Alcami - GMP
Food, Drug, and Cosmetic Act - Section 501 (a)(2)(B)
" A drug shall be deemed to be adulterated if the methods use in, or the facilities or control, used for, its manufacturing, processing, packaging, or holding do not conform, to or are not operated or administered in conformity with current good manufacturing practices.
Average cost to develop a new drug?
$2.6 billion
IV. Evaluation Activities
(A) Analyze data from monitoring, measurement, complaints,...for trending to detect and prevent problems. (B) Conduct internal audits (C) Quality Risk Assessment (RA) (D) Corrective Action (CA) (E) Preventive Action (PA) (F) Promote Improvement
Building and Facilities: Design and Construction Features
(A) Buildings must be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. (B) Plan adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination. (C) Design the adequate flow of materials and persons to prevent contamination. (D) Operations performed within separate or specifically defined areas of adequate size to prevent contamination or mix-ups as follow.
Resources
(A) General: the following resources must be adequate to meet requirements. -building and facilities -equipment -materials must be suitable for their intended purpose -defined manufacturing and packaging process. (B) Personnel (C) Facilities and Equipment (D) Outsource Operations
Manufacturing
(A) Product characteristics are defined from design to delivery. (B) Monitor packaging and labeling processes (C) Examine Inputs (D) Perform and Monitor Operations (E) All Quality systems must address non conformities or deviations.
Record should be retained for:
(A) at least 2 years after FDA approval (B) At least 5 years after FDA submission (C) if not submitted to FDA, 2 years after the study is completed or discontinued.
Management responsibilities:
(A) provide management (B) Structure the organization (C) Create a quality system that meets cGMP regulations related to product SISPQ (D) Senior management (E) Periodic review is required to ensure the quality system remains suitable, adequate and effective.
Quality Systems (4 parts)
(I) Management Responsibilities (II) Resources (III) Manufacturing Operation (IV) Evaluation Activities
Stage 1: Process Design
- Define the knowledge space - Identify critical process parameters - Determine control strategy
Safety Reporting
-Adverse Drug rxn -Adverse event -Serious Adverse Event (SAE) or Serious Adverse Drug Reaction
Drug Product Attributes to Match Target Product Profile (intended use)
-Dosage form -Immediate or extended release -chewable, sublingual, mini-tablets -Coated tablets (fxn and nonfxn coating) -Multi-particulates -Capsules (hard/soft gelatin)
Stage 2: Process Qualification
-Equipment/ Utility/Facility -Process Performance Qualification
Conformity is determined against written specifications for:
-Materials used in the manufacture, processing, packing, or holding of drug products -In-process materials -Drug product Specifications shall include sampling and testing procedures.
Stage 3: Process Monitoring
-Monitoring of critical process parameters as part of APR and other monitoring programs.
Retention of Documents
-Retain any production, control, or dist. record at least 1 year after the expiry date -Retain all components, drug product containers, closures, and labeling record at least 1 year after the expiry date. -Add docs shall be readily available for review -Records may be retained as original records or true copies.
Examples of Production Equipment & Equipment Identifiaction
-Tumble blenders -Mills and sieves -Fluid beds -Encapsulators -Tablet Presses
What is percentage range of a typical API?
0.5%-100%
Encapsulation
000 - larger than a size 4
ICH Q10 Objectives
1) Achieve product realization 2) Establish and maintain a state of control 3) Facilitate Continous Imporovment
Other Responsibilities of Quality Unit
1) Approving or rejecting incoming materials, in-process materials and drug products. 2) Reviewing production records and investigation of any unexpected discrepancies. 3) Ensuring that controls are implemented and completed satisfactory during manufacturing. 4) Ensuring that developed procedures and specifications are appropriate and followed.
What properties do these ingredients need to create a tablet?
1) Easily mixed with other particles 2) Powders must freely flow into the die to produce a consistent weight tablet. 3) Powder compressibility: the property of forming a stable, intact compact mass when pressure is applied. 4) Actual yields and % of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. 5) Yield calculations shall be performed by one person and independently verified by a second person.
