obligate the
`investigator to perform full coverage of the other system.
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`1 “Sterile bulk” refers to sterile active pharmaceutical ingredients (APIs).
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`Novartis Exhibit 2054.005
`Regeneron v. Novartis, IPR2021-00816
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`(2) Inspectional Scope
`Inspections of sterile product drug manufacturers are performed as either Full Inspections or
`Abbreviated Inspections using the systems strategy outlined in Part II –Implementation, of Compliance
`Program 7356.002, Drug Manufacturing Inspections.
`See Part III – Inspectional, of this program for a complete discussion of the coverage requested under
`these inspection options.
`B. INSPECTION PLANNING
`Implement this program when sterile drug manufacturers are inspected as part of a regular statutory
`inspection. CDER will identify firms for inspection based on the risk-based prioritization model on
`annual performance goals, as part of the initiative to ensure risk-based prioritization of inspection
`coverage.
`Consider using a team approach for conducting inspections when appropriate. Utilize investigators
`familiar with sterile drug manufacturing and aseptic processing and consider the participation of a
`microbiologist with expertise in microbial controls. Specifically,
`• All team members should be very familiar with FDA’s Guidance for Industry Sterile Drug
`Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September
`2004).
`Investigators or team members should be well qualified in sterile product manufacturing, and
`have completed formal training courses in parenteral drug manufacture, aseptic technique,
`sterilization methods, and related procedures and equipment. Microbiologists involved should
`have experience in sterility, endotoxin testing, and evaluation of microbial controls in
`manufacturing.
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`•
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`C. PROFILE REPORTING
`Update all applicable profile classes in the profile screen of the FACTS coversheet based on inspection
`findings. The following is a list of sterile product profile classes effective at the time this program was
`implemented. Use the codes corresponding to the product and process type covered.
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`PROFILE
`CLASS
`LVP
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`SVT
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`SVS
`SVL
`SLQ
`SON
`SPW
`CSS
`CFS
`CRX
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`FULL DESCRIPTION
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`Large Volume Parenterals are sterile injectable drugs packaged in containers labeled as
`containing more than 100 mL. Most are terminally sterilized, but some can be sterilized by
`filtration and aseptically processed.
`Small Volume Parenterals are sterile injectable drugs packaged in containers labeled as
`containing less than 100 mL that are terminally sterilized.
`Small Volume Parenterals are sterilized by filtration and aseptically processed.
`Small Volume Parenteral are sterilized by filtration, aseptically filled and lyophilized.
`Sterile liquid (other than suspensions and emulsions)
`Sterile ointment
`Sterile powder
`Sterile bulk drugs that are made by chemical synthesis.
`Sterile crude drugs made by fermentation.
`API sterile or API intermediate/NEC inorganic/mineral
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`I]
`[end Part I
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`PAGE 6 of 38
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`Novartis Exhibit 2054.006
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`PART III - INSPECTIONAL
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`3.1 TYPES OF STERILIZATION
`There are two broad methods to produce a sterile drug product:
`• Terminal Sterilization
`• Aseptic Processing of sterilized unit components
`There are basic differences between the production of sterile drug products using aseptic processing and
`production using terminal sterilization. Terminal sterilization should be utilized when the product and
`container/closure system are able to withstand the terminal sterilization process.
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`A. TERMINAL STERILZATION - The terminal sterilization process usually involves filling and
`sealing product containers under high quality environmental conditions designed to minimize microbial
`and particulate contamination of the product. This minimization of upstream bioburden reduces the
`challenge to the subsequent sterilization process. In most cases, the product, container, and closure have
`low bioburden, but are not sterile at the time of filling. The product is then subjected to a sterilization
`process in its final container.
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`There are various methods of terminal sterilization including:
`• Moist Heat Sterilization
`Irradiation
`•
`• Ethylene Oxide (typically for assembled components/kits)
`Types of sterilization cycles include:
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`1. Overkill method:
`o Generally used for heat stable materials.
`o Designed to provide a significant level of sterility assurance regardless of the number and
`resistance of the actual bioburden organisms in the load.
`o Results in greater heat/exposure input to the product or items being sterilized.
`2. Bioburden Based cycle:
`o Requires studies to determine the number and resistance of the microorganisms found in the
`product and the bioburden load of the incoming components and containers/closures.
`o Cycle development to destroy the microbial load, but not degrade the product.
