cGMP Statues and Regulations Modules 1-12

Generic Drugs

"Abbrev." they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.

Change Type Submission Contents

- A detailed description of the change. - The product invloved. - The manufacturing sites - A description of the method used and studies performed to evaluate the effects of the change on the product quality and data derived from these studies. - Relevant validation protocols and data - A reference list of relevant SOPs

Drug

- A substance recognized by an official pharmacopoeia or formulary - 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. - A substance intended for use as a component of a medicine but not a device, or a component, part or accessory of a device. - Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes

Fermentation

- A vial is removed from liquid nitrogen storage and the preserved microorganisms are streaked on an agar plate. - The isolated colonies are individually transferred to selective agar media for verification of genotype and phenotype. Colonies which are positive on the microbiological tests and are strongly resistant to the antibiotic are selected as the starting inoculum. - Depending on the process, several stages with varying medium composition and increasing volume are used before the inoculum reaches sufficient quantity. The final inoculum, from several hundred liters and up, is usually 5 to 15% by volume of the production fermenter.

Commercial Manufacturing Aspects - Robustness

- Acceptance Criterion - Overall Quality Implementation - Controls - Process Manufacturing - Yield - Continuous performance, quality and consistency

Medicinal products for human use containing a new active substance

- Acquired immune deficiency syndrome - Cancer - Neurodegenerative disorder - Diabetes

Q10 - Commerical Manufacturing

- Acquisition and control of materials - Provision of facilities, utilities, and equipment - Production (including packaging and labeling) - Quality Control and Assurance - Release - Storage - Distribution (Excluding wholesaler activities)

Manufacturing Process - Production related requirements for Biotech products

- Active ingredients - Source materials - Stability testing - Cell bank - Cell lines production -Fermentation/Harvestation/Special Techniques - Process Validation - Manufacturing Parameters (pH, Heat, Impurities) - Compatibility between Excipients and Packaging

Generic Drugs - Hatch-Waxman Act

- Allowed the availability of generic drugs. - Permitting abbreviated application submissions - Do not require animal safety and clinical data to establish safety and effectiveness - Oral dosage, must scientifically demonstrate the bioequivalence with RLD.

Abbreviated NDA components

- CMC - Bioequivalence Data - Administrative info. (labeling, patent certification)

Pediatric Trials - Nonclinical (Toxicity Studies in Animals)

- Characterization of effects with potential clinical relevance. - Designed testing for a general assessment of all organ systems. - Progressively longer treatment duration in 2 species, including rodent and non-rodent. - Data must be collect - Clinical observation: Toxicokinetic, Hematology, and Clinical - Chemistry/Pathology

FDA's Non-Clinical Testing on Drug

- Chemical structure - Proposed indications in humans - Target patient population - Special characteristics of a drug's use pattern - Proposed route of administration - Proposed duration of administration. Testing Areas (Pharmacology and Toxicology)

Medicinal Products as Orphan Medicinal Products

- Community authorization via the centralized procedure is optional for certain product types detailed in Article 3 of Regulation 726/2004. - Medical products containing new active substances not authorized in the community at the date of entry into force of this regulation. - Medicinal products for which a significant therapeutic, scientific or technical innovation can be demonstrated in the interest of patient's health.

Safety Evaluation - Pt 2

- Conducting an evaluation of all existing data from animals and humans are insufficient to support the proposed clinical trials in pediatric age group. - Addressing the pediatric safety concerns that cannot be assessed by clinical studies or standard toxicology studies. - Assessing the safety concerns that cannot be adequate or ethically, and/or safely studied in pediatric patients trials. In such trials, the SAEs are irreversible.

Non-clinical Testing Objectives

- Critical Path Initiative - Product Development Tool-Kit - Improve predictability and efficiency

CMC provides information on the following:

- DS - DP - Placebo Formulation - Labeling info for the labeled products relevant to investigational drug. - An environmental analysis for assessment of the effects of the investigational new drug or biological product on the environment.

Federal Register (1935)

- Daily Supplements of the CFR - Critical Informational Updates - Publishes FDA's issues and activities: - Advance notice - Proposed regulations - Final regulations - Regulatory Agenda - Meetings and Hearings

Q9 - Initiation of QRM

- Define the problem, including pertinent assumptions - Assemble background info on the potential hazard, harm or human health impact relevant to the risk assessment - Identify a leader and necessary resources - Specify a timeline, deliverables and appropriate level of decision making for the risk management process.

Biologics CMC - Info Needed

- Description of all materials and components - Analytical tests - Characterization of biological source materials - Description of critical process controls - Lot release data (includes toxicological testing and planned for clinical trial use) - Stability data

FDA's Role

- Determination of non-clinical testing data - Advice to sponsors on the adequacy of the non clinical data - Independent analysis of the non-clinical results and conclusions - Standards estimated for the minimum lab standards - GLP practice regulation for the non-clinical testing.

Two principles of quality risk management

- Evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient. - The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risks.

FDC Act of 1938 (Evidence of Safety)

- Extending control to cosmetics and therapeutic devices. - Requiring new drugs to be shown safe before marketing-starting a new system of drug regulation. - Eliminating the Sherley Amendent requirement to prove intent to defraud in drug misbranding cases. - Providing that safe tolerances be set for unavoidable poisonous substances. - Authorizing standards of identity, quality and fill of container for foods. - Adding the remedy of court injunctions to the previous penalties of seizures and prosecutions.

FDA Regulatory Law Enforcement - Critical Milestones

- Food and Drugs Act of 1906 - FD&C Act of 1938 - Kefaver Harris Amendments of 1962 - Medical Device Amendments of 1976

Advanced Therapy Medicinal Products

- Gene therapy medicinal products - Somatic Cell Therapy Medicinal Products - Tissue Engineering Products - Combination (w/ medical device) advanced medicinal products

Quality System Principles

- Implementing risk based approaches that allow the FDA and industry to focus on critical areas for improving product safety and quality. - Ensuring that regulatory review, compliance and inspection policies are based on state of the art pharma science. - "Early adoption of new tech advances by the industry" - Including industry application of MODERN quality management techniques, including the implementation of quality system approaches, to all aspects of pharma production and quality assurance. - Enhancing the consistency and coordination of the FDA's drug quality regulatory programs

Different Types of Letters in BLA Review Process

- Issuance of Complete Response (CR) - Information Request (IR) - Discipline Review (DR)

Chemistry, Manufacturing and Controls

- Manufacturing - Testing & Controls - Cleaning Validation - Stability Requirements - Process Controls - Written Procedures - Packaging - Personnel - Facility

Commercial Manufacturing Aspects

- Manufacturing applicability to specific product and its knowledge. - Critical aspects in establishing quality - Process specifications, parameters, controls

CBER Regulates

- More than 14 million units of blood and blood components transfused each year in US - More than 235 million vaccinations given each yr to prevent serious diseases - More than 1 million human tissues transplanted each year to repair injury, restore function, and improve quality of life. - More than 800 active human trials studying experimental cell, gene, vaccine, or blood products for serious diseases such as AIDS, cancer, diabetes and heart disease.

Patent Certifications (Applicable to the RLD)

- Patent not filed (PAR I) - Patent has expired (PAR II) - Patent will expire and the sponsor submitting the ANDA does not intend to market the product before that date. (PAR III) - Patent is invalid or will not be infringed by the proposed drug product. (PAR IV)

Q10 - Product Life Cycle - Technical Activities for new and existing products

- Pharmaceutical Dev. - DS Dev. - Formulation dev. (CCS) - Manufacture of Investigational Products - Delivery system development - Manufacturing process development and scale up - Analytical Method Development Tech Transfer: - New product transfers during development through manufacturing - Transfer within or between manufacturing and testing sites for marketed products.

FDA Modernization Act of 1997: Major provisions under FDAMA

- Prescription Drug User Fees - FDA Initiatives and Programs - Info on Off Label Use and Drug Economics - Pharmacy Compounding - Risk Based Regulation of Medical Devices - Food Safety and Labeling - Standards for Medical Products

CFR Standards

- Primary source of information for the US product registration. - Rules are based upon the Legislative Acts/Statues/Amendments

cGMP Compliance

- Quality Management Systems - Quality Assurance Raw Materials - Establishing robust operating standards and procedures, detecting and investigating product quality deviations, and maintaining reliable testing

Medicinal Products developed via Biotech process.

- Recombinant DNA Technology - Controlled gene expression of gene coding for biologically active protein in prokaryotes and eukaryotes, including transformed mammalian cells. - Hybridoma and Mabs.

Q10 - Product Discontinuation

- Retention of documentation - Sample retention - Continued product assessment and reporting

Viral Clearance - Approaches to Viral Safety

- Selection of cell lines and other raw materials including the growth media, in the absence of undesirable viruses, that may be infectious or pathogenic to humans. - Assessing the capacity of the production process to clear infectious viruses by virus inactivation and virus removal. - Testing of the biotechnology product production processes/steps for the absence of containing infectious viruses. These approaches establish a products' safety and demonstrate purity by removing and inactivating the viruses.

Biologics Development

- Similarities between the Drug & Biologics Development - Distinct development areas are applicable to Biological products - CBER guidance documents are specific to address the distinct development issued for biological products - ICH Guidelines also provide guidance specific to biological products development

ICH Process and Accepted Recommendations

- Single dose toxicity testing - Non clinical safety studies needed for the support of human trials. - Duration of the chronic testing in rodents - Reproductive toxicity studies - Toxicokinetics studies - Pharmacokinetics studies - Genotoxicity studies - Carcinogenicity studies

Biosimilars: Applicable Criteria

- Utilizing same mechanism of action or mechanism for conditions or conditions of use prescribed. - Conditions or conditions of use prescribed for a previously approved biologic product. - The route administration, dosage form and strength, - The manufacturing facility meets the standards assuring that the biologics product remains safe, pure and potent.

CMC - ICH Q7-Q10

- Validity of manufacturing processes. - Validity of controls - Establishing a Quality system: In Process materials, finished drug product testing - Ensure stability (shelf life)

Animal Rule

- Well-understood pathophysiological mechanism of the substance's toxicity and/or prevention of the product. - More than one animal species expected to react with response predictive for humans; and using well-characterized animal model for predicting response in humans. - The endpoint predicts desired effect in humans. - Data on the PK and PD effect of the product or other relevant data in animals allow a selection of effective dose in humans. - The product's effect is reasonably likely to predict the effect in humans.

Biologics CMC - Part 2

-Required validation and process qualification is required - FDA guidance documents applicable - For Biologics, the process needs to be validated (qualified prior to submitting BLA). This requirement is contract to NDA product where process validation is reviewed during the Pre-Approval Program PAI program.

Combination Products

1. A product comprised of 2 or more regulated components, (i.e. drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity. 2. Two or more separate products packaged together in a single package or as a unit and comprised of drug/device products, device and biological

Q10 - Management of Outsourced Activities and Purchased Materials

1. Assessing prior to outsourcing operations or selecting material suppliers, the suitability and competence of the other party to carry out the activity or provide the material to supply chain. 2. Contract between parties 3. Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider. 4. Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain.