Training Requirements of Quality System
1) Evaluation of training needs 2) Provision of training to satisfy these needs 3) Evaluation of effectiveness of training 4) Documentation of training and/or re-training.
Two main types of documentation:
1) Instructions: detailed information telling how something should be done, operated, or assembled. 2) Records: written accounts of what was done. Report-summary of information.
Management Responsibility
1) Leadership 2) Senior management has the responsibility to ensure an effective PQS (pharmaceutical quality system) is in place.
CFR 211.28 Personnel Responsibilities
1) Must maintain good hygiene, wear clean clothing, protective apparel. 2) Practice good sanitation and health habits 3) Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas. 4) Any person who has an apparent illness or open lesions - must report condition and may not work until cleared.
Responsibility of Quality Control Unit (QCU)
1) There should be a quality control unit. 2) Adequate laboratory facilities shall be available to the QCU for testing. 3) QCU is responsible for approving or rejecting all procedure and specification impacting on the identity, strength, quality, and purity of drug product. 4) Responsibilities and procedures of the QCU must be documented and followed.
Enablers (Knowledge Management and Risk Management)
1. Knowledge management is a systematic approach of analyzing, storing, and dissemination information. 2. Quality risk management, a proactive approach to managing risks to quality
The Product Life Cycle (4 steps)
1. Pharmaceutical development 2. Technology transfer 3. Commercial manufacturing 4. Product discontinuation
Percentage that a drug entering clinical trials will be approved?
12%
Patent Medicine Fraud (year)
1905-11
When was the Pure Food & Drug Act enabled?
1906
GMP (1979) / GLP (1979)
21 CFR 210 - 211 (Drugs) 21 CFR 920 (Medical devices) 21 CFR 225 (Animal drugs)
Stability Testing - Storage
25/60 - 3,5,9,12,18, and 24 months 30/65 - storage only for 12 months 40/75 - 1,2,3, and 6 months
Essential Documents: Investigator's Brochure
A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects.
Drug Product
A finished dosage form, for example: tablet, capsule, or solution, that contains a drug substance, generally but not necessarily, in association with one or more other ingredients.
Roles and Responsbilitities - Investigator
A person responsbile for the conduct of the clincal trial at a trial site. Responsiblites: -oversight of staff and contractors -Ensure adequte medical care of trial participants, obtain informed consent -Communication with IRB/IEC -Ensure compliance w/ study protocol -Reponsible for investigational product, its usage, and documention.
Disintegrants
Absorb water to break apart tablet
API
Active pharmaceutical ingredient. Any substance or mixture of substances intended to be used in manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product.
High shear granulation:
Add different particle size materials Add binding solution to bind with ingredients Add shear forces to push the materials together.
IND (More detail)
After a new IND is filed, there is a mandatory 30 day safety waiting period to allow the FDA 30 days to make a safety assessment. If no response, phase I clinical study can begin after 30 days.
Investigational new drug (IND) submission
After pre-clinical
Binders
Aids in compressibility of the tablet
Lubricants
Aids in the flow properties
Operational Qualification Components
Alarm testing Interlock testing and safety devices Operational testing Sequence testing Functional / Cycle Testing
Manufacturing Product and Control Records (MPCR)
An approved Master Batch Record should exist for each product and batch size.
Roles and Responsbilities - Sponser
An inidvidual, company, instituation, or organization which takes responsbility for the intitation, management, and/or financing of a clinal trial. Reponsible for: -quality managment system -quality control and quality assurance systesms -Oversight of Contract Reserach Organizations (CRO) -Medical experitise -Trial design, managment, record keeping -Supplying investigational product.
Test system:
Animal, plant, microorganism to which the test or control article is administered or added for study..
