Unit 1 Pharmaceutical Quality and cGMP

VI IThe

  • Code of Federal Regulations is the list of laws and regulations issued by the executive branch and is essential for ensuring the safety, efficacy, and quality of pharmaceutical products in the United States.

  • Title 21 mainly covers the FDA and CDC, also known as 21 CFR

  • SOP -Standard Operating Procedure (like a recipe/guidleines)


Mandatory Systems -cGMP

  • Current Good Manufacturing Practices is a set of minimum standards for manufacturing set by the FDA to ensure the safety and purity of drug products made in the USA. If a company is found not to be following cGMP, they can get shut down. (Make sure it’s CURRENT because practices will change and everything needs to be up to date.)

  • 21 CFR is a portion of the Code of Federal Regulations that outlines all cGMP for drug, medical device, and biological industries.

  • This includes rules for every aspect of manufacturing, from labeling to release of product for distribution.

  • Harmonization - the people who make sure the guidelines for sending products to other countries are in place.


Drug Saftey

  • A drug is considered safe if the benefits outweigh the risks for the population the drug is intended to treat when used properly (Used in clinical trials to ensure safety and also efficacy)

  • Efficacy refers to whether a drug demonstrates a health benefit over a placebo (fake drug that you don’t say it is one) or other intervention when tested in a clinical trial.

Quality (biopharmaceuticals)

  • Meaning the product is both safe and effective.


The FDA

  • regulates the quality of all drugs and food, ensuring it is safe for everyone involved in the manufacturing process, from production to distribution.

  • Responsibilities: Review and approve or reject applications for new drugs, biologics, and medical devices

  • Oversee manufacturing and distribution activities

  • Review and approve or reject marketing materials

  • Perform research and independent lab testing about certain drugs in support of public health.

FDA On-Site Inspections

  • General CGMP inspections are regularly scheduled audits the FDA conducts at a company every 2-5 years to ensure the company remains compliant.

  • Pre-approval inspections (PAI) are product-specific inspections the FDA performs before approving new drugs for market.

  • For-Cause audits occur when the FDA inspects companies in response to identified issues, such as specific complaints, concerns about the stakeholders involved in the research process, multiple deviations, or FDA-identified events of special interest.

Compliance Verification Includes (FDA Inspector)

  • A thorough review of records, processes, and practices to verify adherence to established regulations. This process often involves examining documentation related to manufacturing, testing, and quality control procedures to ensure that all operational activities align with the standards set forth by cGMP guidelines.

Infractions

  • When an FDA Inspector finds something that doesn’t comply, the inspector gives 15 days for the company to respond and fix it; this also depends on the severity.


To ensure we follow cGMP in our unit, we have..Quality Unit! - Four groups

  1. Quality Assurance (QA) - oversees overall site quality

  2. Quality Control (QC) - tests raw materials, products, and components.

  3. Quality systems - maintains the formalized systems for capturing deviations, corrective actions, and preventive actions.

  4. Training teaches employees how to perform their duties

They also review batch records and confirm calculations, and note process documentation to ensure compliance with quality standards. They also kinda roleplay the FDA to simulate inspections and ensure that all operational processes meet regulatory requirements.


Overview of Documentation Includes

  • SOPs- recent versions

  • Labels

  • Batch records

  • Laboratory data, equipment recipes and cycle printouts

  • Alarm logs (case dependent)

  • Area and equipment logbooks

  • Personnel training records

  • Shipping and receiving paperwork


ALCOA+

  • Attributable - Who and When

  • Legible

  • Contemporaneous = Current

  • Original

  • Accurate

Additional ALCOA+ Documentation Practices

  • Complete - All info is present

  • Consistent - All info is recorded in the order it was generated.

  • Enduring-Info is recorded using an appropriate medium (paper or electronic)

  • Available - The info is accessible over the life of whatever process, product, or activity the doc supports.

  • Record retention policy


Data integrity and Compliance

  • This refers to the completeness, consistency, and accuracy of data over its lifecycle.