Pharmaceuticals Quality System Lifecycle Management (Screenshot)

1. Design the Quality System 2. Develop Processes 3. Implement and Validation 4. Execute

Recombinant DNA Technology - Two methods commonly used to obtain the DNA are

1. Direct Chemical Syntheses 2. Isolation of mRNA and preparation of the cDNA by reverse transcription

New Drug Development Process (Screenshot)

1. Discovery/Screening 2. Pre-Clinical Research (Synthesis and Purification and Animal Testing) [Avg 5-7 yrs] 3. IND -> Clinical Studies (Avg 6-7 yrs) 4. NDA Review 5. Post Marketing (Avg 1 yr, priority 6 mths)

Drug Development Process (Screenshot in computer)

1. Exploratory Drug Discovery 2. Lead Discovery/Lead Optimization 3. Pre-Clinical 4. Clinical Development 5. Registration 6. Post Market Compliance (Label Confirmation/Post Market Compliance)

BLA Review Process is similar NDA review process and divided into 5 phases

1. Filing determinations and review planning 2. Review 3. Advisory Committee meeting preparation and conduct 4. Action 5. Post Action

OTC Categories

1. Generally recognized as safe and effective 2. Generally not recognized as safe and effective. 3. Insufficient data available to permit classification.

Products Eligible for Centralized Procedure

1. Medicinal Products developed via Biotech process. 2. Advanced Therapy Medicinal Products 3. Medicinal Products for Human Use containing a new active substance. 4. Medicinal Products as Orphan Medicinal Products

Outsourcing Facility Rules

1. Must comply with cGMP requirements 2. Are inspected by FDA according to a risk based schedule 3. Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound.

Minimum cGMP Standards

1. Organization and personnel 2. Buildings and Facilites 3. Equipment 4. Control of components and drug product containers and closures. 5. Production and process controls 6. Packaging and Labeling Controls 7. Holding and distribution 8. Lab controls 9. Records and reports 10. Returned and salvaged drug products

Exclusivity Categories (CDER)

1. Orphan Drug Exclusivity (ODE) 2. New Chemical Exclusivity (NCE) 3. "Other" Exclusivity 4. Pediatric Exclusivity (PED) 5. 180-Day Exclusivity

Scale-Up, Commercialization and Tech Transfer

1. Pharmaceutical Development 2. Tech Transfer 3. Commercial Scale Up 4. Product Life Cycle 5. Product Discontinuation (Phase Out) 6. Product Recall

Major Changes after the Kefauver Harris Drug Amendment

1. Required that manufacturers prove the effectiveness of drug products before they go on the market, and afterwards report any serious side effects. 2. Required that evidence of effectiveness be based on adequate and well controlled clinical studies conducted by qualified experts. Study subjects would be required to give their informed consent. 3. Gave FDA 180 days to approve a new drug application, and required FDA approval before the drug could be marketed in the US. 4. Mandated that FDA conduct a retrospective evaluation of the effectiveness of drugs approved for safety - but not for effectiveness - between 1938 and 1962. 5. Allowed FDA to set GMP for industry and mandated regular inspections of production facilities. 6. Transferred to FDA control of prescription drug advertising, which would have to include accurate information about side effects. 7. Controlled the marketing of generic drugs to keep them from being sold as expensive medications under new trade names.

DMF Information

1. Reserved 2. Drug substance, DS intermediate, and materials used in their preparation or drug product. 3. Packaging materials 4. Excipient, colorant, flavor, essence, or materials used in their preparation. 5. FDA accepted reference information

Biologics Licensing - Cooperative Manufacturing Arrangements can be made per FDA guidance

1. Short supply 2. Divided Manufacturing 3. Shared Manufacturing 4. Contract Manufacturing

DDT acceptance in the drug development and regulatory review process applicability in 3 ways.

1. Through an individual drug or biologic app 2. By being an accepted DDT in clinical use. 3. Through the voluntary qualification process established by Cures Act

Fermentation/Contamination - NIH Guidelines - Key Points of P1-LS Conditions

1. Use a closed vessel 2. Culture fluids should be inactivated by validated procedures before removing from the closed vessel. 3. A closed system should be used to collect samples and to add material. 4. Exhaust gasses should be filtered through a HEPA filter before being removed from the closed system 5. The closed vessel should be sterilized by validated procedures before opening 6. Should have emergent procedures for large losses of culture.

Q9 - Risk Assessment (Essential Qs)

1. What might go wrong? 2. What is the likelihood it will go wrong (probability)? 3. What are the consequences (Severity)

US Dept. of Agriculture (1862)

1927 - Bureau of Chemistry became the US Food, Drug and Insecticide Administration. 1930 - US FDA.

Biologics Lot Release Requirements

21 CFR 610.2 Samples of any lot of licensed biologic product (including protocols applicable tests) are required and submitted to CBER for review and confirmatory testing. - This requirement has been waived off for well characterized proteins.

Comparability Protocols - PT 2

A CP may be submitted for a single or multiple related changes and may cover a single or multiple BLAs. 1. Greater predictability regarding the timing of implementation of CMC changes 2. Placing the product into distribution sooner than without the use of a prtcl. 3. More effective planning of the product supply chain.

Patient Package Insert (PPI)

A PPI insert contains info for patients' understanding of how to safely use a drug product

BPCI - Biologics Price Competition and Innovation Act

A biological product may be demonstrated to be "biosimilar" if data show that, among other things, the product is "highly similar" to an already approved biological product.

Other Exclusivity - 3 yrs

A change if criteria are met. - Granted to drug when app or supplement contains reports of new clinical investigations (not bioavailability studies) conducted or sponsored by applicant and essential for approval. - Runs form time of NDA approval - Bars FDA from approving, for 3 yr period, any ANDA or 505b2 app that relies on the info supporting the approval of the drug or the change to the drug for which the info was submitted and the exclusivity granted. 21 CFR 314.108

Post-commercialization changes to cGMP manufacturing: 21 CFR Par 601.12 and 314.70

A change to a product, production process, quality controls, equipment or facilities required to be reported to FDA. Submission Types: 1. A supplement requiring approval prior to distribution 2. Supp. atleast 30 days prior to distribution of the product made using the change. 3. In an annual report, depending on its potential to have an adverse effect on the identity, strength, quality, purity or potency of the product as they may relate to the safety or effectiveness of the product.

Performance Parameter (Process Parameter)

A characteristic of the process that provides assurance of consistency and quality

cGMP for Phase 1 Investigational Drugs - Manufacturing Environment

A comprehensive and systematic evaluation of the manufacturing setting to identify potential hazards. Appropriate actions prior to and during manufacturing to eliminate or mitigate potential hazards to safeguard the quality of the P1 IND.

Comparability Protocol (CP)

A comprehensive, prospectively written plan for assessing the effect of a proposed CMC change on the identity, strength, quality, purity and potency of a drug product or biological product, as these factors may relate to the safety or effectiveness of the product. The CP describes the specific tests and studies to be performed and the acceptance criteria to be achieved to demonstrate the lack of adverse effects of one or more proposed CMC changes on product quality.

Operating Parameter (Process Parameter)

A condition of the manufacturing process that can be directly controlled. Typically, these parameters are physical or chemical. (i.e. temp, process time, column flow rate, buffer pH)

Process Step (Unit Operation)

A discrete manufacturing activity or manipulation that achieves a specific process objective (i.e. cell culture/fermentation, filtration, inactivation, chromatography)

Combination Products - Part 2

A drug, device or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device or biological product where both are required to achieve that intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed. To reflect a change in intended use, dosage form, strength, route administration, or significant change in dose. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device or biological product where both are required to achieve the intended use, indication or effect.

Submission Contents - Annual Report

A list of all products involved change. A full description of and rationale for the implemented changes including: - Site and date - Cross reference to relevant validation PRTCLs - Relevant data from studies and tests performed to evaluate the effects of the change on the product quality. - A statement by the holder of the approved app or license that the effect of the change have been assessed.

BLA Review Process - Under PDUFA

A major amendment may lead to 3 month extension clock. Refuse To File - Decision could be granted on incomplete apps. RTF decision could be based of the following: - Administrative incompleteness - Scientific incompleteness - Inadequate information

Pharmaceutical Quality System (PQS)

A management system to direct and control a pharmaceutical company with regard to quality. The PQS includes the organizational structure, responsibilities, procedures, processes and resources for implementing quality management to ensure continual improvement.

In-House Working Reference Material

A material prepared similarly to the in house primary reference material that is establish solely to assess and control subsequent lots for the individual attribute in question. It is calibrated against the in house primary reference material.

Analytical Test

A measure of a specific attribute (identity, purity, potency, strength)

Adventitious Agent

A microorganism (i.e bacterium, fungus, mycoplasma, mycobacterium, virus, parasite, TSE) that is inadvertently introduced into the production of a biological product.

CMC - CQA

A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.

CMC - Control Strategy

A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in process controls, finished product specifications and the associated methods and frequency of monitoring and control (ICH Q10)

Contract Manufacturing - Quality Agreements - Manufacturing Control Strategy - Process Monitoring and Control

A process monitoring approach should include at least the following: Variables being monitored at appropriate locations in the process, such as: Process parameters, input and in process material attributes, and final product attributes. Sampling plan, including: Sampling locations, sampling or measurement frequency, the sample size to be taken and measured, and statistical criteria appropriate for use to evaluate the process monitoring data.

CMC - CPP

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process products the desired quality.

CMC - Quality Target Product Profile

A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

ANDA - Suitability Petition (SECTION 505J)

A suitability petition can be filed. Contains contrasts and comparisons between the Generic Drug vs. RLD

Contract Manufacturing - Quality Agreements - Residence Time Distribution

A suitable scientific approach should be used to characterize how a material flows through the process. One common approach characterization of RTD for the individual unit operations and integrated system. Probability distribution that describes the amount of time a mass or fluid elements remains in a process, and can be measured through a tracer experiment, online process measurements of appropriate product attributes and/or process modeling.

CMC - QbD

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control. Based on sound science and quality risk management.

Master Virus Seed

A viral seed of a selected vaccine virus from which all future vaccine production will be derived, either directly or via Working Virus Seeds.

Info in Orange Book: Strength

A. If the product is available in one or more strengths then it will have a YES for RLD. B. If there are approved generic products from another manufacturer then the RLD will be NO. C. All the products within the dosage form; route grouping will have a TE code. D. The products that have been discontinued are in the Discontinued Section and do not RLD or TE Codes.

Three principal, complementary approaches have evolved to control the potential viral contamination of biotechnology products:

A. Selecting and testing cell lines and other raw materials, including media components, for the absence of undesirable viruses which may be infectious and/or pathogenic for humans. B. Assessing the capacity of the production processes to clear infectious viruses. C. Testing the product at appropriate steps of production for absence of contaminating infectious viruses.

Drug Price Competition and Patent Term Restoration Act (1984)

ANDA - Amends the FD&C Act to authorize abbreviated apps for the approval of a new drug. - Info to show that the conditions of use prescribed in the labeling proposed for a new drug have been previously approved for a drug that appears on a list prepared by the Secretary of Health and Human Services - A certification relating to patents covering such listed drugs.

Agonist

API must be good to create signaling in the system.

New Molecular Entity (NME)

Active ingredient that contains no active moiety that has been previously approved by the Agency in an application submitted under section 505 of the FD&C or has been previously marketed as a drug in the US

Manufacturers of P1 IND can use to comply with the statutory requirement for cgmp

Adherence to cGMP during manufacture of P1 IND occurs through: Well defined, written procedures, adequately controlled equipment and manufacturing environment, accurately and consistently recorded data from manufacturing (including testing)

ICH Q5B - ANALYSIS OF THE EXPRESSION CONSTRUCT IN CELLS USED FOR PRODUCTION OF R-DNA DERIVED PROTEIN PRODUCTS

Advises on the type of info that are considered valuable in assessing the structure of the expression construct used to produce RDNA proteins

Master Cell Bank

Aliquot of a single pool of cells which generally has been prepared from the selected cell clone under defined conditions, dispensed into multiple containers and stored under defined conditions. The MCB us used to derive all working cell banks.

