Pharmaceuticals: Production, Extraction, and GMP

Good Manufacturing Practices (GMP)

• GMP is a quality assurance system for products intended for human consumption to ensure consistent and controlled production according to quality standards.
• Procedures ensure product safety, purity, quality, and efficacy are met.
• Designed to minimize risks like contamination and errors during production.

Current Good Manufacturing Practices (cGMP)

• cGMP is often used to denote that the GMP follows Current Good Manufacturing Practices
• cGMP involves using up-to-date technologies and systems to comply with the most updated regulations and changes.

Application of GMP

• GMP applies to manufacturing biologics, pharmaceutical drugs, medical devices, implants, cosmetics, and food.
• GMP applies to all manufacturing steps from start to finish
• GMP applies to all within a company from organization and personnel and their responsibilities; and qualifications.
• GMP applies to Calibration and Preventive Maintenance
• GMP applies to Process Limits and Contamination Control
• GMP applies to Buildings and Facilities, Design, Construction and Maintenance
• GMP applies to Quality Control with Samples and Retains
• GMP applies to Records and Reports (Traceability)
• GMP applies to Inspections and Audits, Documentation, Validation, - Packaging and Labelling (Expiration dating and Evidence of tampering)
• GMP applies to Warehousing and Distribution.

Benefits of GMP

• Pharmaceutical companies, healthcare providers, patients, and consumers all benefit from GMP by ensuring the safety and efficacy of products.

Need for GMP

• GMP prevents tragedies, discourages taking shortcuts, and promotes attitudes toward producing quality products.

Studying GMP

• Pharmaceutical and medical device production are governed by GMP requirements.
• GMP compliance allows important knowledge to be have to work in related industries

GxP

• Good Manufacturing Practice (GMP)
• Good Laboratory Practice (GLP)
• Good Documentation Practice (GDP)
• Good Distribution Practice (GDP)
• Good Dispensing Practice (GDP)
• Good Clinical Practice (GCP)

Events that shaped GMP

• 1905: The Jungle leading to modern day FDA due to lack of Purity
• 1906: Food and Drugs Act leading to modern day FDA due to lack of Purity
• 1937: Elixir of Sulfanilamide Tragedy due Safety Issues
• 1938: Federal Food Drug and Cosmetic Act addressed Safety
• 1960: Thalidomide Scandal caused issues in Efficacy
• 1962: GMP Regulations Amendments addressed in Efficacy

Regulatory Bodies

• They license and control the manufacture and sale of healthcare products, guaranteeing compliance through GMP practices
• Each country has its own standards.
• Examples, Food and Drug Administration (FDA, USA), European Medicines Agency (EMA, EU), Health Sciences Authority (HAS, SG)
• More examples: Medicines and Healthcare Products Regulatory Agency (MHRA, UK), Therapeutic Goods Administration (TGA, Australia), Pharmaceuticals & Medical Devices Agency (Japan)
• GMP principles are the same, but differ in approach and guideline enforcement.
• Manufacturers need approval from country-specific authorities before selling in that country.
• Regulatory inspectors visit manufacturing plants to check GMP compliance, performing audits.
• FDA inspects USA sites unannounced, but issues 90-day notices to sites outside USA.
• HSA gives advance notice to Singapore plants.

GMP Document Pyramid

• Regulations: 21 CFRs, PIC/s guide, Australia code of practices, etc
• company Quality Policies (What we must do At corporate level)
• How we must do (company SOPs; Procedures outlining how to execute the process)
• What was done (Records; E.g., batch record, training history - Documentation history)
• There is danger of gaps between different countries (and their GMP standards) over time
• There is need to prevent widening difference and to harmonize the standards from different countries.

Harmonization of Pharmaceuticals

• The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a platform to harmonize standards between the EU, USA and Japan
• It as developed over 40 guidelines where one of the most important one is ICH Q7A GMP Guidance for APIs.
• Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) was Established in 1995 but is Non-legal cooperative arrangement between regulatory countries.
• PIC/S has Over 60 members as of Oct 2024
• HSA became a member of PIC/S in Jan 2000

Benefits of Joining PIC/S

• Training opportunities
• International GMP harmonization
• Networking
• High standards by Complying with PIC/S standards at all times
• Sharing of information which is Voluntary
• Rapid Alert System through the PIC/S

Quality Management System

• Topic 2 reviews Quality Management System
• The elements included are Document Control, Issues Resolution, Audits & Findings, Integration and Staff Competency & Development

Quality

• Totality of the features and characteristics of a product that allows it to meet or exceed pre-defined specifications, thereby satisfying its fitness for intended use.
• Safety is the relative freedom of consumer from risk
• Purity: How many percent is free from impurities?
• Potency: How much is needed? or What is the lethality?
• Stability Product quality remains the same on expiration date as when first packaged
• Consistency the product reproduced batch after batch with meeting specifications?
• Identity: Is the drug what it is?.
• Efficacy: Does it work for its intended indication?