  • The underlying premise is that cGMPs set forth minimum requirements to ensure that drugs meet the standards of the FD&C regarding safety, identity, strength, quality, and purity.y


General Rules for Completing Documentation

  • Record data and sign for actions at the time they occur

  • Use permanent (indelible=unable to delete) ink if writing by hand

  • Write legibly

  • Entries should be complete so that, later, others can understand what happened, who did what, and all other relevant info.

  • Data should be correct.

Not every company has the same format.

  • All companies use military time and use the date format approved by the company. This may record October 5, 2021 as 10-5-2021,10-05-2021,05-OCT-2021 or another format

  • Do NOT use ditto marks (‘‘) to indicate that an entry is the same as the line above.

  • Do not overwrite errors in handwritten docs like turning a 3 into an 8.

  • Do not use correction fluid or any obscure data, even if it’s wrong; it can be used for other purposes.

Always record the date of an entry as when it is being written.

  • Mark unused fields with “N/A”; don’t leave blank unless it says to

  • If a step requires a second person to sign as a verifier, make sure that person actually verifies the action, then signs.

Facilties

  • A biopharmaceutical processing facility has three things coming in and three things going out:

Incoming ——————— Outgoing

Raw Materials Finished products

Personnel ready to work Personnel who have completed work

Utilities Waste and scrap


Facility Regulations

  • Facilities shall provide a suitable size, construction, and location to facilitate cleaning, maintenance, and proper operation.


Packing and Labeling


Container Closure Integrity

  • Container closure integrity is the industry term for evaluating the barrier formed by primary packaging that separates the product and the environment.

  • Before labeling, each container is inspected for a number desfects. The inspection process is designed to identify damaged product, product with a product-specific number of other product-specific defects.

  • So a seal is needed. To ensure safety, stemming from the Tylenol murders.


Label Control

  • Labels are directly regulated by the FDA.

  • Each product has approved labeling, and any variance from that approved label is a CGMP violation.n

  • Labels are tightly controlled.


Warehouse and Distribution

  • Storage - Product storage conditions are defined during product development.

  • By the time a product is being manufactured, the storage conditions are well established.

  • The most common storage parameter is temperature

Distrubition

  • The transport of products within the factory through distributor warehouses to clinics

  • Has two goals: to protect product quality and to ensure product traceability


Temperature Control

  • Active temperature control uses controlled heating and cooling to ensure that the ior of a shipping environment remains at the desired temperature.

  • Passive temperature control uses insulation to reduce the rate of temperature change inside a shipping container.


Recalls and Returned Goods

  • Sometimes distributors return product because it was defective or they ordered too much.

  • A recall is a voluntary action that takes place because manufacturers and distributors carry out thier responsibility to protect the public health and well-being from products that present a risk of injury or gross deception or are otherwise defective.

  • Anyone can check for defectiveness. Either potential or known recalls can happen.


Laboratory Controls

  • Laboratories analyze biopharmaceutical operations from raw materials to finished products, from environmental conditions to released lot stability

  • Testing before, during, and after for all products.


Specification Accuracy

  • Must be scientifically sound (needs to have a science-related reason)

  • Must be approved by Quality

  • Sampling plans must be scientifically sound and resusuly in a respresentative sample

  • Specifications shall identifity the test mthod against which the material is being tested.

Testing

  • Testing shall be performed per approved procedures. Any deviation from the approved process must be investigated. Furthermore, all results must be documented accurately and reviewed to ensure compliance with established quality standards.

  • when a sample is pulled idenifty which batch # etc

  • Lab instruments are calibrated and qualified

  • Test methods are qualified to be repeatable, with the same results every time.

Comparing Results with Specifications

The raw data supporting a result is fully traceable

This is called data integrity and is an area of industry focus for improving compliance

In addition, maintaining accurate records and documentation throughout the testing process ensures transparency and reliability, contributing to overall product quality.

Electronic Signatures and ELecteoinc Records

A SCADA system is building mointoring system that allows facility contol over connected process equipment

A DCS is a computerized control system for a process or plant.