Guidance for Industry
`Q7A Good Manufacturing
`Practice Guidance for Active
`Pharmaceutical Ingredients
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`August 2001
`ICH
`
`\\CDS018\CDERGUID\4286fnl.doc
`08/10/01
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`Guidance for Industry
`Q7A Good Manufacturing
`Practice Guidance for Active
`Pharmaceutical Ingredients
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`(Internet) http://www.fda.gov/cder/guidance/index.htm
`
`or
`
` Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
`Internet: http://www.fda.gov/cber/guidelines.htm.
`Fax: 1-888-CBERFAX or 301-827-3844
`Mail: the Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`August 2001
`ICH
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`Table Of Contents
`
`I.
`
`INTRODUCTION (1) ...........................................................................................................1
`A. Objective (1.1).................................................................................................................................1
`B. Regulatory Applicability (1.2).......................................................................................................2
`C.
`Scope (1.3) .......................................................................................................................................2
`II. QUALITY MANAGEMENT (2) .........................................................................................5
`A. Principles (2.1)................................................................................................................................5
`B.
` Responsibilities of the Quality Unit(s) (2.2)................................................................................5
`C. Responsibility for Production Activities (2.3) .............................................................................6
`D.
`Internal Audits (Self Inspection) (2.4)..........................................................................................7
`E.
`Product Quality Review (2.5)........................................................................................................7
`III. PERSONNEL (3)...................................................................................................................8
`A. Personnel Qualifications (3.1).......................................................................................................8
`B.
`Personnel Hygiene (3.2) .................................................................................................................8
`C. Consultants (3.3).............................................................................................................................9
`IV. BUILDINGS AND FACILITIES (4) ...................................................................................9
`A. Design and Construction (4.1).......................................................................................................9
`B. Utilities (4.2)..................................................................................................................................10
`C. Water (4.3) ....................................................................................................................................10
`D. Containment (4.4)........................................................................................................................11
`E. Lighting (4.5) ................................................................................................................................11
`F.
`Sewage and Refuse (4.6) ..............................................................................................................11
`G.
`Sanitation and Maintenance (4.7)...............................................................................................11
`V. PROCESS EQUIPMENT (5) .............................................................................................12
`A. Design and Construction (5.1).....................................................................................................12
`B. Equipment Maintenance and Cleaning (5.2).............................................................................12
`C. Calibration (5.3) ...........................................................................................................................13
`D. Computerized Systems (5.4)........................................................................................................14
`VI. DOCUMENTATION AND RECORDS (6) ......................................................................15
`A. Documentation System and Specifications (6.1) .......................................................................15
`B. Equipment Cleaning and Use Record (6.2) ...............................................................................15
`C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials (6.3)....16
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`D. Master Production Instructions (Master Production and Control Records) (6.4)................16
`E. Batch Production Records (Batch Production and Control Records) (6.5) ...........................17
`F. Laboratory Control Records (6.6)..............................................................................................18
`G. Batch Production Record Review (6.7)......................................................................................19
`VII. MATERIALS MANAGEMENT (7)..............................................................................19
`A. General Controls (7.1) .................................................................................................................19
`B. Receipt and Quarantine (7.2)......................................................................................................19
`C.
`Sampling and Testing of Incoming Production Materials (7.3) ..............................................20
`D.
`Storage (7.4)..................................................................................................................................21
`E. Re-evaluation (7.5) .......................................................................................................................21
`VIII. PRODUCTION AND IN-PROCESS CONTROLS (8)................................................21
`A. Production Operations (8.1)........................................................................................................21
`B. Time Limits (8.2)..........................................................................................................................22
`C.
`In-process Sampling and Controls (8.3).....................................................................................22
`D. Blending Batches of Intermediates or APIs (8.4)......................................................................23
`E. Contamination Control (8.5).......................................................................................................24
`IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND
`INTERMEDIATES (9) ...............................................................................................................24
`A. General (9.1) ............................................................................................................................24
`B.
