Intro to QA and QC
NSR study protocol
"Not serious risk" devices
SR study protocol
"serious risk" devices
What is true of the 510k process?
-A 510k will be granted if a new device is substantially equivalent to a device that was already in the market prior to 1976 -A 510k is a clearance, not an approval -A 510k will be granted if a new device is substantially equivalent to a marketed device which also got a 510k clearance -A 510k should be filed if significant changes have been made to an earlier approved device
Human Factor
-A discipline that focuses on variables that can affect the performance of individuals using devices. -Medical devices
The Drug importation Act of 1848 requires:
-All medications entering the US to be inspected and analyzed for quality, purity and fitness for medical purposes. -Recognized the US Pharmacopeia (USP) that provides and or sets state-of-the-art standards to ensure the quality of medicines
Active Pharmaceutical Ingredient (API)
-Any substance or mixture of substances intended to be used in the compounding of a drug preparation and that, When used in the production of a drug, becomes an active ingredient of the drug product. -Substances intended to furnish pharmacological activity or other direct effect in the medical diagnosis or treatment
A major benefit of electronic recording is it improves demonstration of compliance to auditors. What is an accepted practice for proper control of electronic records?
-Back up through the company's network and not in a thumb drive -Ensure security to prevent unauthorized access to the system -Store electronic records in a safe repository -Electronic or digital signature software may be employed
Benefits for comapnies maintaining ISO registration
-Certification adds credibility -Conclusions may be drawn -sound decisions can be made -Actions can be taken to improve the business
Benefits of ISO
-Certification adds credibility -Useful data/feedback so that conclusions may be drawn, sound decisions made, actions taken to improve business
Tests for Identity may be:
-Chemical -Biological -Immunological
For ISO 9000 compliance is:
-Compliance is voluntary. -Compliance monitored by paid auditor who provides suggestions for quality
Crisis IUD injuries in the 70s
-Dalkon shield contraceptive intrauterine device. -Promoted infections such as Toxic Shock Syndrome -Led to abortion and infertility
8 components of design control
-Design and Development planning -Design Input -Design Output -Design Review -Design Verification -Design..
Design Review for design control
-Does it meet customer needs -Have procedure/individuals assigned for review -All review activities/results/...
Quality system Regulation
-Equivalent to cGMP for devices
The Biologics control act of 1902 requires:
-Federal government issue pre-market approval for biological drugs -inspection and licensing of any establishment that wants to market a biologic
What is the US Pharmacoeia (USP)?
-First recognized by The Drug importation Act of 1848. -provides and or sets state-of-the-art standards to ensure the quality of medicines
For ISO 9000 standards are:
-Generic -Requires companies to write a quality manual overview of their system
Benefits in external market conditions from ISO registration:
-Higher perceived quality -Competitive advantage -Increased market share -Improved customer demand -Reduced customer quality audits -Quicker time to market
Quality attributes of drugs
-Identity -Purity -Strength -Stability -Consistency -Safety -Efficacy
Raw materials are typically accompanied by a CofA provided by the raw material manufacturer. What is included in the CofA?
-Identity/chemical formula/formula weight of the material -Material Appearance -Signature of the primary manufacturer's QC analyst -Safety Precautions
Benefits in internal operations from ISO registration:
-Improved documentation -Greater quality awareness by employees -Greater operational efficiency and productivity -Enhanced inter-company communications -Reduced scrap/rework expenses
Premarket Approval Application (PMA)
-Innovative devices that is not SE to other devices cleared through 510k -Should provide evidence that device is safe and effective. -Detailed manufacturing section on methods for building and testing device -PAI before approval
What is a data source that would indicate a deficiency in the quality system and thus a need for corrective and preventive action?
-Internal audits -QC test results -customer feedback -service and repair records
ISO ensures conformance by:
-Internal audits -management reviews -customer feedback -corrective and preventive actions -All other measurement information
Devices can be classified as:
-Invasive (implants, stents, pacemakers etc) or -Non invasive (Diagnostic tests and instruments)
Product quality can be insured by complying with:
-Laws-enforcible -Regulations-enforcible -guidances-not meant to be enforceable
820.22 Quality Audit
-Must be performed and results documented -Need for CAPA
Design Input for design control
-Performance characteristics/specifications -Documented, reviewed, approved -Intended use -User/patient/clinical requirements -Human factors -Evaluate components and suppliers -Packaging, labels and user instructions
Quality by Design requirement is discussed in the Pharmaceutical cGMPs for the 21st Century and ICH Q8. What is true of quality by design concept?