Specification Tests
Appearance Identification Assay Impurities Dissolution Water content
Investigational New Drug (IND) Application Process
Application to FDA for permission to administer a new drug to humans -Animal pharmacology and toxicology studies (GLP_ -Manufacturing information (GMP) -Clinical protocols and investigator brochures (GCP) Pre-IND meeting with FDA -Outline what studies are still needed - dependent on production and indication -Identify the target populations -Discuss the expected dosing and delivery.etc. -Demonstrate safety preclinically for the First in Human Study (FIH)
CFR Part 211 Section F: Production and Process Controls
Applies to finished drug products: A. Prescription drug products (RX) B. Over the counter drug products (OTC) C. Compound drugs D. Unapproved drugs. A manufacturing procedure must be established, approved, followed and documented. Procedures include but not limited to are production batch records, specifications, standard operating procedures, etc.
Pharmaceutical Development
At the beginning of the product lifecycle, a formulation is developed. Analytical methods are developed and the process is designed through experiments (DOE). Stage 1: Process Design
People strategy
Attract, Develop, and Retain
Data Integrity: ALCOA
Attributable Legible Contemporaneous Original Accurate
Ex vivo
Building a more comprehensive in vitro model. 2-D, 3-D cellular cultures primary cells, organotypic-raft tissue cultures.
Declartion of Helsinki (1963)
Built on principles of Nuremburg Code and ethical duties of physicans to establish guidelines for clinical reserach.
STAR Method - Behavioral Based Interviewing
S - Situation T - Task A- Approach R- Results
Performance Qualification (PQ)
SOP verification Calibration Performance Testing
Phase 1 Clinical Trials
Safety and dosage range --> 70% will continue
In vivo
Should mimic as closely as possible the planned human clinical design (route, duration, schedule)
Process Validation (3 steps) : 2011 FDA Process Validation Guidance
Stage 1: Process Design Stage 2: Process Qualification Stage 3: Process Monitoring
Toxicology:
Study of adverse effects on chemical,physical, or biological agents on people, animals, and the the environemnt.
Pharmacology:
Study of biologically active compounds, how they react in the body and how the body reacts to them; assessment of drug effects (safety)
Pharmacokinetics (PK):
Study of drug actions as they move through the body; the way the body absorbs, distributes, metabolizes and excretes it.
Pharmacodynamics (PD):
Study of the mechanism of action of drugs within the body and how drugs produce their effects in the body.
Flavors or coating agents
Taste masking
Number of volunteers for phase I?
Tens
Line Clearance:
Term line clearance is used for the documented act of conducting any necessary removal of products and materials from a packaging line to prepare the line for the next package. Clearning Cleaning Checking
Serialization:
The application of a unique I>D code to each package unit. November 27, 2017 - Deadline in the US.
Storage and retrieval of records and data
The following should be retained: -Master schedule sheet, copies of protocols, and records of QA inspections -Personnel training and experience and job descriptions -Records and reports of the maintenance and calibration and inspection of equipment.
Required Label Components
The name and address of the manufacturer or the company the name of the drug product lot number + expiration date Special storage condition Strength of active ingredient NDC# - unique identifier for each product and packaging configuration.
Vertical Shear Granulator
There is a mixing and chopper blade that is used during the process to create the final granulation.
Number of volunteers for phase III?
Thousands
Compression
Three part system to give shape and size punch - rod shaped die
Cleaning: Stage 1 - Process Design and Development (TACT)
Time (3 aspects) -Time before cleaning (dirty hold time) -Time of cleaning steps (CPP) -Time after cleaning (cleaning hold time) Action or Application Chemistry Temperature
Convection:
Transfer from one location to another (motion imparted by impeller as in ribbon blender)
How is the packaging method determined?
Type of dosage Dosage regimen Stability of the product in different environments Product administration
MHRA
Uk - Medicines and Healthcare Products Regulatory Agency
FDA
United States - Food and Drug Administration
In vitro
Used to obtain limited safety and efficacy data. Can include biochemical assays or cell culture models.
1933 - Pure Food & Drug Act Exhibits drugs that..
Weight loss drug --> death Hair removal drug --> baldess Eyelash dye --> blinded women Lotions, creams, hairdyes --> caused mercury or lead poisoning.