CMC - Life Cycle

All phases in the life of a product from the initial development through marketing until the product's discontinuation (ICH Q8)

Types of Submissions Subject to eCTD Requirement

All subsequent submissions to these types of apps, including amendments, supplements, and reports even if the original submission was filed before the requirements went into effect: - Non commercial INDs, such as investigator sponsored INDs and expanded access INDs - Submissions for blood and blood components, including source pharma - Submissions for promotional materials for human prescription

CBER Product Jurisdiction - Allergenics

Allergen extracts, allergen patch tests, antigen skin test

DDT Qualification Programs

Allow CDER to work with submitters to guide htem as they develop or refine a DDT for a specific use. Qualifying a DDT will allow sponsors to use the DDT in the qualified context of use during drug development without requesting that CDER reconsider and reconfirm the suitability of the DDT for the qualified context of use.

In-House Primary Reference Material

An appropriately characterized material prepared by the manufacturer from a representative lots for the purpose of biological assay and physiochemical testing of subsequent lots, and against which an in-house working reference material is calibrated.

Marketing Application

An approved product granted via CP, will require post-authorization regulatory activities. - Variations/Renewals All post authorizations via CP.

Drug Compounding

An outsourcing facility as a facility at one geographic location or address that is engaged in the compounding of sterile drugs, has elected to register as an outsourcing facility and complies with all of the requirements of section 503B Drugs compounded by an outsourcing facility can qualify for exemptions from FDA approval requirements, and the requirement to label products with adequate directions for use, but not from cGMP requirements.

Hybridoma Technology (mAbs)

Antibodies are protein components of the immune system in the blood and other body fluids, and they are composed of two heavy and two light polypeptide chains with a total MW of 150k or greater. They are produced in reaction to a specific structural site (determinant) of a foreign substance called antigen (immunogen)

Container Closure System (CCS) - Packaging Component

Any single part of a CCS. Typical components are containers (i.e. ampules, vials, bottles), container liners (i.e. tube liners), closures (i.e. screw caps, stoppers), closure liners, stopper overseals, container inner seals etc.

cGMP - 21 CFR Part 314 and Part 600

Application and licensing submission requirements for new generic drug applicants.

Orange Book

Approved Drug Products with Therapeutic Equivalence Evaluations. - Identifies drug products approved on the basis of safety and effectiveness by the FDA under the FD&C Act. - Publishes patent info on approved drug products.

Reference listed drug

Approved drug product to which new generic versions are compared to show that they are bioequivalent.

Fermentation/Contamination - NIH Guidelines - Safety - Lengthy and Complex Procedures

Are needed to purify the products made by recombinant microorganisms, because all the products reported thus far are intracellular. Some very potent chemical and a large amount of solvents are used.

Bio-Based Products

Are wholly or partly derived from materials of biological origin, excluding materials embedded in geological formations and/or fossilized. In industrial processes, enzymes are used in the production of chemical building blocks, detergents, pulp and paper textiles etc. Using fermentation and bio-catalysis instead of traditional chemical synthesis, higher process efficiency can be obtained, resulting in a decrease in energy and water consumption, and a reduction of toxic waste. As they are derived from renewable raw materials such as plants bio-based products can help reduce CO2 and offer other advantages such as lower toxicity or novel product characteristics.

ICH Q5C - STABILITY TESTING OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS

Aspects of stability test procedures needed to take account of the special characteristics of products in which the active components are typically protein/polypeptides

ICH Q5E - COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS

Assessing comparability of products before and after changes are made in the manufacturing process for the DS or DP. Assists in the collection of relevant technical info which serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety, and efficacy of the DP. Document does not prescribe any particular analytical, non-clinical or clinical strategy. The focus is on the quality aspect.

cGMP Regulations

Assures the identity, strength, quality and purity of drug products

CBER - Required Product License Application/Establishment License Application (PLA/ELA, precursor to the BLA)

Authority with seizure power.

Pre-License Inspection Policy

BLA and Supplements must meet the following: Hold active US license. a contract facility cannot manufacture license product. No FDA inspection in last 2 years. Previous inspection revealed significant GMP deficiencies. Establishment is performing significant manufacturing step Manufacturing process is significant different.

Biological Product Deviation Reporting (BPDR)

BPDR submitted within no more than 45 calendar days from the date when info is received.

Conception of CTD 2003

Became the mandatory format for NDA in the EU and JAPAN. Strongly recommended format of choice for NDAs submitted to the FDA, in the US.

OTC Product

Before 1951 - OTC did not exist. Durham Humphrey Amendment of 1951 - 1. Habit forming drugs 2. Not safe for use unless supervised by healthcare professional 3. Limited to prescription use under a NDA

cGMP Regulations - 21 CFR Part 600

Biological Products General

ICH Q5 (A-E)

Biotechnology Products

FDA Regulatory Law Enforcement Example

Blood work @ hospital who controls it. CLIA - They do the audits for the lab, accredits if the exam is good or bad etc. Increased compliances against blood standards.

CBER Product Jurisdiction - Blood & Blood Products

Blood, Blood Components, Blood Bank Devices, Blood Donor Screening Tests

CBER Product Jurisdiction - Tissue & Tissue Products

Bone, Skin, Corneas, Ligaments, Tendons, Stem Cells, Sperm, Heart Valves

ICH Q5D - DERIVATION AND CHARACTERISATION OF CELL SUBSTRATES USED FOR PRODUCTION OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS

Broad guidance on standards for the derivation of human and animal cell lines and microbes used to prepare biotech/biological products and for the preparation and characterisation of cell banks to be used for production.

Human Drug Compounding

Bulk Drug Substances Used in Compounding - Sections 503A and 503B of the FD&C place limits on the bulk drug substances that can be used in compounding. - State-licensed physicians and pharmacists seeking to operate: 1. Comply with an applicable USP or NF monograph if one exists, and the USP chapter on pharmacy compounding. 2. Are components of FDA approved drug products if an applicable USP or NF monograph does not exists. 3. Appear on FDA's list of bulk drug substances that can be used in compounding if such a monograph does not exist and the substance is not a component of an FDA approved drug product.

CQA - Satisfied Conditions

By or under the direct supervision of a licensed pharmacist in an outsourcing facility may be exempt from certain sections of the FD&C act including section 502F1 AND 505 Drugs compounded in outsourcing facilities are not exempt from the requirements of section 501A2B of the FDC Act

Biologic Product Licensing - Cooperative Manufacturing Arrangements

CBER in conjunction with CDER issued guidance to develop different strategies for biologic product manufacturing and licensing.

Package or Market Package

CCS and Labeling: Associated components such as spoons or dosing cups. External packaging: Cartons or shrink wrap. A market package is the article provided to a pharmacist or retail customer upon purchase and does not include packaging used solely for the purpose of shipping such articles.

Title 21 of the CFR is reserved for rules of the FDA

CFR is divided into 50 titles; these titles (or volume) of the CFR are revised in each calendar year. Updates: Title 21 is issued on approximately April 1st of each year. Order for citations: Title, CFR, Part, Section.

CMC - CTD

CMC information is QUALITY DATA for the drug product manufacturing processes and validation including the shelf life and related parameters. CTD submitted for both drug and biologic product submissions aka NDAs and BLAs.

Dossier Requirements

CTD Modules/EU Requirements - FDA includes more emphasis upon process validation, BLA requirements, establishment registration and license apps. - FDA requires full consideration on 21 CFR Part 312 and Investigational Medicinal Product for interstate commerce, general investigational protocols for human study for review. - Following IND review, CBER safety concerns are discussed, which may result in a 'clinical hold'. - Review of new protocols, amendments and manufacturing processes are required to be submitted periodically for the active IND. - Annual Reports required within 60 days of IND anniversary.

Process Validation

Calibrations must be done 60 days ahead Automation same FDA picks on % yield, if below 90%. If below it shows you are not implementing PPI or better operating practices.

Qualified DDT

Can be included in IND or NDA/BLA submissions without the need for CDER to reconsider and reconfirm the suitability of the DDT as long as: - There are no serious study flaws - There are no attempts to apply the DDT outside the qualified context of us - There are no new and conflicting scientific facts not known at the time the qualification was determined - Qualification may contribute to acceptance and app of DDT across multi drug development programs. Having qualified DDTs that can be utilized by many sponsors and aid in optimizing drug development and evaluation.

QC and Microbial Testing

Can prove or disprove the continuation of the process. If not, process stops and cleaning validation is needed to get back to regular schedule. Inspired by Virus Toxin Law.

CCS Codes - Compatibility

Case 1C - Liquid Based Dosage form that conceivably could interact with its CCS system components Case 2C - Solid Dosage Form until reconstituted; greatest chance for interacting with its container CCS occurs after it is reconstituted. Case 3C - Solid dosage form with low likelihood of interacting with its CCS components.

CCS Codes - Performance

Case 1D: Frequently a consideration Case 2D: May be a consideration Case 3D: Rarely a consideration

CCS Codes - Safety

Case 1S - Typically provided are USP Biological Reactivity Test data, extraction/toxicological evaluation, limits on extractable, and batch-to-batch monitoring of extractables. Case 2S - Typically provided are USP Biological Reactivity Test data and possibly extraction/toxicological evaluation. Case 3S - An appropriate reference to the indirect food additive regulations is sufficient for drug products with aqueous based solvents. Drug products with aqueous based solvents. Drug products with non-aqueous based solvent systems or aqueous based systems containing co-solvents generally require additional suitability information. Case 4S - An appropriate reference to indirect food additive regulations is sufficient Case 5S - An appropriate reference to indirect food additive regulations for all components except the mouthpiece for which USP Biological Reactivity Test data is provided.

EU - Biotech Dev.

Centralized procedure applies for products developed with one of the following - Recomb. DNA, Controlled expression of gene coding for proteins, hybridoma and MABS.

Annual Report

Changes that have a minimal potential to have an adverse effect on product quality shall be documented by the applicant in an annual report.

CBE30/CBE

Changes that have a moderate impact to have an adverse effect on product quality require an applicant to report the change to the FDA in a supplement at least 30 days prior to distribution of the product made using the change. The supplement for such a change is complete and provides the proper info and particular assurances that the change has been appropriately submitted. The product made using such a change may be distributed immediately upon receipt of the supplement by the FDA. These circumstances may include substantial similarity with a type of change that ordinarily involves a CBE supplement or a situation in which the applicant presents evidence that the change has been validated in accordance with an approved Comparability Protocol under 21 CFR 601.12

Prior Approval Supplement (PAS) - Severe impact

Changes that have a substantial potential to have an adverse effect on product quality require an applicant to report the change to the FDA in a supplement to the approved BLA. A PAS must be approved by the FDA prior to distributed of the product manufactured using the change.

Contract Manufacturing: Types of Changes - Minimal Potential

Changes with minimal potential to adverse effect on the identity, strength, quality, purity, or potency of the product impacting safety or effectiveness of the product.

Contract Manufacturing: Types of Changes - Moderate Potential

Changes with moderate potential to adverse effect on the identity, strength, quality, purity, or potency of the product impacting safety or effectiveness of the product.