`o Routine bioburden monitoring of batches and ongoing knowledge of the heat/exposure
`resistance of organisms found in product bioburden, container/closure bioburden and
`environmental monitoring samples.
`Reference to terminal sterilization: PDA Technical Report No. 1 (Revised 2007) Validation of Moist
`Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control.
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`B. ASEPTIC PROCESSING - Aseptic processing presents a higher risk of microbial contamination of
`the product than terminal sterilization. In an aseptic filling process, the drug product, containers and
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`Novartis Exhibit 2054.007
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`closures are sterilized separately and then brought together under an extremely high quality
`environmental condition designed to reduce the possibility of a non-sterile unit. Aseptic processing
`involves more variables than terminal sterilization. Any manual or mechanical manipulation of the
`sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of
`microbial contamination.
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`Some types of aseptic processing involve manual manipulations of sterile components, containers, and
`closures in addition to routine operator interventions in the critical area. Humans are a significant source
`of contamination in traditional aseptic processing, especially in production lines that require operators to
`routinely enter critical areas (Class 100, ISO 5, or Grade A) of the filling line. Aseptic processing
`systems based on more advanced control-based technologies, such as Restricted Access Barrier Systems
`(RABS) and Blow-Fill-Seal systems, are designed to reduce human interventions in the critical areas of
`the fill line while an isolator system completely separates the aseptic filling line from the external
`environment and minimizes employee interaction with the critical area.
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`Note: More information about Isolator Technology and Blow-Fill-Seal systems is found
`in FDA’s 2004 Aseptic Processing Guidance.
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`When conducting inspections of sterile drug manufacturers, it is important to cover systems and areas
`within systems that present the greatest risk of product contamination and/or require strict control of
`processing parameters. For example, if a firm has several aseptic processing lines, cover the line(s) that
`require the most manual manipulations in the Class 100 (ISO 5) areas. If the firm terminally sterilizes a
`number of products, review one that is sensitive to heat and requires a product specific (bioburden
`based) sterilization cycle.
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`Note: For terminal sterilized products that are aseptically filled prior to terminal sterilization, less
`rigorous aseptic controls can be considered.
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`Because of the time limitations often associated with foreign inspections, careful inspection planning is
`particularly important. Prioritize areas for coverage based upon their potential impact on product
`quality.
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`3.2 REPORTING
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`Follow instructions in the current editions of the IOM (Investigations Operations Manual) and Guide to
`International Inspection and Travel in preparing the inspection report.
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`Use Turbo EIR for all reports, both domestic and international, even if a FDA-483 was not issued or was
`issued outside of Turbo EIR. The “Manufacturing / Design Operations” section of the report should be
`organized by the systems described in this program that were covered during the inspection. Briefly
`summarize your review of each covered system in accordance with the key elements outlined in this
`Compliance Program. Add more details and supporting evidence for the systems found to be deficient.
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`PAGE 8 of 38
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`Novartis Exhibit 2054.008
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`3.3 INSPECTION APPROACHES
`If the sterile drug products to be inspected are radioactive drugs, then Compliance Program 7356.002C,
`Radioactive Drugs, should be followed as supplementary guidance. This program should not be used for
`the inspection of Positron Emission Tomography (PET) Drug. Compliance Program 7356.002P is
`specific for PET drugs.
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`This program (CP 7356.002A) should also be used in conjunction with Compliance Program
`7356.002M, Inspection of Licensed Biological Therapeutic Drug Products for the inspection of sterile
`licensed biological products.
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`The CGMP Compliance Program 7356.002 provides general information on the system based approach
`to conducting inspections of drug manufacturers. It describes the six systems (Quality, Facilities and
`Equipment, Materials, Production, Packaging and Labeling, and Laboratory) and the two inspection
`options (Full Inspection and Abbreviated Inspection). It also provides guidance on when each option
`should be selected and discusses what “state of control” means in relation to the systems inspected.
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`Inspections of sterile drug manufacturers are performed as either Full or Abbreviated inspections using
`the systems strategy outlined below.
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`Full Inspections include surveillance or compliance inspections and provide a comprehensive evaluation
`of the firm’s compliance with CGMP. A Full Inspection will normally include an inspection of at least
`four systems, one of which must be the Quality System. Under this program, a Full Inspection should
`include the Facilities & Equipment, and Production Systems due to the critical role these systems play in
`the sterility assurance of finished product.