`Packaging Materials (9.2)............................................................................................................25
`C. Label Issuance and Control (9.3)................................................................................................25
`D. Packaging and Labeling Operations (9.4) .................................................................................26
`X. STORAGE AND DISTRIBUTION (10) ...........................................................................26
`A. Warehousing Procedures (10.1)..................................................................................................26
`B. Distribution Procedures (10.2)....................................................................................................27
`XI. LABORATORY CONTROLS (11) ...................................................................................27
`A. General Controls (11.1) ...............................................................................................................27
`B. Testing of Intermediates and APIs (11.2) ..................................................................................28
`C. Validation of Analytical Procedures - See Section 12. (11.3) ...................................................29
`D. Certificates of Analysis (11.4) .....................................................................................................29
`E.
`Stability Monitoring of APIs (11.5) ............................................................................................29
`F. Expiry and Retest Dating (11.6)..................................................................................................30
`G. Reserve/Retention Samples (11.7) ..............................................................................................30
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`XII. VALIDATION (12) .........................................................................................................31
`A. Validation Policy (12.1) ...............................................................................................................31
`B. Validation Documentation (12.2)................................................................................................31
`C. Qualification (12.3) ......................................................................................................................32
`D. Approaches to Process Validation (12.4) ...................................................................................32
`E.
`Process Validation Program (12.5).............................................................................................33
`F.
`Periodic Review of Validated Systems (12.6) ............................................................................33
`G. Cleaning Validation (12.7)...........................................................................................................34
`H. Validation of Analytical Methods (12.8) ....................................................................................35
`XIII. CHANGE CONTROL (13) ............................................................................................35
`XIV. REJECTION AND RE-USE OF MATERIALS (14)...................................................36
`A. Rejection (14.1).............................................................................................................................36
`B. Reprocessing (14.2) ......................................................................................................................36
`C. Reworking (14.3) ..........................................................................................................................36
`D. Recovery of Materials and Solvents (14.4) ................................................................................37
`E. Returns (14.5) ...............................................................................................................................37
`XV. COMPLAINTS AND RECALLS (15)...........................................................................37
`XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) (16) ..........38
`XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND
`RELABELLERS (17)..................................................................................................................39
`A. Applicability (17.1).......................................................................................................................39
`B. Traceability of Distributed APIs and Intermediates (17.2) .....................................................39
`C. Quality Management (17.3).........................................................................................................39
`D. Repackaging, Relabeling, and Holding of APIs and Intermediates (17.4) .............................39
`E.
`Stability (17.5)...............................................................................................................................40
`F. Transfer of Information (17.6) ...................................................................................................40
`G. Handling of Complaints and Recalls (17.7) ...............................................................................40
`H. Handling of Returns (17.8)..........................................................................................................41
`XVIII. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL
`CULTURE/FERMENTATION (18) .........................................................................................41
`A. General (18.1) ...............................................................................................................................41
`B. Cell Bank Maintenance and Record Keeping (18.2).................................................................42
`C. Cell Culture/Fermentation (18.3) ...............................................................................................42
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`D. Harvesting, Isolation and Purification (18.4) ............................................................................43
`E. Viral Removal/Inactivation steps (18.5).....................................................................................44
`XIX. APIs FOR USE IN CLINICAL TRIALS (19) ..............................................................44
`A. General (19.1) ...............................................................................................................................44
`B. Quality (19.2) ................................................................................................................................45
`C. Equipment and Facilities (19.3)..................................................................................................45
`D. Control of Raw Materials (19.4).................................................................................................45
`E.
`Production (19.5)..........................................................................................................................45
`F. Validation (19.6)...........................................................................................................................46
`G. Changes (19.7) ..............................................................................................................................46
`H. Laboratory Controls (19.8) .........................................................................................................46
`I.
`Documentation (19.9)...................................................................................................................46
`GLOSSARY (20) .........................................................................................................................47
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`Guidance for Industry1
`Q7A Good Manufacturing Practice Guidance for Active
`Pharmaceutical Ingredients
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
`topic. It does not create or confer any rights for or on any person and does not operate to bind
`FDA or the public. An alternative approach may be used if such approach satisfies the
`requirements of the applicable statutes and regulations.
`
`I.
`
`INTRODUCTION (1)
`
`A.