Control Parameters - Tablet Formation
Weight variation Mechanical strength: including hardness and friability Dissolution Content uniformity Visual defects
Alcami locations:
Wilmington, NC Durham, NC Charleston, SC Germantown, WS Edison, NJ St. Louis, MI Weert, Netherlands
Written Procedures and Deviations
Written procedures = required; designed to assure that a drug product has the 1) identity 2) strength 3) quality, and 4) purity as purported. Appropriate organizational units are responsible to 1) draft, 2) review, and 3) approve the procedures including any changes. Quality Control/ Assurance unit must review and approve all documents and deviations associated with the process. Documented at the time of performance (real time) Any deviations from the written procedures shall be 1) recorded and 2) justified.
Pharmacopoeia
a publication, established in 1820, that contains legally recognized standards of identity, strength, quality, purity, packaging, and labeling for drug substances, dosage forms, and other therapeutic products, including nutritionals and dietary supplements.
Non compliance to cGMP =
adulteration
Coloring agents
aesthetics/identification of the tablet
Drug Substance
an API that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.
Second Packaging:
contains like the primary container: additional physical barrier, identification label for the product, lot I.D and expiration date, tamper evident, serialized for track and trace.
Quality is not tested into the product...
it must be built into the process
Direct Compression (Blending):
the mixing together of two or more ingredients to provide a uniform composition of free flowing powders. Content uniformity is a critical requirement for this process.
Drug discovery:
the process of identifying potential new medicines.
Over the counter drug review (1972)
to enhance safety, effectiveness, and labeling
Medical device amendment (1976)
to ensure safety and effectiveness of medical devices
Thalidomide tragedy (1953-1962)
~10,000 children were born with severe birth defect of the arms and legs
Equipment requirements
Calibration of instruments, apparatus, gauges, and recording devices must be performed according to an established writeen program
Essential Documents: CRF and Final Report
Case Report Form (CRF): A printed, optical or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. Clinical study report: a written description of a trial.study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report.
Receipt and storage of untested components, drug product containers, and closures.
Certificate of analysis BSE/TSE statement Residual Solvents
Drug Product Phases - Packaging and Labeling - 3 phases
Clinical phases - simple or complicated kitting -open label - dosage revealed -blinded label - dosage not revealed Validation/Commercial -Unit packaging and commercial labeling
Excipient
Component of a finished drug product other than the API and are added during formulation for a specific purpose
Charge in of components (materials)
Components for a drug product manufacturing shall be weighed, measured or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following: - component name or item code - receiving or lot number - weigh/count in container - bath for which the component was dispensed. Weighing or measuring of components requires a second person verification if it is a manual operation. For automated processes only one person verifies.
Sulfathiazole tragedy (1941) - the birth of GMPs
Contaminated w/ sedative phenobarbital, nearly 300 people died or were injured.
CMO/CDMO
Contract Services Pharmaceutical
"The Jungle" by Upton Sinclair addressed...
Corruption of US meat packing industry
Elements of a Validation Program:
DS - Design Protocols - IQ- Installation Qualification -OQ - Operational Qualification -PQ - Performance Qualification -PV - Process Validation
Annual Product Review (APR)
Data shall be evaluated for each product at least annually, including: review of a representative number of batches whether approved or rejected records associated with the batch a review of complaints, recalls, returned or salvaged drug products.
Receipt of Components
Date of receipt The results of any test or examination An individual inventory record of each material and a reconciliation of the use of each lot of such material.
When things DON"T go according to plan - Deviation Managment
Deviation: an excursion from the approved protocol
Mechanisms of Powder Blending
Diffusion Convection
Typical ingredients for a tablet formulation:
Disintegrants Binders Lubricants Coloring Agents Flavors or coating agents
Documentation
Documentation is the key to GMP compliance and ensure traceability of all development, manufacturing, and testing activities.
Operational Qualification: OQ
Documented evidence establishing confidence that the equipment, software, instrument or ancillary systems operate as intended and are capable of consistent operation within established functional specifications.