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`Full Inspections (PAC 56002A) are conducted
`• when initial inspection of the drug firm is to be conducted;
`• when it is the first inspection conducted as a follow-up to a Warning Letter, regulatory action,
`or significant FDA 483 findings;
`• when information obtained during the Abbreviated Inspection reveals significant deficiencies
`with the firm’s practices and procedures in one or more system areas;
`• when there have been significant changes in the firm’s operations since the last inspection; or
`for surveillance purposes at the District’s discretion because the firm has a history of recurring
`•
`violations, fluctuating in and out of compliance, or when other information (samples,
`complaints, Field Alerts, recalls, etc.) calls into question the firm’s ability to produce quality
`products.
`Abbreviated Inspections (PAC 56002I) may be appropriate if the following two conditions are satisfied:
`
`1. the firm has implemented a formal risk management program that assures effective design and
`control (including maintenance). This includes a risk mitigating design of their processing lines
`that incorporates a modern separation and automation approach (e.g., isolators, closed RABS),
`and upstream bioburden controls. The responsiveness of the firm’s quality system to potential
`hazards is also part of the evaluation, including whether the firm’s program provides robust
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`PAGE 9 of 38
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`Novartis Exhibit 2054.009
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`daily assurance and effective consumer protection through a formal lifecycle quality risk
`management program that proactively uncovers and corrects issues in accord with ICH Q9.
`2. the firm has a record of sustained acceptable compliance history and a strong risk management
`program.
`o the firm produces finished drug products that are terminally sterilized using robust
`sterilization methods. (Note: Terminal sterilization provides a much more robust process to
`ensure sterility); or,
`o the firm has implemented robust risk management that provides daily assurance through
`their overall design and control program;
`o at the start of the inspection, conduct an extensive review of sterility assurance data since
`the last Full Inspection. The review of media fills, sterility testing data, recalls,
`defect/adverse event complaints, and reports reveals no findings of sterility failure of a
`distributed batch, and
`o the firm has a record of satisfactory CGMP compliance (e.g., two consecutive NAI or no
`more than one VAI inspection), with no Class 1 recalls.
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`Microbial controls and sterility assurance should be the main focus of an abbreviated sterile drug
`inspection. The following critical elements of each system (other than the Quality System) should be
`covered in an Abbreviated Inspection under this program:
`• Facilities and Equipment:
`o cleaning and disinfection
`o facility/equipment layout and air handling system for preventing viable and non-viable
`contamination
`o material flow
`o quality control of classified areas, including air pressure balance and HEPA filtration
`o trending data supporting the adequacy of clean room quality
`o documented investigation into discrepancy
`• Materials:
`o microbial and bacterial endotoxin control of incoming materials and components
`o quality of water supply, maintenance, qualification
`o operation of the systems that provide the requisite water and process gases
`o documented investigations into OOS, deviations, and discrepancies
`• Production:
`o observation of adequacy of operator behavior and aseptic techniques during manufacturing
`o production line operations and interventions
`o personnel training in aseptic techniques
`o major production line repair or maintenance issues
`o risk assessment on microbial and bacterial endotoxin controls, including hold times of
`critical steps
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`PAGE 10 of 38
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`Novartis Exhibit 2054.0010
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`o validation of sterilization of equipment, container-closures and supplies
`o media fills design and results
`o documented investigations into, deviations, discrepancies, and OOS results
`• Laboratory:
`o investigations into OOS, deviations, and discrepancies
`o test methods and controls, including adherence to validated methods
`o training and qualifications of laboratory personnel
`o trending of water system test results
`o systems used for recovery, identification and trending of environmental monitoring isolates
`
`3.4 SYSTEM INSPECTION COVERAGE
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`Compliance Program 7356.002, Drug Manufacturing Inspections, lists the areas that should be covered
`when inspecting each of the six systems. This program provides additional guidance, by system, for
`areas of specific concern for sterile drug products.
`
`Attachment A is a list of questions intended to be an aid in conducting inspections and obtaining
`information needed to assess a firm’s operations. The answers do not have to be reported in the EIR
`unless they are relevant. The list of questions covers: moist heat sterilization; dry heat
`sterilization/depyrogenation; aseptic filling; lyophilization; isolators; environmental monitoring; and
`biological indicators.