Contract Manufacturing: Types of Changes - Substantial Potential

Changes with substantial potential to adverse effect on the identity, strength, quality, purity, or potency of the product impacting safety or effectiveness of the product.

FD&C Act Chapter Breakdown

Chapter I: Short Title 2: Definitions 3: Prohibited Acts and Penalties 4: Food 5: Drugs and Devices 6: Cosmetics 7: General Authority 8: Imports and Exports 9: Miscellaneous

Fermentation - Part 2

Chemically defined media are normally used in the inoculum preparation, second stages and production fermentation, because the recombinant microorganisms usually have stringent nutritional requirements. Traces of antibiotics are also added to the medium to help prevent the mutant from taking over the slower growing recombinant cells.

Q9 - Risk

Combination of probability of occurrence of harm and the severity of that harm. Achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm.

Drug Quality and Security Act: Signed into law on NOV 27TH 2013 created a new section 503B in FD&C

Compounder - Outsourcing Facility 503B

Centralized Procedures Paths - Exceptional Circumstances

Conditional Authorizations - Detailed in ANNEZ I to Directive 2001/83/EC

Food and Drugs Act 1906

Congress on June 30, (Roosevelt). Prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs. Brought awareness to: Product Labeling Dangerous Ingredients Intended Use

FDA Guidances Applicability

Consumers & Patients Healthcare Professionals Researchers and Scientists Industry

Elixir of Sulfanilamide (Nov 16 1937)

Containing the poisonous solvent diethylene glycol (anti freeze), killed 107 people, dramatizing the need to establish drug safety before marketing and to enact Food and Drug law. - Flavorful oral anti-infective - Prior to 1962 review of FDA - Post 1962 review of FDA - DERI - Drug Efficacy Review Implementation

505B NDA

Contains full safety and efficacy trial reports conducted by the sponsor.

505B2 NDA

Contains the safety and efficacy data submitted from trials that sponsor did not conduct or obtained a right to reference.

Fermentation/Contamination

Contamination of a fermentation batch by microorganisms and/or phages is not uncommon. It is critical that firm establishes an acceptable level for each type of contamination. Automated equipment and microprocessor controlled instruments will be extensively used to control and monitor the process variables during fermentation. Other novel systems such as immobilization techniques and continuous reactor will be applied to increase the yield and improve the stability of the recombinant culture.

Plasma Products - Quality and Safety

Control of Starting Material - Including donor selection, testing of individual plasma and testing plasma pools for viral markers. Control of manufacturing including validated and controlled protein purification, and evaluating the manufacturing steps that inactivate or remove the microbial contaminants. Both measures ensure product safety.

Plasma Products - Major Areas

Control of starting materials. Including donor selection, testing of individual plasma and testing plasma pools for viral makers. Control of manufacturing, including validated and controlled protein purification and evaluating the manufacturing steps that inactivate or remove the microbial contaminants. Both measures ensure product safety.

Radiation and the FDA

Covered due to at home usage and minimal radiation is ideal and its need to be controlled.

Key Concepts of Continuous Manufacturing - Defining Batches for Continuous Manufacturing

Critical for PMC, recalls, and other compliance decisions. Batch - Specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. Lot - Specific identified portion of a batch, having a uniform character and quality within specified limits, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

Drug Efficacy Study Implementation (DESI)

DESI led to ANDA Evaluated more than 3k individual products and about 16k claims.

DMF Compliance

DMFs requirements under 21 CFR Part 314.420 - Other master files relevant to a biological product under requirements of 21 CFR Part 601. 51 - Any amendments to or annual reports an previously submitted DMFs

EMA Defintion

Decentralized agency of the EU located in london. Began in 1995. The agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharma companies in the EU. EMA protects public and animal health in 28 EU Member states, as well as the countries of the European Economic Area, by ensuring that all medicine available on the EU market are safe, effective and of high quality.

Q10 Continual Improvement - Pharma Development

Design a product and its manufacturing process to consistently deliver the intended performance and meet the needs of patients and healthcare professionals and clients. Approaches to development are also listed in ICH Q8. Exploratory and clinical development studies, while outside the scope of this guidance, are inputs to the development.

Viral Safety Evaluation for PLASMA

Design, contribution, interpretation of studies validating virus inactivation and removal. Plasma derived products manufacturing process should bear an independent and validated inactivation and removal steps with a significant reduction factor. Dossier in the marketing app includes required virological docs, has not been formally retracted then it becomes invalid for CTD compulsory. Manufacturing of plasma derived products must include independent and validated inactivation and removal steps.

Q10 Objective - Establish and Maintain a State of Control

Develop and use effective monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes.

Quality management can serve as a key holder to several operations

Development Facilities, equipment and utilities Material Management Production Lab Control and Stability Testing Packaging and Labeling For Inspection and assessment activities

cGMP CFR - Distribution Records

Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped and lot or control number of the drug product. Section 211.196

Good Review Practice (GRP)

Documented best practice within CDER thats discusses any aspect related to the process, format, content and or management of a product review. GRPs: - Developed over time as superior practices based on experience, and provide consistency to the overall review process of new products - Developed to improve the quality of reviews and review management. GRPs improve efficiency, clarity and transparency of the review process and review management. - Adopted by review staff as standard processes through supervisor mentoring, implementation teams and formal training when necessary.

Pharmaceutical Products 3 Types

Drug Biologic Biopharmaceutical

Differences between Biologics and Drugs

Drug (Small Molecules) - Chemically synthesized - Well Characterized Biologics - Originally derived from living organism. - More complex (not fully characterized)

Differences between Biologics and Drugs

Drug (Small Molecules) - Chemically synthesized - Well characterized Biologics - Originally derived from living organism - More complex (not fully characterized)

Hatch Waxman Act

Drug Price Competition and Patent Term Restoration Act - Allowed the availability of generic drugs. - Permitting abbrev. applications submission - Do not require animal safety and clinical data to establish safety and effectiveness. - Oral dosage, must scientifically demonstrate the bioequivalence with RLD

Generic Drug

Drug which is produced and distributed without the patent protection. The manufacturer can submit a patent application on the generic drug formulation but not on the API

Post-Market Compliance

Drugs - CFR Part 210 and 211 Biologics - 21 CFR Parts 600-680 cGMP refers to requirements in the FD&C Section 501a(2)(B) - All drugs and APIs - For finished formulation: Human and Animal drugs

cGMP Regulations - Minimum requirements

Drugs contain min. requirements for the methods, facilities, and controls used in manufacturing, processing and packing of a drug product.

Role of European Commission

EC aims to identify and remedy obstacles to the biotech industry..

Q10 Continual Improvement - PQS Elements

ENHANCEMENT - Process performance, product quality monitoring system, CAPAs, change management system, management review of process performance and product quality

Q9 - Risk Management

Effectively utilized in many areas of business and government including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies regulating these industries. Protection of the patient as a stakeholder is prime importance. Identify and control quality issues during development and manufacturing.

Over the Counter Drug Review (1972)

Enhance the safety, effectiveness and appropriate labeling of drugs sold without prescription.

Post-Approval Changes: Manufacturer

Entity that engages in cGMP activities including implementation of oversight and controls over the manufacture of drugs to ensure quality.

Post-Approval Changes: Quality unit

Equivalent to QC unit

Q9 - Risk Analysis

Estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms.

Many requirements for containers can be found in the drug product monographs in the USP/NF

Example: - For capsules and tablets, the design characteristics of the container - Injectable products, materials of construction are also addressed (e.g. "Preserve single dose or in multiple dose containers, preferably of Type I glass, protected from light")

Centralized Procedures Paths

Exceptional Circumstances Conditional Authorization Accelerated Assessment

Exclusivity

Exclusive marketing rights granted by the FDA upon approval of a drug and can run concurrently with a patent or not. Prevents the submission or effective approval of ANDAs or applications described in Section 505b2 of the Act and was designed to promote a balance between new drug innovation and generic drug competition.

CQA - Reinstated Section 503A

Exempting compounds from the drug approval provisions of the FDCA and compounding facilities from cGMP mandated by the FDA as long as it complies with the conditions states in Section 503A. CQA also removes from section 503A of the FDC act the provision on solicitation of prescriptions and advertising that had been held unconstitutional by the US Supreme Court in 2002.

Golden Standard is 2 year stability

Expiration Date is 1 day prior to adjust to other countries.

To ensure that statutory patent protection and marketing exclusivity is maintained, and the generic version of the drug is made available for the market, which legislation was amended?

FD&C Act.

Container Closure System

FD&C mandates the need for adequate info related to packaging materials. Section 501A3 of the act states that a drug is deemed to be adulterated if: "A container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health." Section 502: States that a drug is considered misbranded if there are packaging omissions.

In the late 1970s, the FDA had envisioned several different set of cGMPs with separate standards for finished dosage forms, bulk ingredients and other classes of products.

FDA approach is "general regulatory approach", for supplement approach they add when necessary.

Post approval changes

FDA compliance requires defining, establishing, and documenting manufacturing activities of the parties involved in CMO subject to cGMP requirements.

Pharmaceutical Equivalents

FDA considers drug products to be pharmaceutical equivalents if they meet 3 criteria: - They contain the same active ingredients - They are of the same dosage form and route of administration - They are identical in strength or concentration.

OTC

FDA defines OTC drugs as safe and effective for use by the general public without a doctor's prescription.

DDT and PPP

FDA encourages forming groups with public private partnership. A PPP involves at least one non profit org and one for profit org.

CBER Advisory Committee

FDA guidance proposed 3 factors for FDA to consider when referring a matter to advisory committee. - Issues significant to public interest. - Controversial issues - Issues requiring specific scientific expertise CBER will inform 55 days in advance, if it has determined that a Advisory Committee meeting is required.

180 Day Exclusivity

FDA may also grant exclusivity to ANDA for generic drugs. Under the Drug Price Competition and Patent Term Restoration Act, or the Hatch Waxman Act, a company can seek approval from FDA to market a generic drug before the expiration of a patent relating to the brand name drug upon which the generic is based. The first company to submit an ANDA with the FDA has the exclusive right to market the generic drug for 180 days.

Consumer Product Safety Commission (CPSC)

FDA requirement for tamper resistant closures is included in 21 CFR 211.132. CPSC requirements for child resistant closures are included 16 CFR 1700.

ANDA - Citizen's Petition (SECTION 505J)

FDA responds within 90 days to the petition If suitability petition is not accepted, an NDA under Section 505B2 of the FDC Act may be the option

What was surprising about the NECC?

FDA sent a warning letter in 2006. However the company had issues since inception. FDA did not follow up as the facility is under the guidance of the state.

Patents and Exclusivity

FDA will not publish in the Orange Book patent info on unapproved apps or beyond the scope of FDC (process or manufacturing patents). The patents that FDA regard: Claim active ingredient, drug product patents which include formulation/composition, use patents for a particular approved indication or method of using the product, certain other patents as detailed on FDA Form 3542.

Outsourcing Facilities Section 503B (d)(4)

Facilities that meet all of the conditions described in section 503B including registering with FDA as an outsourcing facility and paying an annual establishment fee.

Drug Efficacy Amendments of 1962

First "generic" products marketed. - These products were not approved based upon that these were next generation of the original, innovative, 'old' drug. - After 1962, FDA required applications for these generic version drugs for approval to market.