-Quality does not stop upon successful release of the first lot of product -QbD compliance is mandatory in both European Union countries and in the US -Quality cannot be tested into the final product -Quality encompasses all aspects of the process and product
For GMP regulations compliance is:
-Required by law -Enforced by FDA inspectors
The Kefauver-Harris Amendments to FFDCA 1962
-Required drug makers to prove safety and efficacy of drug before the FDA will approve commercialization. -Use of term cGMP became prevalent. -1963 was first cGMP became published.
List important early GMPs that resulted from sulfathiazole antibiotic crisis
-Segregation of finished batch until all lab tests are done -Lab controls on testing of raw materials and finished products -Adequate supervision of key equipment
Elixir Sulfanilimide crisis of 1937
-Sulfilanimide used to treat strep infections. -Massemgill began to market a liquid sulfa drug called Elixer Sulfanilamide. -The solvent used was highly toxic antifreeze. -107 ppl died from taking the drug
What is a responsibility of the quality control unit (QA/QC) of a drug manufacturing company?
-Testing of raw materials, in-process materials and finished products -Auditing or inspection of contract manufacturing organizations -Keeps track of manufacturing employee education and training records -Checks for discrepancies in data results in laboratory notebooks and computer records
Which of these manufacturing activities or information is entered into equipment logs?
-The name of the technician using the equipment at a given time -The time an activity started and ended -Whether equipment maintenance or cleaning was or is being performed -The manufacturing process for which the equipment is being used for
Design and Development planning for design control
-Timelines for developmental strategy and reviews. -Deliverables for each stage -Personnel and Responsibility assignments
Premarket Notification or 510K process
-To demonstrate that new device is substantially equivalent to another device that had already gone through 510k process. -Marketing clearance, not an approval. -Required when marketing for the first time, or there is a significant change to existing device
Design Transfer for design control
-Written plan for transfer of design components to manufacturing -Develop manufacturing facilities and utilities -Develop and validate manufacturing process...
What applies to level 3 or qualilty assurance system documents?
-are subject to revisions -includes actual work instructions in the form of standard operating procedures (SOPs) -includes documents that should be in front of workers while conducting certain activities -includes information of approved tests and acceptance or passing criteria
What applies to the qualilty system manual?
-describes regulations that the company is required to follow -presents a summary or menu for all associated plans, protocols , procedures, and specifications -defines the company's organizational structure and designate business expectations -designates compliance requirements and expectations across functional areas, sites, or contractors
Design controls
-does not apply to research, but starts with development process -DC SOP should clearly define the point design controls apply -Applies to most Class II and III devices, a few Class I
ISO members are:
-experts appointed by national standards institutes participating on the technical committee.
Design output for design control
-finished design -Evaluate conformance to input requirements/acceptance criteria -Basis for the device master record (DMR)
What is a major benefit in internal operations that comes with a company being ISO certified?
-greater quality awareness by employees -Improved documentation -greater operational efficiency & productivity -enhanced inter-company communications
ISO 9000
-international standards for a generic management system for quality assurance. -Intended to equalize quality systems between companies and countries
Pure food and drug act prohibited:
-interstate commerce of misbranded and adulterated foods, drinks, and drugs -Mandated label warnings on habit-forming drugs -Had to list habit-forming drugs (11 total) mainly CHAM (cocain, heroin, alcohol, and morphine)
What is part of acceptance activities under quality system regulations?
-receiving and acceptance of device parts from suppliers -receiving and acceptance of raw materials from suppliers -receiving and acceptance of in-process materials during different stages of the manufacturing process -acceptance activities for the finished device
820.25 Personnel
-sufficient personnel with ETE background -Training; identify need, written procedures, document training
The QC group:
-testing components, in-process materials, and finished products -Developing, validating, and performing assays -Proving analytical support for process validation and monitoring
What applies to product risks?
-type of risks that is out of a manufacturer's control -could be due to product preference of customers. -could lead to bad consumer perception -could lead to reduced sales
What are the 3 main pathways for marketing a device
1. 2. QSR 3.