Key Areas of Compliance

• Compliance with Drug Quality Attributes
• Lasts till use by date Safety
• No side effects is Effectiveness
• Free from contaminants is Identity
• Correct label is Purity

Quality Management Elements

• The infrastructure Appropriate or "quality system" to make actions Systematic
• To have adequate confidence on a product/service to satisfy its requirements is Quality
• Quality Assurance = to be termed "Quality"

Quality Relationships

• Quality Management is a policy of the organization towards quality that supersedes everything
• Quality Assurance guarantees that that the policy is Concept that ensures the policy is achieved
• GMP deals the risks that cannot be tested, that helps build quality into product
• Quality Control tests of environment and facility, as well as materials

Quality Assurance Principles

• It is said that "QA is the responsibility of all employees who in any way can influence product quality"
• Some aspects of a good QA system include:
• Responsibilities and Properly defined Authorities in job descriptions for personnel
• Standards GMP, GDP, GLP and regulatory guidelines
• To ensure the control of calibrations and validation checks
• Product Sales Need to comply with marketing authorization
• Regular Self-inspection and/or evaluation of product quality and continued Quality Audits to Verify improvements
• Follow the necessary controls during Deviation/Incident; and document it during their Investigation; and Records
• Lastly follow Status and duration tracking during Change Control & Approval

Personnel and Training

• A company should utilize Sufficient and Qualified Personnel
• Personnel in cGAMP requirements and practices
• Employees must be Adequately Trained, as well as being trained in refresher courses
• Good manufacturing practices can also mean knowing the Roles of various Key Personnel. They should work with operations but separate to Quality. It all starts from Quality

Documentation, Data and Records

• Provides assurance that quality related operations follow exactly as they have been planned and approved
• Electronic signature and handwritten signatures shall be: unique, accountable and legally binding.
• Provide standards and practices to be followed in the execution of GMP documents.
• Designed to ensure data is reliable and integral

Data Integrity Principles (ALCOA)

• Attributable, Legible, Contemporaneous, Original, Accurate

Rules on ERROR corrections

• Use single lines and initial/date, dont use correction fluid

Data Integrity Lapses

• A lapse in data integrity could be caused by Time Pressure or Insufficient education
• It can also be cause Fear or Lack of Moral Fibre

Importance of Stand Operating Procedures (SOP)

• It enables consistent operations and control
• Enables consistent drug productions
• SOP must have the Company name
• SOP must have the subject and effective title, as well as Checked by the administrator
• Standard operating processes should also be Descriptive, Concise and Up-to-date for easy references

Definition of Batch/Lot/Unit

• Each process is completed at a unit operation each process is completed at a unit operation before they move to the next.
• The number must be unique to corresponding labels

General Requirements for Records

• Each batch number is for mainitaing all records with their relevant samples/products - This usually applies for an estaimted 1 year after expiry of the batch.
• All records, or copies of such, shall be readily available for authorized inspection during the retention. They have to be easy to trace in a Quality Unit.

Types of Records

• Types of records include the following:
• Equipment use log
• Component drug container
• Master and Batch Production records
• Finally, there would be the distribution log from training

Equipment, Environment and Cleanliess

• To control the environment, a company should keep health precautions during the building design, as well as the design phases of construction and cleaning

Cleanrooms

• Are a controlled environment that maintains conditions like particle count, temperature, humidity and is specified by ISOLness or Eurdode Class.
• Can be used for laboratory work and pharmaceutical development.
• Air Conditioning and Mechanical Ventilation (ACMV) regulates air quality for clean classifications
• Contaminates may include but are limited to: microorganisms, air and skin.