`
`Objective (1.1)
`
`This document is intended to provide guidance regarding good manufacturing practice (GMP) for
`the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for
`managing quality. It is also intended to help ensure that APIs meet the quality and purity
`characteristics that they purport, or are represented, to possess.
`
`In this guidance, the term manufacturing is defined to include all operations of receipt of
`materials, production, packaging, repackaging, labeling, relabeling, quality control, release,
`storage and distribution of APIs and the related controls. In this guidance, the term should
`identifies recommendations that, when followed, will ensure compliance with CGMPs. An
`alternative approach may be used if such approach satisfies the requirements of the applicable
`statutes. For the purposes of this guidance, the terms current good manufacturing practices and
`good manufacturing practices are equivalent.
`
`
`1 This guidance was developed within the Expert Working Group (Q7A) of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
`subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been
`endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process,
`the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United
`States.
`
`Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering
`Committee at Step 4 of the ICH process, November 2000.
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`The guidance as a whole does not cover safety aspects for the personnel engaged in
`manufacturing, nor aspects related to protecting the environment. These controls are inherent
`responsibilities of the manufacturer and are governed by national laws.
`
`This guidance is not intended to define registration and/or filing requirements or modify
`pharmacopoeial requirements. This guidance does not affect the ability of the responsible
`regulatory agency to establish specific registration/filing requirements regarding APIs within the
`context of marketing/manufacturing authorizations or drug applications. All commitments in
`registration/filing documents should be met.
`
`B.
`
`Regulatory Applicability (1.2)
`
`Within the world community, materials may vary as to their legal classification as an API. When
`a material is classified as an API in the region or country in which it is manufactured or used in a
`drug product, it should be manufactured according to this guidance.
`
`C.
`
`Scope (1.3)
`
`This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It
`applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs
`being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by
`this guidance, but should be performed in accordance with GMP guidances for drug (medicinal)
`products as defined by local authorities.
`
`This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell
`culture/fermentation, recovery from natural sources, or any combination of these processes.
`Specific guidance for APIs manufactured by cell culture/fermentation is described in Section
`XVIII (18).
`
`This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma
`derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that
`are produced using blood or plasma as raw materials. Note that cell substrates (mammalian,
`plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early
`process steps may be subject to GMP but are not covered by this guidance. In addition, the
`guidance does not apply to medical gases, bulk-packaged drug (medicinal) products (e.g., tablets
`or capsules in bulk containers), or radiopharmaceuticals.
`
`Section XIX (19) contains guidance that only applies to the manufacture of APIs used in the
`production of drug (medicinal) products specifically for clinical trials (investigational medicinal
`products).
`
`An API starting material is a raw material, an intermediate, or an API that is used in the
`production of an API and that is incorporated as a significant structural fragment into the
`structure of the API. An API starting material can be an article of commerce, a material
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`purchased from one or more suppliers under contract or commercial agreement, or produced in-
`house. API starting materials normally have defined chemical properties and structure.
`
`The company should designate and document the rationale for the point at which production of
`the API begins. For synthetic processes, this is known as the point at which API starting
`materials are entered into the process. For other processes (e.g., fermentation, extraction,
`purification), this rationale should be established on a case-by-case basis. Table 1 gives guidance
`on the point at which the API starting material is normally introduced into the process.
`
`From this point on, appropriate GMP as defined in this guidance should be applied to these
`intermediate and/or API manufacturing steps. This would include the validation of critical
`process steps determined to impact the quality of the API. However, it should be noted that the
`fact that a company chooses to validate a process step does not necessarily define that step as
`critical.
`
`The guidance in this document would normally be applied to the steps shown in gray in Table 1.
`However, all steps shown may not need to be completed. The stringency of GMP in API
`manufacturing should increase as the process proceeds from early API steps to final steps,
`purification, and packaging. Physical processing of APIs, such as granulation, coating or
`physical manipulation of particle size (e.g., milling, micronizing) should be conducted according
`to this guidance.
`
`This GMP guidance does not apply to steps prior to the introduction of the defined API starting
`material.