Purity can be assessed at 2 levels:
1. Product Level 2. Process Level
Over the years, the Quality control unit has been broken down into 2 groups:
1. Quality Assurance (QA) 2. Quality Control (QC)
Consistency of product quality is achieved by adherence with 4 on-going processes. What are the 4 processes?
1. Validation 2. Documentation 3. Continuous improvement 4. Testing
Upstream Bioprocess
1. rDNA construction 2. Strain engineering 3. Inoculum Development 4. Media Development 5. Optimization of culture conditions
The ISO system consists of more than:
20,000 systems and guidelines
In the risk management lecture, the highest possible risk score for any given process equals ________, and the lowest possible score equals _______.
27,1
Pareto principle implies that a manufacturer may be able to avoid ________ % of failures by addressing ______ % of the possible causes for failure.
80,20
What is not true of the 510k process?
A 510k application must be submitted to the FDA 120 days before planned marketing date
In 1963 1st set of cGMP published:
A drug...shall be deemed adulterated...if methods do not conform to cGMP requirements such as Safety, Identity, strength, quality, and purity characteristics which it purports to possess
Which device is least likely to be required to comply with quality systems regulations during its development stage?
A machine that measures blood cholesterol levels
Thalidomide Crisis (1962)
A sedative marketed to combat morning sickness for pregnant woman, caused birth defects in infants across Europe. -Resulted in the The Kefauver-Harris Amendments to FFDCA 1962
Patent medicines of early 20th century
Administered as drugs but no proven medical benefit. Sometimes called snake oils. May contain drugs such as cocaine, heroin, and morphine
A drug...shall be deemed ____________________...if...the methods used in, or the facilities or controls used for its manufacture, processing, packing, or holding, do not conform to, or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
Adulterated
The Quality control unit shall have the responsibility and authority to:
Approve or reject all components, containers, closures, in-process materials, packaging material, labeling, and drug products. They are responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. They have the responsibility of approving/rejecting all procedures or specifications
The part of quality risk management that involves thinking of what processes or steps might lead the product to fail specifications is:
Risk identification
2004 changes to Pharmaceutical cGMPs for the 21st century characterized by a_________________approach
Risk-Based
Which component of risk quantification is a measure of risk that a product would fail to meet critical quality attributes requirement?
Severity
The amount of API in a given unit of a drug that is effective and safe for a certain indication is its:
Strength
T/F: Not all marketed devices have been tested for safety and efficacy in human subjects
TRUE
The main objective of ICH is to harmonize the ___________________________________.
Technical requirements for the registration of pharmaceuticals for human use
What lead to the Biologics control act of 1902?
Tetanus contaminated serum from a horse. Serum killed children
In 1930 the name of the FDIA was changed to:
The Food and Drug Administration (FDA)
Which of these manufacturing activities or information is not entered into equipment logs?
The date the equipment was installed
Failure to comply with any applicable provisions of FDA's Quality Systems Regulation in CFR21 Part 820 will render a device adulterated and ______________________ is (are) subject to regulatory action.
The device and person responsible
Which of these statements would best describe the stability attribute of a drug?
The quality of the drug does not change from the time the drug is manufactured to the time it expires
What lead to the enactment of the Drug importation act of 1848?
The quinine crisis in the Mexican American War
Raw materials are typically accompanied by a CofA provided by the raw material manufacturer. What is not included in the CofA?
The recipient company's address
What is true of risk scores?
The ultimate goal of risk scores is to rank the risks so one can prioritize what needs to be focused on.
A major benefit of electronic recording is it improves demonstration of compliance to auditors. What is not an accepted practice for proper control of electronic records?
Use hardware or software that would not show if a change had been made in the recorded test results
What is not part of acceptance activities under quality system regulations?
acceptance of design changes
Strength/Potency is a measure of:
biological activity
______________apply to drugs and devices
cGMPs
_____________apply to both marketed and investigational drugs
cGMPs
What are the most common habit forming drugs regulated by the Pure food and drug act?
cocain, heroin, alcohol, and morphine
Quality is assured by manufacturers adherence to__________.
current good manufacturing practices
What does not apply to level 3 or qualilty assurance system documents?
describes regulations that the company is required to follow
What is not a data source that would indicate a deficiency in the quality system and thus a need for corrective and preventive action?