Installation Qualification: IQ
Documented verification that lal key aspects of equipment, instrument, or ancillary systems have been properly selected, constructed, and installed in accordance with the design requirements and established specifications.
Test articles:
Drug, food additive, biological product, color additive, electronic product, medical device for human use.
Fluid Bed Operations: Top Spray/ Grandulation/Drying
Drying: -wet material -fluidized with condition air Top Spray granulation: -dry ingredients are added to the fluid bed -binding solution is sprayed on to the powders -due to the low mechanical forces in the fluid bed the granules are looser and have a lower bulk density.
CFR 211.25 - Personnel Qualifiactions
Each person shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned function. Shall be an adequate number of qualified personnel. Training shall be conducted by qualified individuals on a continuing basis.
Phase III Clinical Studies
Efficacy and monitoring adverse effects
Phase II Clinical Studies
Efficacy and safety --> 30% will continue
Cleaning: Stage 2 (Qualifications)
Equipment IQ (Installation Qualification) Equipment OQ (Operational Qualification) Process Qualification
Equipment cleaning and maintenance
Equipment and utensils cleaned, maintained, and if appropriate sanitized and/or sterilized at appropriate intervals to prevent contamination or malfunctions.
Subpart D-Equipment: Equipment design, size, and location
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size and suitably located to facilitate operations, cleaning and maintenance.
MEA
Europe - European Medicines Evaluation Agency
Regulatory authorities
Every country has its own.
Why compounds fail or slow down in development?
Failure: -Poor PK profile -Lack of efficacy -Toxicity -Market reasons
GCP
Good clinical practices
GLP
Good laboratory practices
GMP
Good manufacturing practices
Tertiary Packaging:
Groups the secondary for shipping and distribution.
Nuremberg code (1947)
Guidelines documented in the judgement by war crimes tribunal at Nuremberg. Set reserach ethics for human experimentation in response to treatment of human subjects at concentration camps during WWII. Introduced principles such as informed consent, lack of coercion, and sound scientific intent.
Number of volunteers for phase II?
Hundreds
Interactional organization
ICH - International Conference on Harmonization WHO - World Health Organization
Installation Qualification Componets
Impact assessment Documentation Verification Utility Supply Verification Equipment List Component Schedules Critical Measuring Instruments Drawings Spare Parts Maintenance (PM)
Sampling plans
In process - potency or critical tests Testing of blends: (top, middle, bottom) Testing of sterile product (beginning, middle, end)
Nonclinical laboratory studies:
In vitro or in vivo experiments in which test articles are studied in test systems under laboratory conditions determine their safety.
Roles and Responsibilites (IRB)
Indepednet body of medical, scientific, and non-scientific members that ensures the protection of the rights, safety, and wel being of human subjects. Responsible for: -Review and approval of documents -Condiseration of investigator's qualification -Review of ongoing trials -Review of incentives/compensation for study particpation
Importance of package labeling?
Information communication Marketing Convenience Security
What type of packaging is used?
Injectable vial Sterile IV bag Ointment/cream Tablet bottle Tablet blister Powder pouch
Studies in humans can only being after IND is reviewed and approved by the FDA and by a...
Institutional Review Board (IRB).
Elixer Sulfanilamide (1937 disaster)
Introduced as an antimicrobial, 107 children died. Highlighted the need for pre-market drug safety testing.
If you didn't document it....
It didn't happen.
Distribution Records:
It is the manufacturer's responsibility to track distribution of the product. Records must include: Lot/Control Number of Drug Product Name and strength of the product Description of the dosage form Name, address, and contact details of customer Quantity supplied Date shipped
MHLW
Japan - Ministry of Health, Labor and Welfare
ICH Q10: Pharmaceutical Quality System (PQS) (Date)
June 2008 Describes an effective pharmaceutical quality system.
Light, ventilation, air filtration, air heating and cooling
Light: adequate lighting must be provided in all areas Ventilation, air filtration, air heating and cooling: (A) adequate ventilation must be provided (B) adequate equipment must be provided for control over air pressure, micro-organisms, dust, humidity, and temperature for the manufacture, processing, packing, or holding of a drug product.