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`Table 1: Application of this Guidance to API Manufacturing
`
`Production of
`Intermediate(s)
`
`Isolation
`and
`purification
`
`Physical
`processing, and
`packaging
`
`Introduction of
`the API starting
`material into
`process
`Introduction of
`the API starting
`material into
`process
`
`Isolation
`and
`purification
`
`Physical
`processing, and
`packaging
`
`Isolation
`and
`purification
`
`Physical
`processing, and
`packaging
`
`Further
`extraction
`
`Physical
`processing, and
`packaging
`Physical
`processing, and
`packaging
`
`Cutting and
`initial
`extraction
`Cutting/
`comminuting
`
`Type of
`Manufacturing
`Chemical
`Manufacturing
`
`API derived
`from animal
`sources
`
`API extracted
`from plant
`sources
`
`Collection of
`organ, fluid,
`or tissue
`
`Collection of
`plant
`
`Herbal extracts
`used as API
`
`Collection of
`plants
`
`API consisting of
`comminuted or
`powdered herbs
`
`Biotechnology:
`fermentation/
`cell culture
`
`“Classical”
`Fermentation to
`produce an API
`
`Collection of
`plants and/or
`cultivation
`and
`harvesting
`Establish-
`ment of
`master cell
`bank and
`working cell
`bank
`Establish-
`ment of cell
`bank
`
`Application of this guidance to steps (shown in gray) used in this type of
`manufacturing
`Production of
`Introduction
`the API
`of the API
`starting
`starting
`material
`material into
`process
`Cutting,
`mixing,
`and/or initial
`processing
`Cutting and
`initial
`extraction(s)
`
`Maintenance
`of working
`cell bank
`
`Cell culture
`and/or
`fermentation
`
`Isolation
`and
`purification
`
`Physical
`processing, and
`packaging
`
`Maintenance
`of the cell
`bank
`
`Introduction of
`the cells into
`fermentation
`
`Isolation
`and
`purification
`
`Physical
`processing, and
`packaging
`
`Increasing GMP requirements
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`II.
`
`QUALITY MANAGEMENT (2)
`
`A.
`
`Principles (2.1)
`
`Quality should be the responsibility of all persons involved in manufacturing.
`
`Each manufacturer should establish, document, and implement an effective system for managing
`quality that involves the active participation of management and appropriate manufacturing
`personnel.
`
`The system for managing quality should encompass the organizational structure, procedures,
`processes and resources, as well as activities to ensure confidence that the API will meet its
`intended specifications for quality and purity. All quality-related activities should be defined and
`documented.
`
`There should be a quality unit(s) that is independent of production and that fulfills both quality
`assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of
`separate QA and QC units or a single individual or group, depending upon the size and structure
`of the organization.
`
`The persons authorized to release intermediates and APIs should be specified.
`
`All quality-related activities should be recorded at the time they are performed.
`
`Any deviation from established procedures should be documented and explained. Critical
`deviations should be investigated, and the investigation and its conclusions should be
`documented.
`
`No materials should be released or used before the satisfactory completion of evaluation by the
`quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release
`under quarantine as described in Section X (10) or the use of raw materials or intermediates
`pending completion of evaluation).
`
`Procedures should exist for notifying responsible management in a timely manner of regulatory
`inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related
`complaints, recalls, and regulatory actions).
`
`B.
`
` Responsibilities of the Quality Unit(s) (2.2)
`
`The quality unit(s) should be involved in all quality-related matters.
`
`The quality unit(s) should review and approve all appropriate quality-related documents.
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`The main responsibilities of the independent quality unit(s) should not be delegated. These
`responsibilities should be described in writing and should include, but not necessarily be limited
`to:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Releasing or rejecting all APIs. Releasing or rejecting intermediates for use
`outside the control of the manufacturing company
`
`Establishing a system to release or reject raw materials, intermediates, packaging,
`and labeling materials
`
`Reviewing completed batch production and laboratory control records of critical
`process steps before release of the API for distribution
`
`Making sure that critical deviations are investigated and resolved
`
`Approving all specifications and master production instructions
`
`6.
`
`Approving all procedures affecting the quality of intermediates or APIs
`
`7.
`
`8.