design input
Unlike drugs, Devices :
do not use chemical action, not dependent on being metabolized by the body, no direct therapeutic effect on the body. Most exert effects locally. Many do not even contact patient
In response to the sulfathiazole antibiotic crisis the FDA:
drastically changed the manufacturing quality controls leading to development of GMPs -These were not actually put into law until after the thalidomide crisis of 1962
ISO system standards are developed by:
experts from business, gov, and other relevant organizations
Records, including complaint files, should be retained:
for the expected life of the device
The FDA drastically changed manufacturing and quality controls in mid 20th century leading to the development of:
good manufacturing practices (GMPs)
ISO 9000 originated:
in Europe; Independent organization
What does not apply to the qualilty system manual?
includes Master Batch records and Executed Batch Records
What is not a major benefit in internal operations that comes with a company being ISO certified?
increased scrap and rework expenses
The latest revisions of ISO 9001 emphasize:
management review and continuous improvement throughout the product's life cycle.
Submission of a________________for a new pharm. or biotech derived product is directed to 1 of 5 centers within FDA
marketing application
For purity at the product level, contaminants:
may cause immunogenic responses in humans
ISO 13485 is for:
medical devices
What least applies to product risks?
pertains to issues that could compromise product yield
ISO members must:
present a consensus position based on the views of their country.
ISO 9001 is for:
quality
ISO 9001 is for:
quality ; emphasizes need for management review and continuous improvement of a product
Adequate laboratories for testing and approval/rejection of components, containers, closures, packaging materials, in-process materials, and drug products shall be available to the:
quality control unit
During the Mexican War of 1848 Soldiers deaths resulting from imported________that turned out to be ineffective against yellow fever
quinine
ICH is committed to:
reducing duplication during research and development of new drugs while safeguarding quality, safety, and efficacy
cGMP includes:
regulations and guidelines applicable for drugs and devices manufactured for human use, including investigational products
In 1933the FDA recommended complete:
revision of the Pure Food and Drugs Act
For GMP regulations standards are:
specific to the industry
In 1901 children died because a___________was used to produce diphtheria antitoxin that killed children
tetanus contaminated serum from a horse
Quality is defined as:
the ability of a product, process, or system to achieve predetermined requirements.
The more potent the drug:
the lower the dose
Laws, regulations, and guidances for quality are used for:
the manufacture, processing, packing, and holding of drug components and the final product
The QA group ensures that:
the manufacturing and laboratory operations are compliant with cGMP regulations
With medical products quality means that:
the product meets the requirements for safety and effectiveness in its intended use
In 1941 Nearly 300 deaths and injuries from sulfathiazole tablets, an antibiotic, tainted with:
the sedative Phenobarbital
Centers within the FDA
CDER-Center for drug evaluation and research CBER-Center for biologics... CDRH-Center for Devices and Radiologic Health -CVM-center for veterinary medicine -CFSAN-Center for Food Safety and Applied Nutrition
cGMPS require compliance with regulations as in:
CFR21 Part 211
CDRH
Center for Devices and Radiological Health; Regulates devices, ensures that commercialized devices are safe and effective; CFR21 Parts 800-1299
___________was appointed to head the new Bureau of Chemistry (BOC) under the US department of agriculture
Charles Wetherill
What is not a responsibility of the quality control unit (QA/QC) of a drug manufacturing company?
Checking accuracy of quarterly or annual earnings reports
Medical device classification system
Classed in classes 1-3
Changes to cGMP published in the:
Code of Federal Regulations (CFR) 21 parts 210 and 211
What applies to ISO9000 but not to GMP regulations?
Compliance is monitored by a paid auditor who provides suggestions for improvement
Which activity is the responsibility of the QC more than that of the QA group?
Conducts stability testing of drug products
Which of these quality attributes is best described by the phrase, "quality should be demonstrated and maintained with each batch or lot manufactured?
Consistency
The primary focus of quality management principles is to meet or exceed _________________ requirements and expectations.
Customer
Which type of record would greatly facilitate the recall of a particular drug batch that has quality issue?
DISTRIBUTION RECORDS
Which of the 8 components of design control involves setting performance characteristics, specifications, and consideration of human factors in the device design?
Design Input
Which of the 8 components of design control involves ensuring that the device conforms to its intended use by testing the performance of initial production units under actual or simulated use conditions?
