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PREP #6 CGMP Requirements for Investigational Products Ji-Eun Kim, RPh, PhD Research Pharmacist Regulatory Affairs Office of Research Compliance December 6, 2016 1
PREP #6
CGMP Requirements for Investigational Products
Ji-Eun Kim, RPh, PhD Research Pharmacist
Regulatory Affairs Office of Research Compliance
December 6, 2016
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CME Disclosure Statement • Northwell Health adheres to the ACCME’s new Standards for
Commercial Support. Any individuals in a position to control the content of a CME activity, including faculty, planners, and managers, are required to disclose all financial relationships with commercial interests. All identified potential conflicts of interest are thoroughly vetted by Northwell Health for fair balance and scientific objectivity and to ensure appropriateness of patient care recommendations. • Course Director and Course Planner, Peter Berger, MD and Tina Chuck, MPH have nothing to disclose. • Ji-Eun Kim has nothing to disclose.
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Objectives • Describe current regulatory requirements
to ensure quality and safety of investigational products used in clinical research
Outline
Case Studies Exercises Regulations Options
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Encapsulation Repackaging Sterile Product
New Product Development
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Encapsulating commercial products
CASE STUDY #1
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Discussion
Where can your research team purchase a blinded product and placebo?
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Definitions
FDA Glossary; 21 CFR 210.3
Drug • A substance intended for use in the diagnosis, cure, mitigation,
treatment, or prevention of disease. • A substance (other than food) intended to affect the structure or
any function of the body.
Drug Product • Drug product means a finished dosage form, e.g., tablet, capsule,
solution, etc., that generally contains an active drug ingredient. • The term also includes a finished dosage form that does not
contain an active ingredient but is intended to be used as a placebo.
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Federal Regulations
• CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL
21 CFR 210
• CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS 21 CFR 211
• BIOLOGICAL PRODUCTS: GENERAL 21 CFR 600
CFR: Code of Federal Regulations
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What is Current Good Manufacturing Practice (CGMP)?
Purpose
• Minimum requirements for methods, facilities and control for processing, manufacturing and packaging of a drug product.
• Intended to prevent manufacturing defects, failures of performance/efficacy, contamination, mix-ups, deviations.
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What is CGMP?
Elements • Organization and Personnel • Buildings and Facilities • Equipment • Control of Components and Drug Product Containers and
Closures • Production and Process Controls • Packaging and Labeling Control • Holding and Distribution • Laboratory Controls • Records and Reports • Returned and Salvaged Drug Products
21 CFR 211 CGMP for Finished Pharmaceuticals
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New York State Rules
Any drug, device or cosmetic shall be deemed to be adulterated and/or misbranded if:
• It is not manufactured in accordance with the good manufacturing practices specified in Parts 210 and 211 of Title 21, Code of Federal Regulations, …….
• At any time it fails to meet standards for purity, potency,
labeling, safety and effectiveness established under the Federal Food, Drug and Cosmetic Act, as amended.
NYS Rules of the Board of Regents, Part 29.7
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How about investigational drugs?
TRUE or FALSE FDA Guidance
EXERCISE #1
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#1 The FDA, recognizing the differences between the manufacture of investigational products and commercial products, believes that it is not necessary that investigational products be made in conformance with current good manufacturing practice (CGMP).
True or False?
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#2 Investigational products, unlike products approved for marketing, have not been subject to the FDA’s CGMP inspectional activities.
True or False?
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FDA Guidance
#1: The FDA, while recognizing the differences between the manufacture of investigational products and commercial products, believes that it is nonetheless vital that investigational products be made in conformance with current good manufacturing practice (CGMP).
#2: Investigational products, like products approved for marketing, have always been subject to the FDA’s CGMP inspectional activities.
FDA Guidance: Preparation of Investigational New Drug Products
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FILL IN THE BLANKS E6 Good Clinical Practices (GCP)
How about the GCP standards?
EXERCISE #2
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Fill in the Blanks
#1 2.12 Investigational products should be manufactured, handled and stored in accordance with applicable _______(a)________.
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#2 5.13. Manufacturing, Packaging, Labeling and Coding Investigational product(s) 5.13.1 ___(b)___ should ensure that the investigational product(s) (including active comparator(s) and ____(c)____, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable ___(d)___ and is coded and labeled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirement(s).