U.S Pharmacopeia 1820

First compendium of standard drugs for the US.

cGMP Regulations - 21 CFR Part 314

For FDA approval to market a new drug

Centralized Procedures Paths - Accelerated Assessment Procedure

Formal accelerated evaluation. The products must represent a therapeutic innovation in interest of PH. 210 Days evaluation period, now reduced to 150 days.

Section 505(b)(1)(D)

Full description of the methods used in, the manufacturing, processing and packing of such drug. This includes facilities and controls used in the packaging a drug product.

Why not patent?

Full formulation is NEVER patented cause then you will lose business. Patent is very rare. If you patent, then 10 yrs are lost in the development and only 10 yrs are actually in market.

CBER Product Jurisdiction - Cellular & Gene Therapy Products

Gene-Based Treatments, Cell-Based Treatments, Cloning

Bioeqiuvalence

Generic drug product must deliver same amount of active ingredient as the RLD. - Dosage form - Strength - Route of Administration - Quality - Performance Characteristics - Intended Use

Recombinant DNA Technology - Construction of a R-DNA Molecule

Genetic information in almost all living cells is stored in the DNA. The expression of DNA into protein involves two major steps: 1. Transcription of DNA into mRNA 2. Translation of mRNA on ribosome into protein.

New Chemical Exclusivity (NCE) - 5 yrs

Granted to a drug that contains no active moiety that has been approved by FDA under section 505b Runs from time of NDA approval Bards FDA from accepting for review any ANDA or 505b2 app for a drug containing the same active moiety for: - 5 yrs if an ANDA does not contain a pargaraph IV certification to a listed patent. - 4 hours if an ANDA is submitted containing a paragraph IV certification to a listed patent - Described in 21 CFR 314.108

Orphan Drug Exclusivity (ODE) - 7 yrs

Granted to rare drugs. - Runs from time of approval of NDA or BLA - Bars FDA from approving any other application for the same drug for the same orphan disease or condition for 7 years. - Covered under the Orphan Drug Act and 21 CFR 316.31

Pediatric Exclusivity - 6 months added to existing Patents/Exclusivity

Grants an additional 6 mths of market protection at the end of listed patents and/or exclusivity for sponsor's drug products containing the active moiety, when the sponsor has conducted and submitted pediatric studies on the active moiety in response to a written request from FDA. Pediatric exclusivity takes on characteristics of 5 yr, 3 yr or orphan exclusivity when it attaches to those protections. Described in the Best Pharma for Children Act and Section 505A of the FDA Modernization act of 1997.

Therapeutic Proteins

Growth Factors Enzymes Cytokines Chemokines Angiogenic Factors Toxins Soluble Receptors/Receptor Antagonists

Q8 - Pharmaceuticals Development

Guidance through the application of scientific approaches and quality risk management. - Pharmaceuticals development section is intended as a comprehensive summary of the product and manufacturing processes. - The aim of pharmaceuticals development should be to design a quality product and its manufacturing processes to constantly deliver the intended performance of the product.

ICH Initiation

Harmonization began in EU, as they moved towards the development of a single market of pharmaceuticals. Later, the WHO Conference of Drug Regulatory Authorities in Paris, in 1989 specified plans for action. The authorities approached International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint regulatory industry initiative on international harmonization and ICH was conceived.

ICH (1990) - Global Drug Development

Harmonization was realized through the tragedies of Thalidomide incident in EU in the 1960s. Whether or not the individual countries developed drugs yet, there was a rapid increase in 1960s-1970s for laws, regulations, and guidelines for reporting and evaluating the data on safety, quality and efficacy of new medicinal products. To harmonize, based upon their technical requirements from country to country, it was necessary to duplicate many time-consuming and expensive test procedures, in order to market new products, internationally.

Q10 - Pharmaceuticals Quality System

ICH Q10 - Describes one comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts. Including GMP regulations and complements Q8 AND Q9. - Applies to the systems supporting the development and manufacture of API and DPs, including biotech, biological products, throughout the product lifecycle.

Safety Evaluation

ICH S2 Guidance on Genotoxicity Testing and Data. - Interpretation for Pharma Intended for Human Use. - Genotoxicity Testing - In-vitro testing for: Bacterial reverse mutation assay for mutagenicity, mammalian cell chromosomal assays to test for clastogenicity - In-vivo testing for; Micronucleus testing for repair mechanisms. Reproductive and Developmental toxicity studies. Considerations between animal and adult populations studies, to evaluate the study design in pediatric age group.

Applications Types

IND - Investigational New Drug NDA - New Drug App ANDA - Abbrev. New Drug App BLA - Therapeutic Biologics App OTC - Drug App for OTC

Types of Submissions requiring Study Data

IND apps (for products that are intended to be distributed commercially) NDA/ANDA/BLA All subsequent submissions to the these types of applications, including amendments, supplements, and reports, even if the original submission was filed before the requirements went into effect.

Q9 - Risk Assessment

Identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Need a well defined problem in with several forms of info to make a well rounded action plan.

Q9 - Risk Evaluation

Identified and analyzed risk against given risk criteria. Risk evaluations consider the strength of evidence for all three of the Qs.

21 CFR Part 210 - Lot = Batch

Identified portion of a batch, having uniform character and quality within specified limits. Or in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.

Biologics CMC - Specific Tests

Identity Constituent materials Mycoplasma Alternate Methods as applicable Applicable CMC guidance documents

cGMP Regulations - 21 CFR Part 210 - Regulatory Action and Compliance

If failure to comply with any regulation set forth in this part and in parts 211 of this chapter in the manufacture, processing, packing or holding of a drug. Compliance - The regulation specifically applicable to the drug product.

Q10 Objective - Achieve Product Realisation

Implement and maintain a system that allows the delivery of products with the quality attributes appropriate to meet the needs of patients..

Generic Drug Enforcement Act (1992)

Imposes debarment and penalties for illegal acts involving abbreviated drug applications.

Pharmaceutical Quality System

Include appropriate processes, resources, and responsibilities to provide assurance of the quality of outsourced activities and purchased materials. 1. Process Performance 2. Product Quality Monitoring 3. CAPAs 4. Change Management and review

Labeling Changes - Annual Report

Include changes to any final printed packaged insert, package label, container label or Medication Guide required under 21 CFR Part 208 include, among other things, editorial or similar minor changes and changes in the information on how the product is supplied that does not involved a change in the dosage strength or dosage form.

Q9 - Risk Control

Includes decision making to reduce and/or accept risks. Purpose - Reduce the risk to an acceptable level. Amount of effort used for risk control should be proportional to the significance of the risk. Including a benefit-cost analysis for understanding the optimal level of risk control.

Drug > Vaccine > Pacemaker

Increased risk and due to lack of control one has on it.

Regulatory Initiatives & Impact

Innovation Globalization Food Safety Regulatory Science Tobacco Transparency Medical Countermeasures Sentinel Initiatives

Contract Manufacturing - Quality Agreements - Manufacturing Control Strategy - Input Material Control

Input Material Control - Input materials are continuously added through a feeder system, over the duration of a production run. - Different batches of input materials can be introduced to the system at different process time points, and variability in input material attributes could affect feeding, introduce process variability into the system, impact RTD models, and potentially affect finished product quality. In addition, transport processes in the integrated system may cause some degree of transformation.

Example risk control questions

Is the risk above an acceptable level? What can be done to reduce or eliminate risks? What is the appropriate balance among benefits, risks and resources? Are new risks introduced as a result of the identified risks being controlled?

Biologic Product Licensing

Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product. Among other things, safety and purity assessments must consider the storage and testing of cell substrates that are often used to manufacture biologics. A potency assay is required due to the complexity and heterogeneity of biologics. The regulations regarding BLAs for therapeutic biological products include 21 CFR parts 600, 601, and 610.

Pharmaceutical Products - Drug

It could be a chemically synthesized product. It could be developed by classical fermentation It could be a chemical product isolated from the natural sources

Pharmaceutical Products - Biopharmaceutical

It could be biologic pharmaceutical product that is derived by a genetic manipulation of a living organism.

Pharmaceutical Products - Biologic

It is a pharmaceuticals product derived from living sources (blood, vaccines, allergenic extracts, tissues)

Q7 - GMP for API

It provides guidance for cGMP for the manufacturing of API under an appropriate system for managing quality. - API must meet the requirements of quality and purity. - 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 related controls. - Does not cover safety aspects of the personnel engaged in the manufacture nor aspects of protection of environment. The controls are inherent responsibilities of the manufacturer and are governed by national laws.

CCS Codes - Protection

L (Protects from Light, if appropriate) S (Protects from solvent loss/leakage) M (Protects sterile products or those with microbial limits from microbial contamination) W (Protects from water vapor, if appropriate) G (Protects from reactive gases, if appropriate)

Labeling Changes - 21 CFR 601.12

Labeling changes requiring supplement submission and FDA approval before distribution of the product. Labeling changes that require supplement submission and FDA approval, but which do not require FDA approval of the supplement before the product with the labeling change may be distributed. Certain safety-related labeling changes to the insert, label, or container to reflect newly acquired info or any other labeling that FDA specifically request to be submitted in a changes being affected supplement.

Drug Efficacy Amendments of 1962

Led to new requirements to market the generics. - Post Drug Efficacy Amendments of 1962, FDA required the submission of ANDA

Durham-Humphrey (1951)

Led to the birth of Rx drugs.

Pharmacy Compounding

Legislation creates a special exemption to ensure continued availability of compounded drugs products which are prepared by pharmacists to provide patients with individualized therapies not available commercially. The law prevents manufacturing under the form of compounding by establishing parameters within which the practice is appropriate and lawful.

Scenario: 2. Addition, deletion, or substitution of sterilization steps or procedures for handling sterile materials in an aseptic operation.

Major impact

Scenario: 1. Changes in the sterilization method (gas, dry heat, irradiation)

Major impact Gamma Irradiation if needed then the dosage will be checked accordingly.

Q10 Continual Improvement - Product Discontinuation

Manage the terminal stage of the product lifecycle effectively. Pre-defined approach should be used to manage activities such as retention of documentation and samples, and continued product assessment and reporting in accordance with regulatory requirements

Guidances

Manufacturer for manufacturing must comply with either the applicable statue or the regulation; or in some cases both.

Biotechnology Products Manufacturing Challenges

Manufacturing Issues - Bioreactor (Desired Product, Contaminant/Impurity Load) - Downstream processing (Desired product, viral clearance/inactivation, removal of in-process reagent) - Removal of host cell proteins and DNA (Need for sensitive assay)

21 CFR Part 210 - In-process Material

Material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product.

Pharmaceutical Equivalents Part 2

May differ in characteristics: - Shape - Release mechanism - Labeling (to some extent) - Scoring - Excipients (including colors, flavors, preservatives)

What is DDT?

Methods, materials or measures that have the potential to faciltate drug development. Ex: Biomarker used for clinical trial enrichment, clinical outcome assessment used to evaluate clinical benefit, an animal model used for efficacy testing of medical countermeasures under the regulations commonly referred to as the Animal Rule.

Scenario: An increase or decrease in production scale during finishing steps that does not involve an equipment change.

Minimal impact

FD&C in 1938 brought awareness for the compliance requirements in the following areas:

Misbranding Drug Advertising Factory Inspections Enforcement

Scenario: An increase or decrease in production scale during finishing steps that involves different equipment

Moderate impact

Scenario: For sterile drug products, elimination of in-process filtration performed as part of the manufacture of a terminally sterilized drug product.