Design Validation
Safe Medical Devices Act of 1990
Design controls, validation, post-marketing surveillance
According to the International Organization for Standardization (ISO) website a standard is a _______________ that provides requirements, specifications, guidelines or characteristics that can be used consistently to ensure that materials, products, processes and services are fit for their purpose.
Document
In 1990, ICH was established between:
EU, Japan, and US-brings together regulatory agencies and pharmaceutical industries
What quality attribute was added as a requirement for drugs prior to marketing in the Kefauver-Harris Amendments of 1962, but not in the Food Drug and Cosmetic Act of 1938?
Efficacy
Which activity is the responsibility of the QA more than that of the QC group?
Ensures that laboratory and manufacturing operations are compliant with cGMP regulations
Of the four levels of quality documentation, which one would be audited by the FDA to look for evidence that a certain manufacturing process was done according to SOPS?
Executed batch records
cGMPs does not include Acts passed by the:
FDA
CFR Part 820
Final rule on cGMP requirements for medical devices in 1996
Federal Food, Drug, and Cosmetic Act 1938 (FFDCA)?
Focus is on truth in labels. Less focus on efficacy. -Required manufacturers to prove safety before marketing. -Required adequate controls -Required labels with directions -First use of GMPs to set tolerances for toxic substances. -Now the main law used by the FDA to regulate drugs and devices.
In 1927 the BOC became the:
Food, Drug and Insecticide Administration (FDIA)
Consistency of product quality is achieved by adherence with 4 on-going processes. Which is not one of the four?
Frequent SOP changes
What was the first internationally harmonized tripartite GMP guidance?
ICH Q7A
cGMPs include guidelines in:
ICHQ7A
________ contains guidelines for quality risk management.
ICHQ9
The main purpose of ISO9000 is to equalize quality systems between manufacturers and countries. _____________ is the only standard in the ISO9000 family that a company or product can be certified against.
ISO 9001
Which quality attribute is normally established by comparison of immunological activity with reference standards that may be obtained from US Pharmacopeia?
Identity
GMP regulations originated:
In the United States by a federal agency
International Organization for Standardization (ISO)
Independent international organization for the purpose of developing business standards and guidelines for quality
What does ICH stand for?
International Conference on Harmonization -Of technical requirements for the registration of pharmaceuticals for human use
One risk analysis tool is the cause and effect or fishbone diagram shown below. It was devised by_________.
Ishikawa
The use of the term "current Good Manufacturing Practice" first became prevalent in the:
Kefauver-Harris Amendments of 1962
Of the four levels of quality documentation, which one would be audited by the FDA to examine assay results?
Laboratory notebooks of QC analysts
In the Wockhardt warning letter, an operator performed in-process tablet testing with the batch record in a separate room, not where the weights were being measured. The batch record is what level of quality documentation?
Level 4 - Other quality documents
Of the 7 main systems making up the quality systems that are the focus of an FDA's CDRH compliance inspection, which occupies the central and most important position?
Management
Medical Device Regulation act 1976
Medical Device Amendments to..
Medical Device Amendments of 1992
More post marketing surveillance, FDA recalls
What has nothing to do with the Biologics Control Act of 1902?
Morphine and heroine ingredient in patent medicines that killed many infants
Drugs and Devices are recognized in the:
National Fromulary or United States Pharmacopeia
What is an acceptable documentation practice?
Never pre-record information
What did ICH Q7A establish?
One global GMP standard for Active Pharmaceutical ingredients
Quality by Design requirement is discussed in the Pharmaceutical cGMPs for the 21st Century and ICH Q8. What is not true of quality by design concept?
Passing of final drug product specifications is sufficient to assure product quality
With the ______________________________ guidance, FDA announced its desire for manufacturers to integrate quality systems and risk management approaches into its existing programs.
Pharmaceutical cGMPs for the 21st Century
Quality Control unit tests would be against:
Pre-determined specifications and would objectively show that the product is acceptable
Which of these information will be found in both device history record and device master record?
Production flow diagram
What was the first federal law to regulate both food and drugs?
Pure food and drugs act of 1906
Which of these quality attributes can be demonstrated by looking at the number of unwanted peaks using an HPLC?
Purity
What are the main areas of ICH guidelines?
Quality Safety Efficacy Multidiscinplinary
CFR 21 Part 11 contains:
Regulations on electronic recording