Fill in the Blanks
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E6 Good Clinical Practices (GCP)
#1 2.12 Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
#2 Manufacturing, Packaging, Labeling and Coding Investigational product(s) 5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP and is coded and labeled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirement(s).
How does CGMP affect your research?
• The sponsor usually ensures the production of ID under CGMP standards in protocol, Investigator’s Brochure & other documents.
• If not, request the sponsor to provide product quality assurance.
If an external sponsor provides
investigational drug(s) (ID)
• The PI assumes sponsor’s responsibilities.
• The PI must ensure CGMP compliance or quality and safety of the ID.
If the PI is the sponsor-investigator
or the PI procures the ID
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Encapsulating commercial products
CASE STUDY #1 Cont’d
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Compounding
http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm339764.htm
What is “compounding”?
• In general, compounding is a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.
• Compounded drug products are not FDA-approved, which means they have not undergone FDA premarket review for safety, effectiveness, and quality.
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Compounding
http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm339764.htm
Why do some patients need compounded drugs?
• Sometimes, the health needs of a patient cannot be met by an FDA-approved medication.
• For example: - Patient allergies to excipients in commercial products - Dose adjustments - Special formulations (e.g., alternative dosage forms, flavors) - Drug shortage
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TRUE or FALSE Federal Law
Compounding Pharmacy?
EXERCISE #3
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True or False?
#1 A blinded drug and placebo product purchased in bulk from a compounding pharmacy are manufactured in compliance with CGMP requirements.
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#2 You cannot purchase modified or compounded drugs from a compounding pharmacy without prescriptions.
True or False?
27 Drug Quality and Security Act (DQSA) Title I: Compounding Quality Act (CQA) Section 503A
Federal Law
Prescription for
identified individuals
By a licensed
pharmacist in a state licensed pharmacy or a
Federal facility, or by a licensed physician
Applicable *USP/NF
To be exempt from CGMP, labeling of drugs & *NDAs/*ANDAs requirements
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Discussion
Can a research team purchase a blinded commercial product and placebo from a compounding pharmacy?
Options Encapsulating commercial products
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CGMP • If you decide to stock blinded
products, • You must purchase blinded
investigational products including placebo from a CGMP-compliant manufacturer.
503A • The PI can issue a prescription
for a specific subject at each dispensation.
• Pharmacist prepares encapsulated products only after receiving a prescription.
• Comply with records, labeling, expiration date and other applicable requirements.
*See the definition in the handout.
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Repackaging commercial products
CASE STUDY #2
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Repackaging
What is “repackaging”?
• The act of taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug.
• Repackaging also includes the act of placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients.
FDA Guidance Draft: Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
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Repackaging
Why do some patients need repackaged drugs?
• To meet the needs of specific groups of patients • To reduce medication errors • To reduce the availability of drug products of abuse • To provide a particular sized container to fit into a particular
device to administer the drug • For convenience for the practitioner administering an injection
to a patient • To reduce cost • Some repackagers repackage both sterile and non-sterile drug
products.
FDA Guidance Draft: Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
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TRUE or FALSE FDA Guidance
Repackaging?
EXERCISE #4
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#1 A nurse draws up a syringe to administer directly to the patient after receipt of a patient-specific prescription or order for that patient.
Question: Repackaging?
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#2 Upon receipt of an individual patient-specific prescription, a licensed pharmacist removes oral tablets from one container and places them into a smaller container to dispense directly to the patient.
Question: Repackaging?
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#3 Drug tablets are packaged from large containers into smaller containers or blister packs in anticipation for dispensations.
Question: Repackaging?
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#4 Creams and lotions are purchased in bulk and packaged into smaller tubes or containers for office use.
Question: Repackaging?
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Repackaging
Who can repackage a drug product?
• Repackaged drug products are generally NOT exempt from any of the provisions of the FD&C Act (CGMP, labeling of drugs & NDAs/ANDAs) related to the production of drugs.
• Therefore, drug products that do not meet the conditions, including drug products repackaged by entities that are NOT state-licensed pharmacies, Federal facilities, or outsourcing facilities, generally must comply with requirements in the FD&C Act and FDA regulations.
FDA Guidance Draft: Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
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Discussion
Can your research team repackage a product and placebo at your site?
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Options Repackaging commercial products
CGMP
• If you decide to stock repackaged products,
• You must purchase blinded investigational products including placebo from a CGMP-compliant manufacturer.
FDA Guidance • The PI can issue a prescription
for a specific subject at each dispensation.