Moderate impact

Scenario: Replacement of equipment with equipment of different design that does not affect the process methodology or process operating parameters.

Moderate impact

Drug vs Biologic

Must be excreted out of the body vs Derived and stays in the system

NDA VS OTC Submission Route

NDA - Premarket approval required - Confidential Filing - Drug product specific - User Fee - Market Exclusivity - Mandated FDA review timelines - Require clinical data for application OTC - No premarket approval - Public process - Active Ingredient specific - No user fees - No Marketing Exclusivity -No mandated FDA timelines - Clinical studies for claims support or to amend monograph only.

ANDA Patent Rights

NDA holder brings the action to patent owner - FDA will not approve the ANDA for 30 months - 1st company that submits ANDA with PAR IV 180 Day Exclusivity for generic drug - Currently, the 180 day exclusivity applies multiple ANDA app. with PAR IV challenging the same RLD on the same first day.

Safety

New drugs were required to be demonstrated before marketing

OTC Drug Product

No doc is needed. - Labeled is written in simple lang. - Available for use in self-diagnosed conditions - Benefits clearly outweigh possible risks - Potential for misuse and abuse is low

When it is licensed does the formulation go to the public?

No, only the label.

Exempted from the eCTD

Noncommercial - products that are not intended to be distributed commercially and include. Investigator sponsored INDs and expanded access iNDs

Biologic Product Naming

Nonproprietary proper name for a new biologic product is determined by submitting an application an dfee to USANC. For well characterized proteins, certain suffix are standard and must be included in nonproprietary name. - Proprietary name request can be submitted after Phase II. Evaluated within 90 days.

Anatogonist

Not good for disease you are using the model for.

Cosmetics vs Rx

Not tested on animals/humans - Not prescribed used for general usage. OTC it will not become habitual. It is given to the public as an option for temporary relief. Efficacy typically decreases with OTCs and consumer products are less controlled.

Acceptance Criteria

Numerical limits, ranges or other suitable measures for acceptance of the results of analytical procedures which the DS or DP or materials at other stages of their manufacture should meet.

DDT - Increased public avaliability

Of qualified DDTs for a specific contact of use is anticipated to benefit PH: 1. Increased availability of effective drugs. 2. Earlier access to medial therapies 3. An enhanced knowledge of the drug under development

Types of Pharmaceutical Formulations

Oral Formulations Parental Formulations (injectables or infusions) - Suspensions, powders, gels, emulsions Topical (active ingredient and a vehicle which contains water, oil, alcohol or propylene glycol, preservatives, emulsifiers, absorption promoter mixtures) Modified Release Formulations (Extended or slow release) Novel Drug Formulations (NMEs, NCEs)

21st Century Cures Act

Originated as qualification program that CDER establish in 2004 under FDA's Critical Path Initiative. The Cures Act amended the FD&C Act and added a new section 507, to establish a process for qualifying DDTs that can be used, as appropriate to support regulatory applications. - INDs - NDAs - ANDAs - BLAs in CDER and CBER

Human Drug Compounding - Part 2

Outsourcing facilities, which register with FDA, compound udner section 503B, and may only use bulk drug substances in compounding that: 1. Are used to compound drug products that appear on FDA's drug shortage list at the time of compounding, distribution, and dispensing 2. Appear on FDA's list of bulk drug substances for which there is a clinical need.

CBER 1930

PHS Hygienic Laboratory became NIH

Japan - PMDA with MHLW

PMDA conducts scientific reviews of marketing authorization apps of pharmaceuticals and medical devices, monitoring of their post-market safety. Obligation is to protect the PH by assuring safety, efficacy and quality of pharma and medical devices. Responsible for providing relief compensation for sufferers from adverse drug reaction and infections by pharma or biological products.

Emergency Use or Authorization

Pandemic or No medication available.. must be an alternative treatment. Reduced pt. size: Statistical planning Probability Forseeability Adverse Event

Drug Importation Act 1848

Passed by Congress requires US Customs Service inspection to stop entry of adulterated drugs from overseas.

Biologics Control Act 1902 (Virus Toxin Law)

Passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat disease in humans. Biologics Manufacturers - License requirement Government inspection and testing on the marketed products.

US FDA initiatives

Pediatric x <21 yrs Oncology AIDS/HIV 21st Century Pharma Initiative

Exceptional Circumstances

Permits

Conditional Authorization EC No. 507/2006

Permits granting of a conditional license, valid for one-year, where there is a specific patient need. - Life Threatening diseases - Designated orphan medicinal products - Medicinal products - Products to be used in Emergency situations.

Q10 - Change Management System

Pharamaceutical Development - Change is an inherent part of the development process and should be documented. The formality of the change management process should be consistent with the stage of pharma development. Tech Transfer - The change management system should provide management and documentation of adjustments made to the process during tech transfer activities. Commercial Manufacturing - A formal change management system should be in place for comm. manufacturing. Oversight by the quality unit should provide assurance of appropriate science and risk based assessments. Product Discontinuation - Any changes after product discont. should go through an appropriate CMS.

Q10 CAPA

Pharmaceutical Development - Product or process variability is explored. CAPA methodology is useful when where CAPA are incorporated into the iterative design and development process. Technology Transfer - CAPA can be used as an effective system for feedback, feedforward and continual improvement. Commercial Manufacturing - CAPA should be used and the effectiveness of the actions should be evaluated. Product Discontinuation - CAPA should be continued after the product is discontinued. The impact on product remaining on the market should be considered as well as other products could have been impacted.

CCS - Quality

Physical, chemical, microbiological, biological, bioavailability, and stability attributes that a drug product should maintain if it is to be deemed suitable for therapeutic or diagnostic use. Conveys safety, identity, strength, quality and purity

Human Blood or Plasma

Plasma is the fluid in blood. - The plasma allows the RBCs and WBC and metabolic products to circulate. - Blood contains about 55% plasma. - Plasma contains approx. 7 to 8% of proteins, primarily albumin, immunoglobins and fibrogens. - Plasma derived medicinal products are developed using plasma from healthy donors. Whole blood donations - Transfusion product production

Human Blood or Plasmsa

Plasma is the fluid in blood. The plasma allows the RBCs and WBCs and metabolic products to circulate. Blood contains 55% plasma. Plasma contain approx. 7 to 8% of proteins, primarily albumin, ummnoglobins and fibrogens. Plasma derived medicinal products are developed using plasma from healthy donors. Whole Blood Donations - Transfusion product production.

Generics - Each new version of a new drug required a submission even if the API was approved by FDA earlier

Post 1962, FDA initiatives included: 1. Development of "Paper NDA" 2. Development of ANDA regulations

Centralized Procedure Details

Pre-submission guidance for app. Request is made 18 months prior to the intended submission date. Eligibility request form is available, along with dates for submission of requests, which are linked to the CHMP meeting dates, per the pre-submission guidance.

Animal Pharmacology

Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.

To put a product out: PAI is needed

Preparation. Registration. NDA takes about 10 mths Unless its a priority review, the FDA would then come sooner to make sure you can produce X amount like 5 months. NDA: Blueprint, label sample, package sample, data.

FDAMA - Prescription User Fees

Prescription User Fee Act of 1992 (PDUFA) Fees reviewed every 5 yrs. - Reduction in new drug apps review time (up to 15 months from previous 30 month average review time)

Tamper Resistant Packing Regulations (1982)

Prevent poisonings such as death from cyanide placed in Tylenol capsules. Federal anti Tampering Act passed in 1983 makes it a crime to tamper with packaged consumer products.

CFR

Primary source of info for US product registration. - Rules are based upon the Legislative Acts/Statues/Amendments - Title of 21 of CFR is reserved for rule of the FDA

Submission Types

Prior Approval Supplement (PAS) Changes Being Effected in 30 Days/Changes Being Effected Supplement Annual Report (AR)

Commercial Distribution

Prior to distributing a product made using a change, the regulations require applicants to demonstrate, through appropriate validation and/or other clinical or non-clinical lab studies, the lack of adverse effect of the change on the identity, strength, quality, purity or potency of the product as they may relate to its safety or effectiveness.

Q9 - Quantitative vs Qualitative

Probability can be calculated vs identifying it in a general category like low, med, high. Both can be combined to make an overall QRE or estimate of relative risk

Q10 - Pharmaceuticals Quality System Cycle

Process Scale Up Implement Release Validate Repeat

Q10 - PQS - Identification of the PQS processes, in regard to their sequences, linkages and interdependencies.

Process maps and flow charts can be used to facilitate PQS

cGMP Compliance - Change in Process Parameters

Process parameters are frequently adjusted over a product's life cycle. Additional knowledge and experience about material attributes, operating and performance parameters, and the way their interaction affects product quality and process performance typically enables a more informed risk assessment and risk ranking. Any change to process parameters outside of an approved validated range should be evaluated with respect to criticality, impact on process performance and product quality, and effectiveness of the overall control strategy and must be reported to FDA. The reporting category selected should be commensurate with the risk of an unintended outcome resulting from changes involving these elements.

Q9 - Risk Reduction

Processes for mitigation or avoidance of quality risk when it exceeds a specified acceptable level. Actions taken to reduce or mitigate the severity and probability of harm. Processes that improve the detectability of hazards and quality risks might also be used as part of a risk control strategy.

Post-Approval Changes: Manufacturing

Processing, packing, holding, labeling operations, testing and quality unit ops.

Q10 Objective - Knowledge Management

Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. Acquiring, analysing, storing and disseminating info related to products, manufacturing processes and components.

Key Concepts of Continuous Manufacturing - Process Dynamics

Product and process understanding form the foundation for effective risk management. Set expectations regarding the science and risk based approach to the control of processes and product quality based on process understanding are the same for continuous manufacturing as traditional batch manufacturing. A function of input material attributes, process condition, or equipment design elements, enables material traceability (the ability to preserve and access the identity and attribute of a material throughout the system) during and after production.

Electronic Orange Book (Feb 2005)

Product info for new generic drug approvals. - NDA application numbers are preceded with "N" - Abbreviated NDA approvals (Generic app numbers are preceded with "A") All product changes received and processed as of the monthly update date Exclusivity info updated monthly and current to the date of the monthly EOB.

Marketing Application Reqs

Product quality, safety and efficacy

Q10 Continual Improvement - Commercial Manufacturing

Product realisation establishing and maintaining a state of control and facilitating continual improvement. PQS -> Assure product quality is consistent and routinely met, suitable process performance is achieved and the set controls are good. Improvement opportunities must be identified and evaluated.

Centralized Approval Process

Products derived from biotech and for new active substances for certain therapeutic areas. An application granted through the Centralized Procedure is valid for the entire European Community. The manufacturer has one EU license to market the product, rather than individual national licenses in EU member states. The medicinal product can be marketed in all member states. The price and reimbursement on a country by country basis. The financial basis and medical products supply aspects are regulated by the National Laws.

Patents

Property right issued by USPTO to an inventor "To exclude others from making, using, offering for sale, or selling the invention throughout the US or importing the invention into the US" for limited time, in exchange for public disclosure of the invention when the patent is granted. 20 years from the date on which the application for the patent was filed in the US.

Orange Book - Proprietary

Proprietary name search will provide ingredient info. Ingredient search for all approved products containing the ingredients will result in a list that will provide approved products by dosage form and route. For each dosage form, route grouping, there will be Reference Listed Drug (RLD) that is the innovator product. Route grouping will have a Therapeutic Equivalence Code (TE Code) Discontinued products will be in the discontinued section.