1983 - Tylenol Bill
Made tampering with pharmaceutical products a federal crime.
Stage 3: Continued Process Verification
Maintaining the validate state
New Drug Application (NDA)
May be filled after Phase III. FDA has 50 days to decide.
Milling: creating a uniform particle size
Mills are used to size particles in wet granulation and blending processes.
cGMP regulations establish:
Minimum requirements for manufacturing, personnel, equipment, control of product, containers/closures, facilities, packaging, holding and distribution procedures and the associated process controls. Ensure that drugs are safe and that requirements are met for 1) quality 2) strength, 3) purity and 4) identity.
What guidelines did the Pure Food & Drug Act enforce?
Mislabeling, misbranding, ingredients labeled, and allowed seizure of illegal food and drugs.
Production Time Limits
Must be established for each completed phase of production process (i.e blending, compression, packaging). A deviation is required if a violation of the established time limit is made. All deviations must be documented and justified.
The Human factor
No matter how automated the process, people are involved, People are key to develop and maintain any GMP system, including Quality
ICH Q9: Quality Risk Management (QRM) (Date)
November 2005 Describes systematic processes for the assessment, control, communication and review of quality risks.
ICH Q8 : Pharmaceutical Development (Date)
November 2007 Describes science and risk-based approaches for pharmaceutical product and manufacturing process development.
Pre-clinical studies:
Object: to determine the safe dose of the drug and to measure toxicity. Model systems: in vitro, in vivo, ex vivo
Why are there tamper evidence requirements?
Oct. 1982 seven deaths due to taking extra-strength tylenol capsules...products had been tampered with and pills were replaced with cyanide.
Primary Packaging:
Packaging component in direct contact with the product for: Physical protection Environmental barrier
Performance Qualification: PQ
Performance will be verified according to an approved performance qualification protocol.
Once a promising compound identified for drug development measure:
Pharmacokinetic properties Potential benefits and mechanisms of action The best dosage form and drug delivery Toxicology and side effect How it affects different groups of people How it interacts with other drugs and treatments It's effectiveness as compared with similar drugs
Phase IV Clinical Studies
Post Marketing Surveillance Trials) are conducted after a drug has been approved and marketed.
Powder Properties
Powder variables Particle size Size dist. Shape Surface texture Cohesivity Surface coating Particle interaction Electrostatic charge Compaction recovery Wear/attrition characterisistics
Testing and Release for Distribution
Prior to release, there must be satisfactory conformance to final specifications: -Drug Product -API Appropriate testing Testing procedure Acceptance criteria Drugs that do not meet established specifications shall be rejected.
What is validation?
Process of establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification and quality attributes.
cGMP: current good manufacturing practices
Promulgated by the US food and drug administration under the authority of the federal food, drug, and cosmetic act.
Kefauver-Harris Amendment (1962)
Proof of efficacy required Authorized FDA to issue GMP rules First Drug GMPs (28 FR6385) in 1963
Common deviations
Protocol generation errors (use caution - typos) Failure to meet acceptance criteria Changes to protocol requirements
Development of ICH Guideline for GCP (1996)
Purpose: in an effort to overcome international GCP inconsistencies throughout the countries, ICH issued the following Guidlines.
Quality Assurance Statement:
Quality assurance inspections of the study and review of the final report of the above referenced study were conducted according to the procedures described in the standard operating procedures of the QAU.
Instruction types:
Quality manual Site master file Procedures Protocols Test methods Specifications
Record and Reports
Records (batch records, lab notebooks, calibration and preventative maintenance, qualification, equip. validation.) Certificate of Analysis (COA) Reports Logbooks
Diffusion:
Redistribution of particles by random motion (vertical or axial motion)
Food, Drug, and Cosmetic Act (1938)
Required safety studies Authorized factory inspections Extended control to cosmetics and devices Prohibits false therapeutic claims Requires safe tolerance for unavoidable poisonous substances