• Pharmacist prepares repackaged products only after receiving a prescription.
• Comply with records, labeling, expiration date and other applicable requirements.
Month Day, Year 42
Outcome of CGMP Non-compliance
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FDA Warning Letter
Producing Adulterated Drugs
• CGMP requirements
Producing Unapproved New Drugs
• Approved NDA or ANDA
Misbranded Drugs
• Labeled with adequate directions for use
An individual or firm compounds a drug product that does not meet the conditions of section 503A.
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Blinding commercial sterile products
CASE STUDY #3
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Discussion
Any issues with this plan?
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Blinding commercial sterile products
CASE STUDY #3 Cont’d
Regulatory Background
• United States Pharmacopeia (USP) Chapter 797 Pharmaceutical Compounding – Sterile Preparations
• NYS Rules for Compounded Sterile Preparations • Northwell policy INF.1158 Medication Vial,
Infusion and Safe Injection Practice Guidelines
Aseptic Manipulations
• FDA Guidance Draft Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities
• Stability • Sterility • Facility policy • Time frames
Beyond-Use Date
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Select applicable considerations for repackaging a commercially available sterile product.
a. Product degradation b. Microbial contamination c. Impurities d. Beyond-use-date assignment
EXERCISE #5
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Discussion
Can the delegated unblinded pharmacist prepare and stock blinded syringes to expedite immediate dispensation upon receiving a drug order?
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Options Blinding commercial sterile products
CGMP/503B
• If you decide to stock the products,
• You must purchase blinded investigational products including placebo from a CGMP-compliant manufacturer/outsourcing facility*.
503A/USP797 • The PI can issue a prescription
or drug order for a specific subject at each dispensation.
• Pharmacist prepares the product only after receiving a prescription or drug order.
• Comply with records, labeling, expiration date and other applicable requirements.
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Outcome of Non-compliance
Outcome of Non-compliance
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Developing new investigational products
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CASE STUDY #4
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EXERCISE #6
TRUE or FALSE ICH GMP Guide Q7
New APIs* in development?
* APIs: Active Pharmaceutical Ingredients
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#1 Appropriate GMP concepts should be applied in the production of APIs.
True or False?
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#2 Process and test procedures should be flexible to provide changes.
True or False?
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#3 APIs are manufactured in suitable facilities using appropriate production and control procedures.
True or False?
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ICH GMP Guide Q7 Active Pharmaceutical Ingredients (APIs) for
use in clinical trials • Appropriate GMP concepts should be applied in the
production of APIs with a suitable mechanism of approval of each batch.
• Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses.
• APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.
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Discussion
What types of information does the PI need to submit to the FDA regarding the product quality and safety assurance?
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FDA Guidance
IND Contents
• Chemistry, manufacturing and control information (CMC) • Sufficient information to assure the proper identification,
quality, purity and strength • Stability data
FDA Guidance: IND prepared and submitted by sponsor-investigators (Draft)
Content and format of INDs for phase 1 studies
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FDA Guidance
Manufacturing of investigational drugs
• Well-defined, written procedures • Adequately controlled equipment and manufacturing
environment • Accurately and consistently recorded data from
manufacturing and testing
FDA Guidance: Guideline on the preparation of IND products
CGMP for phase 1 investigational drugs
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FDA Guidance
Botanical drug development
• Botanical raw material control • Quality control by chemical test • Biological assay
FDA Guidance: Botanical drug development (Draft)
Option Developing new investigational products
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CMC information • Physical, chemical and biological characteristics • Manufacturers • Source and method of preparation • Quality controls (identity, assay, purity, impurities profile) • Formulation • Sterility • Stability data
Current Good Laboratory Practices (CGLP) compliant data FDA pre-IND consultation program
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Outcome of Non-compliance
An IND submission that lacks the proper CMC information could be placed on clinical hold.
FDA may also terminate an IND if it lacks the requisite CMC information.
Generally, however, FDA will not terminate an IND until after first attempting to resolve the issues.
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Other Cases
Online Pharmacy
Dietary Supplements
Packaging Labeling
Questions?
Office of Research Compliance TEL: 516.321.2101
EMAIL: [email protected]
Ji-Eun Kim, RPh, PhD Research Pharmacist
Regulatory Affairs | Office of Research Compliance TEL: 516.321.2128
EMAIL: [email protected]
CONTACT INFORMATION
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Thank You