Centralized Procedures PROS/CONS

Pros: 2005 expanded scope. Assistance available for small/mid businesses. Established procedure for conditional marketing authorizations. Cons: The products must be made available in all 27 countries including Norway and Iceland. Selective filings or withdrawals are not allowed. Labels in all 24 countries languages. One EU trade name.

Comparability Protocols

Prospectively written plan for assessing the effect of a proposed CMC change on product quality. An applicant has the option to submit one or more CPs describing the specific tests, validation studies and acceptance criteria to be achieved in order to demonstrate the lack of adverse effects for specified types of manufacturing changes on product quality.

FDA's Responsibility

Protecting the PH by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and product that emit radiation. Advancing the PH by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science based information they need to use medicines and foods to improve their health.

General Issues with CCS

Protection, compatibility, safety and performance of packaging components and/or systems. 1. Protection 2. Compatibility 3. Safety 4. Performance a. Container Closure Functionality b. Drug Delivery

CGMP

Provide for systems that assure proper design, monitoring and control of manufacturing processes and facilities. Encompass the regulatory process by describing the requirements to be followed by drug manufacturers, applicants and FDA.

1979 Belmont Report

Provided FDA evidence to revise regulations for human subject protections. Provide for wider representation of IRBs and they detail elements of what constitutes informed consent and other provisions.

180 Day Exclusivity Part 2

Provides an incentive of 180 days of market exclusivity to the "1st" generic applicant who challenges a listed patent by filing a paragraph IV certification and running the risk of having to defend a patent infringement suit. Begins either from the date the sponsor begins commercial marketing of the generic drug product, or from the date of a court decision finding the patent invalid, unenforceable or not infringed, whichever is first. May be the sole marketer of a generic competitor to the innovator product for 180 days. FDA does not send letters to the sponsor indicating the grant of exclusivity. Its listed in the orange book.

BPWG (Blood Products Working Group) - smPC

Provides common grounds for product characteristics in the EU

EEC 726/2004

Provides the legal basis for the centralized procedure and describes the marketing application and review processes for the biotech products. - Applications and approval procedures, and amended the responsibilities of EMA. - Regulation 726/2004, established the Committee for Medicinal Products for Human Use (CHMP) Upon positive recommendation from CHMP, the EC makes the final decision about granting a marketing authorization.

CBER 1906

Pure Food and Drugs Act prohibited 'Misbranding and Adulteration'

Pharmaceutical Quality System

Q7 - GMP for API Q8 - Pharmaceuticals Dev. Q9 - Quality Risk Management Q10 - Pharmaceuticals Quality System

Critical aspects of the phase 1 clinical trial initially includes the investigational new drug dosage into human subjects, constituting appropriate cGMP to help ensure subject safety and assess the safety profile.

QC principles to the manufacture of phase 1 IND, which foster cGMP activities that are more appropriate for phase 1 clinical trials, improve the quality of phase 1 investigational drugs, and facilitate the initiation of investigational clinical trials in humans while continuing to protect trial subjects.

Drugs are required to be safe. All requirements are met for the following:

Quality Identity Strength or Potency Purity - This includes manufacturing and testing equipment qualified for use - Operational methods and validations

cGMP Basis of Regulations

Quality, safety, and effectiveness must be designed and built into a product. Quality cannot be inspected or tested into a finished product Each step of the manufacturing process must be controlled to maximize the likelihood that the finished product will be accepted.

21 CFR Part 210 - Actual Yield

Quantity that is actually produced at any appropriate phase of manufacture, processing or packing of a particular drug product.

21 CFR Part 210 - Theoretical Yield

Quantity that would be produced at any appropriate phase of manufacture, processing or packing of particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production.

Centralized Procedure Details pt 3

Rapporteurs and Co-Rapporteurs (CHMP) Are assigned to a particular designated app to assess the proposed medical product's safety and efficacy. A letter of intent must be submitted by the applicant with their intent to submit application, and their appointment of a Rapporteurs and Co-Rapporteurs. All presubmission activities must be completed 7 months prior to the actual submission. Prior to the intended submission date and two-weeks prior to a CHMP meeting, so appointment happens prior to 6 months of submission. The names of of the RAPs are said to the applicant before the start of the eval.

If an EU manufacturer from France is applying for a product application which could be including a Recombinant DNA technology, which of the following will be most appropriately applicable?

Rapporteurs and Co-Rapporteurs, as the members of CHMP will be assigned, to assess the proposed medical product's safety and efficacy.

21 CFR Part 210 - Percentage of theoretical yield

Ratio of the actual yield to the theoretical yield (at the same phase), stated as a percentage.

OTC Drug Monographs

Referred as 'recipe books' considered safe and effective. 1972 FDA initiated the OTC Drug Review Process

Analytical Technique/Methodology

Refers to a general principle/mechanism of operation upon which an analytical procedure is based. (i.e Reverse Phase High Performance Liquid Chromatography, Near Infrared Spec)

Commercial manufacturing

Refers to manufacturing processes that result in a drug or drugs intended to be marketed, distributed or sold. **Exclusion: R&D, Manufacturing Materials for IND, Manufacturing material for veterinary IND.

Analytical Procedure

Refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include, but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, and use of the formulae for the calculation.

Pharmaceuticals product

Regulated compound, or therapeutic formulation developed as a drug product.

OTC Drug Products Regulation

Regulations applicable to Rx drugs apply to OTC. Specific regulation apply to OTC drug product labeling. 21 CFR 201 SUBPART C - Labeling Requirements for OTC Drugs

FDA Modernization Act of 1997

Regulatory Compliance applies to all medical products categories: - Drugs - Biologics - Medical Devices - Food

Marketing Authorization Holder (MAH)

Regulatory obligation to submit any updates to MA via the submission of Variations. Any new information pertaining to the risk/benefits balance.

Drug Development Tools (DDT)

Relied upon to have a specific interpretation and application in drug development and regulatory review. Guidance can be referenced in 21st Century Cures Act.

First Certified Color Regulations (1907)

Requested by manufacturers and users, list seven colors found suitable for use in foods

CCS - cGMP (21 CFR Parts 210 and Part 211)

Requirements for the control of drug product containers and closures.

Biologic Product Licensing - Part 2

Requirements: Purity Safety Potency Approval to market a biologic is granted by issuance of biologics license as part of the approval letter. FDA does not issue a license certificate The US License number must appear on the product labeling.

Technology Transfer

Requirements: Robust Technology Process Validation Bulk cGMP Commercial Scale Up Commercial Release

Prescription Drug Product

Requires a physicians authorization to purchase or have access to use.

PDUFA

Requires drug and biologic manufacturers to pay fees for product applications and supplements, and other services. The act also requires FDA to use these funds to hire more reviewers to assess applications.

Stages of Drug Development

Research - Target Discovery Development Product Registration Commercialization

Transmissible Spongiform Encephalopathy (TSE) Safety Evaluation

Risk Factors Assessments, include: - Donor (High risk) - Derived from Human Blood, Plasma - Virus Contaminants

Procedures enable the GCP practices to be upheld through SOPs

SOPs are how a company applies the law.

ICH Q1A

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

US Manufacturer has issues in managing the post market surveillance in Japan. Per the Japanese Ministry of Health regulations, it is critical that the manufacturer manages the risk assessment and post market surveillance program. The risk management under PMDA regulation apply to which of the following?

Safety specification, pharmacovigilance activities, and risk minimization activities.

CHMP

Scientific guidelines for marketing apps for all pharma, including plasma derived medicinal products. - Draft and final guidances for EMA. - Establish several working groups, which impact plasma derived products.

EMA - Biological Guidelines

Scientific guidelines on biological human medicines help applicants prepare marketing authorization apps. Guidelines reflect a harmonized approach of the EU Member States and the Agency on how to interpret and apply the requirements for the demonstration of quality, safety and efficacy set out in the community directives.

Authority of Seizure Power

Serious ADE. CBER 1944 - PHS Act FDA can determine that the product will be at seizure and the employee must inform the highest power to stop production/outsourcing from the end of that phone call. If they do not comply, they can be taken to court.

Dockets Management

Serves as the official repository for the administrative proceedings and rule making documents for the FDA. System allows consumers to access FDAs administrative proceedings and rule making documents. - Federal Registers - Petitions, supporting documents and comments

Meat Inspection Act 1906

Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.

Pediatric Patients - Principles

Should be given medicines that have been properly evaluated for their use. Product development should include pediatric studies when pediatric use is anticipated.

Q10 - Performance Indicators

Should be identified and used to monitor the effectiveness of processes within the pharmaceutical quality system.

In the EU, the Summary of Product Characteristics (SmPC) defines which of the following?

SmPCs are a key part of the marketing authorisation of all medicines authorised in the European Union and the basis of information for healthcare professionals on how to use a medicine safely and effectively. They are kept updated throughout the lifecycle of a medicine as new efficacy or safety data emerge.

Biologics CMC - Logical Standards

Specific tests to be performed on each lot prior to release. - Potency (Bioassay for in vivo mechanism), final product release by Phase 3 - General Safety Tests - Sterility - Purity (extraneous materials, residual moisture, pyrogenic substances)

21 CFR Part 210 - Acceptance Criteria

Specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan , that are necessary for making a decision to accept or reject a lot or batch.

ICH Q1A

Stability Testing

"Current" in cGMP

State of the art. Old machine cannot stay in the manufacturing area. Must be compliant, calibration must be met and if its not working it must be flagged.

Drug Master File: 21 CFR Part 314.420

Submission of information to the FDA by a person (the drug master file holder) who intends it to be used for: - Permit the holder to incorporate the information by reference when the holder submits an IND under part 312 of submits an application or an abbrev. app or an amendment or supplement to them under this part. - To permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person. - FDA ordinarily neither independently reviews DMF nor approves or disapproves submissions to a DMF. Instead the agency customarily reviews the information only in the context of an application under part 312 or this part.

Centralized Procedure Details pt 2

Submit a presubmission - Meeting allows a platform for discussion with the agency regarding the authorization process. - Meeting happens 6-7 months prior to submission. - Whether a meeting is scheduled or not, the applicant must inform EMA of its intent to submit a submission.

Materials of Construction

Substances (glass, high density polyethylene, resin, metal) used to manufacture a packaging component.

Scale Up - Commercial Scale Up

Successful Scale Up Robust Validations QbD Implementation

Pediatric Patients - Non-Clinical

Sufficient safety information collected to support initiating studies in the pediatric population. Data from clinical studies in adults population. - Other pediatric populations. - Nonclinical studies in adult animals - General toxicity studies. - Core safety pharmacology, genotoxicity tests. - Reproductive and developmental toxicity studies; including juvenile animal toxicity studies.

CCS

Sum of packaging components that together contain and protect the dosage form. This includes 1st pack comp. and 2nd pack comp. if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a CCS.

US vs Johnson (1911)

Supreme court rules that the 1906 F&D Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug.

What is quality risk management?

Systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product lifecycle.

Q9 - Decision Makers

Take responsibility for coordinating QRM across various functions and departments of their organization Assure that a QRM is defined, deployed and reviewed and that adequate resources are available

ICH Q5A - VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN

Testing and evaluation of the viral safety of biotech products derived from characterized cell lines of human or animal origin. Purpose is to provide a general framework for virus testing experiments for the evaluation of virus clearance and the design of viral tests and clearance evaluation studies.