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`3.5 QUALITY SYSTEM
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`As noted in Compliance Program 7356.002, the inspection of the quality system is two-phased. The first
`phase is to evaluate whether the Quality Unit has fulfilled their responsibility regarding the review and
`approval of procedures and assured their suitability for use. The second phase is to assess the data
`collected by the firm to identify potential quality problems. For sterile manufacturing operations, this
`latter objective involves large amounts of data that link to the other inspectional systems. The
`comprehensive review of such data by the firm is an essential element in assuring that products are
`produced with a high degree of sterility assurance. It is therefore important to review the firm’s system
`for using the data to assess the state of control of their manufacturing operations and facility. The data
`summaries and trend reports maintained by the Quality Unit should be reviewed during every
`inspection. During a routine CGMP inspection, this review can help determine which option (Full or
`Abbreviated) to select.
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`The inspection of the Quality System should include the areas listed in CP7356.002. For this program,
`the inspection should include a review of all data and reports that may indicate product contamination
`and sterility assurance issues.
`Records pertaining to quality consist of the following:
`1. Periodic product evaluations, complaints, adverse events, investigations, Field Alert Reports,
`product retain evaluations, complaints, rejected lots, stability, and returned goods that indicate
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`PAGE 11 of 38
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`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`possible product contamination or risks to patients (for example, hazy or cloudy product,
`foreign matter/particulates in injectable products, cracked, and leaky containers).
`2. Discrepancy and failure investigations, such as:
`o All initial positive sterility tests and endotoxin and media fill failures regardless of final
`disposition.
`o Unexpected results or trends.
`o All failures that occurred during validation or revalidation of sterilization / depyrogenation
`processes.
`o All investigations involving media fills / process simulations.
`o Environmental (microbial/viable and particle/non-viable counts) and personnel monitoring
`results that exceed alert or action levels.
`o Process deviations or equipment malfunctions that involve critical equipment, such as
`sterilizers and lyophilizers.
`o Out of Specification (OOS) results for assay, impurities, particulate matter, or reconstitution
`time, if applicable.
`o Product rejects (rejects determined during manufacturing and Quality Control test)
`3. Trends reports/ summaries of quality indicators:
`o For aseptic processing, summary of all media fills performed since last inspection.
`o Environmental monitoring trend data (microbial and particle counts).
`o Personnel monitoring trend data.
`o Summary of water system test results.
`4. Summary of change controls for critical utilities and equipment implemented since the last
`inspection, for example:
`o Sterilizers, lyophilizers, depyrogenation equipment
`o Aseptic processing line
`o Clean steam generator, process gas system
`o WFI and / or Purified Water system
`o Air handling systems
`o Automated building management system
`Every inspection of a sterile drug manufacturer should include a review of the type of information listed
`above and observation of the manufacturing operations occurring in the critical areas. The information
`can be used to select other system(s) to be covered during the inspection.
`
`In addition, the review of summary data and observation of operations can focus the inspection on
`potential problem areas and provides an overview of the effectiveness of the Quality System. The
`inspection of the Quality System may necessitate follow-up within another system. However, this
`coverage does not constitute or require complete coverage of these systems.
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`PAGE 12 of 38
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`Novartis Exhibit 2054.0012
`Regeneron v. Novartis, IPR2021-00816
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`PROGRAM
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`7356.002A
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`3.6 FACILITIES AND EQUIPMENT SYSTEM
`Compliance Program 7356.002 lists the general areas to cover when inspecting the Facilities and
`Equipment System. The areas are applicable to sterile drug products and should be covered if this
`system is selected. The principle objective of an effective sterile drug manufacturing operation from a
`facility and equipment standpoint is to provide suitable protection of product. The inspectional
`evaluation of this objective is again two-part:
`• Review and evaluate the firm’s rationale for, and adequacy of, the facility and equipment
`design (Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance).
`• Evaluate the data that provide information relevant to the state of control of the facility and
`equipment.
`In addition to the review of design elements and data, investigators should look for visible deficiencies in
`the facility and equipment, such as cleanliness, equipment deterioration (e.g., warping, corrosion),
`inaccessible and/or difficult to clean surfaces, and changes to critical equipment or systems that have not
`been qualified which may impact product quality. Investigator should look for aberrant events due to
`facility deterioration, a pattern of recurring and uncorrected maintenance issues, and increase or changes
`in pr