Contaminate Sources

• Can include fine stirred Raw Material
• Shedding process equipment
• Shedding Personnel

Personnel Sources

• Should have Before and During employment health precautions to be protected.
• All who enter, full-time employees and up also must be kept

Cleanliness

• Requires the cleaning, the materials and the chemical and cleaning processes

Good construction habits include

• Good seams of walls and joints
• Resistant materials and dust ledges

Floors shoudl have

• Joint sealinga dn drain
• Proper sloaping
• No porous materials either

Ceillings should be

• No exposed perforations, and designed to be tightly sealed

Buildings should have

• Proper doors
• Properly planned design

What is most important?

• Minimzing pollution

Design for facilities for production

• Design for facilities for utilities
• Follow a sequence of operations and keep a low range.

Process for manufacturing

• Use all the proper equipment and material
• Keep an eagle on operations but know your limits,
• Separate them from other workers with correct materials
• and validate with QA.

Environmental Control

• Controlled environment that maintains conditions like particle count, temperature, humidity during the construction and proper processes
• Can be used for air distribution, and is specified by ISO, Cleanliness, or Air Distribution.
• A company can then install Filters, perform Maintenance, and finally conduct some air sampling.
• To keep air stable and clean: – The more heat and activity the more air must be added – Use of supply must be consistent – Minimize confusion during transitions

Cleanroom utilities

• Includes: 1. compressers 2. water systems 3. stream/heat generators
• These processes must meet clean and consistent standards as well as be safe

Types of Compressor Use:

• Clean Air, Oxygen and other gasses must follow strict manufacturing protocol by being filtered
• These gasses should be Diatomic, Inert, at correct freezing point and stored in the right facility (Dewar)

Utilities have to be carefully purified

Pharmaceutical Water Purification types

• Has to follow the process using reverse osmosis, carbon filters and deionizers.
• Should be checked carefully and consistently for bacteria

WFI

Laboratory Checkups

• Use specific scales and tests to ensure data is clear

Cleaning

• Use sterile equipment to minimize particle counts
• Calibrate for use, but also check it after the clean

Types of sterilization

• Steam
• Heat etc

Monitoring

• Proper inspections and sampling should be performed

Production and Process Control

• Following the area/line rules is key to preventing failure in the line and the need for recalls (SOP)
• Cleaning happens after. (Calibration)
• If there is a problem it has to be addressed. If its an issue, document it.
• With good maintenance, you can make a good product. Always calibrate
• The SOPs should be followed precisely to produce great products

What causes a problem?

• A number of incidents cause problems
• There are plans depending on severity
• Follow safety when there is a problem

Types of problems

• Have the appropriate responses in place to avoid reoccurrence
• Corrective Action
• Preventative Action: Make sure prevent the event, and then verify the effectiveness of the action
• Proper audits and reviews, as well as tracking, allows all teams to handle all situations. It all builds when documentation is built, and a good root cause analysis is performed

Report

• If a Root Cause is known: take action to prevent the event, and improve the business.
• Make sure each report contains the following: – Information – Problem – Solution – Impact Make sure each report contains the following: – Corrective Action – The right people – Verification for Effectiveness – Details of all steps

Final Note

• To end off: Take a new system and add to it to improve its reliability and change it for the better.
• A change control must be performed to see what it needs to approve before affecting production.

Definition of Qualification vs Validation

• Qualification is a process of providing a high degree of assurance equipment, is what if states
• Validation provides consistent documentation

Qualification versus commissioning

• Everything is planned and documented
• Qualification occurs is part of the larger picture
• These phases are necessary for all industries

Important to Validate

• The Masterplan – Is an overview plan
• Process is defined
• Plan has to be followed
• Report comes last

Three types of Validation

• Testing during a long time period- can run upto 5 years
• Stability
• Stress
• A company wants to define their own ranges

Stability test process:

1: What to check 2: During test cycle 3: After: Analyse and submit with confidence

• Validation has high standards that can cost lots of money

Other Aspects

• These include but not limited to: – The time to validate that the material is what the manual says – Data and time of use is correct

Equipment

Isolator Air Sampling Quality Control

Calibration

• Everything with records must be certified that it is accurate All standards are important, not just some

Explore the various categories of pharmaceutical drugs, including those produced through genetic engineering and extraction from natural sources. Understand the characteristics of biopharmaceuticals compared to small molecule drugs. Learn the primary goals of Good Manufacturing Practices (GMP) and the role of the International Council for Harmonisation (ICH).