ICH Q5 Biotechnology: Q5A

Testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin and outlines data that should be submitted in the marketing application/registration package.

Kefauver Harris Drug Amendment (1962)

Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western EU. This amendment ensured drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. Efficacy: It was required by the manufacturers to demonstrate to the FDA the effectiveness of drugs before it could be approved for marketing (Requirement for a higher drug safety)

21 CFR Part 210 - Representative Sample

That consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled.

Container Closure System (CCS) - Secondary Packaging

That is not and will not be in direct contact with the dosage form.

Container Closure System (CCS) - Primary Packaging component

That is or may be in direct contact with the dosage form.

New Biotech Product & Industrial Apps

The 1st in vitro diagnostic reagent containing monoclonal antibodies was approved by FDA in 1981 and the first drug manufactured by recombinant DNA technology was approved a year later.

Hybridoma Technology (Antigens)

The antigens are bacterium, virus or a relatively large molecule, usually has several antigenic determinants, the antiserum prepared by injecting animals with a selected antigen will contain a mixture of antibodies. Monoclonal antibodies are pure antibodies derived from cells which recognize a single determinant (and other structurally similar determinants)

CCS - Extraction Profile

The chromatographic analysis of extracts obtained from a packaging component. A quantitative extraction profile is one in which the amount of each detected substance is determined.

Fermentation/Contamination - NIH Guidelines - Safety

The host commonly used are derived form. E. Coli K-12 E. Coli K-12 cannot be converted into an epidemic pathogen by laboratory manipulation with R-DNA molecules and it will not colonize the human intestinal tract. Hazard of exposure to Recomb. E Coli K-12 will not be any greater than to any of the conventional industrial microorganisms and will probably be less than some of the chemical used in the purification.

Divided Manufacturing

The intermediate product is labeled "for further manufacturing use" as part of a proper name. Each licensed manufacturer must notify the other licenses and the appropriate center regarding the proposed changes in the manufacture, testing or specifications of its product in accordance with 21 CFR 601.12

Bioavailability

The physiological availability of a given amount of a drug, as distinct from its chemical potency. A measure of the amount of drug that is actually absorbed from a given dose. The degree to which a drug or other substance becomes available to the target issue after administration.

Pharmacokinetics (PK) - ADME

The process by which a drug is absorbed, distributed, metabolized and eliminated by the body. The process of absorption, distribution, localization in tissues, biotransformation and excretion.

Advanced Therapy Medicinal Products

The regulation states that all viable human tissue containing products must be considered as ATMPs, regardless of their mode of action. If nonviable products and materials, have pharmacological, immunological and metabolic mode of actions. Nonviable products that do not have that medicinal claim, are considered exempt from the ATMP regulation.

Bioequivalence

The relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability.

Contract Manufacturing

The sponsor holds the license and the contract facilities which are listed in the BLA, are considered to be under the license holder's control. Sponsor establishes, maintains and follows up the procedures for receiving information from contract manufacturing facility on all deviation, compliants and adverse events that may effect product quality. Contract manufacturer information on the product labeling is not required.

Pharmacodynamics (PD)

The study of the action or effects of drugs on living organisms. HOW a drug acts - Pharmacologic response and the duration and magnitude of response observed relative to the concentration of the drug at an active site in the organism. The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of their actions and effects with their chemical structure.

CMC - Quality

The suitability of either a drug substance or a drug product for its intended use. This term includes such attributes as the identity, strength and purity.

21 CFR Part 210 - Potency

Therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data

EU Regulatory Procedures

There are separate guidelines for products registrations between the conventional medicinal products, such as those which are derived from Biotech or any other innovative procedures. A NCE can qualify for each type of product. - Historically, in 1990s the EU regulatory system allowed the registration of NCEs, which qualify for each type of their procedure. The intent is to have single, scientific evaluation ensuring highest quality enters the market. Uniform decisions throughout for the EU community. Centralized Procedure.

Supply chain risks if manufacturer continues to produce without FDA approval

They make vials and put them in quarantine until they get the stamp of approval, this is okay to do since they have done the process validation for the NDA filing

OTC Drug Monograph System (21 CFR PARTS 331-358)

Three NDA routes for OTC drug product submission for market approval. - 505B NDA - 505B2 NDA - 505J ANDA

Fermentation/Contamination - NIH Guidelines

Three levels of physical containment - P1, P2 and P3 for large scale operations (greater than 10 L) with P3 having the highest containment Physical containments, NIH guidelines also define lab biological containment in terms of 3 classes of host vector systems, designated HV-1,2, and 3. Progressively diminishing probability of survival outside the specific growth conditions in the lab

Compounding Quality Act (CQA)

Title I of the DQSA was the CQA which provides for additional FDA oversight of compounding pharmacies. Outsourcing facility which is subject to FDA inspections and is required to pay annual and re-inspection fees.

ICH Mission

To achieve greater harmonization worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource efficient manner.

Hatch-Waxman Act (1984): Public Policy Goals

To ensure the patent protection and market exclusivity for innovative brand name drug manufacturer. To ensure that, once the statutory patent protection and marketing exclusivity, the generic version is made available for the market. Allowed both innovative pharma products and generics products to co-exist. The legislation allowed and expedited the availability of less costly generic drugs in the market. ANDA were accepted which did not require animal testing (safety claims) or clinical data.

Q10 Objective - Facilitate Continual Improvement

To identify and implement appropriate product quality improvements, process improvements, variability reduction, innovations and pharma quality enhancements, thereby increasing the ability to fulfill quality needs consistently.

Q10 Objective - Enablers of Knowledge Management and QRM

To implement Q10 effectively and successfully. providing the means for science and risk based decisions related to product quality.

Orphan Drug Act (1983)

To promote the development of medicinal products for the treatment of rare diseases. "Rare" - Any rare disease or condition which affects less than 200k people in the US Affects more than 200k in the US but for which there is no reasonable expectation that the cost to develop it could be recovered from sales in the US Exclusivity: - Seven years of market exclusivity - Tax credit for clinical research

What is the FDA's mission?

To protect public health. To provide guidance and help ensure safe and effective medical products reach the market in a timely manner.

DDT Mission and Objectives

To qualify and make DDTs publicly available for a specific contact of use to expedite drug development and review of regulatory apps. - To provide a framework for scientific collaboration to facilitate DDT development. - To facilitate integration of qualified DDTs in regulatory review. - To encourage development of DDTs for contacts of use with unmet needs. - To encourage the formation of collaborative groups to undertake DDT development programs to increase the efficiency and lessen the individual resource burden incumbent with DDT development. - To encourage innovation in drug development

Container Closure System (CCS) - Materials of Construction

To the substances (i.e glass, high density polyethylene (HDPE) resin, metal) used to manufacture a packaging component.

Q10 Continual Improvement - Tech transfer

Transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation. Manufacturing process, control strategy, process validation approach and on going continual improvement

CBER Product Jurisdiction - Xenotransplantation

Transplantation of Non-Human Cells, Tissues or Organs into a Human

Hybridoma technology - Additional Details

Tumor bearing mouse develops ascites and ascitic fluid is a rich source of mAbs with the predefined specificity. - New perfusion reactors up to 100 L recently have been designed to grow large quantities of tumor cells. The reactors can be adapted to grow anchorage-dependent normal cells by adding tiny beads made of dextran or synthetic polymers. Because the large scale systems are more efficient, they will replace the conventional roller bottles and spinner bottles for culturing a wide range of mammalian cells.

Recombinant DNA Technology - Construction of a R-DNA Molecule Part 2

Two forms of DNA in a bacterial cell. - Most of the DNAs genes are found in the chromosome, the second is a much smaller circular DNA called a plasmid which can replicate itself in the cell. - Plasmids can be extracted from cells, by softening the cell wall with chemical reagents, and used as the acceptors for DNA coding for the desired product.

Q9 - Quality Risk Management (Screen shot of quality risk management)

Two primary principles of QRM: - The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient. - The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk. - Quality risk management is a systematic process for the assessment control, communication and review of risks to the quality of the drug product across the product lifecycle.

Biologics CMC - Under 21 CFR 314.420 - DMF is a submission to FDA

Type 1 - Reserved, no longer applicable Type 2 - Drug substance, intermediate or DP Type 3 - Packaging material Type 4- Excipient, colorant, flavor or essence or any material in their prep. Type 5 - FDA accepted reference material. DMF Contents per M4Q-CTD Quality format

EU Variations

Type 1A Minor - Notification Procedure (30 Days)/AR/No assessments Type 1B Minor - Notification Procedure (30 Days)/Assessments Type II Minor - App Procedure (30/60/90 days)/Assessment Extension Application - Full Assessment

Contract Manufacturing - Quality Agreements - Manufacturing Control Strategy - Process Monitoring and Control PT 2

Types of analyses for process monitoring data such as: - Univariate analysis based on control limits - Multivariate or process model - Inter and intra batch trend analysis

Harmonization

US/EU/Japan were concurrently developing standards that were similar in principal - Led to ICH. Had a fundamental effect on the FDAs own efforts to develop recommendations for non-clinical testing. FDA has sought to revise its guidelines to reflect the consensus to which the agency has contributed as a part of the ICH process.

US/DS Manufacturing

Upstream: Cell cultivation, isolation, cell banking Downstream: Separation, precipitation, purification

ICH (1990) - Urgency

Urgent need to rationalize and harmonize regulation due to compelling concerns over rising costs of health care, escalation of the cost of R/D and the need to meet the public expectation, and that there should be a minimum of delay in making safe and efficacious new treatments available to patients in need.

Q9 - Risk Identification

Use of info to identify hazards referring to the risk question or problem description. Can be historical or theoretical analysis. Informed opinions or concerns of stakeholders.

In vitro diagnostic

Used as a tool as a sub category to aid the drug.

505J ANDA

Used to obtain approval for a generic product

PDUFA

Uses the fees to pay more reviewers to assess publications.

CBER Product Jurisdiction - Vaccines

Vaccines for Use in Children and Adults, Tuberculin Testing

Centralized Procedures Paths - Conditional Authorization

Valid for 1 year. - Applies to conditions where there are specific patient need. - Applications requires ongoing clinical trials or new clinical study to demonstrate risk/benefits balance.

Marketing Application Renewals

Valid for 5 years. Will be allowed based upon the re-eval of the risk/benefit balance. - Unless there are issues with pharmacovigilance, 5 more years are granted. Periodic Safety Update Reports submitted to reduce requirements of renewals.

21 CFR Part 210 - Concentration of the DS

Weight/Weight Weight/Volume Unit Dose/Volume Basis

Shared Manufacturing

Which two or more manufacturers are registered and licensed for specific aspects of a products manufacture but neither is licensed for the product's total manufacturing process. - All license applications or supplements under a shared manufacturing arrangement should be submitted concurrently to FDA for BLA review. - Lack of 1 or more related applications may results in an RTF action.

cGMP - 21 CFR Part 211:

cGMP for Finished Pharmaceuticals

cGMP Regulations - 21 CFR Part 211

cGMP for Finished Pharmaceuticals

cGMP Regulations - 21 CFR Part 212

cGMP for Positron Emission Tomography Drugs

cGMP - 21 CFR Part 210

cGMP in Manufacturing Processing, packing or Holding of Drugs.

cGMP Regulations - 21 CFR Part 210 (Compliance for Pharmaceuticals Manufacturing)

cGMP in manufacturing Processing, Packing or Holding of Drugs. Minimum cGMP for methods.