`
`9.
`
`Making sure that internal audits (self-inspections) are performed
`
`Approving intermediate and API contract manufacturers
`
`Approving changes that potentially affect intermediate or API quality
`
`10.
`
`Reviewing and approving validation protocols and reports
`
`11. Making sure that quality-related complaints are investigated and resolved
`
`12. Making sure that effective systems are used for maintaining and calibrating
`critical equipment
`
`13. Making sure that materials are appropriately tested and the results are reported
`
`14. Making sure that there is stability data to support retest or expiry dates and storage
`conditions on APIs and/or intermediates, where appropriate
`
`15.
`
`C.
`
`Performing product quality reviews (as defined in Section 2.5)
`
`Responsibility for Production Activities (2.3)
`
`The responsibility for production activities should be described in writing and should include, but
`not necessarily be limited to:
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` 1.
`
` 2.
`
` 3.
`
`Preparing, reviewing, approving, and distributing the instructions for the
`production of intermediates or APIs according to written procedures
`
`Producing APIs and, when appropriate, intermediates according to pre-approved
`instructions
`
`Reviewing all production batch records and ensuring that these are completed and
`signed
`
` 4. Making sure that all production deviations are reported and evaluated and that
`critical deviations are investigated and the conclusions are recorded
`
` 5. Making sure that production facilities are clean and, when appropriate, disinfected
`
` 6. Making sure that the necessary calibrations are performed and records kept
`
` 7. Making sure that the premises and equipment are maintained and records kept
`
` 8. Making sure that validation protocols and reports are reviewed and approved
`
` 9.
`
`Evaluating proposed changes in product, process or equipment
`
`10. Making sure that new and, when appropriate, modified facilities and equipment are
`qualified
`
`D.
`
`Internal Audits (Self Inspection) (2.4)
`
`To verify compliance with the principles of GMP for APIs, regular internal audits should be
`performed in accordance with an approved schedule.
`
`Audit findings and corrective actions should be documented and brought to the attention of
`responsible management of the firm. Agreed corrective actions should be completed in a timely
`and effective manner.
`
`E.
`
`Product Quality Review (2.5)
`
`Regular quality-reviews of APIs should be conducted with the objective of verifying the
`consistency of the process. Such reviews should normally be conducted and documented
`annually and should include at least:
`
`• A review of critical in-process control and critical API test results
`• A review of all batches that failed to meet established specification(s)
`• A review of all critical deviations or nonconformances and related investigations
`• A review of any changes carried out to the processes or analytical methods;
`• A review of results of the stability monitoring program
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`• A review of all quality-related returns, complaints and recalls
`• A review of adequacy of corrective actions
`
`The results of this review should be evaluated and an assessment made of whether corrective
`action or any revalidation should be undertaken. Reasons for such corrective action should be
`documented. Agreed corrective actions should be completed in a timely and effective manner.
`
`III.
`
`PERSONNEL (3)
`
`A.
`
`Personnel Qualifications (3.1)
`
`There should be an adequate number of personnel qualified by appropriate education, training,
`and/or experience to perform and supervise the manufacture of intermediates and APIs.
`
`The responsibilities of all personnel engaged in the manufacture of intermediates and APIs
`should be specified in writing.
`
`Training should be regularly conducted by qualified individuals and should cover, at a minimum,
`the particular operations that the employee performs and GMP as it relates to the employee's
`functions. Records of training should be maintained. Training should be periodically assessed.
`
`B.
`
`Personnel Hygiene (3.2)
`
`Personnel should practice good sanitation and health habits.
`
`Personnel should wear clean clothing suitable for the manufacturing activity with which they are
`involved and this clothing should be changed, when appropriate. Additional protective apparel,
`such as head, face, hand, and arm coverings, should be worn, when necessary, to protect
`intermediates and APIs from contamination.
`
`Personnel should avoid direct contact with intermediates or APIs.
`
`Smoking, eating, drinking, chewing and the storage of food should be restricted to certain
`designated areas separate from the manufacturing areas.
`
`Personnel suffering from an infectious disease or having open lesions on the exposed surface of
`the body should not engage in activities that cou